Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[CH2:10]([N:14]1[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:17]=2[S:16]/[C:15]/1=[N:23]\[C:24](=[O:36])[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1F)[CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:10]([N:14]1[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:17]=2[S:16]/[C:15]/1=[N:23]\[C:24](=[O:36])[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Reactant: CC(C)(O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)sc2ccncc21
Temperature: 2.5 °C
Yield: 90.3 %

Procedure:
3-Methylbutane-1,3-diol (42 mg, 0.4 mmol) in THF (1 mL) was treated with NaH (60%) (16 mg, 0.4 mmol) at room temperature for 20 min. To the above mixture, which was cooled to 0-5° C., was added the product from Example 20B (80 mg, 0.2 mmol) in THF (1 mL). After 20 min. the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 87 mg (90%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (t, J=7.32 Hz, 3H) 1.36 (s, 6H) 1.47-1.55 (m, 2H) 1.88-1.96 (m, 2H) 2.13 (t, J=5.80 Hz, 2H) 4.35 (t, J=5.80 Hz, 2H) 4.54 (t, J=7.63 Hz, 2H) 5.12 (brs, 1H) 7.11 (d, J=8.54 Hz, 1H) 7.61 (d, J=5.19 Hz, 1H) 7.74 (dd, J=8.54, 2.14 Hz, 1H) 8.49 (d, J=5.19 Hz, 1H) 8.68 (s, 1H) 8.72 (s, 1H); MS (ESI+) m/z 482 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>CO.O1CCCC1.[OH-].[Na+]>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccc(N2CCCC2=O)cc1N1CCCS1(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CCCC2=O)cc1N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Using pyrrolidin-2-one (432 mg) and methyl 4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (1.54 g) described in Preparation Example 13 and by the reaction and treatment in the same manner as in Example 1, methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoate (1.12 g) was obtained. The obtained methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoate (1.12 g) was dissolved in a solution of methanol (5 mL) and tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated from the reaction mixture, and the mixture was neutralized with 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoic acid (720 mg). A mixture of the obtained 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoic acid (250 mg), 1-(2,4-dimethylphenyl)piperazine (154 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (242 mg) was dissolved in ethanol (3 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (330 mg).
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]3[C:24](=O)C4=CC=CC=C4[C:21]3=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN.Cl>C(O)C>[CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]([CH3:24])[CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1C=Cc1ccccc1C2=CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc2c1C=Cc1ccccc1C2=CCCN(C)C

Procedure:
9.2 g. of 1-methyl-5-(3-phthalimidopropylidene)-5H-dibenzo[a,d]cycloheptene are dissolved in 100 ml. of ethanol, treated with 1.2 g. of hydrazine hydrate and heated for 6 hours under reflux conditions. An excess of concentrated hydrochloric acid is added, and the mixture is heated for an additional hour under reflux conditions. The reaction mixture is filtered warm. The solid residue is washed with warm ethanol, and the residual ethanol portions are evaporated to dryness. The residue is taken up in ether. The ethereal solution is washed with dilute sodium hydroxide solution, dried and evaporated whereby 1-methyl-5-(3-aminopropylidene)-5H-dibenzo[a,d]cycloheptene remains behind as a thick oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36].CCOCC>O1CCCC1>[S:35]([OH:38])(=[O:37])(=[O:36])[CH3:34].[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][NH2:26])=[CH:19][CH:18]=1)(=[O:15])=[O:16])=[O:6])#[N:2]
