Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O=C1C2C3C(=CC=CC=3C(=O)N1CCCC[N:21]1[CH2:26][CH2:25][CH:24]([N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]1)C=CC=2.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]1[C:53](=[O:54])[C:52]2[CH:55]=[CH:56][CH:57]=[C:50]3[C:51]=2[C:46](=[CH:47][CH:48]=[CH:49]3)[C:45]1=[O:58].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[O:58]=[C:45]1[C:46]2[C:51]3[C:50](=[CH:57][CH:56]=[CH:55][C:52]=3[C:53](=[O:54])[N:44]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][N:21]1[CH2:22][CH2:23][CH:24]([N:27]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:28](=[O:31])[CH2:29][CH3:30])[CH2:25][CH2:26]1)[CH:49]=[CH:48][CH:47]=2
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: CCC(=O)N(c1ccccc1)C1CCN(CCCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1

Procedure:
Following the procedure of part (b) of example 31 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains N-[1-[5-(1,3-dihydro- 1,3-dioxo-2H-benz[de]isoquinolin-2-yl)pentyl]-4-piperidinyl]-N-phenylpropanamide, hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=O)[CH2:9][CH2:8]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:14][OH:15])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=O)CC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1C(=NO)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a suspension of 7-methoxyindanone (5.0 g, 31 mmol) and hydroxylamine hydrochloride (12.9 g, 185 mmol) in 100 mL ethanol was added the solution of sodium acetate (11.4 g, 139 mmol) in 35 mL water at room temperature. The reaction mixture was heated at reflux for 4 h, then stirred at room temperature for 18 h. The suspension was filtered, the white solid was washed with water, ethanol and diethyl ether to give the title compound (5.4 g, 31 mmol, 98%). ESMS m/z 178 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)C.[Li+].[OH-].[OH-].[Na+].C(O)=O>C1COCC1.CCO>[C:27]([O:26][CH:5]([C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:17][CH3:18])[C:7]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:4]([OH:31])=[O:3])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Solvent: C1CCOC1
Product: COc1cccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)c(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of tert-butoxy-[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-acetic acid ethyl ester (12 mg) in THF (0.3 mL) and EtOH (0.1 mL) was added 0.1 mL of 1 M LiOH. The reaction was stirred for 30 min at room temperature, then 0.3 mL each of THF, EtOH, and 1 M NaOH were added. The reaction was heated to 70° C. for 2.5 hours, and then cooled to room temperature. Formic acid was added until pH ˜5. The reaction mixture was directly purified by HPLC (Gemini, 50-100% MeCN/H2O, with 0.1% TFA). The product was lyophilized to give a white powder (8 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]1[N:12]1[CH:20]=[N:19][C:18]2[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]1=2.O.[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39](ON3C(=O)CCC3=O)=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:24]1[C:36]2[CH:35]([CH2:37][O:38][C:39]([NH:1][C@@H:2]3[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]3[N:12]3[CH:20]=[N:19][C:18]4[C:17](=[O:21])[NH:16][C:15]([NH2:22])=[N:14][C:13]3=4)=[O:40])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c(=O)[nH]1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(=O)OCC2c3ccccc3-c3ccccc32)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To 3.31 g (10.61 mmol) of 9-(2-amino-2-deoxy-β-D-glucopyranosyl) guanine was added 72 mL of H2O. To this solution was added a 100 mL 1,4-dioxane solution containing 4.65 g (13.79 mmol) of N-(9-fluorenyl-methoxycarbonyloxy)succinimide. This resulted in a cloudy mixture. To this system was added 0.58 g (6.90 mmol) of NaHCO3. This mixture was stirred for 12 hours at room temperature. At this time, TLC indicated the consumption of starting material and the mixture was concentrated in vacuo to a dry residue. This residue was stirred for 3 hours in 310 mL of Et2O and 145 ml of H2O. The suspension was then filtered and the solid dried in a vacuum oven for 12 hours at 40° C. Thus was obtained 4.28 g (76%) of 9-(2-deoxy-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-β-D-glucopyranosyl)guanine. 1H NMR: (DMSO-δ6): guanine H-8 7.72 (s, 1H), anomeric H-1 5.37 (d, 1H), Fmoc-methine 4.05 (m, 1H). FAB-MS: m/z 535 for (M+1)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[C:8]=1[CH:14]=[N:15]O)[CH2:4][CH3:5])[CH3:2].[OH-].[Na+]>C(O)(=O)C.[Zn]>[CH2:4]([N:3]([CH2:1][CH3:2])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[C:8]=1[CH2:14][NH2:15])[CH3:5]
Reactant: CCN(CC)Cc1ccnc(F)c1C=NO
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN(CC)Cc1ccnc(F)c1CN
Yield: 634.5 %

