Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24].O>C1(C)C=CC=CC=1.ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A solution of ethyl 4-[(3-aminoquinolin-4-yl)amino]butanoate (72.0 g, 263 mmol) in toluene (700 mL) was heated at reflux for 10 minutes and then cooled slightly. Trimethyl orthobutyrate (42 g, 280 mmol) and pyridinium p-toluenesulfonate (1.0 g, 4.0 mmol) were added, and the reaction was heated at reflux under a Dean-Stark trap for two hours while the distillate was periodically removed. The reaction was then stirred overnight at ambient temperature. Charcoal (5 g) was added, and the resulting mixture was heated at reflux for three hours and then filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure to provide an oil that crystallized upon standing. The solid was dissolved in hot methanol (125 mL), and water (50 mL) was added. After one hour, the mixture was cooled in an ice bath to form a precipitate. The precipitate was isolated by filtration and dissolved in dichloromethane. A layer of water was present and was removed. The remaining solution was dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 53.2 g of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:11][CH2:10][CH2:9][C:8]#[C:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:21])=[O:20]
Reactant: NCCC#Cc1ccccn1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=S(=O)(NCCC#Cc1ccccn1)c1ccccc1Cl
Yield: 31818.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 184, from 4-(pyridin-2-yl)but-3-yn-1-amine (16 mg, 0.11 mmol) and 2-chlorobenzene-1-sulfonyl chloride (30 mg, 0.14 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 11.2 mg (35 mmol, 32%) of 2-chloro-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[S:42][C:41]([O:43][C:44]2[CH:45]=[C:46]([CH3:60])[C:47]3[CH:51]([CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[O:50][B:49]([OH:58])[C:48]=3[CH:59]=2)=[N:40][N:39]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:37][C:38]1[S:42][C:41]([O:43][C:44]2[CH:45]=[C:46]([CH3:60])[C:47]3[CH:51]([CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[O:50][B:49]([OH:58])[C:48]=3[CH:59]=2)=[N:40][N:39]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(NC(=O)CNC(=O)OC(C)(C)C)s3)cc(C)c21
Reaction time: 8 h

Procedure:
To a solution of N-tert-butoxy carbonyl-glycine (1.05 g, 6 mmol) in DMF (15 mL) was added HATU (2.85 g, 7.5 mmol), ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.74 g, 5 mmol) and DIEA (1.73 mL). The mixture was stirred at room overnight. The mixture was concentrated to afford the target molecule.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>CO>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8](=[NH:9])[NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[CH3:5]
Reactant: CCOC(C#N)OCC
Reactant: COc1ccc(CN)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(OC)cc1
Temperature: 25 °C
Yield: 107.9 %

Procedure:
A solution of sodium methoxide (23%, 4.1 mL, 16 mmol) in MeOH was added to a solution of diethoxyacetonitrile (22 g, 86 mmol) in MeOH (400 mL) with stirring. The solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. The residue was dissolved in diethyl ethyl (200 mL) and washed with washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was dissolved in MeOH (100 mL), and p-methoxybenzylamine (11 g, 80 mmol) was added. Then this solution was heated under reflux overnight. After cooled to room temperature, the solvent was distilled off under reduced pressur to give the crude title compound (23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>Cl.O1CCOCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)nccc34)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: CC(C)Oc1ncc(-c2nc(-c3cccc4c(CCC(=O)O)nccc34)no2)cc1Cl
Reaction time: 2 h
Yield: 4.5 %

Procedure:
1,1-Dimethylethyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D53; 54 mg, 0.111 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (10 ml) and the mixture allowed to stand at room temperature for 2 h. The solvent was evaporated in vacuo to give a colourless gum which was triturated under dry ether (5 ml) to give a white solid which was dissolved in NMP (0.5 ml) and purified by Mass Directed Preparative HPLC (Supelcosil ABZ+Plus column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid)). The solvent was evaporated in vacuo to give the title compound (2.2 mg)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1)[CH3:2]>[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[N:4][CH:5]=1
Reactant: CCc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Product: CCc1ccc(N)cn1

