Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([N+:24]([O-:26])=[O:25])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Li+].[Cl-].CC1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:24]([O-:26])=[O:25])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]
Reactant: COc1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc(O)c([N+](=O)[O-])n1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl) (3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide (700 mg, 0.0011 mol) in NMP (7.0 mL) was added LiCl (183.79 mg, 0.0043 mol, Sigma Aldrich, India) followed by pTSA (746.63 mg, 0.0043 mol, Sigma Aldrich, India) at room temperature. The reaction mixture was stirred at 180° C. for 2 h. After completion of the reaction (monitored by TLC, 100% EtOAc), the reaction mixture was cooled to room temperature and water (50 mL) was added and the aqueous solution was extracted with EtOAc (25 mL×2). The organic extracts were washed with water (25 mL×2) and brine (25 mL) and dried over anhydrous sodium sulfate and concentrated. The resulting material was purified by silica gel (60-120 mesh) column chromatography eluting with 60-70% EtOAc in petroleum ether to give the title compound as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): δ 12.77 (br. s., 1H), 9.43 (d, J=7.2 Hz, 1H), 8.57 (d, J=4.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.86-7.79 (m, 2H), 7.59-7.54 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H). MS (ESI, positive ion) m/z: 471 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([NH2:11])=[C:9]([N+:12]([O-])=O)[CH:8]=[N:7][CH:6]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cncc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cncc(N)c1N
Yield: 77.7 %

Procedure:
A mixture containing 4-amino-5-nitro-nicotinic acid ethyl ester (78; 15 g, 0.071 mol) and 10% Pd/C (500 mg) in MeOH (500 mL) was stirred under 1 atm of hydrogen at room temperature for 18 h. The reaction mixture filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 4,5-diamino-nicotinic acid ethyl ester 79 (10 g, 80%).
Reaction SMILES: [CH2:1]([C:3]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([CH2:17][CH3:18])[C:4]=1[CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1)[CH3:2].C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:3]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([CH2:17][CH3:18])[C:4]=1[CH2:5][C:6]1[NH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCc1ccc(OC)c(CC)c1CC1=NCCN1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc(OC)c(CC)c1Cc1ncc[nH]1

Procedure:
2-(2,6-Diethyl-3-methoxy-benzyl)-1H-imidazole was prepared from 2-(2,6-diethyl-3-methoxy-benzyl)-4,5-dihydro-1H-imidazole (Example 206), TCCA and DBU in analogy to Example 194e): light yellow crystals; MS (ISP): 245.4 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:8]#[N:9])[CH:2]=[CH2:3].[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[CH:10]=[CH:11][C:12]=1[NH2:13])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=CCOc1cc(C#N)ccc1N
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To the solution of 3-allyloxy-4-nitrobenzonitrile (5.85 g, 28.68 mmol) in ethanol (30 ml), Tin (II) chloride (32 g, 143.4 mmol) was added. The reaction mixture was stirred at reflux for 4 hours and then was cooled to room temperature. NaHCO3 (aq) was added to pH=7 was achieved. Then the reaction mixture was extracted with ethyl acetate (3×). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give desired product (4.5 g, 90%). EI-MS m/z 175 (M+).
Reaction SMILES: OC1C=CC([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH2:14][NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=CC=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CS(C)=O.C(OCC)(=O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][O:24][C:25]1[CH:26]=[CH:27][C:30]([N:15]([CH2:14][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:8]=2)[S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])=[CH:31][CH:32]=1
Reactant: COc1cccc(CBr)c1
Reactant: CCS(=O)(=O)NCc1cnccc1-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(OCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-(4-(4-hydroxyphenyl)-N-(ethanesulfonyl) pyrid-3-ylmethylamine (1.0 equiv.) in DMSO (0.15 M) was cooled to 0° C. Sodium hydride (1.1 equiv.; 60% dispersion in oil) was added; after 20 minutes at 0° C. 3-methoxybenzyl bromide (Aldrich; 1.3 equiv.) was added and the reaction warmed to ambient temperature. After stirring overnight the reaction was diluted with ethyl acetate and washed with 0.1 M potassium carbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative HPLC eluting with 90:10 to 70:30 DCM/ethyl acetate to give the title compound. Anal Calcd for C22H24N2O4S.0.1H2O: C, 64.06; H, 5.86; N, 6.79. Found: C, 63.78; H, 5.89; N, 6.76. MS found 413.0 [M+H]+.
Reaction SMILES: C([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+].N#N>[Pd].CC(C)=O>[NH2:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: N#N
Agent: O=C[O-]
Solvent: CC(C)=O
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reaction time: 10 h
Yield: 88 %

