Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH2:23][C:24](OCC)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCCCCCNc1ccc(CCCO)cc1

Procedure:
By a method analogous to that described in Example 16, ethyl 4-hexadecylaminohydrocinnamate is reduced with lithium aluminum hydride to provide the title compound.
Reaction SMILES: [F:1]C1C=C2C(=CC=1)NC=C2C=O.C(O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31])C=C>>[F:1][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31]
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: NC(=O)n1cc(N=C=O)c2cc(F)ccc21

Procedure:
was prepared from 5-fluoro-1H-indole-3-carbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Cc2nc3ccccc3n2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(Cc2ccc(C(=O)O)cc2)nc2ccccc21
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of methyl 4-[(1-methyl-1H-benzimidazol-2-yl)methyl]benzoate (7.0 g, 25 mmol) in methanol was treated with 2.5 N sodium hydroxide, heated at reflux temperature for 2 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in water and acidified with 6N HCl solution and filtered. The filtercake was air dried to afford 4-[(1-methyl-1H-benzoimidazol-2-yl)methyl]benzoic acid in 81% yield; 1H NMR (400 MHz, DMSO-d6): 7.90 (d, J=8 Hz, 2H), 7.57 (d, J=8 Hz, 1H), 7.49 (d, J=8 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.17-7.20 (m, 2H), 4.39 (s, 2H), 3.70 (s, 3H). LCMS (ESI+) 276 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH:24]1([C:28]([CH2:30]Br)=[O:29])[CH2:27][CH2:26][CH2:25]1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:30]=1[C:28]([CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:29]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)C1CCC1
Product: COC(=O)Cc1c(C(=O)C2CCC2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and bromomethyl cyclobutyl ketone*.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH2:14][C@H:10]([C:11]([OH:13])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][N:18]([CH3:17])[C:11]([C@H:10]1[CH2:14][CH2:15][CH2:16][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: CNCCOCCOCCOCCOCCOCCOCCOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCOCCOCCOCCOCCN(C)C(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 212.5 %

Procedure:
To a solution of Boc-(S)-nipecotic acid (137 mg, 0.60 mmol), N-methyl-2,5,8,11,14,17,20-heptaoxadocosan-22-amine 135c.1 (310 mg, 0.88 mmol) and DIPEA (335 mg, 2.6 mmol) in DMF (3 mL) was added HATU (285 mg, 0.75 mmol). The reaction was stirred for 1 hour and then the DMF was removed under vacuum. The residue was added to saturated aqueous NaHCO3 (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried (Na2SO4) and concentrated to give (S)-tert-butyl 3-(2,5,8,11,14,17,20-heptaoxadocosan-22-yl(methyl)carbamoyl)piperidine-1-carboxylate (720 mg).
Reaction SMILES: [Na].[O-]CC.[Na+].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([OH:16])[C:12]([O:14]C)=O.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH2:25][C:26]#[N:27])[CH:22]=[CH:23][CH:24]=1>C(O)C.O>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]1[C:12](=[O:14])[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:28])([F:17])[F:29])[CH:20]=2)=[C:26]([NH2:27])[O:16]1
Reactant: COC(=O)C(O)c1cccs1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2cccs2)O1
Yield: 12.3 %

Procedure:
A dry, 250-ml, three-neck, round-bottom flask equipped with a mechanical stirrer, addition funnel and a reflux condenser bearing a nitrogen inlet tube was charged with 4.2 g of sodium and 100 ml of absolute ethanol. To the resulting sodium ethoxide solution was added dropwise a mixture of 21.1 g of methyl thien-2-yl-hydroxyacetate and 22.7 g of m-trifluoromethylphenyl-acetonitrile in 20 ml of ethanol. The resulting mixture was heated at reflux for 4-5 hours after which time it was added to 300-400 ml of water and extracted with petroleum ether. The aqueous phase was acidified with aqueous 10 weight percent hydrochloric acid and extracted two times with diethyl ether. The ether extracts were washed twice with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to yield a thick dark oil. This oil was triturated with 20-30% ether/petroleum ether which afforded 4.9 g of the title compound as a tan powder.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[CH3:18][O:17][C:12]1[C:11]([C:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ncccc1C1=CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: COc1ncccc1C1=CCC(=O)CC1
Temperature: 25 °C

