Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:21][CH3:22])[CH3:19])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: CNOC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.5 %

Procedure:
A solution of 4-chloro-2-phenylamino-benzoic acid (10.1 g, 41.0 mmol) in N,N-dimethylformamide (200 mL) at 25° C. was treated with O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (31.2 g, 82.0 mmol), N,O-dimethyl hydroxylamine hydrochloride (7.94 g, 82.0 mmol), and N,N-diisopropylethylamine (45.0 g, 350 mmol). The resulting mixture was stirred at 25° C. for 24 h. At this time, the reaction mixture was diluted with ethyl acetate (600 mL) and washed with water (4×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (silica gel, 100-200 mesh, ethyl acetate/hexanes 10-25%) afforded 4-chloro-N-methoxy-N-methyl-2-phenylamino-benzamide (6.62 g, 56.4%) as a yellow solid. 1H NMR (DMSO-d6) δ ppm 7.93 (s, 1H), 7.20-7.39 (m, 3H), 7.02-7.17 (m, 3H), 6.88-6.99 (m, 2H), 3.50 (s, 3H), 3.20 (s, 3H); MS m/e calcd for C15H15ClN2O2 [(M+H)+] 291.0. Found 291.0; [(M−C2H6NO)+] 230.0. Found 230.0.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[N:10][N:11]2[C:16]([C:17]3[CH:18]=[C:19]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])[CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:14]=[N:13][C:12]=12)=[O:7].[H-].[Na+].[CH3:31]I>CN(C)C=O.C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[N:10][N:11]2[C:16]([C:17]3[CH:18]=[C:19]([N:23]([CH3:31])[C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])[CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:14]=[N:13][C:12]=12)=[O:7]
Reactant: CI
Reactant: O=C(c1ccco1)c1cnn2c(-c3cccc(NC(=O)C4CC4)c3)ccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C(=O)C1CC1)c1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 3.85 g sample of N-[3-[3-(2-furanylcarbonyl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]cyclopropanecarboxamide in 40 ml of dimethylformamide is added 0.384 g of 60% sodium hydride in oil. The mixture is stirred at room temperature under argon for one hour and then 0.65 ml of methyl iodide is added. After stirring overnight at room temperature, several drops of acetic acid are added, the mixture poured onto ice-water and extracted with dichloromethane. The extracts are washed with water, dried over sodium sulfate and the solvent removed under reduced pressure. The residue is dissolved in dichloromethane, filtered through a short pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and hexane added. Cooling gives the desired product as crystals, mp 207°-209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[CH2:24]([C@@H:31]1[CH2:33][O:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:32][C@H:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][N:15]1[CH2:16][CH2:17][C:12]2([O:11][C:10]3[C:20]4[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=3[S:19][CH2:18]2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=4)[CH2:13][CH2:14]1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Reactant: c1ccc(C[C@@H]2CO2)cc1
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@H](O)Cc4ccccc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 208 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane using conditions outlined in procedure Y. M.p.=106° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=8.8 Hz, 1H), 7.08-7.28 (m, 7H), 4.50 (brs, 1H), 3.93 (brs, 4H), 3.07 (s, 2H), 2.76 (m, 4H), 2.60 (m, 2H), 2.33 (m, 2H), 1.95 (m, 2H), 1.83 (m, 2H); LCMS: 466 [M+H];
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH2:31][CH3:32])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].ClC1C=C(C(OO)=[O:42])C=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[C:22]([S:30]([CH2:31][CH3:32])=[O:42])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SCC)cc(C(F)(F)F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(S(=O)CC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of {(R)-4-[(3-ethylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (50.6 mg, 0.10 mmol) in dichloromethane was added 3-chloro-benzenecarboperoxoic acid (m-CPBA) (19.1 mg, 0.11 mmol) at 0° C. After stirring at room temperature for 3 hours, the resulting mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution, 5% methanol in dichloromethane) to afford {(R)-4-[(3-ethanesulfinyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (39.6 mg, 76.2%) as a semisolid. MS cald. for C21H26F3N3O5S2521, obsd. (ESI+) [(M+H)+] 522.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].[Br:15][CH2:16][C:17](Br)=[O:18].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[Br:15][CH2:16][C:17]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])=[C:7]([CH3:12])[CH:8]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Cc1ccccc1NC(=O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1cc(C(=O)CBr)ccc1NC(=O)C(F)(F)F
Yield: 37.6 %

