Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8](=[O:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=2)=[CH:29][CH:28]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)CCC(C(=O)c1cccc(O)c1)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(C(=O)c1cccc(OCc2ccc(Cl)cc2)c1)c1ccccc1C
Temperature: 60 °C
Yield: 87.2 %

Procedure:
A stirred solution of methyl (RS)-5-[3-(hydroxy)phenyl]-4-(2-methylphenyl)-5-oxo-pentanoate (1.68 g) in dimethylformamide (20 mL) is treated with 60% sodium hydride in oil (237 mg). After 15 minutes the mixture is treated with 4-chlorobenzyl chloride (953 mg) and heated at 60° C. for 1 hour. The reaction mixture is evaporated, the residue is dissolved in diethyl ether, washed with water, dried, and evaporated, to give methyl (RS)-5-[3-(4-chlorobenzyloxy)phenyl]-4-(2-methylphenyl)-5-oxopentanoate (2.05 g), in the form of a colouriess oil. [NMR(CDCl3):- 2.0-2.5(4H,m),2.5(3H,s), 3.65(3H,s), 4.8(1H,m),5.0(2H,q),7.0-7.5(12H)].
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.ClCCl.Cl[C:22]1[O:23][C:24]2[C:25](=[C:27]([C:39]#[N:40])[C:28]([CH3:38])=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:30]=2[F:31])[N:26]=1>C(OCC)(=O)C>[F:31][C:30]1[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:28]([CH3:38])[C:27]([C:39]#[N:40])=[C:25]2[C:24]=1[O:23][C:22]([N:11]([CH3:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:26]2
Reactant: CNc1ccccn1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)c3ccccn3)nc2c1C#N
Temperature: 50 °C
Yield: 57.7 %

Procedure:
Diisopropylethylamine (169 μl, 0.944 mmol) and 2-(methylamino)pyridine (102 μl, 0.994 mmol) were added to a dichloromethane (10 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (190 mg, 0.663 mmol), followed by heating under reflux in an oil bath at 50° C. for 3 hours. The reaction liquid was cooled to room, temperature, ethyl acetate (70 ml) was added, followed by washing with water (50 ml) and saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:1) to obtain the entitled compound (137 mg, 57.5%) as a colorless solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].CS(O[CH:17]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18]1)(=O)=O>CC(N(C)C)=O>[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH:17]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18]1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CC(C)N1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCC(Oc2ccc(Cl)cc2Br)C1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Sodium hydride (0.43 g, 60% dispersion in oil) was added portionwise to a stirred solution of 2-bromo-4-chlorophenol (2.1 g) in dimethylacetamide (15 ml). After stirring for 15 minutes, a solution of 1-isopropylpyrrolidin-3-yl methanesulphonate (15 mmol) in dimethylacetamide (15 ml) was added portionwise and the resulting mixture was heated at 90° C. for 18 h. The solvent was evaporated and the residue dissolved in ethyl acetate/water. The solvent phase was washed twice with brine and then dried and evaporated to an oil. Purification was achieved using silica chromatography eluting with dichloromethane/methanol mixtures. This gave the title compound (3.0 g).
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N:12]1[C:20]([NH2:21])=[C:19]2[C:15]([N:16]=[CH:17][NH:18]2)=[N:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[C:46]([O:54][CH2:55][C@H:56]1[O:60][CH2:59][C@H:58]([O:61][S:62]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)(=[O:64])=[O:63])[CH2:57]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.N1C=CC=CC=1>[C:46]([O:54][CH2:55][C@H:56]1[O:60][CH2:59][C@H:58]([O:61][S:62]([C:65]2[CH:66]=[CH:67][C:68]([CH3:71])=[CH:69][CH:70]=2)(=[O:63])=[O:64])[CH2:57]1)(=[O:53])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1.[NH2:21][C:20]1[N:12]=[CH:13][N:14]=[C:15]2[C:19]=1[N:18]=[CH:17][N:16]2[C@H:58]1[CH2:57][C@@H:56]([CH2:55][OH:54])[O:60][CH2:59]1
Reactant: Nc1ncnc2nc[nH]c12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H](COC(=O)c3ccccc3)C2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@@H]1CO[C@H](CO)C1
Temperature: 75 °C
Reaction time: 11 h

