Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[C:15]([O:17]C2CCCCO2)[CH:14]=[C:13]([CH3:24])[C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:2][O:3][C:4]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([CH3:24])[C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cc(OC2CCCCO2)cc(C)c1CN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(O)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
1N Hydrochloric acid (10 mL) was added to 1-[2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzyl]-piperidine (2.33 g, 7.3 mmol) in methanol (30 mL) and the reaction mixture was stirred at ambient temperature for 2 h. The pH of the solution was adjusted to 9 by the addition of saturated aqueous sodium carbonate solution (20 mL) and the aqueous phase was extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a colourless oil. The resultant oil was purified by flash chromatography (silica, 12 g column, ISCO, 0-15% (2N ammonia in MeOH) in DCM) to afford the title compound as a white solid (570 mg, 33%). 1H NMR (CDCl3, 400 MHz): 6.14 (d, J=2.4 Hz, 1H), 5.99 (s, 1H), 3.68 (s, 3H), 3.49 (s, 2H), 2.56-2.46 (m, 4H), 2.25 (s, 3H), 1.65-1.51 (m, 4H), 1.48-1.36 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.CCOCC>[I:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N#CCC(=O)c1cccc(I)c1
Reactant: O=CN(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-(3-iodobenzoyl)acetonitrile (36.2 g, 133.5 mmol) and N,N-diphenylformamide (26.2 g, 133.5 mmol) in toluene (200 ml) was heated at reflux under a nitrogen atmosphere. After 8 h, the reaction mixture was cooled to room temperature and diluted with ether (200 ml) to give 2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (31.2 g) as a solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: CS(=O)(=O)c1ccc(C2=C(c3cc(F)cc(F)c3)C(=O)CC2)cc1
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
To a mixture of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (664 mg, 2.11 mmol), 3,5-difluorophenylboronic acid (832 mg, 5.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.09 mmol), and triphenylphosphine (96 mg, 0.36 mmol) was added 40 mL of 3:1:1 toluene:n-propanol:water and the mixture was purged with nitrogen. After stirring 10 min, diethylamine (1.1 mL, 10.6 mmol) was added and the solution was heated to reflux for 4 h. The mixture was cooled and partitioned between 1M NaOH and EtOAc. The organic phase was washed with water, 1M HCl and brine, and dried over MgSO4. Purification by silica gel chromatography, eluting with 50% CH2Cl2 /hexanes, followed by crystallization from CH2Cl2 /ether/hexanes gave the title compound (223 mg).
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:20]N(C)C=O.CI>C(N(CC)CC)C>[CH3:19][CH:13]1[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([S:1][CH3:20])=[N:3][CH:4]=[N:5]3)=[CH:10][CH:9]=2)=[N:17][NH:16][C:15](=[O:18])[CH2:14]1
Reactant: CN(C)C=O
Reactant: CC1CC(=O)NN=C1c1ccc2c(S)ncnc2c1
Solvent: CCN(CC)CC
Solvent: CI
Product: CSc1ncnc2cc(C3=NNC(=O)CC3C)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To 0.36 g of Compound 56 obtained in Example 18 were added 10 ml of dimethylformamide, 0.2 ml of triethylamine and 0.1 ml of methyl iodide. The resulting mixture was stirred at room temperature for 30 minutes and then concentrated. Thereafter, water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.3 g (79%) of 4,5-dihydro-5-methyl-6-(4-methylthioquinazolin-7-yl)-3(2H)-pyridazinone (Compound 57).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>CN(C)C=O>[F:19][C:17]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([CH2:10][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:18]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1ccc(F)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(F)cc1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
