Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[C:26]1([S:32](O)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:10]=1
Reactant: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Reactant: O=S(=O)(O)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(Oc2c(C)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-{3-chloro-4-[4-methoxy-phenoxy]-5-methyl-phenyl}-2H-[1,2,4]triazine-3,5-dione (1.0 g) and benzenesulfonic acid (0.9 g) in Eaton's reagent (5 mL) was heated at 80° C. for 8 h. The reaction was poured over ice, stirred for 30 min, solids filtered, dried and flash chromatographed on silica gel (30-100% THF/hexanes) to afford the title compound of Step A, 0.66 g.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.N1C=CC=CC=1CC(=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Ic1cccnc1
Agent: CC(=O)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Brc1ccc(Oc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of 3-iodopyridine (602 mg, 2.94 mmol), 4-bromophenol (560 mg, 3.24 mmol), CuBr (23 mg, 0.16 mmol), 1-(pyridin-2-yl)propan-2-one (53 mg, 0.39 mmol), Cs2CO3 (1.92 g, 5.89 mmol), and DMSO (6 mL) was degassed with three vacuum/N2 cycles, heated at 100° C. for 9 h, and then stirred at rt overnight. The reaction was filtered through Celite with EtOAc. The filtrate was washed with H2O (100 mL) and brine (100 mL). The aqueous wash was back extracted with EtOAc (3×40 mL). The organic extracts were combined, dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography (0%-20% EtOAc in hexanes) to give 250 mg of 3-(4-bromophenoxy)pyridine as a clear liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.39-8.42 (m, 2H), 7.58-7.61 (m, 2H), 7.43-7.51 (m, 2H), 7.02-7.07 (m, 2H).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[Cl:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:11]=1[C:12](OC)=[O:13]>C1COCC1>[Cl:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:11]=1[C:12](=[O:13])[CH2:7][C:6]#[N:8]
Reactant: COC(=O)c1c(Cl)cccc1Cl
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 103.4 %

Procedure:
n-Butyl lithium (20.1 mL, 32.2 mmol, 1.6M in hexanes) was added to THF (30 mL) and the solution was cooled to −78° C. Acetonitrile (1.7 mL, 32 mmol) was added dropwise and the reaction stirred at the temperature for 45 minutes. Methyl 2,6-dichlorobenzoate (1.00 g, 4.88 mmol) was dissolved in 2 mL THF and added to the reaction mixture. The reaction stirred at −78° C. for 0.5 hr. The solution was quenched with methanol and warmed to room temperature. The material was diluted with water and 1N HCl. The solution was then extracted with Ethyl acetate, dried, and concentrated to give 1.08 g of desired product at 85% purity. Material used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][SH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[CH2:23](Br)[CH:24]=[CH2:25].CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][S:14][CH2:25][CH:24]=[CH2:23]
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: C=CCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C

Procedure:
N-BOC-cysteine methyl ester (obtained from Sigma-Aldrich, Auckland, New Zealand) (5.00 g, 21.2 mmol) was dissolved in anhydrous DCM (30 mL) under an atmosphere of argon. Triethylamine (3.26 mL, 23.3 mmol) and allyl bromide (2.02 mL, 23.3 mmol) were added. The reaction mixture was stirred at rt for eighteen h before being concentrated in vacuo. The residue was partitioned between EtOAc and 1M hydrochloric acid. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a white solid, 3.22 g, 55%. Rf=0.19 (1/5 (EtOAc/(50/70) petroleum ether).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.C[Si]([CH:19]=[N+:20]=[N-:21])(C)C.C(OCC)C>C1COCC1.C(#N)C>[N+:20](=[CH:19][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1)=[N-:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: CCOCC
Solvent: C1CCOC1
Product: [N-]=[N+]=CC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under an argon atmosphere, p-trifluoromethylphenylacetyl chloride (52) prepared above was dissolved in THF (2 mL) and acetonitrile (2 mL), and cooled to 0° C. To this was slowly added a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 4.00 mL, 8.00 mmol), which was stirred overnight (20 hours) after warming up to room temperature. After being concentrated under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/diethyl ether=1/1) to give 1-diazo-3-[4-(trifluoromethyl)phenyl]propan-2-one (53) as a pale yellow oily substance (666 mg, 2.92 mmol, 72.9%, 2 steps).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([NH2:22])[CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2.N1C=CC=CC=1>CS(C)=O.CO>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([NH:22][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Cl)cc2cccnc12
Solvent: CS(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cc2cccnc12)c1ccccc1
Yield: 60.3 %