Procedure:
To a stirred solution of compound 89 (1.30 g, 0.58 mmol) in acetic acid (34 mL), protected against light exposure, was added dropwise during 24 h, at room temperature, zinc dust (1.63 g, 24.9 mmol). The mixture was then cooled to 0° C. before addition of a 3 N aqueous sodium hydroxide solution (130 mL). After return back to room temperature, the mixture was extracted with dichloromethane (3×200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under reduce pressure. The residue was chromatographed (Al2O3, CH2Cl2/EtOH, 97/3, v/v) to give compound 90 (778 mg, 3.68 mmol) as a yellow oil. Yield 64%; Rf (Al2O3, CH2Cl2/EtOH, 97/3, v/v) 0.54; IR (CCl4) ν 1264, 1413, 1608, 2972 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.98 (t, 6H, J=7.3 Hz), 2.44 (q, 6H, J=7.1 Hz), 3.55 (s, 2H), 3.81 (s, 2H), 7.05 (d, 1H, J=4.9 Hz), 7.95 (d, 1H, J=4.9 Hz).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][S:14][C:15]1[C:20]([NH:21][C:22](=[O:25])[CH2:23]O)=[C:19]([S:26][CH3:27])[CH:18]=[C:17]([CH3:28])[N:16]=1.[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:30]=1[S:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.O>[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:30]=1[S:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH2:23][C:22]([NH:21][C:20]2[C:15]([S:14][CH3:13])=[N:16][C:17]([CH3:28])=[CH:18][C:19]=2[S:26][CH3:27])=[O:25])[CH2:43][CH2:42]1
Reactant: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Yield: 51.4 %

Procedure:
Diethyl azodicarboxylate (1.88 mL, 4.33 mmol) was added dropwise to a solution of N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hydroxyacetamide (373 mg, 1.44 mmol), 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine (1.40 g, 5.34 mmol), and triphenylphosphine (1.34 g, 5.09 mmol) in dimethylformamide (DMF) (20 mL) under stirring with water cooling over 5 minutes. The resultant mixture was stirred at room temperature for 60 minutes, and water (2 mL) was added thereto so as to deactivate the reagent. The reaction mixture was partitioned between 1N hydrochloric acid (30 mL) and ethyl acetate (30 mL). The formed organic layer was extracted with 1N hydrochloric acid (15 mL×2). The formed aqueous layers were combined, and the thus-combined aqueous layer was washed with ethyl acetate (20 mL×2). The pH of the resultant mixture was adjusted to 8 to 9 with 1N sodium hydroxide. The formed aqueous layer was extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine, and dried over sodium sulfate anhydrate, followed by solvent removal under reduced pressure. The residue was purified through silica gel column chromatography (developer: chloroform:methanol=100:3). The obtained oily substances were crystallyzed from ethanol and ether, to thereby yield 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide as colorless crystals (372 mg, yield: 51%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([NH2:14])=[O:13])[CH:11]=1)[NH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([NH2:14])=[O:13])[CH:11]=1)[NH:8][N:7]=[C:6]2[CH:15]1[CH2:16][CH2:17][N:18]([S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH2:19][CH2:20]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Yield: 97.4 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (100 mg, 0.31 mmol) was reacted with 3-chloro-1-propanesulfonyl chloride (63 uL, 0.46 mmol) in the presence of diisopropylethylamine (0.24 mL, 1.38 mmol) in methylene chloride (5 mL) to give the crude title compound (140 mg, 98%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:27])[CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>>[CH3:19][N:20]([CH3:27])[CH2:21][CH2:22][CH2:23][C:24]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:25]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CN(C)CCCC(=O)Cl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)CCCN(C)C)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and 4-dimethylamino-butyryl chloride the title compound was obtained as a light yellow solid (10%), MS: m/e=379 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:22])[C@:14]([N:19]=[C:20]=[O:21])([CH:16]([CH3:18])[CH3:17])N>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][O:12][C:13](=[O:22])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:19][C:20]([O:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1)=[O:21]
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Reactant: CC(C)c1nc(CO)cs1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OCc1csc(C(C)C)n1)C(C)C
Yield: 56.6 %