Procedure:
2,2,2-trifluoro-N-o-tolylacetamide (5.0 g; 24.6 mmol) was dissolved in 20 mL CS2. The mixture was cooled below 10° C. Bromoacetic bromide (10.1 g; 50.0 mmol) was added dropwise. AlCl3 (10.0 g; 75.0 mmol) was added in portions, with drying tube attached to the reaction flask. The reaction mixture was refluxed overnight. After the reaction is complete as monitored by TLC, the upper CS2 layer was removed. The lower layer was added into 7.0 mL ice water mixed with HCl. The product was extracted into CH2Cl2, and dried over MgSO4. The solvent was removed, and the solid was dried to afford 5.0 g of crude product, which was purified by silica gel column chromatography, to afford 3.0 g (yield 38%) of product as yellow solid. 1H NMR (300 MHz; CDCl3), δ 8.40 (s, 1H, Ar—H), 7.87 (brs+d, 3JHH=8.0 Hz, 2H, Ar—H), 7.43 (d, 3JHH=8.0 Hz, 1H, Ar—H), 4.46 (s, 2H, COCH2Br), 2.41 (s, 3H, CH3).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@H:27]1[C:32]([OH:34])=[O:33]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@H:27]2[C:32]([OH:34])=[O:33])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 79.7 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.5 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.33 g, 80%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([Br:14])[Br:13])=[CH:7][CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[Br:13][C:12]([Br:14])=[CH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C=C(Br)Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCc1ccc(C=C(Br)Br)cc1
Yield: 109.6 %

Procedure:
The above ester (3.32 g) in dichloromethane (10 ml) at 0.20° under nitrogen was treated with diisobutyl aluminiumhydride (21 ml). After 1 hour at 0° C. dilute hydrochloric acid was added and the mixture worked up in the normal manner to give 4-(2,2-dibromoethenyl)benzyl alcohol (3.18 g). NMR 1H 7.50(2H,d), 7.41(1H,s), 7.20(2H,d), 4.33(2H,s), 3.65(1H,s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[N:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CC#N>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Temperature: 23 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of technical grade 3-nitropyridone (25 g, 177 mmol) (contains about 20% 3,5-dinitropyridone by weight) in 150 mL of phosphorous oxychloride was heated at 90° C. for 2 h. The excess phosphorous oxychloride was removed by distillation and the remaining oil poured into ice/water. The aqueous solution was extracted with five 300 mL portions of CH2Cl2. The CH2Cl2 extracts were dried (MgSO4), filtered and concentrated in vacuo to yield 26.7 g of crude 4-chloro-3-nitropyridine. To a solution of the crude 4-chloro-3-nitropyridine (26.7 g) in 200 mL of MeCN was added potassium carbonate (25.7 g, 186 mmol) and ethyl 1-piperazinecarboxylate (27.2 mL, 186 mmol). The reaction mixture was stirred at 23° C. for 16 h and then concentrated in vacuo. The mixture was diluted with ethyl acetate (1 L), and the organic solution was washed with water, dried (brine, MgSO4), filtered and concentrated in vacuo to a solid mass. Silica gel chromatography of the mixture gave ethyl 4-(3-nitro-4-pyridinyl)-1-piperazinecarboxylate (34.73 g, 73%): mp 101°-103° C., and ethyl 4-(3,5-dinitro-4-pyridinyl)-1-piperazinecarboxylate (7.07 g, 22%): mp 165°-167° C. Anal. Calcd for C12H16N4O4 : C, 51.42; H, 5.75; N, 19.99. Found: C, 51.26; H, 5.69; N, 19.91. Anal. Calcd for C12H15N5O6 : C, 44.31; H, 4.65; N, 21.53. Found: C, 44.51; H, 4.65; N, 21.36.
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[C:3]([Cl:7])=[C:4](Cl)[Cl:5].[CH3:10][NH:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:10][N:11]1[C:2]([Cl:1])=[C:3]([Cl:7])[C:4]([Cl:5])=[N:12]1
Reactant: CNN
Reactant: ClC(Cl)=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1nc(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 250 g (1 mole) of hexachloropropene in 250 ml toluene, there was added 94.4 g (2.05 moles) of methyl hydrazine dropwise.The temperature of the reaction mixture was maintained in the range of about 50° to about 60° C. by the use of external cooling. When the addition of methyl hydrazine was complete, the reaction mixture was cooled to room temperature and 276 g (2 moles) of potassium carbonate was added. The resulting mixture was carefully heated first to about 60° C., then gradually to about 85° to 90° C. Heatingwas carefully monitored to control occasional exotherm and degassing. Afterabout three hours, the heat source was removed and the reaction mixture wasallowed to cool to room temperature. The reaction mixture was diluted with about 500 ml ice water and extracted with methylene chloride. The organic layer (containing the product) was washed twice with water, dried over magnesium sulfate and concentrated on a rotovac to give a red oil (about 275 ml). The red oil was dissolved in hexane and filtered through a short silica column twice to give 133 g of a yellow oil which solidified. Spectra of the solid were identical to those of the product of Example 1.
Reaction SMILES: Cl[C:2]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:6]1=[O:33])=[O:3].[CH2:34]([NH2:38])[CH2:35][CH2:36][CH3:37]>>[C:27]1([CH2:26][O:25][C:23](=[O:24])[NH:22][CH:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([CH2:4][C:2](=[O:3])[NH:38][CH2:34][CH2:35][CH2:36][CH3:37])[C:6]2=[O:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reactant: CCCCN
Product: CCCCNC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 1,3-dihydro-1-chlorocarbonylmethyl-3-(phenylmethyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one and n-butylamine. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 127°-129° C.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH3:7][O:8][C:9]([C:11]1[CH2:12][N:13]([CH2:17][CH2:18][CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21][CH2:20]2)[CH2:14][CH2:15][CH:16]=1)=[O:10].[CH2:29](O)C>>[CH2:7]([O:8][C:9]([C:11]1[CH2:12][N:13]([CH2:17][CH2:18][CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21][CH2:20]2)[CH2:14][CH2:15][CH:16]=1)=[O:10])[CH3:29]
Reactant: COC(=O)C1=CCCN(CCC2COc3ccccc3C2)C1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=CCCN(CCC2COc3ccccc3C2)C1
Yield: 97.4 %

