Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[N:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(N)cn1
Reactant: COc1ccc(-c2cc(C(Cl)CC(C)C)c(C)o2)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)O)nc3)c(C)o2)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (0.9 g), methyl 5-aminopyridine-2-carboxylate (0.5 g), sodium carbonate (0.5 g) and sodium iodide (0.9 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (6 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid. To the obtained 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid (395 mg) were added ethyl β-alaninate hydrochloride (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg), triethylamine (168 μL) and N,N-dimethylformamide (10 mL) was added. The obtained mixture was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (171 mg, 35%) as an amorphous compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]([C:7]1[CH:28]=[CH:27][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:25])[CH3:24])[C:15]=3[OH:26])[C:9]=2[CH:8]=1)[CH3:6].I[CH3:31].[F-].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]([C:7]1[CH:28]=[CH:27][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:24])[CH3:25])[C:15]=3[O:26][CH3:31])[C:9]=2[CH:8]=1)[CH3:6]
Reactant: COC(=O)C=C(C)c1ccc2scc(-c3cc(C(C)C)cc(C(C)C)c3O)c2c1
Reactant: CI
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=C(C)c1ccc2scc(-c3cc(C(C)C)cc(C(C)C)c3OC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
3-[3-(2-Hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic acid methyl ester (100 mg, 0.24 mmol) was dissolved in DMF (5 ml), and iodomethane (0.0183 ml, 0.29 mmol) and cesium fluoride (149 mg, 0.98 mmol) were added to this solution. The reaction was stirred at ambient temperature under nitrogen overnight, then water (2 ml) was added and the mixture extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine, then dried over MgSO4 and concentrated in vacuo to yield 3-[3-(3,5-di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]but-2-enoic acid methyl ester as a pale yellow solid (101 mg, 98%). 1H NMR (250 MHz, CDCl3): δ 7.85 (d, 1H, J=6.2), 7.80 (s, 1H), 7.46 (s, 1H), 7.40 (dd, 1H, J=0.6, J=8.8), 7.09 (d, 1H, J=1.2), 7.03 (d, 1H, J=1.2), 6.12 (d, 1H, J=0.6), 3.65 (s, 3H), 3.32 (m, 1H), 3.18 (s, 3H), 2.85 (m, 1H), 2.53 (d, 3H, J=0.6), 1.24 (s, 3H), 1.22 (s, 6H), 1.18 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:22]([CH3:38])[CH2:23][CH:24]=[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3]1.N1C=CC=CC=1.[C:45](OC(=O)C)(=[O:47])[CH3:46].C1(C)C=CC=CC=1.[CH3:59][CH2:60][O:61]CC>CN(C)C1C=CN=CC=1.O>[C:45]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([O:21][C:60](=[O:61])[CH3:59])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH:22]([CH3:38])[CH2:23][CH:24]=[C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3]1)(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Reactant: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](OC(C)=O)[C@]2(C)[C@@H](C(C)CC=C(c4ccccc4)c4ccccc4)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3α, 12α-dihydroxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (15.6 g), pyridine (14.8 ml), acetic anhydride (57.4 ml), 4-dimethylaminopyridine (3.71 g) and toluene (60 ml) is stirred at room temperature for about 30 minutes, diluted with ether and water and the layers are separated. The organic solution is washed water, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is crystallized from 25% ether in hexane to give the desired product as an off-white solid.
