Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].S.Cl[CH2:7][C:8]1[NH:9][C:10]([CH3:33])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].O[S:35](O)(=O)=O>COCCOC.O>[SH:35][CH2:7][C:8]1[NH:9][C:10]([CH3:33])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(O)O
Agent: CC[O-]
Agent: S
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A stirred ethanolic solution (200 ml) of an alkaline alkoxide, for example sodium ethoxide (20 g), is saturated, at +10° C., with dry hydrogen sulfide, cooled to -15° C., and added with a solution of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine (25 g) in DME (70 ml). After one hour, the reaction mixture is warmed to 0° C., acidified with H2SO4 (10% water solution; 100 ml) and diluted with water (1400 ml). The precipitate is filtered off, dried in vacuum, and recrystallized from Et2O to give 23 g of 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine, m.p. 145°-147° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[I-:14].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: COc1ccc(CCCCBr)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CCCCI)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture consisting of 30.2 g (124 mmol) 1-(4-bromo-butyl)-4-methoxy-benzene, 19.2 g (128 mmol) sodium iodide and 508 ml acetone was heated to reflux temperature for 1 h. The resulting suspension was cooled to r.t. and the precipitated sodium bromide removed by filtration. The filtrate was stripped off the solvents by vacuum distillation and the residue distributed between water and diethyl ether. After drying of the organic phase over sodium sulphate, vacuum distillation gave 34.9 g (97%) of the title compound as slightly yellow coloured liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([O-])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[CH:28]=[CH:27][N:26]=[CH:25]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH3:2][C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:10][C@@H:9]1[C:21]([N:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[CH2:30][CH2:29][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=[O:22])=[O:7])([CH3:4])[CH3:3]
Reactant: c1cn(CCC2CCCCN2)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)[O-])C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCCCC2CCn2ccnc2)C1
Temperature: 25 °C
Reaction time: 122 h
Yield: 30.3 %

Procedure:
1,4-Di-N-tert-butoxycarbonylpiperazine-2(R)-carboxylate (prepared as described in Preparative Example 2) (0.6946 g, 2.1 mmoles), 2(R/S)-[2-(1H-imidazol-1-yl)ethyl]piperidine (0.49 g, 2.73 mmoles) (prepared as described in Preparative Example 57, Step D) (INO972). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.524 g, 2.73 mmoles), 1-hydroxybenzotriazole (0.3693 g, 2.73 mmoles) and 4-methylmorpholine (0.2765 g, 0.3005 mL, 2.73 mmoles) were dissolved in anhydrous DMF (3 mL) and the mixture was stirred under argon at 25° C. for 122 h. The mixture was evaporated to dryness and chromatographed on silica gel using 2-3%(10% conc. ammonium hydroxide in methanol)dichloromethane as the eluant to give the title compound (0.3127 g, 30%): CIMS: m/z 492.4 (MH+): δ11 (CDCl3) 1.47 (18H, s, CH3), 7.01 (1H, s, Im-H,), 7.05 (1H, s, Im-H4) and 7.63 ppm (1H, s, Im-H2); δC (CDCl3) CH3: 28.2, 28.2, 28.2, 28.4, 28.4, 28.4: CH2: 19.1, 25.9, 26.2, 31.9, 40.8/41.3, 41.7, 43.0, 44.0: CH: 46.0, ˜52.1, 128.4, 137.2: C:˜80.4, 80.6, ˜154.3, ˜154.3 and 169.8.
