Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][S:28]([CH3:27])(=[O:30])=[O:29])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (450 mg, 1.1 mmol) and methanesulfonyl chloride (205 mg, 1.7 mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), and sodium hydrogen carbonate (250 mg, 3.0 mmol) was added thereto. The mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (20:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (88 mg, 21%) as white crystals.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#N.ClC1C=CC(C2(C#N)CCC(=[O:33])CC2)=CC=1.[OH-:36].[K+]>C(O)CO>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([OH:33])=[O:36]
Reactant: N#CC1(c2ccc(Cl)cc2)CCC(=O)CC1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Reactant: [OH-]
Agent: [K+]
Solvent: OCCO
Product: COc1ccc(C2(C(=O)O)CCC(=O)CC2)cc1OC
Yield: 99 %

Procedure:
Following the procedure of Example 1, Part E, but substituting 17.54 gm. (0.058 mole) at 4-cyano-4-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal (prepared in Part D, above) for the 21.87 gm. of 4-(p-chlorophenyl)-4-cyanocyclohexanone, ethylene ketal; and using 17.5 gm. (0.31 mole) potassium hydroxide and 175 ml. ethylene glycol instead of the 22.0 gm. and 220 ml. respectively; there is obtained, after removal of the ether, 19.0 gm. (99% yield) of 4-carboxy-4-(3,4-dimethoxyphenyl)cyclohexanone, ethylene ketal as a gum that gives a reasonably expected infrared spectrum.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][CH2:42][CH2:43]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[F:41][CH2:42][CH2:43][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Reactant: OCCF
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(COCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
To a solution of tert-butyl 4-(4-(hydroxymethyl)phenyl)piperazine-1-carboxylate (100 mg, 0.34 mmol) in THF (1 mL) was added triphenylphosphine (135 mg, 0.51 mmol), 2-fluoroethanol (24 μL, 0.41 mmol) and diisopropylazodicarboxylate (99 μL, 0.51 mmol). The reaction mixture stirred at room temperature overnight. The next day the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated to obtain a crude oil. Purification of the crude material using silica gel chromatography (gradient of 0% to 100% EtOAc in hexanes) afforded tert-butyl 4-(4-((2-fluoroethoxy)methyl)phenyl)piperazine-1carboxylate as a colorless oil (26 mg, 22% yield). 1H NMR (300 MHz, CDCl3) δ 7.27 (d, 2H, J=9.0 Hz), 6.89 (d, 2H, J=9.0 Hz), 4.65 (m, 1H), 4.52 (s, 2H), 4.49 (m, 1H), 3.74 (m, 1H), 3.64 (m, 1H), 3.58 (dd, 4H, J=6.0, 3.0 Hz), 3.13 (dd, 4H, J=6.0, 3.0 Hz), 1.49 (s, 9H); 19F NMR (282.4 MHz, CDCl3): δ−223.01 (m, 1F); 13C NMR (75.5 MHz, CDCl3); δ 154.7, 150.9, 129.4, 129.2, 116.5, 84.3 (82.0), 79.9, 73.0, 68.8 (68.7), 49.3, 44.0, 28.4; HRMS calcd for C18H27FN2O5: 339.20785 found 339.20790.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2ccccc2)cn1
Yield: 24.5 %

Procedure:
To a stirred solution of 5-chloro-2-cyanopyridine (300 mg, 2.17 mmol) in toluene: H2O (7:3) (10 mL) was added Na2CO3 (459 mg, 4.33 mmol) followed by Pd(PPh3)4 (500 mg, 0.43 mmol) and phenylboronic acid (337 mg, 2.60 mmol) at room temperature. The resulting mixture was heated to reflux for 3 hrs. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography (using silica gel 60-120 mesh and 4% ethylacetate in hexane as eluent) to afford 96 mg (24.6% yield) of 5-phenyl-pyridine-2-carbonitrile. LCMS Purity: 97.5%
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:17][CH:18]([OH:34])[CH:19]([NH:29][C:30](=[O:33])[CH2:31][NH2:32])[CH2:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1COCC1.[Br:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](Cl)=[O:54]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:17][CH:18]([OH:34])[CH:19]([NH:29][C:30](=[O:33])[CH2:31][NH:32][C:53](=[O:54])[CH2:52][CH2:51][CH2:50][CH2:49][Br:48])[CH2:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)CCCCBr
Reactant: CCc1cccc(CN(CC(O)C(Cc2cc(O)cc(F)c2)NC(=O)CN)C(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cccc(CN(CC(O)C(Cc2cc(O)cc(F)c2)NC(=O)CNC(=O)CCCCBr)C(=O)OC(C)(C)C)c1
Yield: 87.8 %