Procedure:
(S)-5-((dibenzylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.95 g, 2 mmol), 0.5 g 10 wt % Pd—C and ammonium formate (1.3 g, 20 mmol) were added to 20 mL acetone and the air was replaced with N2. The mixture was heated to reflux and stirred for 10 hours. The mixture was filtered and separated by water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to provide 0.52 g of white solid in 88% yield.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)([F:7])[F:6])C.[OH-].[Na+].Cl>>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]([F:6])([F:7])[C:4]([OH:17])=[O:3])=[CH:13][CH:12]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C(F)(F)c1ccc(C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc(C(F)(F)C(=O)O)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
According to the above-described scheme, 2-(4-acetylphenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2e; 436.0 mg, 1.8 mmol) and 1N NaOH solution (3.0 mL) were put into an eggplant flask, and the mixture was stirred at 100° C. for 1.5 hours. After the reaction, the reaction mixture was neutralized with 5% HCl solution, extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-acetylphenyl)-2,2-difluoroacetic acid (Compound 4e) was obtained with a yield of 96%.
Reaction SMILES: C(OC(COC(=O)C)CNC([C:10]1[C:15](I)=[C:14]([NH2:17])[C:13](I)=[C:12](C(NCC(OC(=O)C)COC(=O)C)=O)[C:11]=1I)=O)(=O)C.[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[C:44](Cl)=[O:45]>CN(C)C(=O)C>[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([NH:17][C:14]1[CH:15]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:45]
Reactant: O=C(Cl)C1CCCO1
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccccc1)c1ccco1
Reaction time: 0.5 h

Procedure:
To a stirred solution of N,N'-bis[2,3-bis (acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (8.73 g, 10 mmol) (prepared as described in EP 431,838) in N,N-dimethylacetamide (30 mL), was added in drops tetrahydrofuran-2-carbonyl chloride (1.8 g, 13 mmol) (prepared as in part A of Example 3) at 0°-5° . After the addition, the mixture was stirred at 0°-5° for 0.5 hour, then at room temperature for 20 hours. Nitrogen gas was purged through the solution for 0.25 hour, and the N,N-dimethylacetamide was removed in vacuo at 40° . The residue was dissolved in ethyl acetate (200 mL), and the solution was washed successively with cold aqueous sodium bicarbonate (2×50 mL), water (2×50 mL) and saturated sodium chloride (2×50 mL). After drying over sodium sulfate, the solvent was removed in vacuo to obtain the title B furanilide as an off-white foamy material (9.27 g, crude). The crude product (7.2 g), upon purification by column chromatography over silica gel (mobile phase: hexane/ethyl acetate) furnished N,N'-bis[2,3-bis(acetyloxy)propyl]2,4,6-triiodo-5-[[(tetrahydro-2furanyl)carbonyl]amino]-1,3-benzenedicarboxamide (6.19 g), m.p. 101°-104°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:4]=1[C:5]([OH:7])=O.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:5](=[O:7])[C:4]2[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH2:17][CH2:18]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc([N+](=O)[O-])c1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
2-Methoxy-6-nitro-benzoic acid (2.0 g, 10.1 mmol), 4-amino-1-benzylpiperidine (1.9 mL, 10.1 mmol), 1-hydroxybenzotriazole (1.43 g, 10.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (1.9 g, 10.1 mmol) were combined in ethyl acetate (25 mL). To this solution was added triethylamine (4.2 mL. 30.3 mmol) and the reaction mixture stirred at 40° C. for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water (2×), 5% sodium bicarbonate, brine (2×), dried over sodium sulfate, and concentrated to afford 3.2 g (86%) of the desired product. LC/MS: tR=1.10 min, 370.28 (MH)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:9]=23)[C:5]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]([NH:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:18])=[CH:16][C:9]=23)[C:5]([C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(C(=O)O)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: NCCN1CCOCC1
Product: CCn1cc(-c2ccnc3[nH]c(C(=O)NCCN4CCOCC4)cc23)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described in Example 15a using 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and 4-(2-aminoethyl)-morpholine afforded the title compound. ESMS [M+H]+: 490.4
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:22])([F:21])[O:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].S([O-])(O)(=O)=O.[Na+].[H][H]>C(Cl)Cl.C(O)(C)C.C(OCC)(=O)C.O>[F:3][C:4]([F:21])([F:22])[O:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][OH:13]
Reactant: O=Cc1ccccc1Oc1cccc(OC(F)(F)F)c1
Reactant: [H][H]
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCc1ccccc1Oc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
Sodium borohydride (1.17 g, 31.2 mmol) was added to a solution of 2-(3-(trifluoromethoxy)phenoxy)benzaldehyde (6.28 g, 22.3 mmol) in a mixture of DCM (20 ml) and isopropanol (10 ml). The reaction mixture was stirred for 16 hours at room temperature. A 10% aqueous solution of sodium hydrogensulphate was added until the evolution of hydrogen had ceased. The mixture was diluted with ethyl acetate (200 ml). Water (200 ml) was added. The phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane (1:2) as eluent, to give 5.34 g of [2-(3-(trifluoromethoxy)phenoxy)phenyl]methanol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]Br)[CH3:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]([O:14][C:15]([CH2:16][CH2:17][CH2:18][CH2:19][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[N:6]=1)=[O:21])[CH3:13]
Reactant: CCOC(=O)CCCCBr
Reactant: Fc1ccc2[nH]c(S)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCSc1nc2ccc(F)cc2[nH]1
Yield: 71.2 %

