Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][OH:29]>CCCCCC.C(OCC)(=O)C>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc(COc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
2-Methylthio-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (from Reference Example 3) was reacted with 3,4-difluorobenzyl alcohol according to the procedures described in Example 1 to afford 2-(3,4-difluorobenzyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine as the higher Rf product (95/5 hexane/ethyl acetate TLC. HPLC/MS: m/e=478 (M+); Rt=4.69 min; 1H-NMR 500 (CDCl3): δ 5.47 (s, 2H), 7.07 (d, J=9 Hz, 1H), 7.18-7.22 (m, 3H), 7.22-7.30 (m, 5H), 7.40 (d, J=2 Hz, 1H), 8.62 (s, 1H). 2-(3,4-Difluorobenzyloxy)-4-(2-chloro-4-thiomethylphenyl)-5-(4-chlorophenyl)pyrimidine was obtained as the lower Rf product which was the by-product of the thiomethyl anion displacement of the 4-chloro substituent on the 4-(2,4-dichlorophenyl) ring. HPLC/MS: m/e=489 (M+1); Rt=4.59 min; 1H-NMR 500 MHz (CDCl3): δ 2.52 (s, 3H), 5.47 (s, 2H), 7.0-7.10 (m, 2H), 7.15-7.21 (m, 3H), 7.24-7.30 (m, 3H), 7.40 (m, 2H), 8.60 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2.[CH2:47]=[CH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:49]1(/[CH:48]=[CH:47]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([O:11][C@@H:12]2[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:13]2[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]3)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(/C=C/c4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Yield: 64.6 %

Procedure:
A mixture of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (75 mg), styrene (33 mg), triethylamine (0.073 mL), palladium (II) acetate (2 mg) and tris(2-methylphenyl)phosphine (6 mg) in acetonitrile (2 mL) was heated for reflux under an argon atmosphere overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-2/1) to give the title compound (50 mg).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:51])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:50])[CH2:12][CH2:13][C@@:14]3([C:30]([CH:32]4[CH2:37][CH2:36][C:35]([CH2:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:53])[CH3:52])(=O)C.C1COCC1.[OH-].[Na+]>CO>[CH2:43]([C:35]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:37][CH:32]([C:30]([C@:14]23[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]2[C@@H:16]2[C@@:11]([CH3:50])([CH2:12][CH2:13]3)[C@@:10]3([CH3:51])[C@@H:19]([C@:20]4([CH3:23])[C@@H:7]([CH2:8][CH2:9]3)[C:6]([CH3:52])([CH3:53])[C@@H:5]([OH:4])[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)=[O:31])[CH2:33][CH2:34]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)C3CCC(Cc4ccccc4)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)C3CCC(Cc4ccccc4)(C(=O)OCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.1 %