Procedure:
1,4-Anhydro-5-O-benzoyl-3-deoxy-2-O-p-toluenesulfonyl-D-ribitol was prepared from 5-benzoyl-3-deoxy-1,2-O-isopropylidene-α-D-ribofuranose by conversion to 5-O-benzoyl-3-deoxy-1-methoxy-α(β)-D-ribofuranose with methanolic HC1, demethoxylation of the latter followed by tosylation of the 2-position with tosyl chloride and pyridine. A mixture of adenine (0.354 g, 2.62 mmol), potassium carbonate (0.362 g, 2.62 mmol), 18-crown-6(0.347 g, 1.31 mmol), and 1,4-anhydro-5-O-benzoyl-3-deoxy-2-O-p-toluenesulfonyl-D-ribitol in DMF (11 mL) was stirred at 75° C. for 11 h. The solvent was removed under reduced pressure. The residue was purified by flash chromatography with 5% MeOH/CHC113 and afforded 0.269 g (0.793 mmol, 60.5%) of the 5'-benzoate of the title compound as a white solid: mp 193°-195° C.; 1H NMR (CDC13): δ2.13-2.22 (m,1H),2.74-2.84 (m,1H),4.12(dd,1H),4.29(dd,1H),4.39-4.50(m,2H),4.59(dd,1H),5.32(m,1H),6.00(s,2H),7.40(t,2H),7.53(t ,1H),7.98(d,1H),8.02(s 1H),8.31(s,1H); UV(MeOH) λmax 260 nm.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14](Cl)[N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Pd]>[NH:1]([C:8]1[N:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][N:13]=[C:12]([CH3:20])[CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc2c(cn1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a flask containing 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (10 mg, 0.03 mmol) in EtOAc (2 mL) and EtOH (2 mL) at room temperature was added a drop of TEA, and Pd/C (10 weight % on activated carbon Degussa type E101, 2 mg). The system was purged with H2 and left stirring at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo to provide 2-anilino-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (8 mg, 91%): LCMS RT: 1.22 min, MH+: 328.3.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:25])[C:23]=1[OH:24].[OH-].[K+].CS(C)=O>CC(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH:21]=[C:22]([Cl:25])[C:23](=[O:24])[C:18]([Cl:17])=[CH:19]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Reactant: Oc1c(Cl)cncc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: O=c1c(Cl)cn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1Cl
Reaction time: 8 h
Yield: 79.6 %

Procedure:
First, 1.129 g of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 1.648 g of 3,5-dichloro-4-hydroxypyridine, and 672 mg of powdered potassium hydroxide were added to 10 ml of dry dimethylsulfoxide. The mixture was allowed to react at 130° C. for 3 hours in a nitrogen atmosphere. The subsequent processes were conducted in the same way as in Example 2. The resultant precipitate was dissolved by heating in dimethylformaldehyde and the solution was decolorized with activated carbon and filtered. Water in an equal amount was added thereto and the solution was allowed to stand overnight to give 1.473 g of crystals of 6-nitro-7-(3,5-dichloro-4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CCO.O>[C:1]([O:4][CH2:5][CH:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added the crude 3a in EtOH solution (about 153 mL) reserved from the previous step at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (2.35 g) in water (60 mL) was added at below −8° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (60 mL) was added at below 10° C. The mixture was warmed to 20-30° C., and H2O (183 mL) was added at this temperature. After being stirred at 20-30° C. for 1 hr, the mixture was further cooled to 0-5° C. and stirred for 1 hr. The mixture was filtered, and the filtered cake was washed with cold 50% EtOH aqueous solution (30 mL). The combined filtrate and washing was concentrated at 40-50° C. under reduced pressure to afford crude 4a as a white powder (18.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH3:10])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[S:19]>CC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([N:9]([CH3:10])[C:18](=[S:19])[O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNc1cccc(OC)n1
Reactant: S=C(Cl)Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(N(C)C(=S)Oc2ccc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To the mixture of 1.38 g of 2-methoxy-6-methylaminopyridine, which is one of the compounds of this invention, and the same amount of anhydrous potassium carbonate in 20 ml of acetone, 2.23 g of O-2-naphthyl chlorothioformate dissolved in 20 ml of acetone was added under stirring at room temperature. After 30 minutes, the reaction mixture was extracted with benzene, washed with water, dried and recrystallized to give 2.75 g of O-2-naphthyl N-(6-methoxy-2-pyridyl)-N-methylthiocarbamate.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]([O:36]C(C)(C)C)=[O:35].S(=O)(=O)(O)O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.CC(C)=O>[CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([O:25][CH2:33][C:34]([OH:36])=[O:35])=[O:24]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
25 g of indometacin, 10 g of potassium carbonate and 190 ml of acetone are stirred at 56° C. for 30 minutes. The mixture is cooled down to 40° C., 0.5 g of benzyltriethylammonium chloride is added, and 15.6 g of tert.-butyl chloroacetate are added dropwise. After 5 hours at 40° C. the reaction is complete (monitored by thin layer chromatography). The mixture is cooled down to 10° C. and 20 ml of concentrated sulphuric acid are then added dropwise in such a way that the temperature does not exceed 25° C. The mixture is stirred at 20° and 25° C. for 6 hours (monitored by thin layer chromatography), about 500 ml of water are added, and the solids are filtered off with suction, are dried in vacuo and are recrystallized from acetone-water.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[O:14][CH3:15])[N:3]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[Cl:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([N:11]=[C:16]=[S:17])=[CH:9][C:8]=2[O:14][CH3:15])[N:3]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)n1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
Step E (4): Dichloromethane (25 mL) was added to a flask charged with 4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-methoxyaniline (0.577 g, 2.57 mmol) and 1,1′-thiocarbonyldi-2(1H)-pyridone (0.597 g, 2.57 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture concentrated in vacuo and the crude product was purified using silica gel chromatography (0-5% EtOAc/chloroform, linear gradient) to afford 3-chloro-1-(4-isothiocyanato-2-methoxyphenyl)-1H-1,2,4-triazole (529 mg, 1.983 mmol, 77% yield) as a off-white solid. LC-MS (M+H)+ 267.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.67 (s, 1 H) 7.79 (d, J=8.55 Hz, 1 H) 6.98 (dd, J=8.70, 1.98 Hz, 1 H) 6.91 (d, J=1.83 Hz, 1 H) 3.97 (s, 3 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9](Br)=[N:10][C:11]([CH:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]2)=[CH:12][CH:13]=1)(C)(C)C.[CH3:25][C:26]1([CH3:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[NH2:7][C:8]1[C:9]([N:29]2[CH2:30][CH2:31][C:26]([CH3:32])([CH3:25])[CH2:27][CH2:28]2)=[N:10][C:11]([CH:14]2[CH2:15][N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH2:19]2)=[CH:12][CH:13]=1
Reactant: CC1(C)CCNCC1
Reactant: CN1CC(c2ccc(NC(=O)OC(C)(C)C)c(Br)n2)CN(C)C1=O
Product: CN1CC(c2ccc(N)c(N3CCC(C)(C)CC3)n2)CN(C)C1=O
Temperature: 25 °C

