Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>N1CCCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:20][CH2:19][C:18]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCNCC1
Product: COc1ccc(C2(C#Cc3ccccn3)CCC3(CC2)OCCO3)cc1OC1CCCC1

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.15 g, 0.42 mmol) and 2-bromopyridine (0.040 mL, 0.42 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)-palladium(0) (0.02 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80° C. for 0.5 h. Water was added and the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-pyridylethynyl)cyclohexane as a white foam. mp 41°-42° C. 1H-NMR (400 MHz, CDC3) δ 8.58 (d, J=4.6 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21 (m, 2H), 7.17 (d, J=8.5 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 3.99 (s, 4H), 3.84 (s, 3H), 2.25 (m, 2H), 2.15 (m, 4H), 1.8-2.0 (m, 8H), 1.59 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].Cl[C:44]1C=CC(Cl)=C[C:45]=1[S:51](Cl)(=O)=O>>[S:51]1[C:45]2[CH:44]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]4[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=3)[NH:25][CH:24]=[C:23]4[CH:32]3[CH2:33][CH2:34][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:36][CH2:37]3)[CH:17]=[CH:18][CH:19]=2)(=[O:10])=[O:11])=[CH:2]1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5csc6ccccc56)c4)cc23)CC1
Yield: 6 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting 1-benzothiophene-3-sulfonyl chloride (82 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 3.9 mg the title compound (6%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>CCOC(C)=O>[F:1][C:2]1[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Temperature: 0 °C

Procedure:
To a stirred solution of the compound of Step B, Example 3, (48.9 gm, 292.8 mmol) and concentrated H2SO4 (100 mL), under N2, was added a 26 mL mixture of HNO3 (69-71%) and concentrated H2SO4 dropwise at 25°-35° C. (ice-bath). The resultant solution was stirred at room temperature for 10 minutes. 400 mL of ice water was added portionwise to the solution at 0° C. (ice-bath) followed by the addition of EtOAc (1.5 L). The organic layer was separated, dried (MgSO4) and evaporated to dryness to give the title compound of Step C as a tan solid (60.0 gm), 96%; m.p. 200°-202° C.; IR (nujol, cm-1): 1703.5 (C=O); 1H NMR δ: 4.79 (s,2H), 7.26-7.29 (d,1H), 7.63-7.64 (d,1H), 11.05 (s,1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>>[CH:9](=[C:8]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]1[CH2:2][NH2:1])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C=O
Reactant: NCc1ccccn1
Product: CC(C)C=C1C=CC=NC1CN
Yield: 85.5 %

Procedure:
The procedure is carried out as described in Example 1(a) but with the use of 216 g (2 mols) of 2-aminomethylpyridine and 144 g (2 mols) isobutyraldehyde. After a reaction time of 2 hours at 35°-40° C., subsequent distillation leaves 277 g (1.71 mols) of isobutylidene-2-aminomethylpyridine; yield 85.5% of theory; b.p. 69° C./200 Pa.
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2)([O-:5])=[O:4]>CN(C)C=O.C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:13]1[CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2
Reactant: II
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(I)c2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
A mixture of silver sulfate (100 g, 0.32 mol) and iodine (82 g, 0.32 mol) in N,N-dimethylformamide (700 mL) and ethanol (1400 mL) was treated with 5-nitro-2,3-dihydro-1H-indole I (48 g, 0.29 mol). The resulting mixture was stirred at 25° C. for 1.5 h, filtered and the filter pad washed with ethyl acetate. The filtrate was concentrated in vacuo to a volume of approximately 500 mL. This solution was treated with a 1.0N aqueous sodium thiosulfate solution (100 mL) and a saturated aqueous sodium chloride solution (400 mL). The resulting precipitate was collected by filtration, washed with water and petroleum ether, and dried in vacuo to afford 7-iodo-5-nitro-2,3-dihydro-1H-indole II (83.9 g, 98.9%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.18 (d, J=2.20 Hz, 1H), 7.80 (d, J=1.46 Hz, 1H), 7.03 (broad s, 1H) 3.65 (t, J=8.97 Hz, 2H), 3.17 (t, J=8.60 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:7]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[CH2:20][O:21][S:29]([CH3:28])(=[O:31])=[O:30])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(Br)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)n1c(-c2cc(COS(C)(=O)=O)ccc2-n2cncn2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a round bottom flask is added [3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]methanol (583 mg, 1.4 mmol) in CH2Cl2 (5 mL), followed by the addition of methansulfonyl chloride (0.15 mL, 1.9 mmol) and triethylamine (0.4 mL, 2.9 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with saturated NaHCO3 (10 mL), extracted with EtOAc (3×10 mL). The organic layer is separated, washed with brine, dried under anhydrous Na2SO4 (500 mg), filtered and concentrated to afford methanesulfonic acid 3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]-triazol-1-yl-benzyl ester (690 mg, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.O.[NH2:11][NH2:12]>>[NH:11]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)[NH2:12]
Reactant: OCc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: NNc1ccc(CO)cn1