Procedure:
Ethyl 4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl)-1-benzylcyclohexanecarboxylate (Example 55, 0.9 g) was taken in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.28 g in 4 ml water) was added and stirred for about 6 hours at room temperature. Completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and the residue was taken in water, extracted with DCM, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.45 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.12-4.23 (m, 2H) 4.56 (s, 1H); 4.71 (s, 1H); 7.03-7.05 (m, 2H); 7.23-7.25 (m, 3H); MASS: 685 (100%).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH2:27])[CH:23]=3)[N:18]=2)[CH2:8]1>>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:27][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:23]=3)[N:18]=2)[CH2:8]1
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2nc(NC3COc4ccccc43)ccc2c1
Product: CC(C)NC(=O)Nc1ccc2nc(NC3COc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from isopropyl isocyanate and N2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine; MS: m/e=363.3 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][P:15]([OH:18])([OH:17])=[O:16])=[C:10]([OH:19])[CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+]>O>[NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][P:15]([OH:18])([OH:17])=[O:16])=[C:10]([OH:19])[CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OP(=O)(O)O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](Cc1ccc(OP(=O)(O)O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of Compound 5, (S)-methyl 2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)propanoate, (10.0 g, 34.3 mmol) in 40 mL of water at 15-20° C. was added 22.89 mL (4.0 eq) of 6 N NaOH. When the pH reached 7-8 the solution was passed through a filter for clarification. After clarification, the pH adjustment was continued. After the base was added, the rxn was stirred at 25° C. for 60 mins (pH=12.06). After 60 mins the reaction mixture was acidified with 4.0 eq 6N HCL (137 mmol, 22.89 mL). The final pH was adjusted to 1.8. After 10 mins the rxn mixture became cloudy and 200 mL of IPA was added. The slurry was stirred for 30 mins and the solid was filtered and washed with IPA. The solid was dried in the vacuum oven at 40° C. overnight to afford Compound 6, (S)-2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)propanoic acid (7.85 g, 99% purity, 87% yield, 99.6% ee). 1H NMR (400 MHz, Deuterium Oxide) δ 7.24 (dd, J=8.3, 1.3 Hz, 1H), 6.91 (d, J=2.1 Hz, 1H), 6.83 (dd, J=8.3, 2.2 Hz, 1H), 4.25 (dd, J=8.0, 5.2 Hz, 1H), 3.35-3.05 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@H:10]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[O:15][CH2:14][CH2:13][N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1.[Cu](C#N)[C:33]#[N:34]>CN(C=O)C>[C:33]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@H:10]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[O:15][CH2:14][CH2:13][N:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:11]1)#[N:34]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CSc2ccccc2Br)C1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CSc2ccccc2C#N)C1
Temperature: 150 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution (7.8 mL) of tert-butyl (6R,7R)-6-{[(2-bromophenyl)sulfanyl]methyl}-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (424 mg) in DMF was added copper cyanide (139 mg), and the mixture was stirred under an argon atmosphere at 150° C. overnight. The reaction mixture was filtered through celite, distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (146 mg).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12]([C:14]1[CH:29]=[C:28]([C:30](=[NH:33])[NH:31]O)[CH:27]=[C:26]([CH3:34])[C:15]=1[O:16][CH2:17][C@@H:18]([OH:25])[CH2:19][NH:20][C:21](=[O:24])[CH2:22][OH:23])[CH3:13]>>[CH2:12]([C:14]1[CH:29]=[C:28]([C:30]2[N:33]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=3)[O:10][N:31]=2)[CH:27]=[C:26]([CH3:34])[C:15]=1[O:16][CH2:17][C@@H:18]([OH:25])[CH2:19][NH:20][C:21](=[O:24])[CH2:22][OH:23])[CH3:13]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: Cc1cc(C(=O)O)sc1C=O
Product: CCc1cc(-c2noc(-c3cc(C)c(C=O)s3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide; LC-MS: tR=0.92 min; [M+1]+=460.17; 1H NMR δ 1.22 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.65 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 3.20-3.28 (m, 1H), 3.39-3.47 (m, 1H), 3.70-3.80 (m, 2H), 3.84 (d, J=5.5 Hz, 2H), 3.92-4.00 (m, 1H), 5.30 (d, J=5.3 Hz, 1H), 5.54 (t, J=5.8 Hz, 1H), 7.69 (t, J=5.5 Hz, 1H), 7.76 (s, 2H), 8.07 (s, 1H), 10.17 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: N#Cc1ccc(Br)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(N2CCN(c3ccc(C#N)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 18.6 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (2.74 g, 10.0 mmol) synthesized in Reference example 61 and 4-bromobenzonitrile (2.73 g, 15 mmol), the reaction was carried out in the same manner as Example 23 to synthesis the title compound 700 mg (yield 19%). Melting point was 255 to 257° C. (ethanol).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16](Br)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[O:29]1[C:40]2[C:41]3[C:36]([C:37](B(O)O)=[CH:38][CH:39]=2)=[N:35][CH:34]=[CH:33][C:32]=3[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:16]([C:37]2[C:36]3[C:41]4=[C:32]([CH2:31][CH2:30][O:29][C:40]4=[CH:39][CH:38]=2)[CH:33]=[CH:34][N:35]=3)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccc2c(-c3ccc4c5c(ccnc35)CCO4)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Yield: 20.5 %

Procedure:
Pd(PPh3)4 (4 mg, 0.0037 mmol) was added to a mixture (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (5E) (16 mg, 0.037 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (6A) (23 mg, 0.073 mmol) and K2CO3 (0.083 mL 2 M in water, 1.66 mmol) in 1,2-dimethoxyethane (2 mL). The reaction mixture was flushed with nitrogen, microwaved at 120° C. for 90 min and the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by prep-HPLC to provide 6B as a white solid (4 mg as TFA salt, 18%). LCMS-ESI+ (m/z): 527.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[S:19])[NH:8][C:7]1=[O:20])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].S(OC)(O[CH3:27])(=O)=O>O>[CH3:27][S:19][C:9]1[C:10]2[NH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[N:13][C:14]=2[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7](=[O:20])[N:8]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCCn1c(=O)[nH]c(=S)c2[nH]c(C(F)(F)F)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCn1c(=O)nc(SC)c2[nH]c(C(F)(F)F)nc21
Temperature: 80 °C
Yield: 95.6 %

