Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([C:14]([C:16]2[C:21]([N:22]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)(=[O:28])=[O:27])COC)=[CH:20][C:19]([Cl:40])=[CH:18][N:17]=2)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.O>OS(O)(=O)=O.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[C:13]([C:14]([C:16]2[C:21]([NH:22][S:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)(=[O:28])=[O:27])=[CH:20][C:19]([Cl:40])=[CH:18][N:17]=2)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccnc1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of (3-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-pyridin-2-yl)-carbamic acid tert-butyl ester (25 mg, 0.0394 mmol) in 5% H2SO4 in TFA (4 mL) and water (1 mL) was stirred at 50° C. for 6 h. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution until pH 7-8. The mixture was extracted with EtOAc (2×15 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified to afford N-[2-(2-amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (9.3 mg) in 48% yield. ESMS m/z (relative intensity): 491 (M+H)+ (100).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.[C:22](OC(=O)C)(=[O:24])C>C(O)=O>[CH:22]([NH:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12)=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: O=CO
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 1 h

Procedure:
In 60 ml of formic acid is dissolved 3.2 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and the solution is cooled to 0°-5° C. With stirring, 20 ml of acetic anhydride is added dropwise to the solution during 30 minutes. The mixture is stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. The solvent is evaporated off under reduced pressure and the residue is dissolved in methyl ethyl ketone. The solution is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then evaporated off under reduced pressure and a diisopropylether-hexane mixture is added to the residue to bring about solidification. The solid is then collected by filtration to give 3.1 g of the above-identified compound as a light-yellow powder.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH3:5].Cl>O1CCOCC1>[CH2:1]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCc1cc(OC2CCNCC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.1 %

Procedure:
1,1-Dimethylethyl 4-[(6-pentyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 7) (2.20 g, 5.52 mmol) was dissolved in dioxane (10 ml) and the solution was treated with a solution of hydrogen chloride in dioxane (4M, 12.5 ml). The mixture was stirred under nitrogen overnight at room temperature, and then concentrated in vacuo. The residue was applied to a SCX-2 ion exchange cartridge (70 g) which had been preconditioned with methanol. The cartridge was washed with methanol, and then eluted with 10% aqueous 0.88 s.g. ammonia in methanol. The relevant basic fractions were concentrated in vacuo to give the title compound (1.88 g); LCMS RT=2.70 min, ES+ve m/z 299 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[N:17]=[CH:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]([OH:26])[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)(=O)C>[OH:26][C:14]1[C:13]2[CH2:12][NH:11][CH2:20][CH2:19][C:18]=2[N:17]=[CH:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1cnc2c(c1O)CN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(c1O)CNCC2