Procedure:
A solution of 2.18 g (15 mmol) of 4-(hydroxymethyl)-2-isopropylthiazole, 15.8 mmol of α-isocyanato-valine methyl ester and 1.5 mmol of 4-dimethylaminopyridine in 75 ml of dichloromethane was heated at reflux for 5 h. The resulting solution was washed successively with 10% citric acid, aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography of the residue using 5% ethyl acetate in chloroform provided 2.67 g (57%) of the pure desired compound, Rf 0.46 (4% methanol in chloroform). NMR 1H NMR (DMSO-d6) δ1.26 (d, J=8 Hz, 3H), 1.32 (d, J=7 Hz, 6H), 3.27 (heptet, J=7 Hz, 1H), 3.63 (s, 3H), 4.10 (pentet, J=8 Hz, 1H), 5.02 (s, 2H), 7.47 (s, 1H), 7.8 1 (d, J=8 Hz, 1H). Mass spectrum: (M+H)+ =287.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[C:11](OCC)(=O)[CH:12]=[O:13]>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[NH:9][C:12](=[O:13])[CH:11]=[N:10]2
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=c1cnc2cc(F)c(F)cc2[nH]1
Reaction time: 8 h

Procedure:
A mixture of 4,5-difluoro-1,2-benzenediamine (0.60 g) and 50% ethyl glyoxalate in toluene (0.87 ml) in ethanol (25 ml) was heated under reflux for 2 hours then cooled. After refrigeration overnight, the resulting solid was collected and washed with ice-cold ethanol and dried under vacuum to give a solid (0.57 g; 75%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][CH:9]2[CH2:12][N:11]([CH2:13][CH2:14][C:15](O)=[O:16])[CH2:10]2)=[CH:6][CH:5]=1.S(Cl)([Cl:24])=O>>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][CH:9]2[CH2:12][N:11]([CH2:13][CH2:14][C:15]([Cl:24])=[O:16])[CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Product: O=C(Cl)CCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Yield: 100 %