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11].Cl.CN([CH:45](CC)[C:46](O)=[O:47])C.C[CH2:52][N:53]([CH:57](C)C)[CH:54]([CH3:56])C.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C.CO>[CH3:57][N:53]([CH3:52])[CH2:54][CH2:56][CH2:45][C:46]([O:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:11])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:30])=[O:47]
Reactant: CCCCCC/C=C\COC(=O)CCCCCCCC(O)CCCCCCCC(=O)OC/C=C\CCCCCC
Reactant: CCN(C(C)C)C(C)C
Reactant: CCC(C(=O)O)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCC/C=C\COC(=O)CCCCCCCC(CCCCCCCC(=O)OC/C=C\CCCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
The alcohol 9 (0.083 g, 0.147 mmol) was dissolved in 20 mL of dichloromethane and to it dimethylaminobutyric acid hydrochloride (0.030 g, 0.176 mmol) was added followed by Hunig's base (0.045 g, 0.44 mmol) and DMAP (2 mg). To this mixture EDCI (0.034 g, 0.176 mmol) was added and the reaction mixture was stirred at room temperature overnight and the TLC (silica gel, 10% MeOH in CH2Cl2) showed complete disappearance of the starting alcohol. The reaction mixture was diluted with CH2Cl2 (40 mL) and washed with saturated NaHCO3 (50 mL), water (60 mL) and brine (60 mL). The combined organic layers were dried over anhyd. Na2SO4 and solvents were removed in vacuo. The crude product thus obtained was purified by Combiflash Rf purification system (40 g silicagel, 0-10% MeOH in CH2Cl2) to isolate the pure product (0.062 g, 62%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.74-5.58 (m, 2H), 5.51 (dtt, J=9.7, 6.8, 1.3 Hz, 2H), 4.95-4.75 (m, 1H), 4.61 (d, J=6.8 Hz, 4H), 2.35-2.24 (m, 8H), 2.22 (d, J=7.9 Hz, 6H), 2.09 (q, J=6.9 Hz, 4H), 1.83-1.72 (m, 2H), 1.60 (dd, J=14.4, 7.2 Hz, 4H), 1.49 (d, J=5.7 Hz, 4H), 1.41-1.13 (m, 30H), 0.88 (t, J=6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.72, 173.36, 135.40, 123.35, 74.12, 60.18, 58.95, 45.46, 34.30, 34.11, 32.45, 31.67, 29.38, 29.35, 29.17, 29.07, 28.84, 27.53, 25.28, 24.93, 23.16, 22.59, 14.06. MW calc. for C41H75NO6 (MH+): 678.04. found: 678.5.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C1(S(O[CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:38](=[O:40])[CH3:39])(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH2:28][CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[NH:37][C:38](=[O:40])[CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccccc1OCCCOS(=O)(=O)c1ccccc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1ccccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 45.6 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.4 g, 16 mmol), N-[2-(3-phenylsulfonyloxypropoxy)phenyl]acetamide (5.3 g, 16 mmol), K2CO3 (2.2 g), and acetonitrile (50 ml) was stirred and refluxed for 5 hours. The reaction was poured into water, and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed (water and brine), dried (MgSO) and the solvent was concentrated to afford 6.0 g of a thick, brown oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel. Concentration of the appropriate fractions afforded 3.0 g of a beige solid. This was recrystallized from ethyl acetate to yield (with concentration of the mother liquors) 2.2 g (33%) of N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)l-piperidinyllpropoxy]phenyl]acetamide as a beige solid, m.p.=118-120° C.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[N:6]=[CH:7][N:8]([S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[C:9]=1[CH2:10][CH2:11][CH3:12])=[O:4].O>C(O)C>[OH:4][CH2:3][C:5]1[N:6]=[CH:7][N:8]([S:13]([N:16]([CH3:17])[CH3:18])(=[O:14])=[O:15])[C:9]=1[CH2:10][CH2:11][CH3:12]
Reactant: CCCc1c(C=O)ncn1S(=O)(=O)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(CO)ncn1S(=O)(=O)N(C)C
Yield: 93.7 %

Procedure:
Sodium borohydride (139 mg) was added to a stirred solution of 4-formyl-N,N-dimethyl-5-propyl-1H-imidazole-1-sulphonamide (450 mg) in absolute ethanol (5 ml) under nitrogen. After 3 h the mixture was poured into water (30 ml) and extracted with dichloromethane (3×15 ml). The combined, dried organic extracts were evaporated to give a solid (425 mg) which was triturated with ether (2×10 ml) to give the title compound (350 mg), m.p. 86°-88°.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[Cl:13][CH2:14][C:15](Cl)=[O:16].Cl>O>[Cl:13][CH2:14][C:15]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[C:7]([F:12])[CH:8]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCl)c1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Aluminium trichloride (210.2 g) was added to 1,2-difluorobenzene (200.0 g) at room temperature. The obtained slurry was heated to 50° C., then chloroacetyl chloride (198.0 g) was added over 50 minutes. The reaction mixture was stirred for an additional 60 minutes, then added slowly to a mixture of ice (786.0 g), water (196.0 g) and 37 wt % hydrochloric acid (297.0 g), during the addition the temperature was kept below 60° C. After the addition, the reaction mixture was heated to 60° C. and the layers separated. The organic layer was washed twice with a 20 w/v % sodium chloride solution (200.0 mL). 2-Chloro-1-(3,4-difluorophenyl)ethanone (270.2 g) was obtained by vacuum distillation of the organic layer.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:29]O.Cl>CO.O.C(Cl)Cl>[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](COC2CCCCC2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1COC1CCCCC1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
Cis-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.13 g, 3.06 mmol) was dissolved in MeOH (14 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.128 g, 3.21 mmol) dissolved in water (1.400 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.197 mL, 3.21 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (15.80 mL, 94.82 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (423 mg, 41%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.12-2.15 (m, 14H), 2.93-3.04 (m, 1H), 3.10-3.31 (m, 2H), 3.35-3.50 (m, 2H), 3.70 (s, 3H), 3.83-3.94 (m, 1H), 4.05-4.15 (m, 1H), 5.75 (s, 1H). MS m/z 339 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:11]3[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3C(F)(F)F)c(-c3ccc(OC)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3C(F)(F)F)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 85 mg (0.17 mmol) 6-({5-(4-methoxyphenyl)-6-[2-(trifluoromethyl)phenyl]furo[2,3-d]pyrimidin-4-yl}amino)hexanoic acid methyl ester in 2.5 ml dioxan and add 0.5 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.5 ml 1 N hydrochloric acid and 6 ml ethyl acetate. Separate the organic phase, dry over sodium sulphate, filter and concentrate by evaporation. 68 mg (82% of theor.) of the target compound is obtained.