Procedure:
In a similar fashion using route 14 general procedure 26, benzenesulfonyl chloride (72 μl, 0.57 mmol), 6-chloroquinolin-8-ylamine (67 mg, 0.38 mmol) in pyridine (150 μl, 1.89 mmol) gave the title compound (73 mg, 61%) after trituration from DMSO/MeOH (1:2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:20]([O:15][CH:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)[CH2:11]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCN(c2ccc3cc[nH]c3c2)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(c2ccc3cc[nH]c3c2)C1
Yield: 91.8 %

Procedure:
A homogeneous, colorless solution of 1-(1H-indol-6-yl)pyrrolidin-3-ol (0.1036 g, 0.512 mmol), tert-butylchlorodimethylsilane (0.093 g, 0.615 mmol) and imidazole (0.087 g, 1.281 mmol) in DMF (2.56 mL) was stirred overnight. The mixture was diluted with EtOAc (75 mL), washed with water (4×25 mL) and brine (25 mL) successively, dried over MgSO4, and concentrated in vacuo. The residue was triturated with hexanes to give the desired product (0.1600 g, 0.470 mmol, 92%).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[N+:8]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])([O-:10])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:8]([C:11]1[CH:12]=[C:13]([NH:14][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
36.24 g (362 mmol) Acetylacetone, 10.00 g (72 mmol) 3-nitroaniline, and 1.25 g (7.2 mmol) 4-toluenesulfonic acid are dissolved in 100 ml toluene. The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with eluent dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(Cl)CCl.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[C:12](=[O:14])[NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)[CH:7]=[CH:6][C:5]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-((2S)-2-tert-Butoxycarbonylamino-2-carboxy-ethyl)-2-methoxycarbonylmethoxy-benzoic acid methyl ester of Step F (51 mg, 0.12 mmol) is stirred in CH2Cl2 (1.2 mL) at 0° C. under N2. EDC (24 mg, 0.12 mmol) is added and the reaction mixture is stirred for and additional 10 minutes. 4-Methoxybenzyl amine (0.18 μl, 0.14 mmol) is then added and the reaction is allowed to warm to RT overnight. The reaction is diluted with CH2Cl2 (25 mL) and is subsequently washed with 2N HCl (2×25 mL) and then saturated NaHCO3 (2×25 mL). The organics are then dried over MgSO4, filtered and and purified by flash column chromatography to provide 5-[(2S)-2-tert-butoxycarbonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:12])=[C:5]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2)#[N:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:3]1[C:4]([CH3:12])=[C:5]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2]
Reactant: Cc1c(C#N)cnc2c1CCN2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1c(C#N)cnc2[nH]ccc12
Reaction time: 16 h

Procedure:
A mixture of 5-cyano-4-methyl-7-azaindoline (52 mg, 0.33 mmol) and manganese dioxide (130 mg, 1.5 mmol) in chloroform (10 mL) was stirred for 16 h and then was filtered through celite, washing through with chloroform followed by methanol. The filtrate was evaporated in vacuo to give the title compound as a tan solid:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[N:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)[N:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1N
Product: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1NC(C)=O
Yield: 61 %

Procedure:
In acetic anhydride, 1.00 g of ethyl 4-amino-2-(4-benzylpiperazino)pyrimidine-5-carboxylate (the compound synthesized in Referential Example 60) was refluxed for 1 hour. After allowing the reaction mixture to cool down, acetic anhydride was distilled off and the resulting viscous oil was purified by silica gel column chromatography to obtain 0.68 g of the above-identified compound (yield: 61%).
Reaction SMILES: [C:1](O)(=O)C1C=CC=CC=1.[N:10]1[C:17]([NH2:18])=[N:16][C:14]([NH2:15])=[N:13][C:11]=1[NH2:12]>O.[NH4+].[O-][Mo]([O-])(=O)=O.[O-][Mo]([O-])(=O)=O>[CH4:1].[C:11]1([NH2:12])[N:13]=[C:14]([NH2:15])[N:16]=[C:17]([NH2:18])[N:10]=1.[C:11]1([NH2:12])[N:13]=[C:14]([NH2:15])[N:16]=[C:17]([NH2:18])[N:10]=1
Reactant: O=C(O)c1ccccc1
Agent: O=[Mo](=O)([O-])[O-]
Agent: Nc1nc(N)nc(N)n1
Agent: [NH4+]
Solvent: O
Product: C