336 μl 2,2,2-Trifluoroethanol were dissolved in 10 ml dimethylformamide. 243 mg sodium hydride were added and the mixture stirred at room temperature for one hour. Then 1.0 g 2-Bromomethyl-4-fluoro-benzonitrile were added in one portion and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was poured on 50 ml water and extracted five times with portion of 25 ml ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=4:1 to obtain 750 mg 4-Fluoro-2-(2,2,2-trifluoro-ethoxymethyl)-benzonitrile.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH:28]=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCn2cnc3ccccc32)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2n1CCOCc1ccccc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (−75° C.) light orange solution of 3.79 g 1-(2-benzyloxy-ethyl)-1H-benzoimidazole in 80 ml THF under argon atmosphere was added dropwise 9.4 ml n-butyllithium solution (1.6 M in hexanes) for 15 min (temperature of the solution below −71° C. during the addition; reaction mixture turning to orange). When addition was complete, stirring at −75° C. was continued for 1 h 30. The reaction mixture was then treated with 1.44 ml DMF within 5 min and stirring at −75° C. was continued for 4 h. Then 40 ml of saturated NH4Cl-solution was added to the reaction mixture which was subseqently allowed to warm to r.t. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on silica gel using a gradient from cyclohexane to cyclohexane/EtOAc 65:35 to give 1.09 g 1-(2-benzyloxy-ethyl)-1H-benzoimidazole-2-carbaldehyde as viscous yellow oil. MS 281.0 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:15](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(O)cc2ccccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a stirred solution of 3-hydroxy-1-naphthalenecarboxylic acid (6.67 g, 35.4 mmol) and oxalyl chloride (3.86 mL, 44.2 mmol) in DCM (150 mL) was added 3 drops of DMF. The mixture was stirred at room temperature for 3 h., the solvent was removed under reduced pressure and methanol (150 mL) was added. After stirring at reflux for 15 min the solvent was removed under reduced pressure, the residue was purified by column chromatography (10%, 20% and 30% EtOAc/hexane) to give the title compound as a yellow solid (2.5 g, 35%). 1H NMR (DMSO-d6) δ 10.10 (s, 1H), 8.61 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.47 (m, 2H), 7.38 (d, 1H), 3.93 (s, 3H); MS m/z 201.1 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[CH:12]=[CH2:13].[CH3:14][CH:15]([NH2:18])[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(O)C>[F:1][C:2]1[C:3]([CH:12]=[CH2:13])=[C:4]([NH:18][CH:15]([CH3:14])[CH:16]=[CH2:17])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=CC(C)N
Reactant: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C=Cc1c(F)ccc([N+](=O)[O-])c1NC(C)C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 1,3-difluoro-4-nitro-2-vinylbenzene (150 mg, 0.81 mmol) in DMF (3 mL) was added a mixture of 1-methylallylamine in ethanol (0.4 mL). Potassium carbonate (0.224 g, 1.62 mmol) was added and the mixture stirred at RT for 1 h. A further portion of 1-methylallylamine in ethanol (0.3 mL) was added and stirring was continued for 1 h, and then the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 2-6% EtOAc in cyclohexane) affording the title compound as a yellow oil (134 mg, 70%). 1H NMR (CDCl3, 300 MHz): 8.06 (1H, dd J=9.4, 5.7 Hz), 7.23 (1H, bs), 6.62 (1H, t, J=9.3 Hz), 6.48 (1H, dd, J=18.0, 11.6 Hz), 5.81-5.62 (2H, m), 5.64 (1H, dt, J=11.6, 1.3 Hz), 5.12-5.00 (2H, m), 4.38-4.25 (1H, m), 1.27 (3H, d, J=6.6 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]([C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:14][CH:15]=1)(=[O:37])[CH3:36]
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(N)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of the compound of Example 48[(2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(4-aminobenzyl)amino]-4-methyl-pentanoic acid amide (250 mg, 0.60 mmol) and Et3N (120 mg, 1.2 mmol) in CH2Cl2 (20 mL) was treated with acetyl chloride (56 mg, 0.72 mmol). After stirring for 18 h, the reaction was concentrated, chromatographed using silica gel flash chromatography (1% methanol/CH2Cl2) to afford the titled compound (110 mg, 41%). MS (ESI), (M−H)− 422.9; 1H NMR (CDCl3) δ 7.67 (d, 2H, J=8.0), 7.28-7.46 (m, 6H), 7.12 (br s, 1H), 6.24 (br s, 1H), 5.19 (br s, 1H), 4.48 (dd, 2H, J=50, 15), 4.27 (t, 1H, J=7.0), 2.18 (s, 3H), 1.80-2.01 (m, 1H), 1.12-1.32 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[C:8]([N+:20]([O-:22])=[O:21])[C:3]=1[NH:4][CH2:5][CH2:6]O.P(Cl)(Cl)(Cl)(Cl)[Cl:24].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[C:8]([N+:20]([O-:22])=[O:21])[C:3]=1[NH:4][CH2:5][CH2:6][Cl:24]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1NCCCl
