Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22](O)[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:29]1(=[O:39])[N:33]([CH:22]2[CH2:23][CH2:24][C@@:25]3([CH3:26])[CH:20]([CH2:19][CH2:18][C@@H:17]4[C@@H:16]3[CH2:15][CH2:14][C@@:13]3([CH3:28])[C@H:12]4[CH2:11][CH2:10][C@@H:9]3[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:21]2)[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(N5C(=O)c6ccccc6C5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of dihydrocholesterol (5.0 g, 12.9 mmol, Aldrich), phthalimide (2.0 g, 13.6 mmol, Aldrich), and triphenylphosphine (3.8 g, 13.6 mmol, Aldrich) in THF (20 ml, Aldrich) stirred at 0° C. under a nitrogen atmosphere was added dropwise diethylazodicarboxylate (2.3 ml, 145 mmol, Aldrich). Upon the completion of addition the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated in vacuo to a residue. This residue was dissolved in 50 ml hexane/ethyl acetate 95/5 and a precipitate formed. The mixture was filtered. The filtrate was concentrated to dryness in vacuo, dissolved in 25 ml of hexane/ethyl acetate 95/5 and chromatographed on 200 g silica gel eluent 2 L hexane/ethyl acetate 95/5 then 1 L hexane/ethyl acetate 90/10). A 76% yield of the desired 3-phthalimidocholestane (5.43 g) was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](=[O:22])[NH:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC[C@@H]3C)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 3-[(2S)-2-methylpiperidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (98 mg, 0.33 mmol) in dichloromethane (30 mL) was added pyridine (104 mg, 1.31 mmol), and then Tf2O (186 mg, 0.66 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (200 mg, crude).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([O:24][CH3:25])[N:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:26].[Br:27]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([O:24][CH3:25])[N:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH2:26][Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(C)c2)ccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(N(C(=O)OC(C)(C)C)c2ccc(Br)c(CBr)c2)ccc1C#N
Temperature: 95 °C
Yield: 162.2 %

Procedure:
To a solution of tert-butyl 4-bromo-3-methylphenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (2.85 g, 6.81 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (0.909 g, 5.11 mmol) and azobisisobutyronitrile (0.042 g, 0.26 mmol). The mixture was refluxed under nitrogen at 95° C. for two hours. The reaction was cooled to room temperature, water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude tert-butyl 4-bromo-3-(bromomethyl)phenyl(5-cyano-6-methoxypyridin-2-yl)carbamate (4.12 g). The product was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].N12CCN(CC1)CC2>>[CH3:18][O:17][C:13](=[O:16])[C:14](=[CH2:15])[CH:11]([OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCCc1ccccc1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OC)C(O)CCCCc1ccccc1
Reaction time: 120 h

Procedure:
A mixture of 8.4 g (52 mmol) of 5-phenylpentanal, 8.95 g (104 mmol) of methyl acrylate and 200 mg of 1,4-diazabicyclo[2.2.2]octane is allowed to stand at room temperature for 120 hours.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:10]([OH:12])=[O:11])=O)(C)(C)C.O1CCOCC1>Cl>[ClH:21].[NH2:8][CH:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CCc1ccccc1Cl)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: NC(CCc1ccccc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.2 %

Procedure:
2-(tert-Butoxycarbonylamino)-4-(2-chlorophenyl)butanoic acid (2.25 g) was dissolved in 4 N HCl in dioxane (20 mL, 11 eq) and stirred at room temperature for 1 h. The solution was then concentrated delivering product as a yellow solid (1.49 g, 83% yield).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12](OCC(C)C)=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5].CO.O>C1(C)C=CC=CC=1>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[CH2:12][OH:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)COC(C)O[C@H](C)CO
Yield: 85.1 %