Reactant: CC(C)(C)OC(=O)NCCSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trans-N-cyanomethyl-2-[4-(tert-butoxycarbonylaminoethylsulfanyl)-benzenesulfonylmethyl]cyclohexanecarboxamide (0.35 g, 0.706 mmol) in tetrahydrofuran (2 mL) at room temperature was added dry methanesulfonic acid (0.183 mL, 2.82 mmol). The reaction mixture was stirred overnight at room temperature. Ether (200 mL) was added. The supernatant was decanted. The residue was triturated twice with ether (50 mL each) and was then precipitated from methanol/ether, giving the title compound as its mesylate salt. MS [ESI, (M−H)−] m/z=394 amu.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:26]([OH:27])[C:25]3[C:20](=[N:21][CH:22]=[CH:23][N:24]=3)[C:19]2=[O:28])=[N:16][CH:17]=1.O>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:19]([O:28][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])[C:20]3[C:25](=[N:24][CH:23]=[CH:22][N:21]=3)[C:26]2=[O:27])=[N:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccccc1)OC1c2nccnc2C(=O)N1c1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Phenyl chloroformate (141 g.) is added, with stirring and whilst keeping the temperature at about 5° C., to a suspension of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (158 g.) in anhydrous pyridine (1,580 cc.). When the addition is complete, the reaction mixture is heated to a temperature of about 60° C. The heating is continued for one hour. Water (4,750 cc.) is added to the reaction mixture after it has been cooled to a temperature of about 20° C. The product which crystallises is filtered off and washed with water (2×250 cc.), acetonitrile (150 cc.) and diisopropyl ether (250 cc.). After drying, 6-(5-chloropyrid-2-yl)-7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]-pyrazine (169 g.), which melts at 193° C., is obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:15]=3)[O:10]2)[CH2:5]1)(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][C:6]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:39][O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)=[O:23])[CH:15]=3)[O:10]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)N1CCCC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(±)-(E)-3-[1′-Acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid (crude compound from STEP B, 590 mg) was dissolved in DCM (30 ml) and TEA (0.498 ml, 3.59 mmol). EDC (513 mg, 2.68 mmol) and HOBt (362 mg, 2.68 mmol) were added and the mixture was stirred for 10 min at RT. NH2OTHP (251 mg, 2.15 mmol) was added and the solution was stirred overnight at RT and was then partitioned between 5% NaHCO3 and DCM. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 99:1 to 97:3) to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide that was dissolved in DCM and treated with 4 M HCl in dioxane for 3 h. The precipitate was collected by filtration and washed with DCM to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-N-hydroxy-acrylamide as pale yellow powder (404 mg).
Reaction SMILES: CC1(C)C2C=CC([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=CC=2C(C2SC=CN=2)=CC1.[CH3:29][C:30]1([CH3:59])[C:39]2[CH:38]=[CH:37][C:36](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:35][C:34]=2[C:33]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:32][CH2:31]1>>[CH3:29][C:30]1([CH3:59])[C:39]2[CH:38]=[C:37]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH:36]=[CH:35][C:34]=2[C:33]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[CH:32][CH2:31]1
Reactant: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CCC3(C)C)cc1
Product: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-3-yl)ethynyl]benzoic acid (Compound 78), 27.0 mg (0.07 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-3-yl)ethynyl]benzoate (Compound 68) was converted into the title compound (colorless solid) using 5.9 mg (0.14 mmol) of LiOH in H2O.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9](Br)=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(C#C[Si](C)(C)C)cc(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
A mixture of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.61 g, 6.93 mmol), TMS-acetylene (1.18 mL, 8.32 mmol), Pd(PPh3)2Cl2 (496 mg, 0.693 mmol), CuI (132 mg, 0.693 mmol), and i-Pr2NH (1.95 mL, 13.9 mmol) in THF (11 mL) was stirred for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with EtOAc, and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 1% to 2% EtOAc in hexanes) to afford the desired product (2.15 g, 79%).