Procedure:
The starting material is prepared as follows: Ethyl 6-benzyloxycarbonyl-4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate (Example 1i) is hydrogenated with palladium on carbon as the catalyst in glacial acetic acid to obtain ethyl 4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate, which is treated with benzyl bromide in a mixture of triethylamine and DMF at 60° for 48 hr to obtain ethyl 6-benzyl-4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate. Treatment of this material with an excess of phosphorous oxychloride at reflux for 5 hr affords the required ethyl 6-benzyl-4-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:5]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:4][N:3]=1.Cl>C(O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:8]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:5]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:4][N:3]=1
Reactant: CCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nc(C)ncc1C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nc(C)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
The product of example 1B (3.5 g, 4.91 mmoles) was suspended in 50 ml of ethanol. Concentrated hydrochloric acid (2.1 ml) was added and the mixture was stirred for 11/2 hours at room temperature. The solution was concentrated under vacuum and the resulting residue was diluted with water. Potassium acetate was added in portions until the pH was neutral. Ether (5 ml) was added and the mixture was stirred. The sticky solid which formed was dissolved in chloroform. The chloroform solution was dried over sodium sulfate and then concentrated. The resulting residue was crystallized from ether to provide 2.08 g of the desired product. M.p. 164°-166° C. 1H NMR (CDCl3) δ0.85 (t, 3H, J=7 Hz), 1.25 (m, 2H), 1.32 (t, 3H, J=7 Hz), 1.50 (m, 2H), 2.24 (s, 3H), 3.38 (t, 2H, J=7 Hz), 4.30 (q, 2H, J=7 Hz), 4.73 (s, 2H), 7.00 (m, 4H), 7.42 (dd, 1H, J=8 Hz, J=1Hz), 7.50-7.62 (m, 2H), 7.75 (dd, 1H, J=8 Hz, J= 1Hz), 8.02 (s, 1H).
Reaction SMILES: [Br-].[CH:2]1([CH2:6][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:36][N:37]([CH3:57])[C:38]([C:40]1[N:41]=[C:42]([C@H:45]([CH2:54][CH:55]=O)[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[O:43][CH:44]=1)=[O:39].O>O1CCCC1.C1(C)C=CC=CC=1>[CH:2]1(/[CH:6]=[CH:55]\[CH2:54][C@@H:45]([C:42]2[O:43][CH:44]=[C:40]([C:38]([N:37]([CH3:57])[CH3:36])=[O:39])[N:41]=2)[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc([P+](CC2CCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C(=O)c1coc([C@H](CC=O)CC(=O)OC(C)(C)C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1coc([C@H](C/C=C\C2CCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A suspension of (cyclobutylmethyl)(triphenyl)phosphonium bromide (Preparation 122) (680 mg, 1.65 mmol) in anhydrous tetrahydrofuran (13 ml), under a nitrogen atmosphere, at 0° C., was treated with sodium bis(trimethylsilyl)amide 1M in tetrahydrofuran (1.65 ml, 1.65 mmol) over a period of 5 minutes. The bright orange mixture was stirred at 0° C. for 1 hour. A solution of tert-butyl (3R)-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}-5-oxopentanoate (Preparation 118) (428 mg, 1.38 mmol) in toluene (4 ml) was added to the mixture and stirred at 0° C. for 30 minutes and allowed to warm to room temperature for a further 30 minutes. Water (2 ml) was added and the solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with dilute aqueous of potassium sodium tartrate solution and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 9:1 (hexane:ethyl acetate) gradually changing to 1:1 (hexane:ethyl acetate) to afford the title compound as a colourless oil (282 mg).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH:15]=[CH2:16])[CH2:13][O:12][C:11](=[O:14])[O:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:14]=[C:11]1[O:10][CH2:9][C:8]([CH:15]=[CH2:16])([C:6]([OH:7])=[O:5])[CH2:13][O:12]1
Reactant: C=CC1(C(=O)OC(C)(C)C)COC(=O)OC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1(C(=O)O)COC(=O)OC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of 2-oxo-5-vinyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester (200 mg, 0.88 mmol) in dichloromethane (4 mL) was stirred at 0° C. Trifluoroacetic acid (2 mL) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 3 h. The solvent was evaporated and the residue was triturated with diethyl ether/iso-hexanes (1:1) to afford the title compound (135 mg, 90%) as a white solid. 1H NMR (300 MHz, d6-DMSO) 64.51 (d, J=10.5 Hz, 2H), 4.67 (d, J=10.5 Hz, 2H), 5.38 (d, J=17.6 Hz, 1H), 5.43 (d, J=10.7 Hz, 1H), 5.83 (dd, J=17.6, 10.7 Hz, 1H), 13.5-14.0 (br s, 1H). LCMS (m/z) 173.2 [M+H], Tr=0.62 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:4]([CH:26]=O)[CH:3]=1.CO.C[O-].[Na+].Cl>C(=O)(OC)OC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:9][CH2:10][CH2:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:26][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCCN(Cc1ccc(OC)cc1)c1ccc(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COC(=O)OC
Solvent: CO
Product: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccc(OC)cc2)CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
To a solution of methyl 5-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)pentanoate (45.7 g) in dimethyl carbonate (900 ml) was added a methanol solution of sodium methoxide (28%, 26.4 g) and then the mixture was stirred at 50° C. under nitrogen atmosphere for 6 hours. The resultant was cooled to 0° C., followed by addition of water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from hexane-ethyl acetate to give methyl 8-bromo-1-(4-methoxybenzyl)-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (32.2 g) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[N:16]([CH2:17][CH2:18][CH3:19])[C:15](=[O:20])[NH:14][N:13]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C>[CH2:17]([N:16]1[C:15](=[O:20])[NH:14][N:13]=[C:12]1[CH2:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1)[CH2:18][CH3:19]
Reactant: CCCn1c(CSc2ccc([N+](=O)[O-])cc2)n[nH]c1=O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CCCn1c(CSc2ccc(N)cc2)n[nH]c1=O
Yield: 89.1 %

Procedure:
1-nitro-4-[(4-propyl-1H-1,2,4-triazole-5-one-3-yl)methylthio]benzene (0.5 g), reduced iron (0.5 g) and calcium chloride (0.1 g) were added to 85% aqueous solution of ethanol (15 ml), and the mixture was refluxed for 2 hours. The reaction solution was filtered with. Celite, and the solvent of the filtrate was distilled off. The residue was purified by basic silica gel column chromatography (elution solvent: ethyl acetate) to give 4-[(4-propyl-1H-1,2,4-triazole-5-one-3-yl)methylthio]aniline (0.4 g) as pale brown crystals.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[O:5][CH2:4]1.[C:12]([O-:15])(=[O:14])[CH3:13].[K+]>CS(C)=O>[C:12]([O:15][CH2:2][CH:3]1[O:8][C:7]2=[CH:9][S:10][CH:11]=[C:6]2[O:5][CH2:4]1)(=[O:14])[CH3:13]
Reactant: BrCC1COc2cscc2O1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCC1COc2cscc2O1
Reaction time: 1 h
Yield: 90 %