Procedure:
2-Ethyl-5-nitropyridine (16.3 g) was dissolved in IMS (200 ml) and hydrogenated at ambient temperature at 1 atmosphere using 10% palladium charcoal (0.5 g) as the catalyst. The mixture was filtered to remove the catalyst and the filtrate evaporated to give 5-amino-2-ethylpyridine as an oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:14][C:15]=1[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1F
Reactant: Nc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added 3-fluorobiphenyl-4-ylboronic acid (1.623 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(D) (0.334 g), and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization (THF/diisopropyl ether) to give the title compound (1.528 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][CH2:26][CH2:27][C:28]1[C:33]([OH:34])=[C:32]([C:35]([CH3:37])=[O:36])[CH:31]=[CH:30][C:29]=1[OH:38].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([O:38][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:28]([CH2:27][CH2:26][CH3:25])[C:33]=1[OH:34])(=[O:36])[CH3:37]
Reactant: CCOC(=O)CCCCC(Br)c1ccc(Cc2ccccc2)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OC(CCCCC(=O)OCC)c2ccc(Cc3ccccc3)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 9.75 g. of ethyl 6-(4-benzylphenyl)-6-bromo-hexanoate, 5.03 g. of 2,4-dihydroxy-3-propylacetophenone, 3.57 g. of potassium carbonate, and 1.0 g. of potassium iodide in 175 ml. of acetone was heated to reflux for about 86 hours. The reaction was evaporated in vacuo and the residue was purified by chromatography over silica gel eluting with a 0-20% ethyl acetate gradient in hexane. The appropriate fractions were pooled and evaporated, giving 2.5 g. of the desired product which was used for the subsequent hydrolysis. NMR was consistent with the compound ethyl 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-6-(4-benzylphenyl)hexanoate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([N:27]4[CH2:36][CH2:35][C:30]5([CH2:34][NH:33][CH2:32][CH2:31]5)[CH2:29][CH2:28]4)=[O:26])[CH:22]=3)[CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[C:6]([CH3:37])[CH:5]=1.[Cl-].Cl[C:40]1[CH:45]=[CH:44][NH+:43]=[CH:42][CH:41]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)CCC.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH3:37])[C:7]([S:11]([N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([N:27]4[CH2:28][CH2:29][C:30]5([CH2:34][N:33]([C:40]6[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=6)[CH2:32][CH2:31]5)[CH2:35][CH2:36]4)=[O:26])[CH:22]=3)[CH2:17][CH2:16][CH2:15]2)(=[O:12])=[O:13])=[C:8]([CH3:10])[CH:9]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCc3ccc(CC(=O)N4CCC5(CCNC5)CC4)cc32)c(C)c1
Reactant: Clc1cc[nH+]cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCc3ccc(CC(=O)N4CCC5(CC4)CCN(c4ccncc4)C5)cc32)c(C)c1

Procedure:
A mixture of 2-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)-1-(2,8-diazaspiro[4.5]decan-8-yl)ethanone hydrochloride (0.15 g, 0.274 mmol), 4-chloropyridinium chloride (0.12 g, 0.821 mmol) and triethylamine (0.15 ml, 1.09 mmol) was refluxed for 15 h in 1-butanol (7 ml). Saturated sodium hydrogen carbonate solution (20 ml) and ethyl acetate (50 ml) were then added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/dichloromethane/-methanol/ammonia (25% aq.), 300:100:50:1) and the desired exemplary compound G-09 was obtained. Yield: 0.1 g (62%). MS, Rt=3.3 min; m/z=589.1 [MH]+
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[CH:9]=[CH2:10].[CH3:12][CH:13]=[CH:14][PH:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[CH2:8]([O:11][PH:15]([CH2:14][CH:13]=[CH2:12])=[O:16])[CH:9]=[CH2:10]
Reactant: CC=C[PH](=O)Cl
Reactant: C=CCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCO[PH](=O)CC=C
Yield: 29.1 %

Procedure:
202 g of triethyl amine (2 mols) were added while stirring at 0° to 5° C. to a solution of 116 g of allyl alcohol (2 mols) in 1 l of anhydrous chloroform and then 249 g of methylvinyl phosphinic acid chloride (2 mols) were added dropwise over a period of about 1 hour. After suction filtration, the solid residue (triethyl amine hydrochloride) was dissolved in water, the emerging oily layer was separated and combined with the filtrate. To remove the chloride ions the filtrate was shaken 4 times, each time with 600 ml of water, dried over sodium sulfate and the chloroform was distilled off in a rotary evaporator. The brown oily residue was distilled under a pressure of 0.01 mm at a temperature of the oil bath of 40° C. 85 g of a colorless liquid were obtained.