Procedure:
Melamine molybdate was prepared in the presence of benzoic acid as follows. 5 grams of melamine, 9.68 grams of benzoic acid, and 250 ml water were dissolved together by refluxing in a 500 ml round-bottomed flask equipped with a stirrer and water-cooled condenser. 13.47 grams of ammonium dimolybdate was dissolved in 25 ml hot water and then added to the first solution. A white precipitate formed immediately.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1S[CH:9]=[CH:10][CH:11]=1)[OH:6].CN[CH2:14][CH2:15]C(C1SC=CC=1)=O>>[CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:15]=[CH:14][CH:9]=[CH:10][CH:11]=1)[OH:6]
Reactant: CNCCC(=O)c1cccs1
Reactant: CNCC[C@H](O)c1cccs1
Product: CNCC[C@H](O)c1ccccc1

Procedure:
In particular, it opens up the possibility of obtaining enantiomerically pure or enantiomerically enriched (S)-3-methylamino-1-(2-thienyl)-1-propanol in a simple manner starting from 3-methylamino-1-(2-thienyl)-1-propanone. Likewise, enantiomerically pure or enantiomerically enriched (S)-3-methylamino-1-phenyl-1-propanol can be obtained in a simple manner starting from 3-methylamino-1-phenyl-1-propanone.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1(SC2C=CC=CC=2)C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1nc2ccccn2c1/C=C/CCOC
Reactant: [H][H]
Agent: [Pd]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2ccccn2c1CCCCOC
Reaction time: 2.5 h
Yield: 48.7 %

Procedure:
Ethyl 3-[(1E)-4-methoxybut-1-en-1-yl]imidazo[1,2-a]pyridine-2-carboxylate (530 mg) and diphenyl sulfide (3.6 mg) were dissolved in ethyl acetate (13 ml), 10% palladium carbon (50% in water) (53 mg) was added and the mixture was stirred in a hydrogen stream at ambient temperature and normal pressure for 2.5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (260 mg).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:1].[ClH:1].[CH3:13][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:9][CH2:8]1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: CN(C)CCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCC1CCN(CCOc2ccc(F)cc2)CC1

Procedure:
In a similar manner to Example 16, a mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (5.5 g), 2-bromoethyl 4-fluorophenyl ether (5.26 g), triethylamine (13.4 ml) and DMF (50 ml) was heated on a steam bath for 16 hours to give 4-(2-dimethylaminoethyl)-1-[2-(4-fluorophenoxy)ethyl]piperidine dihydrochloride, m.p. 260°-262° C.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[C:9]([CH3:21])=[C:10]([CH3:20])[C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[CH:19]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.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.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:22]([NH:29][C:8]1[C:9]([CH3:21])=[C:10]([CH3:20])[C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(Br)cc2c(c1C)OC(C)(C)C2=O
Reactant: NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(NCc2ccccc2)cc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Yield: 66.6 %