Reaction SMILES: C([Li])(C)(C)C.I[C:7](=[CH2:16])[CH2:8][C@@H:9]1[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10]1.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>CCCCCC.C(OCC)C>[CH3:14][C:11]1([CH3:15])[O:10][C@H:9]([CH2:8][C:7]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH2:16])[CH2:13][O:12]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C=C(I)C[C@@H]1COC(C)(C)O1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C(C[C@@H]1COC(C)(C)O1)S(=O)(=O)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl lithium in hexane (1.7M, 7.65 mL) was added dropwise to a solution of (R)-4-(2-iodoallyl)-2,2-dimethyl-1,3-dioxolane (1.21, 6.5 mmol) in diethyl ether (12 mL) at −78° C., and the reaction stirred at −78° C. for 30 min. Sulfuryl dichloride (SO2Cl2, 538 μL, 6.5 mmol) was added, the mixture warmed to room temperature and the solvents removed under reduced pressure. The product was used in the next step with no further purification.
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:21][O:22][C:23](OC)(OC)OC.C(O)(=O)C>ClCCl>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:21]([O:22][CH3:23])=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Temperature: 25 °C
Yield: 32.8 %

Procedure:
A mixture of 2.6 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine, 10 parts of tetramethoxymethane, 0.6 parts of acetic acid and 6.5 parts of dichloromethane was stirred over weekend at room temperature. After evaporation, the residue was treated with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo, yielding 1 part (32.8%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-2-methoxy-1H-benzimidazole; mp. 109.5° C. (compound 115).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.BrC1C=CC(N[C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26](OC)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=C(F)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCN(CCOCCO)CC1.C(Cl)[Cl:67]>>[ClH:67].[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[N:20][CH:21]=1
Reactant: ClCCl
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: OCCOCCN1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cl
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
Diethyl azodicarboxylate (378 μl, 2.4 mmol) was added dropwise to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (292 mg, 0.8 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (629 mg, 2.4 mmol) and 2-(2-morpholinoethoxy)ethanol (196 mg, 1.12 mmol), (prepared as described for the starting material in Example 53), in methylene chloride (10 ml) under nitrogen. The mixture was stirred for 3.5 hours at ambient temperature and the mixture was purified by pouring it directly on to a column of silica and eluting with methylene chloride/acetonitrile/methanol 6/3/1). The purified product was dissolved in methylene chloride/methanol and the insolubles were removed by filtration. 2M Ethereal hydrogen chloride (1 ml) was added to the filtrate and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-morpholinoethoxy)ethoxy)quinazoline hydrochloride (232 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].CN(C)CCN(C)C.C([Li])CCC.[CH2:32]1[O:34][CH2:33]1.B(F)(F)F.CCOCC>O1CCCC1>[OH:34][CH2:33][CH2:32][C:5]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]=1[O:13][CH3:14]
Reactant: C1CO1
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Agent: CN(C)CCN(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1cc(OC)c(OCOC)c(CCO)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
