Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[CH3:34][S:35]([CH:38]=[CH2:39])(=[O:37])=[O:36]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(CCS(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in IMS (2 mL) was added methanesulfonylethene (21 μL, 0.25 mmol) and the resulting mixture allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%). The resulting residue was triturated with EtOAc and cyclohexane and the resulting solid dried in vacuo affording 826 (83 mg, 67%). LCMS (method I): RT 2.65 min, [M+H]+ 555.3. 1H NMR (DMSO, 400 MHz): δ 8.05-8.05 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 4.27 (4 H, brd s), 4.02 (2 H, d, J=7.94 Hz), 3.79 (4 H, t, J=4.57 Hz), 3.72 (3 H, s), 3.42 (2 H, d, J=7.99 Hz), 3.28-3.25 (2 H, m), 3.17 (2 H, t, J=6.52 Hz), 3.05 (3 H, s), 2.89 (2 H, t, J=6.53 Hz), 1.40 (3 H, s), 1.35 (3 H, t, J=7.43 Hz)
Reaction SMILES: [BH4-].[Na+].[OH:3][CH:4]1[CH2:16][CH2:15][C:7]2([CH2:12][CH2:11][CH:10]([CH:13]=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1>C(O)C>[OH:3][CH:4]1[CH2:5][CH2:6][C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[CH2:15][CH2:16]1
Reactant: O=CC1CCC2(CCC(O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC1CCC2(CCC(O)CC2)CC1
Yield: 92.8 %

Procedure:
Sodium borohydride (65.0 mg) was added to a solution of 0.320 g 9-hydroxy-3-formyl-spiro[5.5]undecane in 5 ml of ethanol, at 0° C. under argon atmosphere. After 30 minutes the mixture was quenched with 2 ml. of 0.1N hydrochloric acid and evaporated under reduced pressure; the crude residue was dissolved in 10 ml. of ethyl acetate, the organic layer washed with water was dried over anhydrous sodium sulfate and evaporated to dryness to give 0.300 g of 9-hydroxy-3-hydroxymethyl-spiro[5.5]undecane as a transparent oil. TLC: Rf=0.35 (SiO2 plates, ethyl acetate/n-hexane 65/35). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 3.63 (1H, hept), 3.45 (2H, d), 2.05-0.95 (17H, m).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[F:14])=[N:6][CH:7]=1.Cl.[F:22][C:23]([F:28])([F:27])[CH:24]([NH2:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[CH:7][C:2]([NH:26][CH:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])=[N:3][C:4]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cnccc1-c1ncc(Cl)nc1-c1cccnc1
Reactant: CC(N)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1)C(F)(F)F
Reaction time: 8 h
Yield: 16.5 %

Procedure:
An oven dried resealable Schlenk tube was charged with 5-chloro-2-(3-fluoropyridin-4-yl)-3-pyridin-3-ylpyrazine (Preparation 30, 0.100 g, 0.35 mmol), 1,1,1-trifluoropropan-2-amine hydrochloride (0.063 g, 0.42 mmol), caesium carbonate (0.273 g, 0.84 mmol), BINAP (0.0065 g, 0.01 mmol) and toluene (2 mL). The Schlenk tube was subjected to several cycles of evacuation-backfilling with argon, and palladium(II) acetate (0.0015 g, 0.007 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 100° C. After stirring overnight, the mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and evaporated and the residue was purified by silica gel chromatography (CH2Cl2/MeOH 95:5) to give the title compound (0.021 g, 17%) as an off-white solid.
Reaction SMILES: [NH:1]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[C@H:2]([C:15]([NH:17][C@H:18]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:46]([NH:48][C@H:49]([C:65]([NH:67][C@H:68]([C:74]([OH:76])=[O:75])[CH2:69][CH2:70][C:71](=[O:73])[OH:72])=[O:66])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][S:55]([C:58]1[CH:64]=[CH:63][C:61]([CH3:62])=[CH:60][CH:59]=1)(=[O:57])=[O:56])=[O:47])[CH2:44][OH:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6]CC1C=CC=CC=1.[H][H].O>CO.C(O)(=O)C.[Pd]>[NH:1]([C:77]([O:79][C:80]([CH3:82])([CH3:81])[CH3:83])=[O:78])[C@H:2]([C:15]([NH:17][C@H:18]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:46]([NH:48][C@H:49]([C:65]([NH:67][C@H:68]([C:74]([OH:76])=[O:75])[CH2:69][CH2:70][C:71](=[O:72])[OH:73])=[O:66])[CH2:50][CH2:51][CH2:52][CH2:53][NH:54][S:55]([C:58]1[CH:64]=[CH:63][C:61]([CH3:62])=[CH:60][CH:59]=1)(=[O:57])=[O:56])=[O:47])[CH2:44][OH:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:3][CH2:4][C:5](=[O:6])[OH:14]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1

