Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[I-].[CH3:23][N:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:34][N+](C)(C)C)=[CH:25]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:34][CH:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:24]([CH3:23])[CH2:25]3)[C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COC(=O)CC1(n2c(=O)[nH]c3ccccc32)CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CC1(n2c(=O)n(CC3CN(C)c4cccc(C)c43)c3ccccc32)CCCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
To a mixture of [1-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-cyclohexyl]-acetic acid methyl ester (115 mg, 0.40 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (200 mg, 0.58 mmol) in DMF (2.5 mL) was added K2CO3 (110 mg, 0.80 mmol). The mixture was stirred at 100° C. for 4 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 30% EtOAc in Hexane as the eluent to afford the desired {1-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-cyclohexyl}-acetic acid methyl ester (131 mg, 74%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2CNC(=O)OC(C)(C)C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCN1CCC[C@@H]1CNC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H]1CCCN1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinylmethylcarbamate (D108, 2.07 g, 6.1 mmol) in 16 ml of dichloromethane, cooled to 0° C., were added 4 ml of TFA. The reaction mixture was allowed to warm-up to r.t. and then it was stirred at this temperature for 30 mins. The title compound (1.06 g, y=88%) was isolated after purification by SCX. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00-7.66 (m, 5 H) 4.90-5.20 (m, 2 H) 3.12-3.24 (m, 1 H) 2.97-3.09 (m, 1 H) 2.84-2.97 (m, 2 H) 2.61-2.82 (m, 2 H) 1.44-1.83 (m, 3 H) 1.14-1.40 (m, 1 H)
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19](=[NH:23])OCC)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.Cl.Cl[CH2:26][CH2:27][CH2:28][CH:29]([CH:34]1[CH2:39][CH2:38][CH2:37][C:36]([CH3:41])([CH3:40])[O:35]1)[C:30]([NH:32][NH2:33])=O>>[CH3:40][C:36]1([CH3:41])[O:35][CH:34]([CH:29]2[CH2:28][CH2:27][CH2:26][N:32]3[N:33]=[C:19](/[CH:18]=[CH:17]/[C:7]4[CH:8]=[CH:9][C:10]([N:11]5[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]5)=[C:5]([O:4][CH3:3])[CH:6]=4)[N:23]=[C:30]23)[CH2:39][CH2:38][CH2:37]1
Reactant: CC1(C)CCCC(C(CCCCl)C(=O)NN)O1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCCC(C)(C)O2)ccc1-n1cnc(C)c1

Procedure:
5.2 mg of a diastereomer mixture, 8-(6,6-dimethyltetrahydropyran-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine, was obtained according to the method in Example 113 from ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride obtained in Example 1 (47 mg) and 5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)-valeric acid hydrazide hydrochloride (36 mg). The diastereomer mixture was separated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: 30% ethanol-hexane) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (0.75 mg), the title optically active compound with a retention time of 14 minutes and positive optical rotation (0.21 mg), the title optically active compound with a retention time of 16 minutes and negative optical rotation (0.13 mg) and the title optically active compound with a retention time of 24 minutes and negative optical rotation (0.54 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])([OH:3])=O.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>CCCCCCC>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][C:1]2=[O:3]
Reactant: O=C(O)CCc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CCCCCCC
Product: O=C1CCc2c(Cl)cccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
33.5 g (181 mmol) of the 1-(2-carboxyethyl)-2-chlorobenzene and 83.4 ml of thionyl chloride are placed in a reaction vessel and stirred at 80° C. for one hour. The excess thionyl chloride is subsequently taken off and the residue is admixed with 200 ml of heptane. The reaction mixture is stirred for 30 minutes and the solvent is subsequently removed in an oil pump vacuum. The residue is taken up in 536 ml of methylene chloride and, while cooling in ice, 48.4 g (363 mmol) of aluminum trichloride are added a little at a time over a period of 10 minutes. The resulting reaction solution is stirred at 0° C. for another 2 hours before the reaction mixture is poured onto 300 ml of ice water. After the aqueous phase has been separated off and extracted once with 60 ml of toluene, the combined organic phases are washed with 80 ml of water and with 100 ml of saturated NaCl solution. After drying over magnesium sulfate, the solvent is removed in an oil pump vacuum. 29 g (96%) of the desired product are isolated.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH:19]1[CH:23]=[N:22][N:21]=[N:20]1>>[C:1]([N:19]1[CH:23]=[N:22][N:21]=[N:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: c1nnn[nH]1
Product: CCCCCCCCCCCCCCCC(=O)n1cnnn1