Reaction SMILES: C[Si](O[C:6]([O:10][CH3:11])=[C:7](C)[CH3:8])(C)C.ClC1C=[C:15](C=CC=1)[C:16]([O-:18])=[O:17].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC)(=O)C(C)=C.C(OCCN(C)C)(=O)C(C)=C>CO.C(#N)C.O1CCCC1>[C:16]([O:18][CH:7]([CH3:8])[CH2:6][O:10][CH3:11])(=[O:17])[CH3:15]
Reactant: O=C([O-])c1cccc(Cl)c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCN(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: COCC(C)OC(C)=O

Procedure:
A 500 mL four-necked round-bottom separable flask was equipped with a condenser tube, a dropping funnel, a nitrogen inlet, a stirrer and a thermometer. Tetrahydrofuran (THF) of 250 parts by weight and dimethylketene methyl trimethylsilyl acetal of 2.32 parts by weight, which is an initiator, were poured into the flask through the dropping funnel, followed by sufficient nitrogen substitution. Then, 0.2 part by weight of 1 mol/L acetonitrile solution of tetrabutylammonium m-chlorobenzoate, which is a catalyst, was injected with a syringe. Methyl methacrylate (hereinafter may be referred to as MMA) of 93.3 parts by weight was added dropwise with the dropping funnel for 60 minutes. While cooling the separable flask, the temperature was kept below 40° C. One hour later, dimethylaminoethyl methacrylate (hereinafter may be referred to as DMMA) of 40.0 parts by weight was added dropwise for 20 minutes. After one hour reaction, methanol of 0.5 parts by mass was added to terminate the reaction. The thus-obtained copolymer THF solution was reprecipitated in hexane, filtrated, dried in vacuum and then purified, thus obtaining a polymer. To the amine-containing polymer obtained in this manner of 60 parts by weight, propylene glycol monomethyl ether acetate (hereinafter may be referred to as PGMEA) of 40 parts by weight was added and uniformly mixed to obtain a polymer solution B1. For the polymer solution B1, GPC was measured with HLC-8220 equipped with an RI detector (manufactured by Tosoh Corporation), using THF as the developing solvent and a molecular weight standard polymer as the standard polystyrene, thus obtaining the molecular weight distribution and mass average molecular weight. The amine value was 115 mg KOH/g. The mass average molecular weight Mw was 9,900. The number average molecular weight Mn was 8,320. The molecular weight distribution Mw/Mn was 1.19 (MMA/DMMA mass ratio: 7/3).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-].[CH3:19][C@H:20]1[N:25]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[N:38]=[CH:37][CH:36]=[N:35]2)=[O:27])[CH2:24][C@H:23]([CH:39]=O)[CH2:22][CH2:21]1>CO>[C:39]([C@H:23]1[CH2:24][N:25]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[N:38]=[CH:37][CH:36]=[N:35]2)=[O:27])[C@H:20]([CH3:19])[CH2:21][CH2:22]1)#[CH:1]
Reactant: C[C@@H]1CC[C@@H](C=O)CN1C(=O)c1ccccc1-n1nccn1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CC[C@@H](C)N(C(=O)c2ccccc2-n2nccn2)C1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A mixture of potassium carbonate (0.556 g, 4.02 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.837 g, 4.36 mmol) in methanol (35 mL) under an atmosphere of nitrogen was cooled to 0° C. To this mixture was added a solution of (3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine-3-carbaldehyde (1.00 g, 3.35 mmol) in methanol (12 mL) dropwise. The reaction was allowed to warm slowly to RT and stir for 17 h. The mixture was concentrated in vacuo, treated with water, and extracted with ethyl acetate. The organic fraction was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to provide [(2R,5S)-5-ethynyl-2-methylpiperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 295.3 for M+H+, and [(2R,5R)-5-ethynyl-2-methylpiperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 295.2 for M+H+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH3:16])[CH2:9][N:10]2[C:14]([SH:15])=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(C1C=CC=[C:29]2[C:30](NC(=O)[C:28]=12)=[S:31])CC>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH3:16])[CH2:9][N:10]2[C:14]([S:15][S:31][CH2:30][CH2:29][CH3:28])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: C[Si](Cn1ncnc1S)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCc1cccc2c1C(=O)NC2=S
Solvent: ClC(Cl)Cl