Procedure:
1.0 g (0.024 mole) of sodium borohydride was suspended at room temperature in a solution of 5.0 g (0.02 mole) of isobutyl (R)-(+)-2-(1-isobutoxyethoxy)propionate dissolved in 20 ml of toluene. Thereto was dropwise added slowly 7.0 ml (0.12 mole) of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the resulting mixture was stirred at 40° C. for 7 hours, at room temperature overnight and at 60° C. for 2 hours to give rise to a reaction. To the reaction mixture was added 20 ml of water, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to extraction with 20 ml of toluene. The two organic layers were combined and washed with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 3.0 g (yield: 84.4%) of an oily title compound (diastereomixture).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12]>CCOCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(O)CCCC=Cc1ccco1
Solvent: CCOCC
Product: OCCCCC=Cc1ccco1
Reaction time: 1.5 h

Procedure:
6-(2-Furyl)-5-hexenoic acid (3.6 g) in ether (25 ml) was reduced according to the method of Intermediate 15, except that the reaction time was 1.5 h, and there was no purification by FCC. The title compound was obtained as a pale yellow oil (2.89 g), t.l.c. (hexane-ether 1:1) Rf 0.17.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:28])[CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:28])[CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])[CH:23]=2)[CH2:18]1)[CH3:13]
Reactant: CCOC(=O)CC1CCc2cc(O)ccc2C1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: CCOC(=O)CC1CCc2cc(OCCNC(=O)OC(C)(C)C)ccc2C1

Procedure:
The title compound is prepared according to the procedure of Example 19 except that (2-bromo-ethyl)-carbamic acid tert-butyl ester is used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (6-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester is used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][C:15](OC(C)=O)=O>>[CH3:14][C:15]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:2]=2[N:1]=1
Reactant: Nc1c(C(=O)O)cccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2c(C(=O)O)cccc2c(=O)o1
Temperature: 140 °C
Yield: 89 %

Procedure:
2-Aminoisophthalic acid (50.0 g; 276.0 mmol) and Ac2O (250.0 ml; 5.00 V) were combined and heated to 140° C. for 4 h. The reaction mixture was cooled to room temperature and distilled under high vacuum on the rotary evaporator. The remaining AcOH was removed by azeotropic distillation with toluene. The residue was slurried with ethyl ether, filtered, and the solid was dried under vacuum to provide the desired intermediate (50.3 g, 89% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 2-(Tetrahydro-2H-pyran-2-yl)ethyl methanesulfonate (142 mg) was added and the reaction was continued for 3 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give crude material (250 mg). The material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to give 75 mg of material which was recrystallised from ether/light petrol yielding the title compound as a solid, 54 mg.
Reaction SMILES: [CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH2:20])[C:18](=[O:21])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:29]([CH2:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:1]([C:8]1[CH2:9][S:10][C@@H:11]2[CH:19]([NH:20][C:37](=[O:38])[CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18](=[O:21])[N:12]2[C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12

Procedure:
The crude methyl 3-benzyl-7-amino-3-cephem-4-carboxylate was dissolved in dry dichloromethane (3 ml.) and the solution cooled to -20°. Dry triethylamine (22 mg) in dichloromethane (0.5 ml) was added followed by phenoxyacetyl chloride (36 mg) in dichloromethane (0.5 ml). After 15 minutes the solution was washed with water (× 2), dried and evaporated. Chromatography on silica afforded methyl 3-benzyl-7-phenoxyacetamido-3-cephem-4-carboxylate (II) as a white solid (61 mg). A sample recrystallised from ethyl acetate/60°-80° petroleum ether had m.p. 161°-162°.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29]C)=[O:28])=[N:22][C:21]=3[CH:35]=2)[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4]>CO>[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([OH:29])=[O:28])=[N:22][C:21]=3[CH:35]=2)[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1cc(OCc2ccc3oc(-c4ccccc4C(=O)OC)nc3c2)c2c(n1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(OCc2ccc3oc(-c4ccccc4C(=O)O)nc3c2)c2c(n1)CCCC2
Reaction time: 72 h
Yield: 35.4 %