Procedure:
The title compound is prepared from [2-bromo-6-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester (as prepared in the previous step) and 4,4-dimethylpiperidine (US 2003236247) following the literature procedure of Buchwald (Org. Lett., 4, 2885-8 (2002)). The residue obtained is purified by silica gel chromatography with an appropriate solvent mixture. After isolation, removal of the BOC protecting group from the resulting intermediate is carried out by stirring at RT in TFA-DCM (1:2), monitoring by TLC for completion, and then concentration in vacuo.
Reaction SMILES: CCOCC.Cl.[NH2:7][C@H:8]([C:20]([NH:22][C@H:23]([C:34]([NH:36][C@H:37]([C:47]([NH:49][C@H:50]([C:60]([NH:62][C@H:63]([C:76]([OH:78])=[O:77])[CH2:64][CH2:65][C:66](=[O:75])[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:61])[CH2:51][O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:48])[CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:35])[C@@H:24]([CH3:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:21])[CH2:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:79]([C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95])[C@H:80]([C:84](ON1C(=O)CCC1=O)=[O:85])[CH:81]([CH3:83])[CH3:82]>C1COCC1.CN(C=O)C.CCN(CC)CC>[NH:79]([C:94]([O:96][C:97]([CH3:99])([CH3:98])[CH3:100])=[O:95])[C@H:80]([C:84]([NH:7][C@H:8]([C:20]([NH:22][C@H:23]([C:34]([NH:36][C@H:37]([C:47]([NH:49][C@H:50]([C:60]([NH:62][C@H:63]([C:76]([OH:78])=[O:77])[CH2:64][CH2:65][C:66](=[O:75])[O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:61])[CH2:51][O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:48])[CH2:38][O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:35])[C@@H:24]([CH3:33])[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:21])[CH2:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:85])[CH:81]([CH3:82])[CH3:83]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@@H](N)CC(=O)OCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O)[C@@H](C)OCc1ccccc1
Reaction time: 8 h

Procedure:
Boc-Asp(OBzl)-Thr(Bzl)-Ser(Bzl)-Ser(Bzl)-Glu(OBzl)-OH (50.0 g, 46 mmol) was deprotected with HCl (4.15 N) in THF and worked up as usual to give 45.4 g of white solid. It was dissolved in THF (1.5 liters) and treated with ether (7 liters). On standing at 0° overnight a white solid powder was obtained (44.0 g, mp 179°-184°). Part of this material, HCl.H-Asp(OBzl)-Thr(Bzl)-Ser(Bzl)-Ser(Bzl)-Glu(OBzl)-OH (43.7 g, 42.7 mmol) was then dissolved in 500 ml of DMF, cooled to 0°, and treated with Boc-Val-OSu (15.4 g, 49 mmol) and Et3N (10 ml). The mixture was stirred for 15 hours during which time more Et3N (7.9 ml) was added in several portions maintaining the reaction slightly basic. The insoluble matter was removed by filtration and the filtrate evaporated to dryness. The oily residue was dissolved in CH2Cl2, washed with 5% HOAc, H2O, dried (Na2SO4), and evaporated to a smaller volume (0.5 liter) when treated with petroleum ether. The product crystallized slowly during overnight standing. It was recrystallized from THF and i-PrOH to yield, 26.3 g (51.4%); mp 174°-177°; α]D25 =+0.84° (c, 1, THF).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[S:2].[CH2:5]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([Si](C)(C)C)[CH2:12][CH2:11]1)=[O:9])[CH3:6]>C(OCC)C>[CH2:5]([O:7][C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:1]([Cl:4])=[S:2])[CH2:14][CH2:15]1)=[O:9])[CH3:6]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)N1CCN([Si](C)(C)C)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCN(C(=S)Cl)CC1
Temperature: 25 °C