Reaction SMILES: [C:1]([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[CH3:28][O:27][C:25]([CH2:24][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:10]2[CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:20][CH2:19][C:11]1=2)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2C1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-boc-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (450 mg, 1.65 mmol) was dissolved in DMF (7 mL) and stirred at room temperature. The vessel was flushed with argon and sodium hydride (67.0 mg, 1.65 mmol) was added. After 30 minutes, methyl bromoacetate (253 mg, 1.65 mmol) in DMF (2 mL) was added and the mixture stirred overnight. The solvent was removed in vacuo and the residue partitioned between brine (20 mL) and ethyl acetate (2×40 mL). Combined organics were dried (sodium sulphate), concentrated in vacuo and adsorbed onto silica for purification by flash chromatography (0-40% ethyl acetate/isohexane). This gave tert-butyl 5-methoxycarbonylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a pale yellow foam (387 mg, 68%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:14][C:15]([Si](C)(C)C)([F:20])[C:16]([F:19])([F:18])[F:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[F:14][C:15]([F:20])([C:16]([F:19])([F:18])[F:17])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of methyl 4-acetylbenzoate (700 mg, 3.85 mmol) in tetrahydrofuran (7.7 mL) were added (pentafluoroethyl)trimethylsilane (1370 mg, 6.93 mmol) and tetrabutylammonium fluoride (tetrahydrofuran solution, 1 mol/L, 5.7 μL, 5.78 mmol) at 0° C., and the mixture was stirred at room temperature overnight. To the solution was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→70:30) to give methyl 4-(2,2,3,3,3-pentafluoro-1-hydroxy-1-methylpropyl)benzoate (765 mg, 67%) as a pale yellow viscous material.
Reaction SMILES: C([N:4](C(=O)C)[C:5]1[NH:6][C:7](=[O:14])[C:8]2[NH:9][CH:10]=[N:11][C:12]=2[N:13]=1)(=O)C.[O:18]1[CH2:22][CH2:21][O:20][C:19]1(CC([O-])=O)CC([O-])=O>>[CH:10]1[N:11]([CH2:19][O:18][CH2:22][CH2:21][OH:20])[C:12]2[N:13]=[C:5]([NH2:4])[N:6]=[C:7]([OH:14])[C:8]=2[N:9]=1
Reactant: O=C([O-])CC1(CC(=O)[O-])OCCO1
Reactant: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Product: Nc1nc(O)c2ncn(COCCO)c2n1

Procedure:
On monitoring this reaction by thin layer chromatography, it was determined that the condensation of diacetyl guanine with dioxolane-diacetate in the presence of acidic catalyst produced N7 -isomer first, which was partially converted to N9 -isomers to reach an equilibrium in the ratio of 3/2 in favor of N9 -isomers. Under these condensation conditions, pure N7 - or N9 -acyclovir diacetate could be converted to give the same equilibrated mixture. This observation resulted in one of the embodiments of the improved process for the production of acyclovir of the present invention. When diacetyl quanine (4) almost disappeared during the condensation reaction, the reaction mixture was concentrated to dryness in vacuo, during which time the ratio of N9 /N7 -isomer continuously changed from approximately 3/2 to nearly one spot (N9 -isomer) as indicated by thin layer chromatography. The pure acyclovir diacetate (5) was obtained by simply washing with chloroform in good yield. It was surprising to learn that the ratio of N9 /N7 -isomers could be significantly manipulated in this manner.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH2:16][NH:15][C:14]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[N:22][C:13]2=3)[CH2:4]1.CO>C(Cl)Cl.O=[Mn]=O>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[N:15][C:14]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[N:22][C:13]2=3)[CH2:4]1
Reactant: COc1ccc2c(n1)N(CCN1CC[C@@H](O)[C@@H](CN)C1)C(=O)CN2