Procedure:
To a solution of the product from Step 5 (60 mg, 0.12 mmol, 1.00 eq.), triethylamine (33 μL, 0.24 mmol, 2.00 eq.), and anhydrous THF (0.6 mL) is added bromovaleryl chloride (15 μL, 0.11 mmol, 0.95 eq.) under N2 with stirring. The reaction mixture is stirred for 2 hours, then diluted with ethyl acetate, quenched with 1N HCl, and washed with 10% NaHCO3. The organic layer is dried over MgSO4, filtered, and then concentrated in vacuo, yielding product as a white solid (63 mg, 80% crude yield). Calculate mass for C31H43BrFN3O6: 651.23 (mass calculated for Br79 isotope). Mass found for C31H43BrFN3O6: (LCMS) ES+: 676.1 (M+Na), ES− 652.0 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=3Cl)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].CN1CCOCC1.CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[NH:12][C:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=3[NH:22][CH2:23][C@@H:24]([OH:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: NC[C@@H](O)c1ccccc1
Reactant: COC(=O)c1cccc2nc(-c3c(Cl)cc[nH]c3=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 85 °C
Yield: 71.7 %

Procedure:
In a 40 mL vial, 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazole-4-carboxylic acid methyl ester (0.91 g, 3.00 mmol), (S)-2-amino-1-phenylethanol (822 mg, 5.99 mmol) and N-methylmorpholine (909 mg, 988 μL, 8.99 mmol) were combined with DMF (20 mL) to give a black suspension. The vial was sealed and heated in a dry block at 85° C. for 6.5 hr and allowed to cool to room temperature over the weekend. The reaction was diluted with water and the resulting precipitate was washed with water and hexanes yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid methyl ester (0.87 g, 71.8% yield) as a light purple solid. LC/MS calcd for C22H20N4O4 (m/e) 404.0, obsd 405.2 (M+H); 1H NMR (DMSO-d6): 13.53 (s, 1H), 11.26 (d, J=5.8 Hz, 1H), 10.85 (t, J=5.1 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.76-7.82 (m, 1H), 7.55 (d, J=7.3 Hz, 2H), 7.34-7.42 (m, 3H), 7.26-7.34 (m, 2H), 6.22 (d, J=7.5 Hz, 1H), 5.80 (d, J=4.5 Hz, 1H), 4.85-5.00 (m, 1H), 3.98 (s, 3H), 3.64-3.77 (m, 1H), 3.53-3.63 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8]2.[Br:17]Br.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>CO>[Br:17][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[N:11]2
Reactant: BrBr
Reactant: COc1cccc2ccc(C(F)(F)F)nc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Br)c2ccc(C(F)(F)F)nc12
Reaction time: 2 h