Procedure:
Example 2 is repeated to react palmitoyl chloride with tetrazole in a molar ratio of 1:2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH2:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCN)CC1

Procedure:
Batch size: 42.2 g (120 mmol) 2-{2-[4-(tert-butoxycarbonyl)-piperazin-1-yl]-ethyl}-isoindolin-1,3-dione and 11.6 ml (240 mmol) hydrazine-hydrate in 450 ml ethanol.
Reaction SMILES: [C:1]1([C:7]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=4[NH2:41])[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54](Cl)(=[O:59])[CH2:55][CH2:56][CH2:57][CH3:58].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:48]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=4[NH:41][C:54](=[O:59])[CH2:55][CH2:56][CH2:57][CH3:58])[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:23][CH:24]=3)=[N:11][N:10]=[N:9]2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc(C(=O)N2CCOCC2)cc1OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound ([3]-(34)-587) (0.07 g) prepared in Example 38 and 4-dimethylaminopyridine (0.01 g) were dissolved in dry pyridine (1 ml). Valeryl chloride (0.043 g) was added dropwise by a syringe while cooling on ice. The mixture was stirred at room temperature for 2 hours, then, poured into water (20 ml), extracted with chloroform (10 ml) twice, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the compound ([3]-(35)-587') (0.08 g) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[CH:19]=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc3ccccc23)cn1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 96.8 %

Procedure:
A mixture of 2,4-dichloroquinazoline (61 mg, 0.31 mmol), 5-amino-2-methoxy pyridine (40 mg, 0.32 mmol) and sodium acetate (38 mg, 0.46 mmol) in 3 mL of solvent (THF:water/1:1) was stirred at 60° C. for 45 min. The reaction mixture was diluted with 25 mL of ethyl acetate. It was washed with saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by chromatography (40% ethyl acetate/hexanes) on silica gel to give the title compound (86 mg, 0.30 mmol, 98%). 1H NMR (CDCl3): 8.38 (d, J=3.0 Hz, 1H), 8.07 (dd, J=8.7 and 3.0 Hz, 1H), 7.89-7.79 (d, J=8.4 Hz, 1H), 7.86 (m, 2H), 7.59-7.53 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [C:1](=[O:38])([O:16][CH2:17]/[C:18](/[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)=[C:19](/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)\[CH2:20][OH:21])[O:2][CH2:3][CH2:4][CH2:5][CH:6]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][O:8][N+:9]([O-:11])=[O:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:41].O>ClCCl>[N+:13]([O:12][CH:6]([CH2:7][O:8][N+:9]([O-:11])=[O:10])[CH2:5][CH2:4][CH2:3][O:2][C:1]([O:16][CH2:17]/[C:18](/[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][CH:29]=1)=[C:19](/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)\[C:20]([OH:41])=[O:21])=[O:38])([O-:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/CO)c2ccccc2)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.4 %

Procedure:
To a solution of 4.5 g of 4,5-bis(nitrooxy)pentyl (2Z)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 50 mL of dichloromethane, 4.13 g of Dess-Martin reagent was added and the resulted mixture was stirred at 25° C. for 45 min. Then 250 uL of water was added and the mixture was stirred at RT for 15 min. Then the mixture was filtered through a pad of silica gel and evaporated. The crude was dissolved in a mixture of THF and t-BuOH (25 mL/25 mL). To this solution was added 6.8 mL of 2-methyl-2-butene followed by the addition of 20 mL of phosphoric acid (1.2M soln) and 20 mL of NaClO2 (1M soln). The resulted mixture was stirred at RT for 30 min. The organic phase was separated and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over Na2SO4, filtered, and then evaporated. The crude was purified by flash chromatography to afford 2.6 g of the titled compound as white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.77 (d, 2H), 7.44 (d, 2H), 7.17 (s, 3H), 7.12 (t, 2H), 5.51 (s, 1H), 5.35 (s, 2H), 5.00 (dd, 1H), 4.72 (dd, 1H), 4.13-4.10 (m, 2H), 3.06 (s, 3H), 1.87-1.80 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][CH2:15]3)=[O:13])=[N:7][C:6]=2[CH:24]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>C(Cl)Cl>[N:14]1([C:12](=[O:13])[CH2:11][S:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:24][C:6]=3[N:7]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Reaction time: 8 h
Yield: 60 %

