Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[H-].[Na+].Cl>CN(C=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:21]=1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 500 mL of dry round-bottomed flask were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (12, 8.0 g, 15.2 mmol) and anhydrous benzyl alcohol (128 mL). To another 250 mL of dry round-bottomed flask were charged NaH (60% in mineral oil, 2.44 g, 60.8 mmol) and anhydrous DMF (40 mL). The suspension was stirred at 0° C. in an ice-water bath. Benzyl alcohol (27 mL) was added drop-wise via a syringe. A solution was slowly formed and it was transferred to the nucleoside suspension quickly under a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred. The reaction was complete after 3 h and cooled to ambient temperature. It was neutralized by the addition of 4 N HCl to ca. pH=7 (12 mL). The solution was concentrated under reduced pressure (4 mbar, 90° C. bath). The cloudy residue was diluted with dichloromethane (100 mL) and washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated under reduced pressure to an oily residue. This was purified by column chromatography (Analogix, 0 to 8% gradient of MeOH in DCM). The product eluted at 4% MeOH in DCM. The product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a white foam solid (4.57 g, 11.7 mmol, 77.2%).
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[O:23][CH3:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[CH3:27]I.O>CN(C)C=O>[C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:10]=1[O:23][CH3:24])([CH3:27])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)c1cccc(Sc2ccccc2Cl)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C#N)c1cccc(Sc2ccccc2Cl)c1OC
Reaction time: 0.33 h
Yield: 102.3 %

Procedure:
A solution of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenylthio)phenyl]acetate (3.2 g) in dimethylformamide (10 ml) was added dropwise to a mixture of sodium hydride (65%, 330 mg) and dimethylformamide (20 ml) in 10 minutes at temperature below 10° C. After stirring the mixture at the same temperature for 20 minutes, methyl iodide (2.5 g) was added to the mixture. The mixture was stirred at the same temperature for 15 minutes and then at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and then evaporated under reduced pressure to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenylthio)phenyl]propionate (3.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]([NH2:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[CH3:34][CH:35]([CH3:39])[C:36](Cl)=[O:37]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:19]([NH:21][C:36](=[O:37])[CH:35]([CH3:39])[CH3:34])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(=O)NC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetamide (137b, 20 mg, 60 μmol) in THF (2 ml) was cooled to 0° C., and potassium 2-methylpropan-2-olate (18.6 mg, 170 μmol) was added. The mixture was stirred at 0° C. for 10 min, and a solution of 2-methylpropanoyl chloride (30 mg, 280 μmol) in THF (0.5 ml) was added. Stirring was continued for 30 min at 0° C. Then the sample was concentrated in vacuo and purified by semi-prep. HPLC go give white solid material, 14 mg (59%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH:20]=[CH2:21].O>CN(C=O)C>[F:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][C:8](=[O:10])[N:9]([CH2:21][CH:20]=[CH2:19])[C:4]=2[CH:3]=1
Reactant: C=CCI
Reactant: O=c1cnc2ncc(F)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)cnc2ncc(F)cc21
Yield: 46.5 %

Procedure:
7-Fluoropyrido[2,3-b]pyrazin-2(1H)-one (306 mg, 1.855 mmol) was suspended in dry DMF (10 mL) under argon at rt, and the stirred suspension was treated with K2CO3 (845 mg, 6.12 mmol) and allyl iodide (223 μl, 2.41 mmol). It was then stirred for 1 h before addition of water (100 ml). The mixture was then extracted with DCM (2×200 ml) and 5% MeOH/DCM (100 ml). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated and purified by column chromatography on silica with a 0-10% MeOH in DCM gradient to give the desired product as a yellow solid (177 mg, 47%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12]C2CCCCO2)=[CH:10][CH:9]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C=CC(O)=CC=1)O>C(Cl)Cl>[C:8]1([CH:20]=[CH:19][C:11]([OH:12])=[CH:10][CH:9]=1)[OH:7].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: c1cc(OC2CCCCO2)ccc1OC1CCCCO1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Oc1ccc(O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C1CCOCC1
Reaction time: 12 h