Procedure:
To a mixture of 3-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-2-methoxy-pyridine (as prepared in the previous step, 211 mg, 0.854 mmol) in acetonitrile was added aqueous HCl (5 mL, 5 mmol, 1M). The mixture was stirred at room temperature until HPLC indicated consumption of starting material. The reaction mixture was poured onto saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2) to afford 4-(2-methoxy-pyridin-3-yl)-cyclohex-3-enone.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Si]([O:39][S:40]([C:43](F)(F)F)(=O)=[O:41])(C)(C)C.O=O>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:9][CH2:10][C@@:11]1([C:26]#[CH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@H:12]1[O:25][S:40]([CH3:43])(=[O:41])=[O:39])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CCN(CC)CC
Product: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirring mixture of 4 (3.58 g, 8.72 mmol) and Et3N (6.1 ml, 43.6 mmol) was added Me3SiOSO2CF3 (2.56 mL, 13.0 mmol) at 0° C. under positive pressure of dry Ar. The mixture was stirred for 30 min at the same temperature, and then partitioned between CH2Cl2 and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4) and evaporated. The residue was dissolved in DMSO (12 mL). To this solution was added Pd(OAc)2 (98 mg, 0.44 mmol), and the mixture was stirred for 36 h under positive pressure of O2. The mixture was partitioned between EtOAc and brine. The organic layer was dried (Na2SO4), evaporated, and chromatographed on a silica gel column (hexane/EtOAc=5/1) to give 5 (3.13 g, 88%) as a white solid.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[C:17]([C:27]2[CH:32]=[C:31]([CH3:33])[C:30]([CH3:34])=[CH:29][C:28]=2[CH3:35])[O+]=1.[PH3:36]>C(O)CCC>[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[C:17]([C:27]2[CH:32]=[C:31]([CH3:33])[C:30]([CH3:34])=[CH:29][C:28]=2[CH3:35])[P:36]=1
Reactant: Cc1cc(C)c(-c2cc(-c3ccccc3)cc(-c3cc(C)c(C)cc3C)[o+]2)cc1C
Reactant: P
Agent: F[B-](F)(F)F
Solvent: CCCCO
Product: Cc1cc(C)c(-c2cc(-c3ccccc3)cc(-c3cc(C)c(C)cc3C)p2)cc1C

Procedure:
2.1 g (4.4 mmol) of 2,6-bis(2,4,5-trimethylphenyl)-4-phenylpyrylium tetrafluoroborate in 150 ml of n-butanol were used as starting material. The autoclave product obtained after the reaction with PH3 was evaporated to about 50 ml under reduced pressure at about 80° C. The solid which precipitated was filtered off with suction, washed with n-pentane and subsequently dissolved in toluene. The toluene solution was then washed with water until the aqueous phase was neutral. After removing the solvent and washing with a little n-pentane, the residue was dissolved in dichloromethane. The resulting solution was diluted with methanol and then evaporated under reduced pressure at 30° C. until a solid precipitated. The solid was filtered off with suction, washed with a little n-pentane and subsequently dried in a high vacuum. Yield: 0.8 g (45%) of light-yellow solid.
Reaction SMILES: [O:1]=[C:2]([NH:8][CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].I[CH3:17].[H-].[Na+]>CN(C=O)C>[O:1]=[C:2]([N:8]([CH3:17])[CH2:9][C:10]1[N:11]=[CH:12][CH:13]=[CH:14][N:15]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)NCc1ncccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N(C)Cc1ncccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution ethyl 2-oxo-2-[(pyrimidin-2-yl)methylamino]acetate from the previous step (1.0 g, 4.8 mmol) and iodomethane (0.5 mL, 8 mmol) in DMF (15 mL) was cooled to 0° C. and NaH (0.23 g of a 60% dispersion in mineral oil, 5.7 mmol) was added. The cooling bath was removed and the mixture was stirred at ambient temperature for 18 hours. Ethanol was added to quench the reaction and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient of 80-100% EtOAc in hexanes. The solvent was removed under reduced pressure from the fractions containing product to give the title compound as an oil. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (m, 2H), 7.45 (m, 1H), 4.74 (m, 2H), 4.32, 4.13 (two q, rotamers, J=7 Hz, 2H), 3.08, 3.00 (two s, rotamers, 3H), 1.30, 1.08 (two t, rotamers, 3H); ES MS M+1=224.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[C:4]([N+:15]([O-])=O)[C:3]=1[OH:18].O.[Sn](Cl)Cl>>[NH2:15][C:4]1[C:3]([OH:18])=[C:2]([Cl:1])[CH:13]=[C:12]([Cl:14])[C:5]=1[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(NC1CC1)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1c(O)c(Cl)cc(Cl)c1C(=O)NC1CC1
Yield: 93 %