Procedure:
150 Milligrams of Boc-Glu(OBzl)-Ser-Leu-Arg-Ser-Lys(Tos)-Glu-OH was dissolved in a mixture of 30 ml of methanol with 30 ml of 10%-acetic acid, to this solution was added a small amount of palladium black and stirred for 18 hours under the conditions of introducing hydrogen gas. After completion of the reaction, the catalyst was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, the residue thus obtained was added water and was lyophilized to obtain the desired product.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:2]([CH3:4])([CH3:3])[CH3:1])[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](O)COC(=O)C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
A solution of (S)-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyethyl pivalate (3H) (0.4582 g, 1.15 mmol) and perchloric acid, (70%, 0.138 mL, 2.3 mmol) in tert-butyl acetate (10 mL) was stirred at room temperature for 3 h. The reaction mixture was quenched with solid sodium bicarbonate (0.5 g) for 1 h. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate (3×). The combined organic layer was dried (MgSO4), filtered and concentrated to give (S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethyl pivalate (3I) that was used in next step without further purification. (S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethyl pivalate (31) from above reaction was dissolved in MeOH (1 mL) and THF (7 mL). Sodium hydroxide (2 M, 0.75 mL, 1.5 mmol) was added and the reaction mixture was stirred at room temperature overnight. Additional sodium hydroxide (2 M, 0.75 mL, 1.5 mmol) was added and reaction mixture was stirred for an additional 24 hours. The reaction mixture was then diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 3J as a white solid (0.1889 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.72 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.46-7.05 (m, 7H), 4.60 (dd, J=10.5, 4.5 Hz, 1H), 3.77 (dd, J=11.4, 4.2 Hz, 1H), 3.46 (dd, J=11.4, 4.2 Hz, 1H), 2.71 (s, 3H), 1.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7]O.[CH2:9]([N:11](CC)[CH2:12]C)C.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:9][N:11]([CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[CH3:12]
Reactant: CCN(CC)CC
Reactant: Cc1ccsc1CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccsc1CN(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In 200 ml of methylene chloride were dissolved 20.8 g of 3-methyl-2-thenyl alcohol and 27.1 ml of triethylamine, and 12.9 ml of thionyl chloride was added thereto dropwise at -15° C. to -10° C. over a period of 30 minutes, after which the resulting solution was further subjected to reaction at the same temperature for 30 minutes. The reaction mixture was poured into ice water, and the organic layer was separated and then dried over anhydrous magnesium sulfate. Subsequently, the dried organic layer was added dropwise with ice-cooling to a solution of 95 g of dimethylamine in 550 ml of ethanol, and the resulting mixture was allowed to stand overnight at room temperature. The solvent was removed by distillation under reduced pressure, after which 100 ml of water was added to the residue, and the resulting mixture was adjusted to pH 10 with potassium carbonate, and then extracted with 200 ml of ethyl acetate. The extract was washed with 50 ml of a saturated aqueous sodium chloride solution and dried over anhydrous potassium carbonate, after which the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was distilled under reduced pressure to obtain 19.0 g (yield 75%) of 2-(dimethylamino)methyl-3-methylthiophene having a boiling point of 85°-86° C./14 mmHg.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C@@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24]C(C4C=CC(OC)=CC=4)=O)=[CH:20][CH:19]=3)[CH:12]=2)[CH2:7]1)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[CH3:1][N:2]([CH2:4][CH2:5][C@@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[CH:12]=2)[CH2:7]1)[CH3:3]
Reactant: COc1ccc(C(=O)Oc2ccc(COc3ccc4c(c3)CC[C@@H](CCN(C)C)C4)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CC[C@@H]1CCc2cc(OCc3ccc(O)cc3)ccc2C1
Yield: 30 %