Procedure:
In a 50 mL Schlenk tube 1.00 g of to 2-(bromomethyl)-2,3-dihydrothieno[3,4-b][1,4]dioxine was combined with 0.5 g (0.0051 mol) potassium acetate and 25 mL DMSO. The tube was sealed and stirred for 1 h at 100 C. At this time TLC indicated complete consumption of starting material. The reaction was poured into water and extracted with ether. After removing the ether under reduced pressure column chromatography was performed using 90% methylene chloride in hexane to isolate a light yellow oil in 90% yield. The structure and purity were confirmed by 1H/13C NMR and GC-MS.
Reaction SMILES: [OH:1][C@@H:2]([C@H:7]1[CH2:11][NH:10][CH2:9][C@@H:8]1[OH:12])[C@H](O)CO.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O1CCCC1>CN(C)C(=O)C>[CH2:24]([O:23][C:21]([N:10]1[CH2:9][C@H:8]([OH:12])[C@@H:7]([CH2:2][OH:1])[CH2:11]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H]1CNC[C@@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Reaction time: 1 h

Procedure:
Process B: (3R,4S)-4-[(1S,2R)-1,2,3-Trihydroxypropyl]pyrrolidin-3-ol (0.76 g) and triethylamine (0.60 mL) were dissolved in N,N-dimethylacetamide (12 mL). While this solution was chilled in an ice water bath, benzyl chloroformate (0.58 mL) was added dropwise and the mixture was stirred for 1 hour, followed by addition of tetrahydrofuran (12 mL) and further stirring for 30 min. The insoluble material in the reaction mixture was then filtered and washed with a 1:1 mixture of N,N-dimethylacetamide and tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was dissolved in a mixture of ethanol (32 mL) and water (7 mL), followed by addition of sodium periodate (1.85 g) and stirring at room temperature for 1 hour. The insoluble material in the reaction mixture was filtered and washed with ethanol. The filtrate and the washings were combined and sodium borohydride (242 mg) was added. This was followed by stirring at room temperature for 1 hour, addition of acetone (2 mL) and concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate: methanol=20:1) to give (3R,4R)-(1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl)methanol as a milky white syrup (828 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:29][O:30][C:31]1[CH:55]=[CH:54][C:34]([CH2:35][O:36][C:37]([NH:39][C:40]2[NH:41][C:42](=[O:53])[C:43]3[N:44]=[CH:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=3[N:48]=2)=[O:38])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:46]1[CH:45]=[N:44][C:43]2[C:42](=[O:53])[NH:41][C:40]([NH:39][C:37]([O:36][CH2:35][C:34]3[CH:54]=[CH:55][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)=[O:38])=[N:48][C:47]1=2)[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc(OC)cc3)nc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [2-N-(4-methoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.39 (brs, 0.45H), 11.36 (brs, 0.55H), 9.20 (brs, 1H), 8.39 (s, 1H), 8.01 (d, 1H), 7.95 (d, 0.55H), 7.92 (d, 0.45H), 7.82 (s, 0.55H), 7.79 (s, 0.45H), 7.37 (d, 2H), 6.95 (d, 2H), 5.17 (s, 2H), 5.13 (s, 1.1H), 4.93 (s, 0.9H), 4.45 (s, 0.9H), 4.21 (q, 0.9H), 4.08 (s, 1.1H), 4.07 (q, 1.1H), 3.76 (s, 3H), 3.66 (t, 1.1H), 3.49 (t, 1.1H), 3.43 (t, 0.9H), 3.28 (t, 0.9H), 1.25 (t, 1.35H), 1.16 (t, 1.65H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CO.O>[CH:25]1([NH:28][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:27][CH2:26]1
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: NC1CC1
Solvent: O
Solvent: CO
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC1CC1
Yield: 52 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (40 mg, 52%) which was obtained as a white solid after trituration from methanol/water. MS: m/e=385.1 [M+H]+.
Reaction SMILES: O.[CH2:2]([O:8][N:9]=[C:10]([C:14]1[N:15]=[C:16]([NH2:19])[S:17][CH:18]=1)[C:11]([OH:13])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].P(Cl)(Cl)(Cl)=O.[NH2:25][CH:26]1[C:43](=[O:44])[N:28]2[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]3[NH:39][N:38]=[N:37][CH:36]=3)[CH2:31][S:32][C@H:27]12>O1CCCC1.C[Si](CC(N)=O)(C)C.CN(C)C=O>[CH2:2]([O:8][N:9]=[C:10]([C:14]1[N:15]=[C:16]([NH2:19])[S:17][CH:18]=1)[C:11]([NH:25][CH:26]1[C:43](=[O:44])[N:28]2[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]3[NH:39][N:38]=[N:37][CH:36]=3)[CH2:31][S:32][C@H:27]12)=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Reactant: CCCCCCON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
Water (0.1 ml) was added to a suspension of 2-hexyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (2.0 g) in tetrahydrofuran (20 ml). Phosphorus oxychloride (1.4 g) was added thereto at 0° to 5° C. and the mixture was stirred for 20 minutes at the same temperature. Trimethylsilylacetamide (1.3 g) was added thereto, the mixture was stirred for 20 minutes at the same temperature, phosphorus oxychloride (1.4 g) was added thereto, the resulting mixture was stirred for 20 minutes at 0° to 5° C., dimethylformamide (0.75 g) was added thereto and the resulting mixture was stirred for 1 hour at the same temperature. The resulting solution was at a time added at -20° C. to a solution of 7-amino-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (3.3 g) in a mixture of tetrahydrofuran (30 ml) and trimethylsilylacetamide (6.8 g). The resulting mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was post-treated according to similar manners to those of the aforementioned Examples to give 7-[2-hexyloxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1H-1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][OH:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.O.Cl[CH2:25]Cl>CN(C)C=O>[CH3:18][N:16]([CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][CH2:11]1)[CH2:13][CH2:14][O:15][CH3:25])[CH3:17]
Reactant: CN(C)C(CCO)C1(c2ccc(Cl)cc2)CCC1
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 3-[1-(4-chlorophenyl)cyclobutyl]-3-dimethylaminopropan-1-ol (7.8 g) in dichloromethane (150 ml) and dimethylformamide (4 ml) was treated at 0° C. with a solution of thionyl chloride (14 ml) in dichloromethane (7 ml). The mixture was stirred at room temperature for 45 minutes, then heated at reflux for 15 hours, cooled, poured into water and washed with dichloromethane. The aqueous phase was basified and extracted with ether. The extract was evaporated and the residue was dissolved in methanol (50 ml) and treated with sodium methoxide (1 g). The solution was heated under reflux for 17 hours and then concentrated to about 10 ml and diluted with water to 150 ml. The aqueous solution was extracted with ether and the extracts back-extracted with 3N hydrochloric acid. The acidic extracts were basified and extracted with ether. The ethereal extracts were dried and evaporated to give an oil which was mixed with petroleum ether (b.p. 40-60) (20 ml). The resulting mixture was filtered and evaporated to give N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methoxypropylamine as an oil the boiling point of which was not determined.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([NH2:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:15]([NH:23][C:24]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([NH2:14])=[O:13])=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCNc1nc[nH]c1C(N)=O
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CCCCCN(C(=S)NC(=O)c1ccccc1)c1nc[nH]c1C(N)=O
Reaction time: 8 h
Yield: 139.1 %