Procedure:
Reduction of 4,6-dichloro-N-cyclopropyl-3-hydroxy-2-nitrobenzamide with tin (II) chloride hydrate using the conditions as described in Step B yielded 2-amino-4,6-dichloro-N-cyclopropyl-3-hydroxybenzamide (93%).—1H NMR (CD3OD): δ 6.67 (s, 1H), 2.86 (m, 1H), 0.79 (m, 2H), 0.62 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]([OH:11])[CH:5]=1)[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:11][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]([I:10])=[CH:8][N:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1cc(O)ncc1I
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOc1cc(OCc2ccccc2)ncc1I
Temperature: 70 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a mixture of 4-ethoxy-5-iodopyridin-2-ol (800 mg, 3.02 mmol) in THF (10 mL) was added (bromomethyl)benzene (619 mg, 3.62 mmol) and silver carbonate (1665 mg, 6.04 mmol). The mixture was stirred at 70° C. for 16 h. The reaction residue was filtered and the filtrate was concentrated. The mixture was diluted with H2O and extracted with DCM. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(benzyloxy)-4-ethoxy-5-iodopyridine (800 mg, 1.915 mmol, 63.4% yield) was used to next step without further purification: 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.45-7.43 (m, 2H), 7.38-7.36 (m, 3H), 6.22 (s, 1H), 5.33 (s, 2H), 4.12-4.07 (m, 2H), 1.48 (t, J=6.8 Hz, 3H); ES-LCMS m/z 355.9 (M+H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[C:20]([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].CO>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:20]3[N:21]=[C:17]([CH:14]4[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]4)[NH:18][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: Cc1cccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2ccc3c(c2)OCO3)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2[nH]c(C3CCNCC3)nc2-c2ccc3c(c2)OCO3)n1
Reaction time: 4 h
Yield: 96.6 %