Product: CCCSSc1ncnn1C[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of 1.4 g (0.004 mol) of bis(4-fluorophenyl)methyl(5-mercapto-1H-1,2,4-triazol-1-ylmethyl)silane in 10 mL of chloroform at 25° was added 1.1 g (0.005 mol) of propylthiophthalimide. The mixture was stirred two hours, filtered, and evaporated. The residue was flash chromatographed using 0-10% ether/methylene chloride to give 1.5 g of the title disulfide as a thick oil: ir (neat) 2950, 1585, 1495, 1230, 1160, 1104, 820 cm-1 ; nmr (CDCl3) δ 0.7 (3H, s), 1.0 (3H, t), 1.7 (2H, m), 2.8 (2H, t), 4.2 (2H, s), 7.1 (4H, m), 7.5 (4H, m), 7.8 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH3:10].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.C(O)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1/[C:9](=[N:21]/[NH:20][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH3:10]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: NNC(=O)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1ccccc1)c1c(O)cccc1O
Temperature: 120 °C
Yield: 56.3 %

Procedure:
1-(2,6-Dihydroxyphenyl)ethanone (100 mg, 0.657 mmol) and benzohydrazide (89 mg, 0.657 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (100 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 7.59 (m, 2H), 7.49 (m, 1H), 7.39 (m, 2H), 7.11 (t, 1H, J=8.0 Hz), 6.45 (m, 2H), 2.35 (s, 3H). ESI-MS: 271.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:37][CH2:38][NH:39][C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([O:12][CH2:37][CH2:38][NH:39][C:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NCCO)c1ccccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCCNC(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of (2 S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoic acid (3.95 g, 8.27 mmol), N-(2-hydroxyethyl)[2-(phenylmethoxy)phenyl]carboxamide (1.8 g, 6.63 mmol), and 4-(dimethylamino)pyridine (84 mg) in 40 mL of anhydrous dichloromethane was added slowly 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC) (2.0 g, 10.34 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice followed by the addition of brine. The organic layer was separated, dried through MgSO4 and concentrated under reduced pressure. Chromatography (silica gel, 1:2 then 1:1.5 ethyl acetate/hexane) of the residue afforded 3.7 g (73%) of 2-{[2-(Phenylmethoxy)phenyl]carbonylamino}ethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>C1COCC1.CO.[Ni]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1c([N+](=O)[O-])ccc2ncccc12
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2ncccc2c1N

Procedure:
A solution of 5-amino-6-nitroquinoline (25 g, 0.13 mol) in THF (500 mL) and methanol (500 mL) was treated with Raney nickel (7 g) under a hydrogen atmosphere (50.4 psi) on a Parr apparatus for 3.4 hours. Standard work-up gave the 5,6-diaminoquinoline.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>CC(N(C)C)=O>[NH:6]1[CH2:7][CH:3]([CH2:2][O:1][C:12]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=3)[CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:4][C:5]1=[O:8]
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Reactant: O=C1CC(CO)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2cc3ncccc3c(OCC3CNC(=O)C3)n2)ccc1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
45 mg (0.38 mmol) 4-hydroxymethylpyrrolidin-2-one was placed in 1 ml dimethylacetamide and 16 mg (0.29 mmol) sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg (0.34 mmol) of 6.1 was added and the mixture was stirred for 2 h at 50° C. and overnight at 25° C. The reaction mixture was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried.
Reaction SMILES: [C@@H:1]1([N:10]2C=CC(N)=NC2=O)[O:9][C@H:6]([CH2:7]O)[C@@H:4](O)[C@H:2]1O.[C:18](OC(=O)C1C=CC=CC=1)(=O)[C:19]1C=CC=CC=1>CN(C=O)C>[C:1]([NH2:10])(=[O:9])[C:2]1[CH:4]=[CH:6][CH:7]=[CH:19][CH:18]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 282.4 %

Procedure:
To a suspension of cytidine (100 g, 0.411 mol) in DMF (2.06 L) is added benzoic anhydride (102.4 g, 0.452 mol). The mixture was stirred at room temperature for 20 h. The DMF was removed in vacuo and the residue was triturated with diethyl ether. The resulting solid was collected by suction filtration and washed with diethyl ether (2×200 mL). Further drying in vacuo at room temperature gave the N4 benzamide (140.6 g, 98.3%). A portion of this material (139.3 g, 0.401 mol) was dissolved in anhydrous pyridine (1.2 L) and was treated with 1,3-dichloro-1,1,3,3-tetraisopropyl-disiloxane (141.4 mL, 0.441 mol) at room temp. The solution was stirred at room temperature overnight. The mixture was concentrated to near dryness in vacuo and coevaporated with toluene (3×200 mL). The residue was treated with EtOAc (1.8 L) and washed with HCl (2×200 mL, 0.05 N), NaHCO3 (5%, 2×400 mL). The organic layer was washed dried (Na2SO4), filtered, and evaporated to dryness. Compound 4-1 (256.5 g, >100%) was isolated as a white foam and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[C:22]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])([CH3:25])([CH3:24])[CH3:23].O1CCOCC1.C(N(C(C)C)C(C)C)C>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:29][C@H:28]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:31])[CH3:30])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O)C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 25 %

Procedure:
To ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (2.44 g, 8.28 mmol, see Example 2) and L-alanine t-butyl ester hydrochloride (2.26 g, 12.4 mmol), were added 1,4-dioxane (5.52 mL) and N-ethyl-N-isopropylpropan-2-amine (4.33 mL, 24.8 mmol). The reaction mixture was then heated in a microwave at 140° C. for 10 minutes. The reaction mixture was diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 3 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (0.815 g) as a light yellow amorphous solid after flash chromatography. MS (m/z)=338(M+H-tBu)+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[NH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O>[CH2:11]([N:10]1[CH2:2][CH2:3][N:4]([CH2:8][CH2:7][OH:6])[C:5]1=[O:9])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: O=C1OCCN1CCCl
Solvent: O
Product: CCCCN1CCN(CCO)C1=O
Yield: 72 %

Procedure:
6.17 g of 3-(2-chloroethyl)oxazolidin-2-one and 6.45 g of 1-aminobutane were stirred together for 30 hours at room temperature and then at reflux for 6 hours. The cooled reaction mixture was diluted with water and extracted with ether. The organic extracts were dried and concentrated to give 5.53 g (70%) of crude 1-butyl-3-(2-hydroxyethyl)imidazolidin-2-one. A dry 250 ml flask equipped with nitrogen inlet, refluxcondenser and stirring bar was charged with 1.34 g of hexane washed 60% NaH/oil and 40 ml of dry DMF. To this was slowly added 5.23 g of 1-butyl-3-(2-hydroxyethyl)imidazolidin-2-one in 10 ml of THF. After the initial reaction had subsided the reaction mixture was heated at 60° C. for 2 hours. 3.1 ml ofiodoethane was injected dropwise into the reaction mixture and it was refluxed for 16 hours. The reaction mixture was cooled and quenched with dilute HCl and ether. The ether layer was washed with brine, dried and concentrated to give 5.15 g (85.5%) of crude product. Kugelrohr distillation at 120°-125° C./0.2 mm gave colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=[O:6])[CH3:2]>CCOC(C)=O.CCO.CCOC(C)=O.O=[Pt]=O>[CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH2:18][C:19]1[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc([N+](=O)[O-])cc1)Cc1cc(Cl)cc(Cl)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A suspension of PtO2 (250 mg) in EtOAc (5 mL) was added to a solution of ethyl[(3,5-dichlorobenzyl) (4-nitrobenzyl)amino](oxo)acetate (2.00 g, 4.86 mmol) in EtOH/EtOAc (2/1, 90 mL) under H2 (1 atm). The reaction mixture was stirred vigorously at rt for 30 min. The reaction mixture was filtered over a pad of Celite and silica gel to remove the catalyst. The solvents were removed under reduced pressure. The residue was purified by flash chromatography over silica gel (c-Hex/EtOAc 2/1) to give the title compound as a pale yellow oil (1.21 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.05 (m, 5H), 6.71 (m, 2H), 4.39 (m, 4H), 4.25 (br s, 2H), 1.36 (m, 3H). HPLC (Condition A), Rt: 3.4 min (HPLC purity: 94.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:35][C:36]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:39]4[CH2:40][CH2:41][C:36]([F:42])([F:35])[CH2:37][CH2:38]4)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Reactant: FC1(F)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCC(F)(F)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 35 (50 mg) in 1-methyl-2-pyrrolidinone (3 mL) is added N,N-diisopropylethylamine (0.03 mL) and 4,4-difluoropiperidine from Preparation No. 37 (50 mg). The reaction mixture is stirred at room temperature overnight and then heated at 50° C. for 4 hrs. The mixture is cooled to room temperature and poured into water to precipitate the product. The crude solid is recrystallized from CH2Cl2/hexanes to afford 51.5 mg (84%) of the title compound as a white solid.