Procedure:
A suspension of 5-fluoro-1H-benzoimidazole-2-thiol (168 mg, 1 mmol), 5-bromo-pentanoic acid ethyl ester (188 mg, 0.9 mmol, 145 μl) and K2CO3 (276 mg, 2 mmol) in acetone (2 ml) is refluxed for 3 h. It is cooled down and filtered over a short plug of silica gel and rinsed with AcOEt. The solvent is removed in vacuo. The crude is purified by flash chromatography on silica-gel (AcOEt/heptane, 1:2), yielding the title compound (190 mg) in 64% as a brown oil: tR=1.87 min (LC-2), ESI-MS (pos.): m/z 297.28 [M+H]+, ESI-MS (neg.): m/z 295.30 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.25 (t, 3H, CH3), 1.79 (br. t, 4H), 2.36 (br. t, 2H, CH2CO), 3.28 (br. t, 2H, SCH2), 4.14 (q, 2H, CH2O), 6.93 (dt, 1Harom), 7.20 (dd, 1Harom), 7.41 (dd, 1Harom).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:12].N1CCCCC1.O>C(O)C>[C:11]([C:13](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:12]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)C(C#N)=Cc1ccc(O)c(O)c1
Yield: 63.8 %

Procedure:
2 g (15 mmol) 3,4-Dihydroxybenzaldehyde, 3 g (21 mmol) of tert-butyl cyanoacetate and 0.5 ml of piperidine in 50 ml ethanol were heated to reflux for 1 hour, poured into water, filtered, washed and dried to yield 2.5 g (yield 66%) of tert-butyl α-cyano-3,4-dihydroxycinnamate as a yellow solid.
Reaction SMILES: CN.[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[C:24]([BH3-])#[N:25].[Na+].C(O)(=O)C>C1COCC1>[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([CH:9]([NH:25][CH3:24])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
2.0 M methylamine solution in THF (18 mL, 36.0 mmol) was added to a solution of 1-(4-biphenylyl)-2-(4-morpholinyl)ethanone (2.52 g, 8.93 mmol ) in anhydrous THF (20 mL), The reaction mixture was stirred at room temperature for 1 h and then sodium cyanoborohydride (1.68 g, 26.79 mmol) and acetic acid (1 mL) were added. The resulting mixture was stirred at room temperature for 72 h until the starting material was consumed completely. At this point, saturated K2CO3 solution (40 mL) was added to and after stirring for 15 min, the solution was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over Na2SO4 and concentrated. The resulting residue was isolated by column chromatography on silica gel (MeOH/EtOAc, 1:10) to yield [1-(4-biphenylyl)-2-(4-morpholinyl)ethyl]methylamine as an off-white solid(1.40 g, 53%), MS (ES) m/e 296[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([OH:20])[CH:7]=1.[N:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:3]([O:2][CH3:1])=[O:32])=[CH:7][C:8]=1[O:20][C:38]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)N1CCCC1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(O)c1)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OC(=O)N2CCCC2)c1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
(S)-2-Benzyloxycarbonylamino-3-(4-benzyloxy-3-hydroxy-phenyl)-propionic acid methyl ester (434 mg) was dissolved in dichloromethane (7 ml) and a solution of 1-pyrrolidinylcarbonyl chloride (200 mg) in dichloromethane (2 ml) was added. Triethylamine (0.22 ml) was added dropwise followed by a catalytic amount of DMAP. The mixture was stirred and heated at 40° C. overnight. The reaction was monitored by HPLC/MS and further portions of 1-pyrrolidinylcarbonyl chloride (400 mg) and triethylamine (0.4 ml) were added and heating continued at 55 C for 48 hours. The reaction mixture was diluted with dichloromethane and washed with dil HCl, with aq sodium bicarbonate and with brine. Drying (MgSO4) and evaporation gave the crude product. Silca gel chromatography, eluting with mixtures of ethyl acetate-hexane gave pyrrolidine-1-carboxylic acid 2-benzyloxy-5-((S)-2-benzyloxycarbonylamino-2-methoxycarbonyl-ethyl)-phenyl ester as a colourless gum, 364 mg; Rf 0.3 (ethyl acetate-hexane 1:1); HPLC/MS retention time 7.31 min, m/z 533 (MH+).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.P([O-])([O-])([O-])=O.P([O-])([O-])(O)=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[CH2:37]([N:43]1[C:47]([SH:48])=[N:46][N:45]=[N:44]1)[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:48][C:47]3[N:43]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[N:44]=[N:45][N:46]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCCCCCn1nnnc1S
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 2 h
Yield: 53 %

