Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[C:3]([O:8][C@@H:9]1[C@@H:17]([CH2:18]I)[C:16](=[O:20])[O:15][CH2:14][C@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12](=[O:29])[O:11][C@H:10]1[CH3:30])(=[O:7])[CH:4]([CH3:6])[CH3:5].[F:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:3]([O:8][C@@H:9]1[C@@H:17]([CH2:18][C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)[C:16](=[O:20])[O:15][CH2:14][C@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12](=[O:29])[O:11][C@H:10]1[CH3:30])(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: Fc1ccc(I)cc1
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CI
Agent: [Pd]
Agent: II
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1Cc1ccc(F)cc1
Temperature: 22 °C
Reaction time: 0.02 h
Yield: 37.6 %

Procedure:
To a suspension of freshly ground zinc dust (139 mg, 2.13 mmol) in an oven-dried flask containing a stir bar were added DMF (200 μL; just covered the dust) and iodine (54 mg, 0.21 mmol), and the mixture was stirred for 1 min. To the mixture was added a solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(iodomethyl)-6-methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (273 mg, 0.53 mmol) in DMF (1 mL) slowly at 40° C. After 15 min, the reaction mixture was cooled to ambient temperature (about 22° C.) and a solution of Pd2(dba)3 (12 mg, 0.01 mmol), (o-tol)3P (16 mg, 0.05 mmol), and 1-fluoro-4-iodobenzene (80 μL, 0.69 mmol) in DMF (900 μL) was added to the reaction and the reaction was warmed back to 40° C. and stirring continued for 1.5 hr. The mixture was cooled, diluted with EtOAc (2 mL), and filtered through a 0.45 micrometer (μm) fritted filter disc. The solution was diluted with EtOAc (100 mL), washed with H2O (3×), dried over MgSO4, filtered, and concentrated. Purification by column chromatography (SiO2, 0→20% EtOAc/hexanes) gave the title compound (96 mg, 38%) as a white, glassy solid: mp 58-66° C.; 1H NMR (300 MHz, CDCl3) δ 7.08 (m, 2H), 6.95 (m, 2H), 5.22-5.14 (m, 3H), 4.93 (m, 1H), 4.80 (m, 1H), 3.46 (m, 1H), 3.00-2.80 (m, 2H), 2.64 (m, 2H), 1.44 (s, 9H), 1.31 (d, J=6.4 Hz, 3H), 1.25 (d, J=7.0 Hz, 3H), 1.25 (d, J=7.0 Hz, 3H); ESIMS m/z 503.3 ([M+Na]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN1CCOCC1.[CH:18]([NH2:21])([CH3:20])[CH3:19].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:18]([NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=1)([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: O=C(O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)c1cccc(O)c1
Reaction time: 16 h

Procedure:
3-Hydroxybenzoic acid (0.966 g, 7.0 mmol), N-methylmorpholine (2.3 mL, 21 mmol), iso-propylamine (1.78 mL, 21 mmol) and CH2Cl2 (30 mL) were dissolved together and hydroxybenzotriazole (1.03 g, 7.7 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.47 g 7.7 mmol) was added; stirred 16 h, diluted with CH2Cl2 (70 mL) and the organic phase was washed with satd aq NaHCO3, H2O, 0.3 N HCl, H2O, and satd aq NaCl, dried (Na2SO4) and concentrated to afford 443 mg as a white foam. 1H NMR (CDCl3): d 7.23 (m, 3), 6.90 (m, 1), 4.22 (m, 1), 1.25 (d, 6).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[CH:38]=O>>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[CH2:38][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]2[C:16]3[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:19]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc2ccccc2o1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc5ccccc5o4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and benzofuran-2 carbaldehyde. MS (ESI) m/z 509.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5].CCN(C(C)C)C(C)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.CCOC(C)=O>[CH3:18][S:19]([O:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5])(=[O:21])=[O:20]
Reactant: CC(=O)C(C)(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)C(C)(C)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a solution of 4-hydroxy-3,3-dimethylbutan-2-one (9.7 g, 84 mmol) and DIPEA (16.04 mL, 92 mmol) in DCM (50 mL) cooled to 0° C. was dropwise added methanesulfonyl chloride (7.16 mL, 92 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3, sat. NaCl, dried (MgSO4), filtered and concentrated to yield 2,2-dimethyl-3-oxobutyl methanesulfonate (14.6 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.21 (2H, s), 3.04 (3H, s), 2.21 (3H, s), 1.25 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[N:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(OCC)(=O)C.[Pd+2].Cl[Cu]>[F:41][C:38]1[CH:37]=[N:36][C:35]([C:4]2[C:5]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13]3)=[N:6][C:7]([S:9][CH3:10])=[N:8][C:3]=2[O:2][CH3:1])=[N:40][CH:39]=1
Reactant: Fc1cnc(Br)nc1
Reactant: COc1nc(SC)nc(NC2CCCN(C(=O)OC(C)(C)C)C2)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Cu]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: COc1nc(SC)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1ncc(F)cn1
Temperature: 100 °C