Procedure:
To a solution of 4-(pentylamino)-1H-imidazole-5-carboxamide (4.0 g, 0.020 mol) in DCM (50 mL) was added benzoyl isothiocyanate (3.3 mL, 0.024 mol). After being stirred overnight, the solid formed was filtered to give the crude product (10 g, ca 60% purity, 80% yield). This product was used for next step without further purification. LCMS calculated for C17H22N5O2S(M+H): 360.1; found: 360.1.
Reaction SMILES: [CH:1]1([C:7]#[CH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>CN(C=O)C.CCCCCC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH:1]1([C:7]#[C:8][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC1CCCCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(C#CC2CCCCC2)nc1
Temperature: 100 °C
Yield: 84.1 %

Procedure:
Add cyclohexylacetylene (1.54 mL, 11.6 mmol), dichlorobis(triphenylphosphine)palladium (200 mg, 0.28 mmol), copper iodide (100 mg, 0.53 mmol), and triethylamine (2.0 mL, 14.3 mmol) to a solution of 6-chloronicotinonitrile (1.38 g, 9.9 mmol) in DMF (4 mL). Heat the mixture in a sealed flask for 3 h at 100° C. Cool the mixture to room temperature, dilute with 1:1 hexane/EtOAc (100 mL) and wash with an aqueous 10% sodium chloride solution (3×30 mL). Collect the organic layer, concentrate in vacuo, and purify the residue by silica gel chromatography (90g silica, hexane/EtOAc 95/5 to 85/15 gradient) to obtain the desired intermediate (1.75 g, 83%)