Procedure:
Another functionalization substance may be 2-[2-(undec-10-enyl)-4-(tetrahydro-2H-pyran-2-yloxy) phenoxy]tetrahydro-H-pyran. This molecule may be synthesized from 2-[4-(tetrahydro-2H-pyran-2-yloxy) phenoxy]tetrahydro-2H-pyran using any prior art process. The intermediate may be synthesized by first adding dihydropyran (0.83 mL, 9.1 mmol) and pyridinium p-toluenesulfonate (0.11 g, 0.45 mmol) to a solution of hydroquinone (0.25 g, 2.3 mmol) in CH2Cl2 (3 mL). This reaction mixture is then stirred for about 12 hours and diluted with 10 mL of CH2Cl2. The mixture is subsequently washed by 3×5 mL of NaHCO3 and 1×5 mL brine, dried over MgSO4, and concentrated to a white solid. Silica gel chromatography (4:1 hexane/ethyl acetate) provides the di-tetrahydropyran hydroquinone as a white solid (0.48 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([NH:7][CH3:8])=[CH:5][CH:4]=1.Br[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([N:7]([CH3:8])[CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: CNc1ccc(OC)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)CCOc2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 24.7 %

Procedure:
Compound 6a (0.20 g, 1.46 mmol) and compound 5a (0.32 g, 1.46 mmol) were stirred in acetonitrile (10.0 mL) for 30 mins and then diisopropylethylamine was added dropwise (0.40 mL, 2.92 mmol). The reaction was then stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated, purified by column chromatography to isolate the compound 6 as a colorless oil (0.10 g, 0.36 mmol, 25% yield). MS (ESI, positive) m/z calcd. for C16H20NO3 [M+H]+: 274.14, found: 273.96. 1H NMR (CDCl3, 400 MHz) δ 6.86 (d, J=8 Hz, 2H), 6.70-6.78 (m, 6H), 4.06 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 3.64 (t, J=5.6 Hz, 2H), 2.98 (s, 3H).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=N.CN([CH:13]=[C:14]([C:17](=[O:23])[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)C#N)C.[OH-].[Na+]>C(O)C>[NH2:9][C:7]1[C:14]([C:17]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:23])=[CH:13][NH:5][N:6]=1
Reactant: N=C(N)NN
Reactant: CN(C)C=C(C#N)C(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: Nc1n[nH]cc1C(=O)c1cccs1
Yield: 17.7 %

Procedure:
To a mixture of aminoguanidine nitrate (17.1, 125 mmol) and α-[(dimethylamino)methylene]-β-oxo-2-thiophenepropanenitrile (3) (20.6 g, 100 mmol) in commercial absolute ethanol (120 mL) is added 10N NaOH (5 g of solid NaOH in 12.5 mL of water). The reaction mixture is refluxed for 6 hrs and the solvents removed at reduced pressure on a rotary evaporator. Water (250 mL) is added and an initial precipitate forms and is filtered (13.3 g, 68.8 mmol, 69%). On further standing the aqueous layer deposits an additional quantity of the titled compound (3.42 g, 17.7 mmol, 18%), yielding product (4) as a tan solid (total 16.72 g, 86.5 mmol, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[S:18]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)(=[O:20])=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.1 %

Procedure:
To 4-methoxybenzenamine (580 mg, 4.71 mmol) and triethylamine (1.48 mL, 10.7 mmol) in dichloromethane (10 mL) was added methyl 4-(chlorosulfonyl)benzoate (1.00 g, 4.28 mmol). This mixture was stirred for 16 hours at room temperature. The reaction was diluted with dichloromethane (50 mL) and washed consecutively with water, 10% citric acid, and brine. The organics were dried over sodium sulfate and concentrated via rotovap. The resulting crude material was chromatographed on silica gel using 100% dichloromethane as eluent affording Methyl 4-(N-(4-methoxyphenyl)sulfamoyl)benzoate as a white crystalline solid (400 mg, 30% yield)
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][NH:15][CH2:16][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>[CH2:17]([O:19][C:20]([N:15]1[CH2:14][CH2:13][C:10]2[NH:11][C:12]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]=2[CH2:16]1)=[O:21])[CH3:18]
Reactant: O=[N+]([O-])c1cccc2c3c([nH]c12)CCNC3
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)N1CCc2[nH]c3c([N+](=O)[O-])cccc3c2C1
Reaction time: 15 h
Yield: 55.9 %