Procedure:
THF solution (2 ml) of 2-(R)-[2-(N,N-dimethylamino)ethyl]-6-[4-(4-methoxyphenylcarbonyloxy) phenylmethoxy]tetralin (330 mg) was added dropwise to THF suspension (4 ml) of lithium aluminum hydride (60 mg) under ice-cooling. 1N aqueous sodium hydroxide solution was added the reaction mixture to make the mixture basic, and the precipitate was removed by celite filtration. After the filtrate was concentrated, the residue was purified using silica gel chromatography (development solvent; ethyl acetate-methanol), and recrystallized (ethyl acetate-hexane) to give the titled compound (70 mg).
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2.Br[CH2:17][C:18](=[CH2:24])[C:19](OCC)=[O:20].C([O-])(O)=O.[Na+]>O1CCCC1.[Zn].C1(C=CC(O)=CC=1)O>[CH3:15][C:2]1([CH2:3][O:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:24][C:18](=[CH2:17])[C:19](=[O:20])[O:1]1
Reactant: CC(=O)COc1cccc2cccnc12
Reactant: C=C(CBr)C(=O)OCC
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CC(C)(COc2cccc3cccnc23)OC1=O
Temperature: 0 °C
Yield: 81.7 %

Procedure:
To a solution of 7a (0.60 g, 3 mmol) in dry tetrahydrofuran (60 ml) were added activated zinc powder (0.26 g, 3.9 mmol), hydroquinone (6 mg), and ethyl 2-(bromomethyl)acrylate (0.78 g, 4 mmol). The mixture was refluxed under nitrogen atmosphere for 6 h (monitored by TLC). After cooling, it was poured into an ice-cold 5% HCl solution (300 ml), neutralized with 1.0N NaHCO3, and extracted with CH2Cl2 (60 ml×3). The dichloromethane extracts were combined and washed with water, dried over Na2SO4, and then evaporated to give a residual oil which was purified by column chromatography on silica gel using CH2Cl2 as the eluent to afford the title compound (0.66 g, 82%). UV λmax (log ε): 250 (4.69) (0.1N HCl in MeOH), 237 (4.60) (MeOH), 238 (4.64) (0.1N NaOH in MeOH); 1H-NMR (CDCl3): δ1.61 (s, 3H, 2'-CH3), 2.84 (dt, 1H, 3'-H), 3.48 (dt, 1H, 3'-H), 4.25 (d, 1H, OCH), 4.32 (d, 1H, OCH), 5.66 (t 1H, vinylic H), 6.26 (t, 1H, vinylic H), 7.13-8.91 (m, 6H, Ar--H). Anal. Calcd for C16H15NO3.1/8H2O: C, 70.77; H, 5.65; N, 5.16. Found: C, 70.80; H, 5.75; N, 5.08.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][C:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([SH:47])=[CH:43][CH:42]=1)([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC#N>[CH3:39][C:33]([O:40][C:41]1[CH:42]=[CH:43][C:44]([S:47][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:45][CH:46]=1)([CH3:32])[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S)cc1
Reactant: FC(F)(F)c1ccc(-c2nc(COC3CCCCO3)c(CCl)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 250ml round-bottom flask equipped with a magnetic stir-bar and N2inlet was added 5-(chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (7.87g, 20.09mmoles, 1eq) and dry CH3CN (100ml, 0.27M). Solid cesium carbonate (16.4g, 50.22mmoles, 2.5eq) was added all at once followed by the quick addition of ethyl 2-methyl-2-(4-sulfanylphenoxy)propanoate (5.79g, 24.11mmoles, 1.2eq) in dry CH3CN (10ml). The reaction was allowed to stir at room temperature for 2hours at which point the solvent was removed under reduced pressure. The resulting residue was partitioned between EtOAc and 1N NaOH. After the phases were separated the organic fraction washed with H2O, brine and dried over Na2SO4. After filtration the volatiles were removed in vacuo to yield the titled compound in >100% yield. Sometimes because of the difficult separation between the thiophenol and the product, the crude product was carried forward without purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[C:21](=[N:23][OH:24])[CH3:22].[H-].[Na+].CO>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:22][C:21]1[C:3]2[CH:4]=[C:5]([N:8]3[CH2:12][CH2:11][N:10]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:18]=4[CH3:19])[C:9]3=[O:20])[CH:6]=[CH:7][C:2]=2[O:24][N:23]=1
Reactant: CC(=NO)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccncc1N1CCN(c2ccc3onc(C)c3c2)C1=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 13.6 %