Procedure:
To a solution of 4.66 ml of 85% thiophosgene in 200 ml of ethyl ether, cooled to -76° is added, while stirring and under nitrogen, a solution of 7 g of 1-ethoxycarbonyl-4-trimethylsilylpiperazine in 35 ml of ethyl ether over a period of 20 minutes. The mixture is allowed to warm up to room temperature overnight. The suspension is filtered and the filtrate is evaporated to dryness. The residue is crystallized from methylene chloridehexane to give 4-ethoxycarbonyl-1-piperazinylthiocarbonyl chloride, m.p. 107°-111°.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl.[OH-].[Na+]>ClCCCl>[O:1]([C:8]1[CH:9]=[C:10]([NH:11][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([OH:15])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=Cc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
The 3-(phenoxy)aniline (555 mg, 3 mmol) and 3-hydroxybenzaldehyde (366 mg, 3 mmol) were dissolved in 7 mL of 1,2-dichloroethane. Acetic acid (0.189 mL, 3.15 mmol) and solid NaBH(OAc)3 (1.01 g, 5 mmol) were added. The mixture was stirred at room temperature for 3 h, then acidified with 1 N HCl solution. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with methylene chloride. The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 609 mg (69%) of the desired N-(3-phenoxyphenyl)[[3-hydroxyphenyl]methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=291.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].C1(OC(=O)O[CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][N:37]([C:40]5[C:48]6[CH:47]=[CH:46][S:45][C:44]=6[CH:43]=[CH:42][CH:41]=5)[CH2:36][CH2:35]4)[CH:27]=3)[CH2:22][CH2:21][C:20]2=[O:49])C=CC=CC=1>C1COCC1>[S:45]1[CH:46]=[CH:47][C:48]2[C:40]([N:37]3[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:26]4[CH:27]=[C:28]5[C:23]([CH2:22][CH2:21][C:20](=[O:49])[N:19]5[CH2:18][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:24][CH:25]=4)[CH2:39][CH2:38]3)=[CH:41][CH:42]=[CH:43][C:44]1=2
Reactant: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1COCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoroethanol (0.10 ml) was dissolved in anhydrous THF (3 ml) under a nitrogen atmosphere and sodium hydride (about 55% oil) (60 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. The obtained solution was ice-cooled again and, under a nitrogen atmosphere, a solution (3 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester (0.25 g) obtained in Example 5 in anhydrous THF was added using a cannula. The reaction mixture was stirred at room temperature for 18 hr under a nitrogen atmosphere. To the reaction mixture was added ice water to discontinue the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated by filtration. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (90 mg) as a colorless oil.
Reaction SMILES: C([Al]CC(C)C)C(C)C.[CH3:10][CH:11]([CH2:16][C:17](OC)=O)[C:12](OC)=O.Cl.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29]>ClCCl.O>[CH3:12][C:11]1[CH:16]=[CH:17][N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:10]=1
Reactant: Nc1ccccc1O
Reactant: COC(=O)CC(C)C(=O)OC
Agent: CC(C)C[Al]CC(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1ccn(-c2ccccc2O)c1
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Diisobutylaluminum (100 mL of 1.0 M, 100 mmol) was added dropwise to a solution of dimethyl 2-methylbutanedioate (7.6 g, 48 mmol) in dichloromethane (15 mL) at −78° C., and the solution was stirred for 1 h. A suspension of 2-aminophenol HCl salt (6.6 g, 45 mmol) in water (110 mL) was added initially dropwise with vigorous stirring, then in small portions. About midway through the addition, the cooling bath was removed to help facilitate stirring. The mixture was stirred vigourously at room temperature overnight, then filtered over celite and the filter cake was washed several times with dichloromethane. The filtrate was separated, and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organics were washed with brine (50 mL), dried over MgSO4, concentrated and purified by column chromatography (0-40% EtOAc/hexane) to give 2-(3-methylpyrrol-1-yl)phenol (3.7 g, 48%) as a yellow oil. ESI-MS m/z calc. 173.2. found 174.3 (M+1)+; Retention time: 1.51 minutes (3 min run).