Procedure:
3.4 ml of sulphuric acid (100% strength) are added to a solution of 2.54 g (7.5 mmol) of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride in 170 ml of absolute ethanol and the whole is boiled under reflux for 35 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo. The residue is dissolved in water while cold and is extracted with diethyl ether. The aqueous phase is rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. 2.30 g (97.4%) of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether and melts at 177°-178°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:13]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(Cl)n1

Procedure:
A mixture of 40 g 6-chloro-2-pyridinecarboxilic acid and 150 ml SOCl2 is refluxed 4 hrs. After removing excess SOCl2 there is obtained 44 g 6-chloro-2-pyridinecarboxylic acid chloride, m.p. 76° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].CO.Cl[CH:12]([CH3:15])[C:13]#[N:14]>CN(C)C=O>[C:13]([CH:12]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH3:15])#[N:14]
Reactant: CC(Cl)C#N
Reactant: c1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C#N)n1cncn1
Temperature: 0 °C
Yield: 70.2 %

Procedure:
In this example, a mixture containing 13.47 gms (0.195 mole) of 1,2,4-triazole and 10.53 gms (0.195 mole) of sodium methoxide in 200 mls of dimethylforamide was refluxed until no further evolution of the methanol by-product was observed. The reaction mixture was then cooled to 0° C. and then 19.23 gms of 2-chloropropionitrile dissolved in 25 mls of dimethylforamide were added dropwise with stirring. The mixture was then stirred overnight (about 12 to 14 hours) at room temperature and then filtered. The dimethylforamide was then removed by vacuum evaporation. The residue was dissolved in methylene chloride and filtered through neutralized silica gel. The filtrate was evaporated affording 16.73 gms of the title compound as a brown liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][P:23]([CH:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:27]([CH3:29])[CH3:28])([OH:25])=[O:24])[C:17]([O:19]CC)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][P:23]([CH:26]([NH:30][C:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:27]([CH3:29])[CH3:28])([OH:25])=[O:24])[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)CP(=O)(O)C(NC(=O)CCc1ccccc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)CC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
The crude ethyl 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoate (222 mg) obtained in the above step (f) was dissolved in a mixed solvent of ethanol:water (10:7) (3.4 ml). The mixture was added with 1 N aqueous sodium hydroxide (0.6 ml) and stirred at room temperature for 3 hours, at 50° C. for 2 hours, and then at room temperature for 16 hours. The reaction mixture was acidified with hydrochloric acid and the organic substances were extracted with ethyl acetate, and then the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue was concentrated to obtain crude 6-benzyloxycarbonylamino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid (181 mg, 86%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]2[C:17](=[CH:18][CH:19]=1)[CH:16]1[O:20][CH:12]2[CH2:13][NH:14][CH2:15]1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][S:2]([N:14]1[CH2:13][CH:12]2[O:20][CH:16]([C:17]3[C:11]2=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:19][CH:18]=3)[CH2:15]1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Methanesulfonyl chloride (133 mg, 1.16 mmol) was added to a solution of 4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (200 mg, 0.55 mmol) and potassium carbonate (276 mg, 2.0 mmol) in THF (5 mL). The solution was stirred at 70° C. for 1 h. The reaction was then concentrated and purified with silica gel chromatography (0-100% EtOAc in hexanes) to give 10-Methanesulfonyl-4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a light tan solid (150 mg, 54%). MS (m/e) 285 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[O:17][CH3:18])[C:4]([OH:6])=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[O:17][CH3:18])[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(Oc1ccc([N+](=O)[O-])cc1OC)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCC(Oc1ccc(N)cc1OC)C(=O)O