Procedure:
1-[4-Fluoro-3-(1-hydroxyimino-ethyl)-phenyl]-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (220 mg, 0.670 mmol) in DMF (5 mL) was added to a stirred mixture of NaH (19 mg, 0.804 mmol) in DMF (2 mL) under nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature for 21 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was partitioned between ethylacetate and ice water. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 28 mg of the product (14.5% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[CH2:26]([CH:28]([CH2:34][CH3:35])[C:29]([O:31][CH2:32]I)=[O:30])[CH3:27]>C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:32][O:31][C:29](=[O:30])[CH:28]([CH2:34][CH3:35])[CH2:26][CH3:27])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reactant: CCC(CC)C(=O)OCI
Solvent: CCN(CC)CC
Product: CCC(CC)C(=O)OCOC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12

Procedure:
In the same manner as Example 8, 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) was reacted with iodomethyl 2-ethylbutyrate in the presence of triethylamine to give 2-ethylbutyryloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[N:7]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH:6]=[CH:5]2
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc2c(=O)[nH]ccc2cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 9.17 g (51.8 mmol) of 6-fluoro-7-methyl-2H-isoquinolin-1-one in 80 ml DMF were added 20.2 g (62.1 mmol) caesium carbonate and then 8.92 g (56.9 mmol) 4-methoxybenzylchloride. After stirring at room temperature for 90 minutes the reaction mixture was poured into 600 ml water, stirred for 1 h, and then the precipitated product was filtrated by suction. From the mother liquor additional producted was isolated by chromatography with heptane/ethyl acetate (80:20). The combined products were recrystallized from ethyl acetate and 8.39 g 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one were received.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](I)[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:12]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd+2].O1CCOCC1>[F:1][C:2]1[C:3]2[NH:10][C:11](=[O:12])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 80 °C

Procedure:
Under an argon atmosphere, a mixture of 1,4-dioxane (3 ml), palladium 1,1′-bis(diphenylphosphino)ferrocene dichloride (10% mol, 0.0623 mmol, ˜x50 mg), NatBuO (2 eq., 1.26 mmol, 121 mg), were sonicated for 10 minutes at room temperature and 1,1-dimethylethyl 4-({[(2-fluoro-6-iodo-4-methylphenyl)amino]carbonyl}amino)-1-piperidine-carboxylate (D3) (1 eq., 0.623 mmol, 300 mg) was added at room temperature and the mixture was refluxed at 80° C. for one overnight. The reaction mixture was cooled to room temperature, poured onto NH4Cl (saturated solution) and the aqueous solution obtained was extracted with ethyl acetate repeatedly; the organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound (250 mg) that was purified by MDAP to yield the title compound, 30 mg, 11%.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])[CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])[CH:2]=1
Reactant: CC(=NOCCO)c1cccc(-c2ccccc2)c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1cccc(-c2ccccc2)c1
Yield: 84.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 511 mg of 2-[1-(3-biphenylyl)-ethylideneaminooxy]ethanol (prepared as described in Preparation 16), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 916 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([Li])CCC.IC.O>O1CCCC1>[CH:1]1([CH2:6][N:7]2[C:11]([CH3:12])=[CH:10][CH:9]=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [Li]CCCC
Reactant: c1cnn(CC2CCCC2)c1
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnn1CC1CCCC1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A solution of EXAMPLE 63A (727 mg) in tetrahydrofuran (10 mL) was chilled to −45° C. n-Butyllithium (2.3 M solution in hexanes, 2.52 mL) was added dropwise over 5 minutes. The reaction was stirred for 1.5 hours, during which time the temperature increased to −20° C. Iodomethane (0.368 mL) was added dropwise over 3 minutes. The reaction was stirred for 30 minutes between −20 and −15° C. Water (25 mL) was added and the mixture was extracted with ethyl acetate (3×25 mL). The extracts were dried (Na2SO4), filtered, and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([O:23]C)=[O:22].O.[OH-].[K+].Cl>CO>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=[O:22]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Methyl androst-4-ene-3-one-17β-carboxylate (20 g, 60 mmol) was dissolved in 700 ml of a 20:1 solution of methanol:water and potassium hydroxide (7 g) was added and the solution was refluxed under argon for 24 hours. The reaction mixture was then acidified with 5% hydrochloric acid and 250 ml water was added. After aging for 1 hour, the mixture was filtered and dried to yield 18 g (94%) of androst-4-ene-3-one-17β-carboxylic acid as a white crystalline solid.