Procedure:
1M Sodium hydroxide solution (5.0 ml) was added to a solution of methyl 2-[5-((2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy)methyl)benzoxazol-2-yl]benzoate (A) (443 mg) in methanol (20 ml) and the solution was left to stand for 72 hours. Volatile material was removed by evaporation and the residue was dissolved in methanol (10 ml). Water (40 ml) was added and the solution was neutralised with 1M acetic acid (5 ml). The precipitated solid was collected by filtration, dried by azeotroping with ethanol and triturated with ether to give 2-[5-((2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy)methyl)benzoxazol-2-yl]benzoic acid (152 mg), as a white powder, m.p. 229°-231° C; NMR (d6 -DMSO): 1.2(t, 3H), 1.7-1.85(m, 4H), 2.55-2.8(m, 6H), 5.3(s, 2H), 6.8(s, 1H), 7.55(dd, 1H), 7.65-7.9(m, 6H); mass spectrum (+ve FAB, DMSO/methanol/m-nitrobenzyl alcohol (NBA)): 429 (M+H)+ ; microanalysis, found: C, 70.7; H, 5.6; N, 6.1%; C26H24N2O4.0.5H2O requires: C, 71.2; H, 5.7; N, 6.4%.
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13]C)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O>[CH2:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@@H](C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC[C@H]1CC[C@@H](C(=O)O)CC1
Yield: 75.3 %

Procedure:
The cis methyl ester (14, 500 mg) was dissolved in methanol (5 ml) and stirred in a nitrogen atmosphere. A solution of NaOH in aqueous methanol (5 ml; 2.4 g NaOH in 30 ml water which was then diluted to 100 ml with methanol) was added and the mixture stirred for 24 hr at room temperature. The methanol was evaporated, water added, and then extracted with heptane (3×). The aqueous fraction was acidified to approximately pH 4 with dilute HCl, saturated with NaCl, and extracted with EtOAC (3×). The EtOAC extract was washed with water and dried over Na2O4, then evaporated in vacuo to give the cis-carboxylic acid (9, 0.35 g). A small aliquot was esterfied with diazomethane and analyzed by HPLC. Less than 1% of the trans isomer was present. The reaction was repeated on the remaining 400 mg. A total of 626 mg of the cis acid was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[ClH:27].[Cl-].[Na+].[CH3:30]O>>[ClH:27].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:30])=[O:24])=[CH:17][CH:16]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CO
Reactant: N=C(N)c1ccc(N2CCN(c3ccc(CCC(=O)O)cc3)C2=O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)CCc1ccc(N2CCN(c3ccc(C(=N)N)cc3)C2=O)cc1