Procedure:
Palladium on activated carbon (0.010 g) was added to a solution of 4-(4-benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (0.100 g, 0.20 mmol; see Example 5) in methanol (5 mL). The reaction mixture was stirred under hydrogen atmosphere for 4 hours. The mixture was then filtered and concentrated to give 0.070 g (97%) of the title compound as a yellow oil. MS (ESP+) m/z 363.2 (M+1). 1H NMR (300 MHz, CDCl3) δ 7.41 (t, 1H, J=7.8 Hz), 7.29 (d, 1H, J=8.1 Hz), 7.10 (m, 2H), 6.92 (d, 1H, J=7.5 Hz), 6.83 (m, 1H), 5.98 (s, 2H), 3.18 (m, 2H), 2.95 (m, 1H), 2.73 (m, 2H), 2.46 (s, 3H), 1.96 (m, 2H), 1.82 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.BrBr.[Li].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1>[CH2:28]([O:27][C:25](=[O:26])[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: Clc1cc(-c2ccccc2Cl)c(Br)cn1
Agent: BrBr
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2.00 g (6.60 mmol) 5-bromo-2-chloro-4-(2-chloro-phenyl)-pyridine in 66 ml tetrahydrofuran 4.3 ml of a solution of n-butyllithium in hexanes (1.6 M, 6.9 mmol) were added dropwise at −100° C. under argon. Thin layer chromatography showed complete bromine-lithium exchange after 5 min. After addition of 0.71 ml (7.3 mmol) ethyl chloroformate the reaction mixture was allowed to slowly warm to −78° C. and stirred at that temperature for 1 h. The reaction mixture was allowed to warm to room temperature over night. Quenching with a small amount of water was followed by dilution with tert-butyl methyl ether and washing with water and brine. The organic layer was dried with sodium sulfate and concentrated. Column chromatography afforded 1.66 g (85%) of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[C:7]([C:6]1[CH:9]=[C:2]([N:28]2[C@H:27]([CH3:26])[CH2:31][O:30][C:29]2=[O:32])[CH:3]=[CH:4][C:5]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])#[N:8]
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3C#N)CC2)c(C)c1
Yield: 77.8 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 193 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (326 mg) was obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][C:46]([NH:21][C:18]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:47])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CN(C)c1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc2N)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CN(C)c1ccc(-c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc2NC(=O)Cc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-[4-(dimethylamino)phenyl]pyrazin-2-amine (7n) (315 mg, 749 μmol) and 4-(dimethylamino)pyridine (14.8 mg, 121 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyl dimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was hetated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=2/1) to give Compound 11n (200 mg, 300 μmol, 40.0%) as a yellow solid. Rf=0.26 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.23 (s, 6H), 0.95 (s, 9H), 0.97 (s, 9H), 2.95 (s, 6H), 3.50 (s, 2H), 6.52-6.65 (AA′BB′, 2H), 6.75-6.85 (AA′BB′, 2H), 6.95-7.05 (AA′BB′, 2H), 7.10-7.20 (AA′BB′, 2H), 7.56-7.66 (AA′BB′, 2H), 8.04-8.10 (AA′BB′, 2H), 8.82 (s, 1H), 10.41 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.5 (6C), 39.8 (2C), 41.8, 111.3 (2C), 119.5 (2C), 120.3 (2C), 124.4, 128.05, 128.07 (2C), 128.9 (2C), 129.2, 130.4 (2C), 135.8, 142.0, 147.78, 147.84, 150.5, 153.8, 156.6, 169.3; IR (KBr, cm−1) 527, 685, 781, 839, 914, 1080, 1167, 1256, 1371, 1441, 1508, 1607, 1668, 2857, 2928, 2955, 3233.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:28][SH:29].C(N(CC)CC)C>C1COCC1>[F:27][C:5]1[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[C:3]([CH2:2][S:29][CH3:28])[N:4]=1
Reactant: Fc1nc(CCl)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
4-Chloromethyl-2-fluoro-1-triphenylmethylimidazole was treated with methanethiol and triethylamine in THF solution to give 2-fluoro-4-methylthiomethyl-1-triphenylmethylimidazole. This was condensed with t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate as for the starting material of Example 42 to give t-butyl 3-acetoxymethyl-7-(4-methylthiomethylimidazol-2-yl)aminoceph-3-em-4-carboxylate, having the following n.m.r. spectrum in d6DMSO: 1.5 (s, 9H); 2.0 (s, 6H); 3.5 (d, 2H); 3.8 (d, 2H); 4.7 (d, 1H); 5.0 (d, 1H); 5.25 (d, 1H); 5.65 (d, 1H); 7.0 (s, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:23])[N:11]2[C@@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 64.1 %

Procedure:
A mixture of (R)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.075 mmol), β-alanine (535 mg, 6.0 mmol) and NaOMe solution (9 mL, 4.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 22 mg of the title compound. MS: (+) m/z 458.36 (M+1).