Yield: 75.9 %

Procedure:
An amount of 4.5 gm of 2-chloro-3-(4-chlorophenoxy)-6-nitro-N-2-hydroxyethylaniline was dissolved in 40 ml of toluene and mixed with 2.9 gm of PCl5, spontaneous heating and gas generation taking place. After 30 minutes the mixture was shaken with water and sodium bicarbonate solution and is evaporated. 3.6 gm of a yellowy brown oil were obtained (76% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O=[Pt]=O.CCO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)ccc1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Compound 4-3 (2.73 g, 7.76 mmol), EtOH/AcOH (1:1, 60 mL) and PtO2 (0.895 g) were shaken in a Parr apparatus (15 psig of hydrogen) for 10 hrs. The reaction mixture was filtered thru Celite®, washing with ethanol. The solution was concentrated, and the residue was diluted with dichloromethane and washed with saturated NaHCO3. The aqueous layer was again extracted with dichloromethane, and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash chromatography (gradient elution with 15-50% ethylacetate (0.1% TEA) in heptane. The desired product Compound 4-4 was isolated as thick colorless oil (2.55 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=2.3 Hz, 1H), 7.43 (d of d, J=8.5 and 2.3 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 4.22 (m, 2H), 3.91 (s, 3H), 3.52 (m, 1H), 2.82 (m, 2H), 2.8-1.5 (m, 4H), 1.48 (s, 9H); MS (ES+) m/z 253.8 (M-Boc+1); HRMS (FAB+) Calcd for C18H23ClNO4: 352.1316. Found: 352.1329.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][Si](C)(C)C)[CH:19]=2)=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[C:20]([C:18]1[CH:19]=[C:14]([O:13][CH2:12][C@@H:11]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH:15]=[N:16][CH:17]=1)#[CH:21]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(C#C[Si](C)(C)C)c1)Cc1c[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cncc(OC[C@H](Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of Example 14A (400 mg, 0.86 mmol) in THF (6 mL) at room temperature was treated with tetrabutylammonium fluoride (1.0 M solution in THF, 1.12 mL, 1.12 mmol), stirred for 1 hour, treated with ethyl acetate (50 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel with 40% ethyl acetate/hexanes to provide the desired product (290 mg, 86%). MS (APCI) m/e 392 (M+H)+.
Reaction SMILES: C(N(CC)[CH:5]([CH3:7])[CH3:6])(C)C.[C:10]1([CH:16]([O:23][C:24]([C:26]2[N:31]3[C:32](=[O:44])[C@@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:30]3[S:29][CH2:28][C:27]=2[SH:45])=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[O:25]=[C:24]1[CH:7]=[C:5]([CH2:6][S:45][C:27]2[CH2:28][S:29][C@@H:30]3[C@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:32](=[O:44])[N:31]3[C:26]=2[C:24]([O:23][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:25])[CH2:16][O:23]1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S)CS[C@H]12
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CC(=O)OC3)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N,N-Diisopropylethylamine (0.15 ml) was added to a stirred solution of diphenylmethyl-3-mercapto-7β-phenylacetamidoceph-3-em-4-carboxylate (500 mg) and 4-bromomethyl-2(5H)-furanone1 (200 mg) in tetrahydrofuran (10 ml). After stirring at room temperature for 90 mins. the mixture was partitioned between ethyl acetate and aqueous citric acid solution. The organic phase was separated and washed three times with water, then brine, dried over magnesium sulphate and evaporated. The title compound (474 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 1:1 ethyl acetate:hexane going to neat ethyl acetate), m.p. 172°-176° C. from ethyl acetate/hexane. (Found: C, 64.24; H, 4.69; N, 4.51; S, 10.48; C33H28N2O6S2 requires; C, 64.69; H, 4.61; N, 4.57; S, 10.47); υmax (CHCl3) 3400, 1785, 1750, 1680 cm-1. δH (CDC13) 3.23 (1H, d, J 17.0Hz), 3.38 (1H, d, J 17.1Hz), 3.41 (H, d, J 15.2Hz), 3.53 (1H, d, J 15.1Hz), 3.66 (2H, s), 4.62 (2H, s), 4.98 (1H, d, J 4.6Hz), 5.76 (1H, dd, J 4.6 and 8.8Hz), 5.89 (1H, s), 6.56 (1H, d, J 8.8Hz) 6.91 (1H, s) 7.2-7.4 (15H, m).