Procedure:
Sodium t-butoxide (13.9 g, 145 mmol) was added to a mixture of toluene (100 mL) containing 5-bromo-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (12.8 g, 48.2 mmol) synthesized in Reference Example 18, benzylamine (15.5 g, 145 mmol), palladium acetate (541 mg, 2.41 mmol) and BINAP (4.50 g, 7.23 mmol), and the mixture was stirred under heated reflux for 20 hours. After cooled to room temperature, water was added to the reaction solution, and extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0 to 50:50) to give 9.48 g of the title compound (yield: 67%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:28])[CH:21]=[C:22]([OH:27])[C:23]([O:25]C)=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:28])[CH:21]=[C:22]([OH:27])[C:23]([OH:25])=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1
Reactant: COC(=O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-(5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-hydroxy-4-oxobut-2-enoate 7 (2.59 g, 5.7 mmol) in 1,4-dioxane (125 ml) was added 1N HCl (63 ml). The reaction mixture was allowed to stir at 95° C. for 2 h. The crude product was extracted with ethyl acetate (250 ml). The solvent was evaporated under reduced pressure. The solid was crystallized in chloroform and filtered under reduced pressure. Yield 1.61 g (64%). Yellow solid, mp 187-189° C., UV (MeOH) 394 nm (ε 14,917), 320 (ε 5671). 1H NMR (CDCl3-MeOH-d4, 500 MHz): δ 8.17 (d, 1H, J=3.4 Hz), 7.88 (s, 1H), 7.54 (s, 1H), 7.48-7.45 (m, 1H), 7.36-7.30 (m, 1H), 7.17-7.07 (m, 3H), 6.87-6.81 (m, 2H), 5.19 (s, 2H), 3.76 (s, 2H). 13C NMR (DMSO-d6, 125 MHz): δ 184.5, 173.3, 163.2, 161.7, 161.2, 159.8, 158.6, 144.6, 131.9, 130.0, 129.8, 124.5, 123.1, 123.0, 121.5, 116.8, 115.4, 111.6, 103.9, 100.8, 47.3, 29.2. HRMS [M+H]+ calculated mass 444.1059 for C23H17F3NO5. found 444.1042.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (250 mg, 0.76 mmol) in acetonitrile (15 ml) were added 4-fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg, 1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (324 mg, 85%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.C1(N=C=NC2CCCCC2)CCCCC1.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)C(C)C.[CH:61]1[N:65]([CH2:66][O:67][CH2:68][CH2:69]O)[C:64]2[N:71]=[C:72]([NH2:76])[N:73]=[C:74]([OH:75])[C:63]=2[N:62]=1>CN(C)C=O>[CH3:5][CH:3]([C@H:2]([NH2:1])[C:6]([O:8][CH2:69][CH2:68][O:67][CH2:66][N:65]1[C:64]2[NH:71][C:72]([NH2:76])=[N:73][C:74](=[O:75])[C:63]=2[N:62]=[CH:61]1)=[O:7])[CH3:4]
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of Boc-Val and dicyclohexyl carbodiimide (DCC) in dimethylformamide (DMF) in a ratio of 1:2 DCC/Boc-Val was stirred for 1 hr at 0° C. under nitrogen atmosphere. A solution of acyclovir (1) and 4-N,N(dimethylamino)pyridine (DMAP) was added to the reaction mixture, stirred for 18 hrs and then filtered. The solvent of the filtrate was partially removed in vacuo and the impure solution was added dropwise to cold diethyl ether. The resulting precipitate (2) was filtered and dried, followed by acidolytic removal (treating Boc-Val-ACV with trifluoroacetic acid (TFA) for 30 min at 0° C.) of the Boc protecting group to yield Val-ACV (3). Compound (3) was neutralized by triethylamine (TEA) and treated with the amino acid anhydride of Boc-Val for about 5 hrs. The solvent was removed from the reaction mixture in vacuo and the reaction mixture was added dropwise to the cold diethyl ether. The resulting precipitate (4) was filtered, dried and the Boc group was deprotected (acidolytic removal) to yield the desired dipeptide ester of acyclovir Val-Val-ACV (5).
Reaction SMILES: [C:1]1([CH:7]([CH3:22])[CH2:8][O:9][CH2:10][CH2:11][NH:12][S:13]([CH2:16][CH2:17][C:18](OC)=O)(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.[ClH:33].[NH2:34][CH2:35][CH2:36][C:37]1[C:45]2[S:44][C:43](=[O:46])[NH:42][C:41]=2[C:40]([OH:47])=[CH:39][CH:38]=1.C([BH3-])#N.[Na+]>>[ClH:33].[OH:47][C:40]1[C:41]2[NH:42][C:43](=[O:46])[S:44][C:45]=2[C:37]([CH2:36][CH2:35][NH:34][CH2:18][CH2:17][CH2:16][S:13]([NH:12][CH2:11][CH2:10][O:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:22])(=[O:14])=[O:15])=[CH:38][CH:39]=1
Reactant: COC(=O)CCS(=O)(=O)NCCOCC(C)c1ccccc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [BH3-]C#N
Product: CC(COCCNS(=O)(=O)CCCNCCc1ccc(O)c2[nH]c(=O)sc12)c1ccccc1
Yield: 10.1 %

Procedure:
The title compound (0.164 g) was prepared according to the procedure in example 5 part e using methyl 3-[2-(2-phenyl-1-propoxy)ethylaminosulphonyl]propanoate (1.01 g), diisobutylaluminiumhydride (1.5 M in toluene, 3 ml), 7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrochloride (0.89 g) and sodium cyanoborohydride (0.19 g).