Procedure:
The intermediate 8-methoxy-2-(trifluoromethyl)quinoline (2.21 g, 9.7 mmol) in MeOH (15 mL) was treated with a 1.5 N solution of bromine in MeOH (7.8 mL, 11.7 mmol) over a 15 min period. This mixture was stirred 2 h then treated with a 1 N aqueous solution of Na2S2O3 (30 mL) and EtOAc (300 mL). The phases where separated and the organic portion washed with brine, a saturated aqueous solution of NaHCO3, and again with brine. The organic phase was dried with Na2SO4, filtered, and evaporated to afford titled compound as a light brown solid. 1H NMR (CDCl3) 8.70 (dd, J=8.8, 0.6, 1H), 7.86 (d, J=8.8, 1H), 7.85 (d, J=8.4, 1H), 7.02 (d, J=8.4, 1H), 4.10 (s, 3H). LC/MS (Method B) 3.82 min, [M+1]+ 305/307.
Reaction SMILES: Cl[CH2:2][C:3]([Cl:5])=[O:4].[CH2:6]([NH:13][C@H:14]([CH3:17])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:6]([NH:13][C@H:14]([CH3:17])[CH2:15][O:16][CH2:2][C:3]([Cl:5])=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@H](CO)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H](COCC(=O)Cl)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroacetyl chloride (11.6 mL, 120 mmol) was added dropwise at 0° C. to a solution of (R)-2-(benzylamino)propan-1-ol (19.9 g, 120 mmol) and triethylamine (30.5 mL) in toluene (600 mL). The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure and the recovered solids dissolved in EtOAc (500 mL) and then washed with saturated bicarbonate (2×250 mL), H2O (250 mL) and saturated brine (250 mL). The organic phase was then dried (Na2SO4), filtered and concentrated to afford (R)-2-(2-(benzylamino)propoxy)acetyl chloride: MS consistent.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[CH:2]1.[C:11](Cl)(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>O1CCCC1.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Nc1ccc2cc[nH]c2c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of 1H-indol-6-amine (1.0 g, 7.57 mmol), benzyl carbonochloridate (1.421 mL, 9.46 mmol), and potassium carbonate (1.307 g, 9.46 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature for 16 hr. The mixture was diluted with ethyl acetate (150 mL) and insoluble material was removed by filtration. The filtrate was washed sequentially with saturated NaHCO3 solution (50 mL) and brine (50 mL). The organic solution was dried over anhydrous MgSO4. The desired product (1.05 g, 3.94 mmol, 52.1% yield) was isolated as a white solid by ISCO (120 g silica gel, solid loading, 5-30% ethyl acetate/hexane).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.[BH4-].[Na+].O>C1COCC1>[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][CH:5]([CH2:3][OH:2])[CH2:9][C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)c(F)c3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(CO)CN1c1ccc(OCc2ccc(F)c(F)c2)cc1
Yield: 91 %