Procedure:
3-(3-(4-(trifluoromethoxy)phenoxy)azetidin-1-yl)propionic acid (400 mg, 1.31 mmol) was dissolved in thionyl chloride, raised the temperature to reflux for 3 h, spun dry, residuals were washed by an appropriate amount of ethyl ether, generated 423 mg target product, yield was 100%, directly put to the next reaction step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])=[O:21].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C1COCC1>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:16])([F:17])[F:15])[C:5]=1[C:20]([N:22]([C:23]([O:24][CH3:25])=[O:26])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:21]
Reactant: COC(=O)NC(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Sodium hydride (2.61 g, 6.43 mmol) was added to a stirred solution of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid, methyl ester (2.61 g, 6.43 mmol) in dry THF (95 mL) at room temperature under a dry N2 atmosphere. After 1 hour, tert-butyl bromoacetate (1.56 mL, 1.5 eq) was added and the reaction mixture was heated at 60° C. for 2.5 hours. The reaction mixture was cooled to room temperature and the THF was removed. Water (100 mL) was added and the resulting solid was filtered. The resulting solid was washed with water and then petroleum ether and dried in vacuo to provide the title compound as a white solid (2.81 g, 84%). A small portion was recrystallized from petroleum ether:ether, m.p. 126°-128° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][C@@H:4]1[NH:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH:12]=2)[C:5]1=[O:29].[Cl:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=2)[CH:34]=1>>[CH3:1][CH:2]([CH3:30])[CH2:3][C@@H:4]1[N:9]([CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=3)[CH:34]=2)[CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH:12]=2)[C:5]1=[O:29].[ClH:31]
Reactant: COc1cc(-c2cc(CN3CCN[C@@H](CC(C)C)C3=O)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)[C@@H](CC(C)C)C3=O)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
(3S)-3-(2-methylpropyl)-2-oxo-1-[[2-(3,4,5-trimethoxy-phenyl)pyridin-4-yl]methyl]piperazine (100 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (71 mg) were reacted in the same manner as in Example 4 to obtain the title compound as a hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C:25]([NH2:26])=[N:24][C:23]2[N:13]([C@@H:14]3[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:12]=[N:11][C:10]=2[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](C)(C)[CH3:29].Cl>C/C(/O)=C/C(C)=O.[Ag].CN(C)C=O>[CH2:1]([N:8]1[C:25]([NH2:26])=[N:24][C:23]2[N:13]([C@@H:14]3[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]3[O:16][CH3:29])[CH:12]=[N:11][C:10]=2[C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1Cc1ccccc1
Reactant: C[SiH](C)C
Agent: [Ag]
Agent: CC(=O)/C=C(/C)O
Agent: Cl
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)n(Cc3ccccc3)c(N)nc21
Temperature: 70 °C

Procedure:
A 1 L pear shaped recovery flask with stir bar was charged with a mixture of 16 (50 g, 134 mmol), silver acetylacetonate (41 g 200 mmol), TMSH (200 ml of 1N solution in methanol) and dimethylformamide (400 ml). The flask was heated to 70° C. for two hours. The solution was cooled to ambient temperature, neutralized to pH 7 with 1M HCl, and dried to a solid tar. The tar was dissolved in water (500 ml) and filtered through a sintered glass funnel to remove silver salts. The product was evaporated to dryness to remove water and residual solvents and 10 grams (26 mmols) was redissolved in 50 ml of water prior to purification on a Waters Delta-Pak ODS 50 mm×300 mm HPLC column. The N1-Bz-2′-OMe guanosine isomer eluted first and was recovered using a rotary evaporator. The product (7 g, 18 mm, 70%) was identical to an authentic sample by HPLC, UV-, 1H-NMR-spectroscopy. 1H NMR (dmso-d6): 8.02 (s, 1H, H8), 7.26 (m, 5H, ph), 7.02 (bs, 2H, 2NH2), 5.82 (d, J1′,2′=6.4, 1H, H1′), 5.23 (s, 2H, CH2-Bz), 5.18 (d, JOH,3′=4.8, 1H, 3′-OH), 5.04 (t, JOH,5′=5.2, JOH,5″=5.6, 1H, 5′-OH), 4.28 (m, J3′,2′=4.8, J3′,4′=3.2, 1H, H3′), 4.20 (t, J2′,1′=6.4, J2′,3′=4.8, 1H, H2′), 3.90 (m, J4′,3′=3.6, J4′,5′=4.0, 1H, H4′), 3.65-3.53 (m, 2H, H5′, H5″ JOH,5′=5.2, J5′,5″=11.6), 3.33 (s, 3H, OCH3).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:17]1([C:23]([C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:17]1(/[C:23](/[C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=[CH:9]\[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1ccccc1)c1ccnnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\c1ccccc1)c1ccnnc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.46 g, 7.93 mmol) in THF (40 mL) was added NaH (476 mg, 11.9 mmol) in portions at 0° C., the resulting mixture was stirred at 0° C. for 20 minutes, then, the phenyl(pyridazin-4-yl)methanone was added in portions, the resulting mixture was stirred at 0° C. for 4 hour. The LC-MS showed the MS signal of desired product was detected, then, the reaction solution was added sat. aq. NH4Cl at 0° C., then, extracted with AcOEt (3×50 ml), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (petroleum Ether: EtOAc=2:1) to afford (E)-ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate (1.68 g, yield: 83.2%). 1H NMR (CDCl3 400 MHz): δ9.25 (d, J=5.2 Hz, 1H), 9.06 (s, 1H), 7.47-7.32 (m, 4H), 7.30-7.20 (m, 2H), 6.55 (s, 1H), 4.95 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@@H:8]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40]([NH:42][C@H:43]([C:57](O)=[O:58])[CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C>[CH3:38][O:39][C:40](=[O:41])[NH:42][C@@H:43]([CH:44]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:57]([NH:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][CH2:28][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:37])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:58]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 81.8 %