Procedure:
In a 40 mL vial, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (0.025 g, 0.031 mmol), tert-butyl 3-((6-methoxy-2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.15 g, 0.312 mmol), 2-bromo-5-fluoropyrimidine (0.083 g, 0.468 mmol) and CuCl (0.031 g, 0.312 mmol) were combined, then purged with argon. Then degassed DMF (3 mL) followed by Cs2CO3 (0.407 g, 1.249 mmol) were added to the vial. The reaction was then heated at 100° C. for 18 h. The mixture was cooled, diluted with ethyl acetate, washed with water, dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The material was purified by column chromatography on silica gel (0-100% EtOAc in hexanes) to afford the desired product. MS (m/z)=451 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[Cl:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35](Cl)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:29].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reactant: ClCCCc1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (410 mg, 1.00 mmol), 4-(3-chloropropyl)pyridyl hydrochloride (480 mg, 2.5 mmol), potassium carbonate (480 mg) and potassium iodide (40 mg) in DMF (15 ml) was heated at 60° C. for 15 hours. After cooling to ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (10 ml) and 2M sodium hydroxide (2 ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and concentrated hydrochloric acid-(0.5 ml) was added. The resulting solid was filtered off and was purified by preparative C18 HPLC using a gradient of methanol/water (0% to 80%) as eluant. After evaporation of the methanol, concentrated hydrochloric acid (0.3 ml) was added and the solution was evaporated to dryness. After trituration with acetone, the solid was filtered off and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazoline hydrochloride (243 mg, 48%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])C=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:11][C:8]([C:12]1[CH:13]=[C:14]([C:2](=[CH2:1])[C:3]([OH:5])=[O:4])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])([CH3:9])[CH3:10]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C(=O)O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A solution of malonic acid (Aldrich, 4.36 g, 41.9 mmol), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (Aldrich, 5.00 g, 20.9 mmol), piperidine (Aldrich, 0.18 g, 2.10 mmol) and acetic acid (0.13 g, 2.10 mmol) in toluene (100 mL) was warmed at reflux (water removed using a Dean-Stark trap). After 5.5 h malonic acid was added (4.36 g, 41.9 mmol) and the reaction mixture was warmed at reflux for 12 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was chromatographed (SiO2, flash, methanol-methylene chloride, 5:95) to give 2.43 g (42.1% yield of (E)-1-(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl propenoic acid as a white solid.
Reaction SMILES: Cl.Cl.[OH:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([F:31])=[C:26](F)[C:27]=2[F:29])[C:22](=[O:32])[C:21]([C:33]([OH:35])=[O:34])=[CH:20]1)[CH3:18].Cl>O.CS(C)=O>[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([F:31])=[C:26]([N:7]3[CH2:8][CH2:9][N:4]([OH:3])[CH2:5][CH2:6]3)[C:27]=2[F:29])[C:22](=[O:32])[C:21]([C:33]([OH:35])=[O:34])=[CH:20]1)[CH3:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: ON1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(O)CC3)c(F)c21
Temperature: 100 °C
Yield: 81.1 %

Procedure:
1-Hydroxypiperazine dihydrochloride (3.94 g) (which is prepared in Preparation 1), triethylamine (21 ml) and dimethylsulfoxide (30 ml) are added to 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.07 g), which is prepared according to the procedure described in Japanese Patent First Publication No. 30964/1981, and the mixture is heated at 100° C. for 30 minutes. After cooling to room temperature, water (200 ml) is added to the mixture and the pH is adjusted to 7.0 with dil. HCl. The precipitated crystals are filtered, washed with water and dried. The product is recrystallized from a mixture of dimethylformamide and water to yield 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (4.3 g) as pale yellow needles, m.p. 253°-260° C. (decomposed with foaming) (which starts to color brown at around 234° C.).
Reaction SMILES: [C:1]([NH:4][NH2:5])(N)=[NH:2].Cl.[CH:7]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([N:20]=[C:21]=[S:22])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:2][C:1]1[N:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([CH:7]3[CH2:9][CH2:8]3)=[CH:11][CH:12]=2)[C:21]([SH:22])=[N:5][N:4]=1
Reactant: N=C(N)NN
Reactant: S=C=Nc1ccc(C2CC2)c2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 15 h
Yield: 50.6 %