Procedure:
Melting point: from 260° C. (decomp.) The product was also obtained by reacting 1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one with methanolic hydrochloric acid. Rf value: 0.49 (Reversed Phase Plate RP8; 10% sodium chloride solution/methanol=4:6)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=O)[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][F:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.C[O+](C)C.Cl.[NH:39]1[CH2:42][CH2:41][CH2:40]1.CCN(CC)CC>C(Cl)Cl.C1COCC1.C([O-])(O)=O.[Na+]>[N:39]1([C:16]2[O:17][C@H:13]3[CH2:12][C@H:11]([CH2:19][F:20])[C@@H:10]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C@H:14]3[N:15]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CF)C[C@@H]2O1
Reactant: C1CNC1
Agent: C[O+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC[C@H]1C[C@@H]2OC(N3CCC3)=N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-4,5-bis(benzyloxy)-6-(fluoromethyl)hexahydrobenzo[d]oxazol-2(3H)-one (193 mg, 0.503 mmol) in DCM (4 mL) at room temperature was added 4 A molecular sieves (130 mg) followed by trimethyloxonium tetrafluoroborate (372 mg, 2.52 mmol). The mixture was stirred at room temperature under N2 for 24 h. Azetidine hydrochloride (236 mg, 2.52 mmol) and a solution of Et3N (279 mg) in THF (2.0 mL) was added. The mixture was stirred at room temperature for another 48 h. The reaction was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (2×15 mL). The extracts were dried with Na2SO4 and the solvents were evaporated to give the crude product. This was purified by silica gel column, eluted with 2%-5% 2 M NH3 MeOH solution in DCM to yield (3aS,4R,5R,6S,7aS)-2-(azetidin-1-yl)-4,5-bis(benzyloxy)-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole as a white solid (80.0 mg, 38%). MS m/z 425.2 (M+1, 100%); 1H NMR (500 MHz, CDCl3) δ 7.28-7.36 (m, 10H), 4.93-4.96 (m, 1H), 4.77 (d, J=11.7 Hz, 1H), 4.71 (d, J=11.1 Hz, 1H), 4.65 (d, J=11.7 Hz, 1H), 4.54 (dd, J=9.0 Hz, 5.0 Hz, 1H), 4.49 (d, J=11.2 Hz, 1H), 4.43-4.46 (m, 1H), 4.43 (d, J=11.1 Hz, 1H), 4.34 (dd, J=9.0 Hz, 4.7 Hz, 1H), 4.20 (dd, J=8.3 Hz, 3.7 Hz, 1H), 3.88-3.99 (m, 4H), 3.86 (t, J=4.3 Hz, 1H), 3.53 (t, J=5.7 Hz, 1H), 2.09-2.19 (m, 4H), 1.81-1.87 (m, 1H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>C(Cl)Cl>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A stirred solution of 5.3 g (29.0 mmol) of cyanuric chloride in 200 mL of DCM was cooled to −10° C. A solution of 5.3 g (29.0 mmol, 1.0 equiv.) of N-BOC piperazine and 6.2 g (29.0 mmo, 1.0 equiv.) of Proton Sponge® in 40 mL of DCM was then added dropwise over 20 min. to the cyanuric chloride solution. The resulting mixture was allowed to warm to RT and stirred 2 h. The reaction mixture was quenched by pouring into 150 mL of a 5% aqueous citric acid solution and extracted with DCM (2×100 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography eluting with hexanes/EtOAc 3:1 afforded 8.6 g (85%) of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) δ 3.86 (m, 4H), 3.49 (m, 4H), 1.42 (s, 9H); low resolution MS (ES+) m/e 335 (MH+);TLC (hexanes/EtOAc 20:1) Rf=0.10. Intermediate 2: tert-butyl-4-{4-chloro-6-[[3-(4-chlorophenyl)propyl](methyl)amino]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.Cl.[NH:34]1[C:42]2[CH2:41][CH2:40][NH:39][CH2:38][C:37]=2[N:36]=[CH:35]1>C(OCC)(=O)C.C(N(CC)CC)C>[C:12]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([N:39]2[CH2:40][CH2:41][C:42]3[NH:34][CH:35]=[N:36][C:37]=3[CH2:38]2)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: c1nc2c([nH]1)CCNC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(CC(c1ccccc1)c1ccccc1)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
To a suspension of 3,3-diphenylpropionic acid (14 mg, 0.06 mmol) and HOBt (9 mg, 0.07 mmol) in ethyl acetate (1.5 mL) a solution of EDC (12 mg, 0.06 mmol) in ethyl acetate (0.5 mL) was added. The resulting mixture was shaken for 20 min at room temperature and then 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (12 mg, 0.06 mmol) and triethylamine (0.02 mL) were added. After shaking for 16 h the mixture was washed with brine (2×2 mL), and the organic phase was concentrated. 12 mg (60%) of the title amide was obtained.
Reaction SMILES: [C:1]1(=[O:9])[C:8]2[N:4]([CH:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>ClCC(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:5]2[N:4]3[C:8](=[CH:7][CH:6]=2)[C:1](=[O:9])[CH2:2][CH2:3]3)=[O:16])=[CH:13][CH:12]=1
Reactant: O=C1CCn2cccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: ClCC(Cl)(Cl)Cl
Product: O=C1CCn2c1ccc2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a stirred mixture of 12.1 g compound (1) and 8 g AICI3 in 40 ml tetrachloroethane was added dropwise 5.3 g 4-chlorobenzoyl chloride during 1 hour. The mixture was stirred at 40°-45° C. for 2 hours. The reaction mixture was added into 100 g ice-water. The organic layer was dried over MgSO4. Evaporated to dryness, 7 g crude product was obtained. Recrystallized from ethanol, 5.5 g of (3) was obtained as a white solid, mp 165°-166.5° C., yield 72%.