Reaction SMILES: [ClH:1].[CH2:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2OC)(=[O:12])[CH3:11]>O.C(O)CCC>[ClH:1].[C:10]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[NH:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: NCc1ccccc1
Reactant: COc1cc(C)nc2ccc(NC(C)=O)cc12
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CC(=O)Nc1ccc2nc(C)cc(NCc3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A warm solution of benzylamine hydrochloride in water (1 mL) was added to a mixture of 6-acetamido-4-methoxy-2-methyl-quinoline (1.0 g, 4.3 mmol) in n-butanol (10 mL) after which complete solution occurred. The solution was stirred for 3 days at 100° C. under a nitrogen atmosphere, cooled, and the precipitated solid filtered, washed with ether, and dried to afford 1.0 g (75%) of 6-acetamido-4-benzylamino2-methyl-quinoline hydrochloride. A solution of this material (0.76 gm, 2.49 mmol) in 25% hydrochloric acid (12 mL) was heated for 5 hr at 90° C. and subsequently cooled. The precipitated solid was filtered, washed with water, dried at 50° C. under high vacuum for several hours to give 0.38 gm (58%) of 6-amino-4-benzylamino-2-methyl-quinoline. This material was dissolved in glacial acetic acid (3 mL) to which was added dropwise a solution of 2-chlorocinnamoyl chloride in glacial acetic acid over a 5 min period. The reaction mixture was stirred for 1 hr at room temperature and diluted with diethyl ether (25 mL). The solid was filtered, washed with ether, and dried by suction. It was then dissolved in a hot mixture of methanol (50 mL) and water (25 mL), cooled, and 5N sodium hydroxide added to give a yellow precipitate that was filtered, washed with water, and dried under high vacuum. Recrystallization from isopropanol afforded the title compound as pale yellow crystals; yield 0.32 g (52%), m.p. 253-4°, MS (FAB): m/z 428 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]([CH2:26][C:27]([NH:29][NH2:30])=[O:28])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:26][C:27]2[O:28][C:34]([OH:36])=[N:30][N:29]=2)[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC(=O)NN)Cc2ccc(Cl)cc2)c1
Solvent: C1COCCO1
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(Cc2ccc(Cl)cc2)Cc2nnc(O)o2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of the Intermediate obtained in step b above (1 eq.) in dioxane was added triphosgene (1.5 eq.) under nitrogen. The reaction was stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The layers were separated, the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with Hept/EtOAc/DCM/MeOH: 50/50/0/0 to 50/50/95/5) to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-(5-hydroxy-[1,3,4]oxadiazol-2-ylmethyl)-amide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:36][NH:37][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NCCO)c3)c2)n1
Temperature: 25 °C
Yield: 21 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess ethanolamine in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.045 g, 21%) as a white solid. MS (ISP) 514.0 [(M+H)+]; mp 103° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[NH:16][C:17]4[CH:27]=[CH:26][C:25]5[C:20](=[C:21]([OH:31])[CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=5)[C:18]=4[N:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.C([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40])(C)(C)C.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[NH:16][C:17]4[CH:27]=[CH:26][C:25]5[C:20](=[C:21]([OH:31])[CH:22]=[C:23]([C:28]([NH:40][C@@H:39]([CH2:41][C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=6)[C:38]([OH:37])=[O:48])=[O:29])[CH:24]=5)[C:18]=4[N:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)O)cc(O)c54)[nH]3)c2)cc1C