Procedure:
A mixture of tert-butyl[(2S)-4-(2-aminophenyl)-1-{[tert-butyl(diphenyl)silyl]oxy}butan-2-yl]carbamate (5, 242 mg, 0.466 mmol), N-(methoxycarbonyl)-β-phenyl-L-phenylalanine (6, 225 mg, 0.752 mmol) (or any other suitable carboxylic acid), HATU (318 mg, 0.836 mmol) and DMAP (50 mg, 0.409 mmol) was dissolved in dry Py (2 ml) and the mixture was stirred at room temperature under N2 for 13 h. Quenched with water (0.5 mL), then diluted (DCM), washed with 5% KHSO4 in water, then saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purified through a chromatographic cartridge of silicagel (12 g) eluted with 10% to 30% EtOAc in hexane to give 305 mg (82% yield) of title compound as white foam, MS: m/z=822.2 (MNa+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH2:28]O)=[C:21]3[C:25]([OH:27])=[O:26])=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2].[NH2:39][N:40]1[C:44]([N:45]2[CH:49]=[CH:48][CH:47]=[N:46]2)=[N:43][N:42]=[C:41]1[SH:50].O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)[C:13]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[C:21]([C:25]([OH:27])=[O:26])=[C:20]([CH2:28][S:50][C:41]4[N:40]([NH2:39])[C:44]([N:45]5[CH:49]=[CH:48][CH:47]=[N:46]5)=[N:43][N:42]=4)[CH2:19][S:18][C@H:17]23)=[O:14])=[O:10])[C:5](=[O:37])[C:4]1=[O:38])[CH3:2]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CO)CSC23)c2ccc(O)cc2)C(=O)C1=O
Reactant: Nn1c(S)nnc1-n1cccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(-n5cccn5)n4N)CS[C@H]23)c2ccc(O)cc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 294.78 mg. of 7-[2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)acetamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, 3-acetate and 136.6 mg. of 4-amino-5-(1-pyrazolyl)-4H-1,2,4-triazole-3-thiol in 10 ml. of water is adjusted to pH 6.5 with an aqueous solution of sodium bicarbonate. A 5 ml. portion of acetone is added producing solution. This solution is stirred at 60°-63° C. for 5 hours, then stripped free of acetone under reduced pressure, cooled to room temperature and filtered. The filtrate is acidified to pH 2.0 with 2 N hydrochloric acid. The resulting solid is filtered and dried giving 192 mg. of the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[O:5][CH2:6][CH:7]=[O:8])=O>C(O)(=O)C>[CH3:14][O:13][C:9]1[C:4]2[O:5][C:6]([CH:7]=[O:8])=[CH:1][C:3]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(C=O)c1OCC=O
Solvent: CC(=O)O
Product: COc1cccc2cc(C=O)oc12

Procedure:
2-(2-Formyl-6-methoxyphenoxy)acetaldehyde, dimethyl acetal (31 g) was heated to reflux in glacial acetic acid (120 ml) overnight. The mixture was then cooled and the solvent removed in vacuo to give a red oil. Purification by Kugelrohr distillation gave the title compound (17 g) as a pale yellow oil which solidified on standing.