Procedure:
20.0 g (139 mmol) (6-chloropyridin-3-yl)methanol are heated under reflux overnight in 400 ml of a 35% strength aqueous hydrazine hydrate solution. The mixture is concentrated, toluene is added, the mixture is concentrated again and the residue is stirred with a mixture of methylene chloride, methanol and diethyl ether. The crystalline residue (hydrazine hydrochloride) is filtered off, the filtrate is concentrated and the residue is dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018, 10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (NIS, 12.03 g, 53.45 mmol, 1.05 equiv) at 25° C., and the resulting reaction mixture was stirred at 25° C. for 2 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc-hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled down to 0-5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc-hexane (2×25 mL), and dried in vacuo to afford the crude, (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 15.1 g, 17.15 g theoretical, 88%) as off-white powders, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1019: 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07 (t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 1H, J=7.8, 8.7 Hz); C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:31][NH:32][CH3:33]>C1COCC1>[C:27]([O:26][C@@H:20]([C:4]1[C:3]([CH2:2][N:32]([CH3:33])[CH3:31])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CBr)cc2ccccc2c1-c1ccc(Cl)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CN(C)C)cc2ccccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(3-(bromomethyl)-1-(4-chlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate (12 mg, 0.0245 mmol) in THF (1 mL) was added dimethylamine (2 M in THF, 0.12 μL). The reaction mixture was stirred at room temperature for 1 h. Removal of the solvent in vacuo followed by purification of the residue by flash chromatography (silica gel, ethyl acetate/hexanes) provided 8 mg of the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H33ClNO3: 454.2. Found: 454.2, 456.1.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34]#[N:35])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34]#[N:35])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C#N)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C#N)cccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-cyano-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH2:25]([N:27]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH2:28][CH3:29])[CH3:26]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:36][CH:35]=2)=[C:9]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:36][CH:35]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(Nc2cc(C(=O)OC)c(C(=O)OC)cc2Nc2ccc(N(CC)CC)cc2)cc1