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(C(=O)N[C@@H](Cc6ccccc6)C(=O)O)cc(O)c54)[nH]3)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxy-3H-naphtho[1,2-d]imidazole-7-carboxylic acid (0.05 g, 0.1 mmol) in DMF (0.5 mL) at room temperature was added phenylalanine tert butyl ester hydrochloride (0.11 mmol). A cocktail solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.021 g, 0.11 mmol), triethylamine (0.3 mmol) in DMF (0.5 mL) was added and the reaction was agitated at room temperature for 18 hours. 1 ml water was added to the reaction mixture resulting in the formation of a tan precipitate. the mixture was filtered and allowed to dry. The solid mass was transferred into vial and dissolved in 90% trifluoroacetic acid (1 mL). The solutions were agitated for 6 hrs then concentrated under reduced pressure. The residures were taked up in DMSO and subjected to Gilson HPLC purification. The title compound was abtained as solid.(0.006 g, 10%). MS(ES) m/z 556 [M+H].
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:42][O:43][CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:40](=[O:41])[N:15]3[C:16]([C:37]([OH:39])=[O:38])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][NH:29]C(OC(C)(C)C)=O)[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:42][O:43][CH2:44][CH2:45][CH2:46][NH2:47])[C:10]([NH:12][CH:13]2[C:40](=[O:41])[N:15]3[C:16]([C:37]([OH:39])=[O:38])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][NH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCN)CS[C@H]12)c1csc(N)n1
Yield: 54.6 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-[1-(2-tertbutoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.8 g.), conc. hydrochloric acid (1.6 ml.) and methanol (60 ml.) were treated in a similar manner to that of Example 6-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:2]=1.[C:15](Cl)(=O)/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: Nc1ccccc1Nc1cccnc1
Solvent: Cc1ccccc1C
Product: C(=C/c1nc2ccccc2n1-c1cccnc1)\c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirred suspension of N-(3-pyridyl)-o-phenylenediamine (0.93 g, 5 mmol; Kirsch, P.; Schoenleben-Janas, A.; Schirmer, R. H. Liebigs Ann. Org. Bioorg. Chem., 1995, 7, 1275) in xylene (60 ml) was added (E)-cinnamoyl chloride (0.83 g, 5 mmol). After stirring at the room temperature for 1 h, the resulting mixture was heated to reflux removing water using a Dean-Stark apparatus for 11 h. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved into ethyl acetate (100 ml), washed consecutively with saturated aqueous sodium bicarbonate solution (50 ml) and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. The residue was purified by column chromatography (silica gel, 165 g; n-hexane/ethyl acetate (3/2 to 1/1)) to give 0.77 g (34%) of brown solids. Recrystallization from isopropyl ether yielded 0.50 g of the titled compound as pink solids.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[O:18]=[C:19]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:22][CH2:21][N:20]1[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][N:40]=1)[C:34](OC)=[O:35]>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:34](=[O:35])[C:33]2[CH:38]=[CH:39][N:40]=[C:31]([N:20]3[CH2:21][CH2:22][N:23]([CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:19]3=[O:18])[CH:32]=2)=[CH:12][CH:11]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccncc3)C2=O)c1
Yield: 48 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 4-fluorobenzylamine to react with methyl 2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinate, N-(4-fluorobenzyl)-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 48% yield: mp 161-163° C.; 1H NMR (300 MHz, CDCl3) δ 8.67-8.50 (m, 3H), 8.37 (d, J=5.1 Hz, 1H), 7.49-7.20 (m, 5H), 7.02-6.96 (m, 2H), 6.84 (br s, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.45 (s, 2H), 4.09 (t, J=8.1 Hz, 2H), 3.42 (t, J=8.1 Hz, 2H); MS (ES+) m/z 405.8 (M+1).