Reaction SMILES: [C:1](=[O:40])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:20][C@:14]12[CH2:13][CH2:12][C@H:11]([C:21]3[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=3)[C@@:10]1([CH3:28])[CH2:9][CH2:8][C@H:7]1[C@H:15]2[CH2:16][CH2:17][C@H:18]2[C@:6]1([CH3:29])[CH2:5][CH2:4][C@H:3]([O:2][C:1]([NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:40])[CH2:19]2
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Reactant: NCCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]12CC[C@H](OC(=O)NCCCC(=O)O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 53.9 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (20 mg, 0.036 mmol) in CH2Cl2 was added 4-aminobutanoic acid (37.1 mg, 0.36 mmol, 10 eq), DIEA (18.6 mg, 0.144 mmol, 4 eq) and DMAP (16.1 mg, 0.144 mmol, 4 eq). The resultant mixture was stirred at 40° C. for 16 h and then purified via preparative TLC to afford 4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)carbonylamino)butanoic acid (10 mg, 53.5%) as a white solid. LRMS (M−H+) m/z 514.4. 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.82 (m, 1H), 3.03 (m, 2H), 2.44-2.48 (m, 1H), 1.08-2.15 (m, 25H), 0.87 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][NH2:16]>ClCCl>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][NH:16][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: NCc1c(F)cccc1F
Reactant: COc1cccc(N=C=O)c1
Solvent: ClCCl
Product: COc1cccc(NC(=O)NCc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 3-methoxyphenyl isocyanate (1.0 g, 6.7 mmol) in anhydrous dichloromethane (10 mL) was treated with 2,6-difluorobenzylamine (960 mg, 6.7 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture was filtered, and washed with dichloromethane to give a white solid (1.47 g, 50.3%), MS (CI) m/z 293.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[CH:9]1.[S]>>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Agent: [S]
Product: CC1=C(c2ccncc2)SCC(=O)N1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
The mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin3(4H)-one (2.14 g) and sulfur (10.7 g) was heated under stirring at 140° C. for 1.5 hours and then cooled to room temperature. The solid was extracted with methanol by using Soxhlet extractor. Methanol was removed under reduced pressure and the residue was dissolved in 50 ml of 2N hydrochloric acid. The insoluble solid was removed by filtration ad the filtrate was adjusted to pH 7.2 by 2N aqueous sodium hydroxide. The precipitates were collected by filtration and the filtrate was extracted with chloroform (20 ml×5 times) and evaporated to dryness. After combined with the above solid, the residue was recrystallized from isopropyl alcohol to give 5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.88 g, yield 76.5%) as light yellow plates.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)[CH2:2][CH2:3][CH3:4].[I:14]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([O:5][C:6]1[C:11]([I:14])=[C:10]([NH2:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCCOc1cc(N)cc(C)n1
Solvent: C1CCOC1
Product: CCCCOc1nc(C)cc(N)c1I
Reaction time: 0.03 h

Procedure:
2-butoxy-6-methylpyridin-4-amine (31 g, 0.17 mol) was dissolved in THF (500 mL), and then N-iodosuccinimide (32 g, 0.14 mol) was added portionwise at −78° C. The reaction mixture was stirred at the same temperature for 2 min. The reaction was quenched by addition of water, and the resulting mixture was extracted with ethyl acetate (2×600 mL). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated. The crude was purified by silica gel column chromatography (petroleum ether) to afford 2-butoxy-3-iodo-6-methylpyridin-4-amine. 1H NMR (400 MHz, CDCl3): δ 6.10 (s, 1H), 4.49 (m, 2H), 4.29 (t, J=6.4 Hz, 2H), 2.284 (s, 1H), 1.75 (m, 2H), 1.50 (m, 2H), 0.98 (t, J=7.6 Hz, 3H). LRMS calc'd for (C10H151N2O) [M+H]+, 307; found 307.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[F:20][C:21]1[N:22]=[CH:23][C:24]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(F)nc3)cc2)c1

Procedure:
3-[4-(6-Fluoro-pyridin-3-yl)-phenoxymethyl]-benzoic acid was prepared using the procedure described above for the synthesis of Example 4 from 3-(4-iodo phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 2-fluoropyridine-5-boronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=324.