Procedure:
To a 0° C. solution of compound 50 (160 g, 0.45 mmol) in dry CH2Cl2 (5 mL) was added methanesulfonyl chloride (70 μL, 0.90 mmol)) followed by dropwise addition of pyridine (100 μL, 1.40 mmol). The reaction was stirred overnight under N2. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with 1N HCl (10 mL), water (2×10 mL), and saturated NaCl (2×10 mL). Dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the product was purified by column chromatography (EtOAc/hexanes 1:1) to afford 54 as a pale yellow solid (117 mg, 60%); MS m/z: 434 (M+H)+. Anal. Calcd. For, C19H19N3O3S2: C, 52.63; H, 4.42; N, 9.69; S, 22.19. Found: C, 52.69; H, 4.49; N, 9.54; S, 22.11.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[CH2:14][CH2:13]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cc(C)cc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
58 mg of the target compound (0.16 mmol, 19.5%) was obtained using 1-(3,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [OH:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C@@H:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: Ic1ccc(I)cc1
Reactant: O[C@H]1CN2CCC1CC2
Product: Ic1ccc(O[C@H]2CN3CCC2CC3)cc1

Procedure:
3-(R)-Hydroxyquinuclidine (the product of Reference Example 1, 0.64 g, 5.0 mmol) was treated with 1,4-diiodobenzene (1.98 g, 6.0 mmol) according to the procedure of Example 14A. The title compound was purified by flash chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as a solid (0.50 g, yield, 15%). 1H NMR (MeOH-d4, 300 MHz) δ 1.41–1.54 (m, 1H), 1.59–1.73 (m, 1H), 1.73–1.86 (m, 1H), 1.92–2.05 (m, 1H), 2.09–2.17 (m, 1H), 2.71–2.97 (m, 5H), 3.24–3.34 (m, 1H), 4.44–4.52 (m, 1H), 6.72 (d, J=8.8 Hz, 2H), 7.55 (d, J=9.2 Hz, 2H) ppm. MS (DCl/NH3): m/z 330 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:61])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C@:13]23[CH2:57][CH2:56][C@@H:55]([C:58]([CH3:60])=[CH2:59])[C@@H:14]2[C@@H:15]2[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:54])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]3[CH2:53][C:37]5([CH2:40][C:39]([C:47]([O:49]C(C)C)=[O:48])([C:41]([O:43]C(C)C)=[O:42])[CH2:38]5)[CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]2)[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1.CO>[O:61]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C@:13]23[CH2:57][CH2:56][C@@H:55]([C:58]([CH3:60])=[CH2:59])[C@@H:14]2[C@@H:15]2[C@@:28]([CH3:31])([CH2:29][CH2:30]3)[C@@:27]3([CH3:32])[C@@H:18]([C@:19]4([CH3:54])[C@@H:24]([CH2:25][CH2:26]3)[C:23]([CH3:34])([CH3:33])[C:22]([C:35]3[CH2:53][C:37]5([CH2:38][C:39]([C:41]([OH:43])=[O:42])([C:47]([OH:49])=[O:48])[CH2:40]5)[CH:36]=3)=[CH:21][CH2:20]4)[CH2:17][CH2:16]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 12 h
Yield: 2.5 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-dioxidothiomorpholino)propyl)amino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (90 mg, 0.104 mmol) in dioxane (3 mL) and MeOH (2 mL) was added 1N NaOH (2 mL, 2 mmol). The mixture was stirred at 50° C. for 12 h. The crude product was purified by preparative HPLC using method 14. The fractions containing the expected product were combined and concentrated to give 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-dioxidothiomorpholino)propyl)amino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylic acid as a white solid (2 mg, 2.46%). MS: m/e 779.5 (M+H)+, 2.31 min (method 2). 