Procedure:
A solution of 5-15 (0.7 g, 2.7 mmol) in EtOH (10 mL) was treated with 10% Pd/C (0.14 g) and hydrogenated at balloon pressure. The solution was filtered through Solka-Floc and evaporated to give 5-16 as a tan oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)[CH2:24][C:23]([CH3:38])([CH3:37])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([NH:26][CH2:27][CH2:28][NH2:29])[CH2:24][C:23]([CH3:38])([CH3:37])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCNC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(NCCN)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1

Procedure:
A solution of the product of Step A (42.9 mg, 0.07 mmol) in 2.5 mL of 20% TFA in CH2Cl2 was stirred at rt for 1 h. The reaction mixture was concentrated to give the product which was used without further purification.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([CH3:14])[CH2:9]2)=N)[CH3:4].C([OH:17])C>O>[CH2:3]([O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([CH3:14])[CH2:9]2)=[O:17])[CH3:4]
Reactant: CCO
Reactant: CCOC(=N)C12CC1CN(C)C2
Agent: Cl
Solvent: O
Product: CCOC(=O)C12CC1CN(C)C2

Procedure:
Crude 3-methyl-3-azabicyclo[3.1.0]hexane-1-carboximidic acid ethyl ester dihydrochloride (obtained as described below) is boiled under reflux for 3 hours in 30 ml of ethanol and 0.6 ml of water. After evaporation, the resultant residue is made alkaline with an aqueous sodium bicarbonate solution. Extraction with methylene chloride gives the title compound (M.Pt. of napthalene-1,5-disulphonate 161°-165°).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].[H][H].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C=O>[CH2:3]([C:5]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
In 100 ml of N,N-dimethylformamide was suspended 11 g of 50% sodium hydride which had been washed with n-hexane and the suspension was stirred under ice cooling. Thereafter, 37.6 g (0.2 mole) of diethyl ethylmalonate was added dropwise thereto and stirring was continued until evolution of hydrogen ceased. Subsequently, a solution of 31.51 g (0.2 mole) of p-chloronitrobenzene in 50 ml of N,N-dimethylformamide was added dropwise. At the end of the dropwise addition, the mixture was heated on an oil bath at 100° C. for 9 hours and N,N-dimethylformamide was distilled off in vacuo. The residue was extracted with ethyl acetate and the ethyl acetate layer was washed with 5% hydrochloric acid and saturated sodium chloride solution and then dried over magnesium sulfate. The ethyl acetate was distilled off in vacuo and the residue was subjected to chromatography on silica gel eluting with a mixture of benzene and n-hexane (1:1) to give 48.64 g (0.157 mole, 79% yield) of diethyl 2-ethyl-2-(4-nitrophenyl)malonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH:17]12[CH2:23][CH:21]([O:22]1)[CH2:20][NH:19][CH2:18]2>>[CH:21]12[CH2:23][CH:17]([O:22]1)[CH2:18][N:19]([C:14]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16])[CH2:20]2
Reactant: C1NCC2CC1O2
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Product: COc1ccc(C(=O)N2CC3CC(C2)O3)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with 6-oxa-3-azabicyclo[3.1.1]heptane by following the similar procedure as described in Step-6 of Intermediate-22.