Procedure:
6-Nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 0.99 mmol) was dissolved in CH2Cl2 (2.5 mL) with sat. aq. K2CO3. Ethylchloroformate (130 mg, 1.2 mmol) was added at 0° C. The reaction was brought to room temperature and stirred for 15 h. The layers were separated and the aqueous layer was extracted with CHCl3 (3×5 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated affording ethyl-6-nitro-1,3,4,5-tetrhydro-2H-pyrido[4,3-b]indole-2-carboxylate as an orange semi-solid (160 mg, 56%). 1H NMR (CDCl3, 300 MHz) δ 8.17 (d, 1H, J=8.1 Hz), 7.78 (d, 1H, J=7.6 Hz), 3.19 (t, 1H, J=8.1 Hz), 4.73 (s, 2H), 4.18-4.23 (m, 4H), 2.91-2.98 (m, 2H), 1.30-1.39 (t, 3H, J=6.9 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:26])=[N:8][C:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(-c2ncccn2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cnc(-c2ncccn2)nc1Cl
Temperature: 25 °C
Yield: 82 %

Procedure:
A suspension of 1.62 g (6.5 mmol) 4-hydroxy-[2,2′]bipyrimidinyl-5-carboxylic acid ethyl ester in 16 ml POCl3 was heated at reflux for lh. The solution was cooled to RT and poured into 100 ml ice-water. The pH of the solution was adjusted to 8 with sat. NaHCO3-solution. The water phase was extracted three times with 80 ml CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 95:5) to give 1.43 g (82%) 4-chloro-[2,2′]bipyrimidinyl-5-carboxylic acid ethyl ester as a light brown solid, MS (EI): 264.1 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: O=C(O)/C=C/c1cccc(O)c1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)/C=C/c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Under nitrogen, to a solution of (2E)-3-(3-hydroxyphenyl)-2-propenoic acid (330 mg, 2.0 mmol) in THF (20 mL), was added 1-methylpiperazine (400 mg, 4.0 mmol), HOBT (810 mg, 6.0 mmol), HBTU (760 mg, 2 mmol), followed with 4-methylmorpholine (670 μL, 6.0 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated and the residue was purified with reverse phase HPLC (5% MeCN/H2O→60% MeCN/H2O) to afford the title compound as a white solid (397 mg, 81%). MS (S+) m/e 247 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C@@H:14]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C@H:20]3[C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]3[C:28]([C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[NH:36][C:37](=[O:43])OC(C)(C)C)=[O:29])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O>[C:8]1([C@@H:14]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C@H:20]3[C@@H:15]2[CH2:16][CH2:17][CH2:18][N:19]3[C:28]([C@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[NH:36][C:37](=[O:43])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:29])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CCC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 65.1 %

Procedure:
TFA (1 ml) was added to tert-butyl ((1R,2S)-2-{[(4aR*,5R*,10bR*)-5-phenyl-3,4,4a, 5,6,10b-hexahydrobenzo[h]-1,6-naphthyridin-1(2H)-yl]carbonyl}cyclohexyl)carbamate (69 mg, 0.14 mmol), and the mixture was stirred at room temperature for 3 min. Ice was added to the reaction solution, and the mixture was basified with 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in dimethylacetamide (2 ml), benzoyl chloride (28 mg, 0.17 mmol) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g), and eluted with hexane-ethyl acetate (7:1-3:1, v/v) to give the title compound (45 mg, 65%) as a colorless amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.C(O)=O.[ClH:37]>C(O)C>[ClH:37].[ClH:37].[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:31]1[CH2:30][CH2:29][N:28]([CH:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[CH2:33][CH2:32]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
2,4-Dimethoxybenzaldehyde (6.7 g; 40.3 millimoles) and 11.5 g (39.9 millimoles) of bis(4-fluorophenyl)methylpiperazine were melted in an oil bath at 100° C., and 2.0 ml (53.0 millimoles) of formic acid was added dropwise. The mixture was stirred under heat for 30 minutes, and allowed to cool to room temperature. A mixture of 8 ml of conc. hydrochloric acid and 80 ml of ethanol was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 5.1 g (yield 25.0%) of 1-(2,4-dimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:19]([CH2:20][CH2:21][CH3:22])[C:18](=[O:23])[N:17]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:16]=2)=[CH:9][CH:8]=1)[CH3:2].[I:35]I>S([O-])([O-])(=O)=O.[Ag+2].C(O)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:19]([CH2:20][CH2:21][CH3:22])[C:18](=[O:23])[N:17]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)[N:16]=2)=[CH:9][C:8]=1[I:35])[CH3:2]
Reactant: CCCn1c(CCc2ccc(OCC(=O)OCC)cc2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCCn1c(CCc2ccc(OCC(=O)OCC)c(I)c2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.6 %