10 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 500 ml of tetrahydrofuran, then to this solution was added 7.01 ml (46.44 mM) of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C. in a dry ice-acetone bath. To this cooled mixture was added dropwise 29.1 ml of n-butyllithium (1.6M-hexane solution), then stirred for 30 minutes. Next, 26.4 ml (2.091M solution) of tetrahydrofuran solution of ethylene oxide and 0.5 ml of boron trifluoride-diethyl ether (BF3 ·Et2O were added to the reaction mixture. 10 Minutes after, the dry ice-acetone bath was removed from the reaction equipment, then 2 hours later, the reaction mixture was concentrated to obtain the residue and 500 ml of diethyl ether was added thereto, and washed 4 times with 200 ml of water, further washed 4 times with 200 ml of a saturated sodium chloride aqueous solution, next dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was treated by a silica gel column chromatography [diameter 6 cm×length 30 cm, eluent: ethyl acetate:n-hexane=(2:3), "Wakogel C-200"] to yield 8.5 g of 1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene. Colorless needless crystals. Melting point: 121°-123° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH3:38])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>CO.O1CCCC1.[C].[Pd]>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH3:38])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 5 h
Yield: 52.8 %

Procedure:
10% Palladium carbon (0.6 g.) was added to a solution of p-nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylate (anti isomer, 1.16 g.) in methanol (20 ml.) and tetrahydrofuran (40 ml.), and the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure for 5 hours. After removing the catalyst from the reaction mixture, the filtrate was concentrated under reduced pressure. Water (30 ml.) and ethyl acetate (60 ml.) were added to the residue, and the mixture was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate and shaked sufficiently. The aqueous layer was separated and ethyl acetate (90 ml.) was added to the aqueous solution. The aqueous layer was adjusted to pH 2.5 with 10% hydrochloric acid with stirring under ice-cooling, and the ethyl acetate layer was separated. The remaining aqueous layer was extracted with ethyl acetate (30 ml.), and the extract and the ethyl acetate layer were combined together, washed with an aqueous solution of sodium chloride, dried and then concentrated under reduced pressure. The residue was washed with diisopropyl ether to give 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylic acid (anti isomer, 0.47 g.). The compound was colored at 210° C. and decomposed at above than 250° C.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])=O)(=O)OC.O.[NH2:29][NH2:30]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:30]=[N:29][C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=2[CH:17]=1
Reactant: O=C1CCCCCCC1=O
Reactant: NN
Reactant: COc1ccccc1C(=O)CP(=O)(OC)OC
Solvent: O
Product: COc1ccccc1-c1cc2c(nn1)CCCCCC2

Procedure:
yellow oil. MS (EI): 268.2 (M+). Prepared from cyclooctane-1,2-dione, [2-(2-Methoxy-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(Cl)(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][CH2:30][CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: CCCCN(C(=O)c1cc(OC)c(OC)cc1I)c1ccnc2cc3c(cc12)OCO3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2cc(OC)c(OC)cc2c2cnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Yield: 24 %

Procedure:
A mixture of the N-(6,7-Methylenedioxyquinolin-4-yl)-N-(butyl)-2-iodo-4,5-dimethoxybenzamide (1.0 mmol equiv.), Pd(OAc)2 (0.2 mmol equiv.), P(o-tolyl)3 (0.4 mmol equiv.), and Ag2CO3 (2.0 mmol equiv) was heated to reflux in DMF (30 mL per mmol equiv.) with stirring. The reaction mixture was allowed to cool to room temperature, diluted with CHCl3, and filtered through Celite. The sicciate was extensively washed with 10% CH3OH in CHCl3. The filtrate was concentrated in vacuo and the residue chromatographed on silica gel using chloroform:methanol to provide the title compound; (24% yield); reaction time 45 min; mp 224° C. (dec.); IR (KBr) 1654; 1H NMR (CDCl3); δ 0.99 (t, 3H, J=7.4), 1.62 (m, 2H), 2.09 (m, 2H), 4.07 (s, 3H), 4.14 (s, 3H), 4.49 (m, 2H), 6.19 (s, 2H), 7.50 (s, 1H), 7.61 (s, 1H), 7.70 (s, 1H), 7.92 (s, 1H), 9.40 (s, 1H); 13C NMR (CDCl3) δ 13.7, 20.2, 31.2, 50.6, 56.3, 56.4, 100.7, 102.0, 102.2, 107.4, 108.8, 111.7, 114.9, 119.5, 127.4, 141.1, 143.7, 147.1, 147.5, 149.8, 150.3, 154.1, 164.0; HRMS calcd for C23H22N2O5H, 406.1529; found 406.1534.