1H NMR (400 MHz, DMSO-d6) δ 6.02 (s, 1H), 5.48 (d, J=4.5 Hz, 1H), 4.71 (s, 1H), 4.60 (s, 1H), 3.12 (d, J=4.8 Hz, 5H), 3.01 (br. s., 4H), 2.91 (br. s., 5H), 2.72-2.64 (m, 1H), 2.57-2.49 (m 6H), 2.17-1.96 (m, 2H), 1.82 (d, J=5.8 Hz, 5H), 1.67 (m, 8H), 1.53-1.17 (m, 12H), 1.13 (s, 3H), 1.05 (m, 6H), 0.97 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:25])([O:23][CH3:24])[CH3:22])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:62][CH:63](Br)[CH3:64])(=[O:61])[CH3:60].Cl>O.CN(C)C=O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:22])([O:23][CH3:24])[CH3:25])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([O:13][CH:63]([O:62][C:59](=[O:61])[CH3:60])[CH3:64])=[O:12])=[N+:2]=[N-:3]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OC(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A mixture of 739 mg of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid, 76 mg of potassium carbonate and 3 ml of dimethylformamide was stirred at 20° C. for 10 minutes and after cooling the mixture to 0° to 50° C., 0.6 g of 1-bromoethyl acetate was slowly added thereto. The mixture was stirred for 20 minutes at 0° to 5° C. and for one hour at 20° C. and then a mixture of 40 ml of iced water and 1.5 ml of N hydrochloric acid were added thereto. The mixture was vacuum filtered and the product was rinsed with water and dried to obtain 761 mg of the syn isomer of 1-acetoxyethyl 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=O)[CH:2]=[CH2:3].C(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.CO[CH:32](OC)[CH2:33][NH2:34].O1CCOCC1>O1CCOCC1>[CH2:1]([N:4]1[CH:32]=[CH:33][N:34]=[C:5]1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1sccc1-c1ccc(Cl)cc1Cl
Reactant: COC(CN)OC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sccc1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of N-allyl-3-(2,4-dichlorophenyl)thiophene-2-carboxamide (8.60 g, 27.5 mmol) in DCM (309 mL, 4820 mmol) was added phosphorus pentachloride (6.54 g, 31.4 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.51 mL, 2.00 mmol) and the mixture was heated to 60° C. for 2 hrs. The reaction was cooled to room temperature and aminoacetaldehyde dimethyl acetal (33.9 mL, 311 mmol) was slowly added. The resulting mixture was heated at 60° C. for 2.5 hrs. To the reaction mixture was added 4 M hydrochloric acid in 1,4-dioxane (200 mL, 783 mmol) and the mixture was stirred at 60° C. overnight. After cooling to room temperature, the suspension was filtered through a Celite pad and the solid residue was washed with 1,4-dioxane. The filtrate was evaporated down and the resulting residue was dissolved in water (300 mL) and extracted with EtOAc (2×150 mL). The water layer was basified by addition of solid NaHCO3 until pH 9, and the aqueous was extracted with EtOAc (3×300 mL). All organics were combined and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, elution with 8-25% EtOAc in DCM) to give crude product which was further purified by column chromatography (SiO2, elution with 45% MeCN: 50% DCM: 5% EtOAc) to provide 7.12 g of product (76%). LC/MS (FA), ES+ 337. NMR (400 MHz, d6 DMSO) δ: 7.80 (d, J=5.3 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.35 (dd, J=2.0, 8.3 Hz, 1H), 7.26 (d, J=5.3 Hz, 1H), 7.13 (d, J=1.3 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.98 (d, J=1.3 Hz, 1H), 5.47-5.58 (m, 1H), 4.98-5.02 (m, 1H), 4.75-4.82 (m, 1H), 4.19-4.23 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[O:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]3[CH:13]=[C:12]2[C:14]2[O:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc(-c2cc3cc(S(C)(=O)=O)cnc3[nH]2)o1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc3cc(S(C)(=O)=O)cnc3n2Cc2ccc(F)cc2)o1
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of the compound obtained in Example 11 (3) (20 mg) in N,N-dimethylformamide (2 ml), 60% sodium hydride (4.4 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 30 minutes, followed by addition of 4-fluorobenzyl bromide (26 mg), and the reaction mixture was stirred for further 30 minutes. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with toluene. The organic layer was washed with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 18 mg of the desired product as a yellow powder.