Procedure:
To 7-aminocephalosporanic acid (150.0 g.) was added 0.2 M phosphate buffer solution (3 l.), which was prepared by dissolving sodium biphosphate dihydrate (62.1 g.) and disodium hydrogen phosphate (25.5 g.) in water (3 l.), and the resulting mixture was adjusted to pH 6.5 with 2 N aqueous solution of sodium carbonate. To the mixture was added 1-hexyl-1H-tetrazole-5-thiol (154.6 g.) and the resulting mixture was stirred for 2 hours at 60° to 65° C. and at pH 6.0 to 6.5 with bubbling of nitrogen gas. The reaction mixture was adjusted to pH 3.5 with conc. hydrochloric acid under ice-cooling. Precipitates were collected by filtration and washed with water, and methanol (4 l.) and conc. hydrochloric acid (400 ml.) were added thereto. The mixture was stirred for 2 hours and an insoluble material was filtered off. The filtrate was treated with an activated charcoal and adjusted to pH 3.5 with 28% aqueous solution of ammonia. Precipitates were collected by filtration, in turn washed with water, acetone and diethyl ether and dried to give powder of 7-amino-3-(1-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (116.38 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: O=c1[nH]c2nccc(Oc3cccc(NS(=O)(=O)c4cccc5ccccc45)c3)c2[nH]1
Yield: 57 %

Procedure:
Method K was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and naphthalene-1-sulfonyl chloride to afford the title compound as a brown solid (32 mg, 57%). 1H-NMR (δ, ppm, DMSO-d6): 6.09 (d, 1H, HPy,5, J=6.0 Hz), 6.68 (m, 2H, Harom), 6.87 (d, 1H, Harom, J=8.5 Hz), 7.20 (ps t, 1H, Harom, J=8.0 Hz), 7.60 (ps t, 1H, Harom, J=7.5 Hz), 7.65-7.73 (m, 3H, Harom+Py,6), 8.08 (d, 1H, Harom, J=8.0 Hz), 8.12 (d, 1H, Harom, J=7.5 Hz), 8.23 (d, 1H, Harom, J=8.5 Hz), 8.67 (d, 1H, Harom, J=8.5 Hz), 10.83 (s, 1H, NHSO2), 11.08 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.48, 108.98, 113.81, 114.02, 114.77, 124.06, 124.40, 127.03, 127.33, 128.21, 129.13, 129.97, 130.73, 133.74, 133.92, 134.60, 139.14, 141.21, 143.88, 147.15, 154.13, 155.01. HRMS (EI): m/z [M+H] calcd for C22H17N4O4S: 433.0971; found: 433.0969.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16][N:17]2[C:21](=O)C3=CC=CC=C3C2=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=CC=CC=1.CSC1[NH:35][C:34](=[O:36])[C:33]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[CH:32][N:31]=1>N1C=CC=CC=1>[CH2:1]([N:7]([CH2:14][CH2:15][CH2:16][NH:17][C:21]1[NH:35][C:34](=[O:36])[C:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)=[CH:32][N:31]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:6]
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Solvent: c1ccncc1
Product: CCN(CCCNc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
Substituting ethyl iodide (10.31 g) for n-propyl iodide and using the corresponding molar proportions of the other reagents in the method of example 15(i) gave 2-[N-(3-aminopropyl)-N-ethylamino]pyridine (2.32 g) as an oil. (ii) 2-[N-(3-aminopropyl)-N-ethylamino]pyridine (1.0 g) and 2-methylthio-5-(4-chlorobenzyl)pyrimid-4-one (0.99 g) were heated together under reflux in pyridine (2.5 ml) for 28 hr. After stripping the residue was crystallized from ethanol and recrystallized from ethanol/water to give 2-[3-(N-ethyl-N-pyrid-2-ylamino)propylamino]-5-(4-chlorobenzyl)pyrimid-4-one 0.9 H2O, 1.23 g (79%) m.p. 86°-89° C.