Procedure:
2.0 g (5.54 mmol) (RS)-1-[4-(3,4-Difluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester is dissolved in 50 ml THF. 1.05 g (27.7 mmol) of sodium borohydride is added and the reaction mixture boiled under reflux for 24 hours. Water is added and the product is extracted with ethyl acetate to yield 1.68 g (91%) of a yellowish solid. MS: m/e=334.3 (M+H)+.
Reaction SMILES: [C:1]([N:4]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[C:5]([O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([CH:19]2[CH2:23][S:22][CH:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[S:20]2)=[CH:13][C:12]=1[O:36][CH3:37])=[O:6])(=[O:3])[CH3:2].[CH:45](N(C(C)C)CC)(C)[CH3:46].[O:54](CC)[S:55]([C:58]([F:61])([F:60])[F:59])(=[O:57])=[O:56]>ClCCl>[O-:57][S:55]([C:58]([F:61])([F:60])[F:59])(=[O:56])=[O:54].[C:1]([N:4]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N+:40]=1[CH2:45][CH3:46])[C:5]([O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C@H:19]2[CH2:23][S:22][C@H:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[S:20]2)=[CH:13][C:12]=1[O:36][CH3:37])=[O:6])(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: COc1cc(C2SCC(c3cc(OC)c(OCCOC(=O)N(Cc4ccccn4)C(C)=O)c(OC)c3)S2)cc(OC)c1OC
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[n+]1ccccc1CN(C(C)=O)C(=O)OCCOc1c(OC)cc([C@H]2CS[C@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1OC
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[-N-acetyl[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonyl]aminomethyl]pyridine (32) (FIG. 26) (0.049 g, 0.076 mmole), diisopropylethylamine (8 μl, 0.076 mmole) and 5 ml anhydrous dichloromethane were cooled to 0° C. under a nitrogen atmosphere. Ethyl triflate (10 μl, 0.076 mmole) was added. The reaction was allowed to warm to room temperature and was stirred for 12 hours. The solvent was removed in vacuo and the remaining residue redissolved in 0.5 ml acetone. The acetone solution was purified by flash column chromatography using 100% ethyl acetate-10/1CHCl3MeOH-4/1CHCl3 /MeOH as eluent. The product was isolated as a 1.6/1.0 trans/cis mixture of diastereomers as a white foam (0.047 g. 75%).
Reaction SMILES: C1C=C([O:7]O)C(C(O)=O)=C(C(O)=O)C=1.[C:15]([O:23][CH2:24][CH:25]1[S:29][CH2:28][CH2:27][O:26]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:15]([O:23][CH2:24][CH:25]1[S:29](=[O:7])[CH2:28][CH2:27][O:26]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: O=C(OCC1OCCS1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: O=C(OCC1OCCS1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Monoperoxyphthalic acid, magnesium salt (MMPP, 28 g) was added portionwise under vigorous stirring to a mixture of 2-benzoyloxymethyl-1,3-oxathiolane (example 2) (20 g), tetrabutyl ammonium bromide (0.4 g) in methylene chloride (200 ml), and water (200 ml). The mixture was stirred at room temperature for 30 minutes and the organic layer was collected. The aqueous phase was extracted with methylene chloride (3×75 ml) and the combined organic layer was washed first with water (2×100 ml), then with brine solution (100 ml), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate as eluant to give 18.5 g (86%) of pure product as a mixture of cis- and trans-isomers in a ratio of 1:2 respectively.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H](N)[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].C[Si](C)(C)N[Si](C)(C)C.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30].[NH3:31]>C(#N)C.O>[CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:24]([NH:25][C:26]([C@H:27]([NH2:31])[C:28]3[CH:1]=[CH:2][CH:3]=[CH:12][CH:29]=3)=[O:30])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13]
Reactant: N
Reactant: CN1CCCC1=O
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: O
Solvent: CC#N
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
21.4 g of 7-aminodesacetoxycephalosporanic acid were suspended in 450 ml of acetonitrile, and then 17.7 g of hexamethyldisilazane were added to the suspension. The mixture was heated to 65° C. for 2 hours under a nitrogen atmosphere and then cooled to 15° C. 22 g of N-methylpyrrolidone were added. After 10 minutes, 22.5 g of D(-)-phenylglycyl chloride hydrochloride were added and the mixture was stirred at 15° C. for 4 hours and then added to 500 ml of water at 10° C. Aqueous ammonia was then added to the reaction mixture to precipitate the desired product which, after 10 hours, was filtered off and dried. 25 g of cephalexin [7-(D-α-aminophenylacetamido)desacetoxycephalosporanic acid] were obtained. Iodometric assay against an authentic sample showed that the product was 98.7% pure.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:16]#[N:17])[CH2:10][CH2:9][CH:8]([S:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:18][Mg]Br.C1(C)C=CC=CC=1.CCCCCC.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH:1]1([CH2:4][C:5]2([CH:16]([NH2:17])[CH3:18])[CH2:6][CH2:7][CH:8]([S:11][CH2:12][CH:13]3[CH2:14][CH2:15]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: N#CC1(CC2CC2)CCC(SCC2CC2)CC1
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: CC(N)C1(CC2CC2)CCC(SCC2CC2)CC1
Reaction time: 0.25 h