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CC[C@@H](O)[C@@H](CN)C3)c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-{2-[(3S,4R)-3-(aminomethyl)-4-hydroxy-1-piperidinyl]ethyl}-6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (170 mg; 0.508 mmol) in DCM:MeOH: 10:1 was added MnO2 (156 mg; 1.52 mmol). The reaction mixture was stirred at ambient temperature under N2 for 2 days, filtered, and concentrated to obtain the product (142 mg; 84%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2)[CH:2]=[CH2:3].Cl.[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.N>CN(C)P(=O)(N(C)C)N(C)C.O>[C:21]12([C:31]([O:19][CH:6]([CH2:5][NH:4][CH2:1][CH:2]=[CH2:3])[CH2:7][O:8][C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[CH2:11][C:12](=[O:18])[NH:13]4)=[O:32])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: C=CCNCC(O)COc1cccc2c1CC(=O)N2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: C=CCNCC(COc1cccc2c1CC(=O)N2)OC(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
1.35 g of 4-(3-allylamino-2-hydroxypropoxy)oxindole are converted into the hydrochloride, are then dissolved in 15 cc of hexamethyl-phosphoric acid triamide and allowed to stand at room temperature for 70 hours with 1.45 g of adamantane-1-carboxylic acid chloride. The mixture is poured into water, is rendered alkaline with a 10% ammonia solution and is extracted with methylene chloride. The evaporation residue of the methylene chloride phase is chromatographed on silica gel with methylene chloride and 1% of methanol, and the resulting title compound is converted into its hydrogen oxalate. M.P. 170°-172° from ethanol.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:29][F:30])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:12]=2[CH3:28])[CH2:5][O:4]1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO>[F:1][CH2:2][C:3]1([CH2:29][F:30])[O:4][CH2:5][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:39])[C:12]=2[CH3:28])[CH2:7][O:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a toluene/methanol (10:1) (20 ml) solution of the 2-(((4-((2,2-bis(fluoromethyl)-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (305 mg, 700 mmol) obtained in the step (7d), a toluene/methanol (10:1) (5 ml) solution of 3-chloroperbenzoic acid (167 mg, 630 μmol as the content was regarded as 65%) was added dropwise at −50° C. to −60° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 2 hours in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (215 mg, yield: 68%) as a light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.Cl.[CH3:26][O:27][C:28](=[O:32])[C@@H:29]([CH3:31])[NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:26][O:27][C:28](=[O:32])[C@H:29]([NH:30][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(=O)[C@@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Yield: 82.1 %

Procedure:
(R)-2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester (508 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (500 mg), D-alanine methyl ester hydrochloride (214 mg), HBTU (634 mg), and DIEA (364 uL).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[N:13]1[S:14][N:15]=[C:16]2[CH:21]=[C:20]([C:22](O)=[O:23])[CH:19]=[CH:18][C:17]=12.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[CH:19]=[CH:18][C:17]4=[N:13][S:14][N:15]=[C:16]4[CH:21]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2nsnc2c1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2nsnc2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzo[c][1,2,5]thiadiazole-5-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.90-8.51 (m, 1H), 8.98 (s, 1H), 9.57 (s, 1H). MS (DCI/NH3) m/z 315. Anal. Calculated for C16H18N4OS.HCl: C, 54.77; H, 5.46; N, 15.97. Found: C, 53.82; H, 5.31; N, 16.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N+:6]([O-])[C:7]=1[CH3:8].C(O)(=[O:19])C>>[Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH2:8][OH:19]
Reactant: CC(=O)O
Reactant: CCCCc1nc2c(cc(Br)c(C)[n+]2[O-])[nH]1
Product: CCCCc1nc2nc(CO)c(Br)cc2[nH]1
Temperature: 120 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
8.0 g (0.02817 mole) of the compound obtained in step 5 was dissolved in 20 ml of anhydrous acetic acid. The resulting solution was stirred for 1 hour at 120° C., and evaporated under reduced pressure to remove anhydrous acetic acid. Thereafter, the residue was dissolved in a mixture of 30 ml of methanol and 40 ml of 3N LiOH. The resulting solution was refluxed for 1 hour, evaporated under reduced pressure to remove methanol, neutralized with 1N HCl and extracted with ethyl acetate(50 ml×3). The organic layer was dried over Na2SO4. The residue was concentrated under reduced pressure and purified with column chromatography(hexane:ethyl acetate =1:2) to obtain 5.3 g of the title compound(yield 66%).