Procedure:
To a mixture of 3-pentyl-6-thioxo-8-(trifluoromethyl)-1,3,6,7-tetrahydro-2H-purin-2-one (0.15 g, 0.49 mmol) in a solution of sodium hydroxide in water (2 M, 2 mL) was added dimethyl sulfate (0.056 mL, 0.59 mmol). The reaction mixture was heated at 80° C. for 1.5 h, quenched with acetic acid and extracted with methylene chloride. The organic layer was dried (MgSO4), concentrate and purified by silica gel chromatography (0-20% EtOAc in hexane) to provide the product as a yellow solid (0.15 g, 95% yield). LCMS calculated for C12H16F3N4OS (M+H): 321.1; found: 321.1.
Reaction SMILES: [C:1]1([C:7](=[N:38][O:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:21])=[C:15]([CH2:18][CH3:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]1([C:7](=[N:38][O:39][CH2:40][C:41]([OH:43])=[O:42])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[S:21])=[C:15]([CH2:18][CH3:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3ccccc3)[C@H]2SC1
Yield: 97.1 %

Procedure:
The solution of benzhydryl 7-[2-phenyl-2-tertbutoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.0 g) and anisole (2.0 ml) in trifluoroacetic acid (8 ml) was stirred for 90 minutes at ambient temperature. The resultant solution was evaporated under reduced pressure and the residual oil was dissolved in an aqueous solution of sodium bicarbonate. After the solution was washed with ethyl acetate, the solution was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate (100 ml). The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 7-[2-phenyl-2-carboxymethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid (syn isomer, 1.3 g), mp. 103° to 107° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:26]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([N:1]2[CH2:6][CH2:5][C:4](=[CH:7][C:8]3[CH:24]=[CH:23][CH:22]=[C:10]([O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][N:13]=4)[CH:9]=3)[CH2:3][CH2:2]2)=[O:33])[CH:26]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a mixture of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine (80.0 g, 0.216 mol) and phenyl pyridin-3-ylcarbamate (48.6 g, 0.227 mol) in acetonitrile (650 mL) was added dropwise diisopropylethyl amine (55.8 g, 0.432 mol). A solution formed after ˜45 min of stirring. The slightly turbid solution was stirred at ambient temperature for 18 h. TLC showed a prominent product spot with traces of both starting materials and two other fast moving spots. The solution was concentrated in vacuo to a viscous oil. This was partitioned between dichloromethane (600 mL) and water (500 mL). The aqueous layer was extracted with 200 mL of dichloromethane. The combined organic layers were washed with successive portions of 500 mL of 5% sodium hydroxide, and 200 mL of water, then dried over magnesium sulfate and concentrated in vacuo to 139.5 g of a viscous oil. This was dissolved in 350 mL of warm (50° C.) methyl t-butyl ether. Soon after a solution formed, solid began separating. The crystallizing mixture was kept at −10° C. for 4 h and filtered. The solid was rinsed with 60 mL of methyl t-butyl ether and pressed dry under suction. Further drying in vacuo at 28° C. for 16 h and then at 35° C. for 6 h provided 93.2 g (95%) of product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=2)=[CH:2]1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>>[CH:14]1([CH:10]([C:9]2[CH:8]=[N:7][C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:13][CH:12]=2)[OH:11])[CH2:16][CH2:15]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(-c2ccoc2)nc1
Product: OC(c1ccc(-c2ccoc2)nc1)C1CC1

Procedure:
Synthesized using compound 47b (168 mg, 0.97 mmol) and cyclopropylmagnesium bromide (3.88 mL, 1.94 mmol, 0.5 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Yellow oil. Yield: 140 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.35-0.44 (m, 1H), 0.49 (td, J=9.6, 5.0 Hz, 1H), 0.55-0.70 (m, 2H), 1.16-1.25 (m, 1H), 2.71 (br, s, 1H), 4.04 (d, J=8.2 Hz, 1H), 6.89 (dd, J=1.9, 0.6 Hz, 1H), 7.44 (dd, J=8.0, 0.8 Hz, 1H), 7.48-7.50 (m, 1H), 7.75-7.79 (m, 1H), 8.02 (dd, J=1.4, 0.8 Hz, 1H), 8.56 (dd, J=2.2, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=2.8, 3.6, 19.1, 76.0, 108.6, 119.8, 126.8, 134.4, 137.3, 141.1, 143.8, 147.6, 150.9; MS (ESI): m/z=216.27 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: Clc1nc(N2CCc3ccccc32)c2nc[nH]c2n1
Reaction time: 17 h
Yield: 96.4 %