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 3.94 g (24 mmol) of 4-(N,N-diethylamino)-aniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with dichloromethane/methanol 400:15 and the product fractions are concentrated by evaporation and again chromatographed on silica gel with ethyl acetate/hexane 1:1. The product fractions are concentrated by evaporation, yielding the title compound in the form of green crystals, FAB-MS: 518 [M+ ], 519 [M+ +H].
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19]Cl)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:46]([SH:49])[CH:47]=[CH2:48].[Cl-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19][S:49][CH2:46][CH:47]=[CH2:48])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCS
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzhydryl 7-(2-phenylacetamido)-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (25 g) in N,N-dimethylformamide (150 ml) were added triethylamine (6.42 ml) and 2-propene-1-thiol (8.0 ml), and the mixture was stirred at 25° C. for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride (1.5 l), followed by collecting the precipitated solid by filtration, which was washed with water and diisopropyl ether, and then dried to give benzhydryl 7-(2-phenylacetamido)-3-allylthiomethyl-3-cephem-4-carboxylate-1-oxide (24.2 g).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClCCl>[C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][OH:32])[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: C=CCOC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: C=CCOC1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
5 g of (d) was dissolved in 125 ml of a methanol/dichloromethane mixture (30:70) containing 4% (m/v) of para-toluene sulphonic acid (PTSA). This was stirred at ambient temperature for 3 h. The reaction mixture was then neutralised, washed with water and dried. After evaporating off the solvents, the crude product obtained was purified over silica to produce a white solid: 2 g (yield: 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Cl:8][C:6]1[CH:5]=[C:4]([B:9]2[O:10][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:11]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(O)C(C)(C)O
Product: CC1(C)OB(c2cc(Cl)cc(Cl)c2)OC1(C)C
Yield: 73 %

Procedure:
The title compound (73%, oil) was prepared from 3,5-dichlorophenylboronic acid and pinacol.
Reaction SMILES: [C:1]([C:4]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:5]1[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[C:14]([O:23][CH2:24][CH:25]([CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[OH:26])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:14]([O:23][CH2:24][CH:25]([CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:26][C:6](=[O:7])[CH:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]1([C:1](=[O:3])[CH3:2])[OH:13])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)Cl
Reactant: CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)C1C=CC=CC1(O)C(C)=O
Yield: 71 %

Procedure:
In analogy with the preceding examples, 2-acetylsalicyloyl chloride is reacted with 1,3-dioctanoylglycerol which, upon work up as before, yields 71% of the desired 1,3-dioctanoyl-2-(2-acetylsalicyloyl)glycerol as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from {2-amino-4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (200 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (160 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([OH:23])[CH3:22]>O1CCOCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15](=[NH:16])[O:23][CH2:21][CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)CCCOc1cccc(CN2CCCCC2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
An ice-cold solution of 4-(3-piperidinomethylphenoxy)butyronitrile (0.9 g) prepared as described in Example 17 in a mixture of ethanol (5 ml) and dioxan (5 ml) was saturated with hydrogen chloride gas. The mixture was left for 16 hours during which time the temperature rose to ambient. The solvent was then removed by evaporation to yield a hydrochloride salt of ethyl 4-(3-piperidinomethylphenoxy)butyrimidate as a colourless oil. The imidate salt was mixed with 4-methylcarbamoylmethyl-o-phenylenediamine (0.6 g) prepared as described in Example 8 and ethanol (38 ml) and the mixture was heated under reflux for 41/2 hours. The solvent was removed by evaporation in vacuo and the residue dissolved in water. The aqueous solution was washed with ethyl acetate and then aqueous ammonia solution (S.G. 0.880) was added until the solution was alkaline. The solution was extracted with ethyl acetate and the extracts were washed and dried. Partial removal of the ethyl acetate caused crystallisation of 5-methylcarbamoylmethyl-2-[3-(3-piperidinomethylphenoxy)propyl]benzimidazole (m.p. 111°-115° C.) as colourless crystals. [Formula I E=--(CH2)3.O, J is hydrogen, R1 =methyl, R2 =H, NR3R4 =piperidino, m=1, and p=1].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:35])=[C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[O:10][C:5]2=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:35])=[C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(Br)nc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(Br)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-bromo-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (343 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (307 mg, 94%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[C:18]1([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:28]4[N:24]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: OB(O)c1ccnn1-c1ccccc1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Fc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccccc4)cc32)cc1

Procedure:
The title compound, light brown solid (26 mg, 21%), MS (ISP) m/z=355.2 [(M+H)+], mp 194° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (100 mg, 344 μmol) and commercially available 1-phenyl-1H-pyrazol-5-ylboronic acid [CAS No. 1238702-56-1] (83.9 mg, 447 μmol).