Procedure:
A mixture of (4-{2-[5-Oxo-4-propyl-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-ethyl}-phenoxy)acetic acid ethyl ester (180 mg, 0.38 mmol), iodine (105 mg, 0.42 mmol), silver sulfate (131 mg, 0.42 mmol) and ethanol were stirred at room temperature. After 3.5 h, more iodine (86 mg) and silver sulfate (106 mg) were added and stirred for another 0.5 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried and evaporated to dryness to afford the product (217 mg, 95%). 1HMR (400 MHz, CDCl3) δ 8.15 (d, 2H, J=8.4 Hz), 7.73 (s, 1H), 7.67 (d, 2H, J=8.4 Hz), 7.18 (m, 1H), 6.67 (d, 1H, J=8.0 Hz), 4.66 (s, 2H), 4.26 (q, 2H, J=7.6 Hz), 3.68 (t, 2H, J=7.3 Hz), 3.05 (t, 2H, J=7.4 Hz), 2.82 (t, 2H, J=7.3 Hz), 1.7 (m, 2H), 1.29 (t, 3H, J=7.6 Hz), 0.96 (t, 3H, J=7.6 Hz); ESMS m/z (relative intensity) 604.2 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH:20]=O)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][N:34]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][N:45]2[CH2:46][CH2:47][CH:42]([N:34]([CH2:33][C:31]3[CH:30]=[CH:29][C:28]4[O:23][CH2:24][CH2:25][O:26][C:27]=4[CH:32]=3)[C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:43][CH2:44]2)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(OCc2ccccc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To 30 mL of a dichloromethane solution containing 1.20 g of (4-benzyloxy-2-oxoquinolin-1(2H)-yl)acetaldehyde, 40 mL of a dichloromethane solution containing 1.71 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.25 g of acetic acid were added, and stirred at room temperature for 90 min. To the reaction mixture, 1.37 g of sodium triacetoxyborohydride was added, and stirred at the same temperature for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1], to give 2.10 g of tert-butyl (1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a white solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(CC)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Product: CCC(CC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 168-170° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=1.8 Hz, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.78 (s, 1 H), 4.82-4.78 (m, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 1.88-1.74 (m, 2 H), 1.70-1.60 (m, 2 H), 0.88 (t, J=7.5 Hz, 6 H); HRMS (ESI) calcd for C17H19N3OCl3 (M+H)+: 386.0594; found m/z 386.0614.
Reaction SMILES: [OH-:1].[Li+].[C:3]([O:7][C:8]([NH:10][C@H:11]([CH:32]1[CH2:36][C@@H:35]([CH3:37])[C:34](=[O:38])[O:33]1)[CH2:12][C@@H:13]([CH:29]([CH3:31])[CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>COCCOC.O>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:12][C@@H:13]([CH:29]([CH3:31])[CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:16]=1)[C@@H:32]([OH:1])[CH2:36][C@@H:35]([CH3:37])[C:34]([OH:33])=[O:38])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: [OH-]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C2C[C@@H](C)C(=O)O2)C(C)C)ccc1OC
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
28.5 ml of 1N lithium hydroxide solution are added to 3.6 g of 2-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-butyl}-4(R)-methyl-tetrahydrofuran-5-one in 210 ml of 1,2-dimethoxyethane/water (2:1) at room temperature. The reaction mixture is stirred at room temperature for a further 1 hour and then concentrated by evaporation. Ice and 10% aqueous citric acid solution are added to the residue. Repeated extraction with chloroform yields the crude title compound: Rf (ethyl acetate/hexane=1:1)=0.05; HPLC Rt =16.41 minutes.