Procedure:
189 mg of 2,6-dichloropurine, 4 ml of butanol and 143 mg (1.2 equivalents) of indoline are mixed and brought to a temperature of 80° C. for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 262 mg of expected product are obtained in the form of beige-colored crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[N:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[H-].[Na+].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26]>CN(C=O)C>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([N:10]=[C:2]2[N:3]([CH2:24][C:25](=[O:26])[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1]2)(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2[nH]c3ccccc3s2)cc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cn2c(=NS(=O)(=O)c3ccc(C)cc3)sc3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 20 (930 mg, 3.01 mmol) in DMF (15 mL) at room temperature was added NaH. After the effervescence subsided, 2-bromo-4′-methylacetophenone (775 mg, 3.36 mmol) was added. The reaction was first stirred at room temperature for an hour and then heated at 80° C. until completion (by TLC). The mixture was allowed to cool before being poured on ice (400 mL). A precipitate dropped out. It was filtered and washed with cold water and dried to give a pale yellow powder in quantitative yield: mp 180-182° C.; 1H-NMR (DMSO-d6) 2.35 (s, 3H), 2.43 (s, 3H), 5.86 (s, 2H), 7.33 (m, 3H), 7.42 (m, 3H), 7.57 (d, 1H), 7.64 (d, 2H), 7.91 (d, 1H), 7.97 (d, 2H); Anal. (C23H20N2O3S2) C, H, N.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH2:19][CH:20]=[CH2:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH2:19][CH2:20][CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCc1cc(C(=O)OC)ccc1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1O[Si](C)(C)C(C)(C)C
Yield: 80.7 %

Procedure:
A solution of methyl 4-(t-butyldimethylsilyloxy)-3-(2-propen-1-yl)benzoate (14.4 g) (obtained as described in International patent application, publication no. WO 91/11999) in methanol (280 ml) was catalytically hydrogenated over 10% palladium on carbon (2.9 g) at 3 atmospheres pressure for 2 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:3 v/v), to give methyl 4-(t-butyldimethylsilyloxy)-3-propylbenzoate (B) (11.7 g) as an oil; NMR: 0.25(s, 6H), 0.95(t, 3H), 1.0(s, 9H), 1.5-1.7(m, 2H), 2.6(t, 2H), 3.9(s, 3H), 6.8(d, 1H), 7.8(dd, 1H), 7.8(s, 1H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:15][C@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([O:16][C:17]3[CH:22]=[C:21]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)[CH:20]=[CH:19][C:18]=3[C:28]3[N:29]=[N:30][NH:31][N:32]=3)[CH2:13]2)[CH2:8][N:7]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:5])C.[OH-].[Na+]>CO>[C:36]([O:35][C:33]([N:7]1[C@H:6]([C:4]([OH:5])=[O:3])[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([O:16][C:17]3[CH:22]=[C:21]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)[CH:20]=[CH:19][C:18]=3[C:28]3[N:29]=[N:30][NH:31][N:32]=3)[CH2:13]2)[CH2:8]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CCOC(=O)[C@@H]1C[C@@H]2C[C@@H](Oc3cc(-n4cccn4)ccc3-c3nn[nH]n3)CC[C@H]2CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](Oc3cc(-n4cccn4)ccc3-c3nn[nH]n3)C[C@@H]2C[C@H]1C(=O)O
Temperature: 50 °C
Yield: 32.7 %

Procedure:
To 0.129 g of the material from Step B, above, dissolved in 10 mL MeOH is added 0.72 mL 1N NaOH. The reaction is heated to 50° C. overnight. 0.72 mL 1N NaOH is then added and heated for four more hours. Upon completion, the reaction is concentrated in vacuo, redissolved in water and acidified to pH 3, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography eluting with 10% MeOH/CHCl3 provides 0.040 g of the title compound (32.8% yield), which is used directly in the following step.