Procedure:
1-(cyclopropylmethyl)4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile (2 g; 8.0321 mmol) was dissolved in toluene (30 mL) and methylmagnesium bromide (8.6 ml; 12mL of a 1.4M solution in 3:1 toluene/hexane) was added and the reaction mixture was heated to reflux for 16 hours. The reaction was cooled to 0C. and methanol (12 mL) was added and the mixture was stirred for 15 minutes before adding sodium borohydride (0.315 g; 8.514026 mmol) and stirring for 0.5 hours at room temperature. The reaction was carefully quenched with 1 M hydrochloric acid (24 mL) and then extracted into ethyl acetate and purified using a 40M Biotage cartridge using 5% (2M ammonia in methanol)/DCM to yield (1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl)amine. (1.6 g, 75%)
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20]C)=[O:19])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.CO.O>[C:9]([O:8][P:6]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)c1cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(OCc1cccc(C(=O)O)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate (0.1 g, 0.3 mmol) in THF (3 mL), methanol (3 mL), water (3 mL) was added lithium hydroxide (0.035 g, 0.81 mmol). The reaction mixture was stirred at rt for 1 h. After this time, the organic solvents were removed under reduced pressure, and EtOAc (30 mL) was added to the residual material followed by acetic acid (30%). The organic layer was washed with water (2×10 mL), dried over Na2SO4 and concentrated under vacuum to afford 3-((di-tert-butoxyphosphoryloxy)methyl)benzoic acid (80 mg, 0.23 mmol). 1H NMR (400 MHz, DMSO-d6): 1.41 (s, 18H), 5.00 (d, J=8, 2H), 7.52 (t, J=7.6, 1H), 7.62 (d, J=7.6, 1H), 7.90 (d, J=8.0, 1H), 7.99 (s, 1H). LCMS-m/z: 343.2.
Reaction SMILES: C(N(C(C)C)CC)(C)C.I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:40])[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([OH:37])=[O:36])=[C:29]([O:38][CH3:39])[CH:28]=2)[CH2:19][CH2:18]1>C(Cl)Cl>[CH3:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([NH:23][C:24](=[O:40])[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([O:37][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:36])=[C:29]([O:38][CH3:39])[CH:28]=2)[CH2:21][CH2:22]1
Reactant: CCCCCI
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCOC(=O)COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Reaction time: 16 h

Procedure:
30 ml of diisopropylethylamine and 1.3 ml of 1-iodopentane were added to a solution of 1.84 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy )- 3-methoxycinnamamide (Example 172) in 50 ml of methylene chloride. The solution was stirred for 16 hours, while it was refluxed. After reaction, the reaction solution was washed three times with 200 ml of an aqueous sodium thiosulfate solution and once with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Then, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 1.56 g of N-(trans-4-methylcyclohexyl)-4-(pentyloxycarbonylmethoxy) -3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[CH:36]([S:39](Cl)(=[O:41])=[O:40])([CH3:38])[CH3:37]>>[CH:22]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([S:39]([CH:36]([CH3:38])[CH3:37])(=[O:41])=[O:40])[CH2:2]5)[CH:26]=[CH:25][C:8]=4[C:9]=3[N:10]=2)=[N:21][CH:20]=[N:19]1)([CH3:24])[CH3:23]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(=O)(=O)C(C)C)C3)ccc1-2

Procedure:
Following the procedure for 395, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene free base 235, diisopropylethylamine and isopropylsulfonyl chloride were reacted. The reaction mixture was loaded directly onto a silica column with no aqueous work-up to give 321 isolated as a solid (57 mg, 25%). LCMS: RT=12.20 min, [M+H]+=474. 1H NMR δ (ppm) (CDCl3): 8.39 (1 H, d, J=8.20 Hz), 7.93 (1 H, s), 7.21 (1 H, dd, J=8.21, 1.89 Hz), 7.06 (1 H, d, J=1.84 Hz), 5.96-5.88 (1 H, m), 4.42 (2 H, t, J=5.00 Hz), 4.29 (2 H, t, J=8.23 Hz), 4.15 (2 H, t, J=7.30 Hz), 3.84-3.78 (1 H, m), 3.43 (2 H, t, J=5.03 Hz), 3.16 (1 H, t, J=6.84 Hz), 1.64 (6 H, d, J=6.62 Hz), 1.40 (6 H, d, J=6.84 Hz)