Procedure:
A mixture of aminoguanidine hydrochloride (3.18 g, 29 mmol), 1-cyclopropyl-4-isothiocyanatonaphthalene (3.24 g, 14 mmol) and diisopropylethylamine (3 eq) in DMF (20 mL) was stirred at 50° C. for 15 hours. The solvent was removed under reduced pressure, toluene added, and the solvent was evaporated again. Sodium hydroxide solution (2M, 30 mL) was added and the reaction mixture heated at 50° C. for 60 hours. The reaction mixture was filtered and the filtrate neutralized with aqueous HCl (2M). The mixture was re-filtered and the solvent removed under reduced pressure. The residue was purified by silica gel chromatography to yield 5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol (2.0 g, 49%).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([P:11]([CH2:16][P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)C.[OH-].[Li+]>CO.O>[CH2:20]([O:19][P:17]([CH2:16][P:11]([O:13][CH2:14][CH3:15])([C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:25])=[O:3])=[CH:10][CH:9]=1)=[O:12])([O:22][CH2:23][CH3:24])=[O:18])[CH3:21]
Reactant: CCOC(=O)c1ccc(P(=O)(CP(=O)(OCC)OCC)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(CP(=O)(OCC)c1ccc(C(=O)O)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[(Diethoxyphosphorylmethyl)-ethoxyphosphinoyl]-benzoic acid ethyl ester (3c) (1 g, 2.55 mmol) in methanol (25 mL) was slowly added lithium hydroxide (monohydrate, 0.11 g, 2.55 mmol) in water (25 mL). The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to remove methanol and diluted with brine, then extracted with EtOAc (3×100 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were dried over Na2SO4 and concentrated on rotary evaporator. The desired product (3d) was purified by silica gel flash chromatography as a pale yellow oil (0.91 g). 1H NMR (300 MHz, DMSO-d6) δ(ppm)): 1.13 (m, 9H), 2.94 (t, J=18.2 Hz, 2H), 3.85 (m, 6H), 7.88 (m, 2H), 8.02 (m, 2H), 12.60 (bs, 1H), 31P NMR (121 MHz, DMSO-d6) δ, 37.59 and 24.59
Reaction SMILES: [OH-].[Na+].C1(C[O:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])C=CC=CC=1.Cl.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(Cl)Cl>[CH3:30][N:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[O:10][C:11](=[O:12])[C:13]3([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[N:19]=2)=[CH:23][CH:24]=1)[CH3:31]
Reactant: CN(C)Cc1ccc(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(C2=NC3(CCCCC3)C(=O)O2)cc1
Reaction time: 1 h
Yield: 72.6 %

Procedure:
0.7 ml of 2N aqueous sodium hydroxide solution was added to a solution of 100 mg (0.25 mmol) of 1-[[[4-[(dimethylamino)methyl]phenyl]carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester in 1 ml of tetrahydrofuran, and the mixture was refluxed under heating overnight. After the mixture was neutralized by concentrated hydrochloric acid, the reaction mixture was distilled off under reduced pressure. 3 ml of methylene chloride, 126 mg (1.25 mmol) of triethylamine and 96 mg (0.5 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the residue, the mixture was stirred for 1 hour. The reaction mixture was distilled off under reduced pressure, an aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 52 mg (68%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH:21]([CH3:23])[CH3:22])=[C:9]3[C:15]([CH2:16][CH2:17][CH3:18])=[CH:14][C:13](=[O:19])[O:12][C:10]3=2)[O:5][C@H:4]([CH3:24])[C@H:3]1[CH3:25].N(C(OCC)=O)=NC(OCC)=O.P(C)(C)C.C(Cl)C(O)=O.[OH-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.CC#N>[OH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH:21]([CH3:23])[CH3:22])=[C:9]3[C:15]([CH2:16][CH2:17][CH3:18])=[CH:14][C:13](=[O:19])[O:12][C:10]3=2)[O:5][C@H:4]([CH3:24])[C@H:3]1[CH3:25]
Reactant: CCCc1cc(=O)oc2c3c(cc(OC(C)C)c12)O[C@H](C)[C@@H](C)[C@H]3O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CP(C)C
Agent: O=C(O)CCl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCc1cc(=O)oc2c3c(cc(OC(C)C)c12)O[C@H](C)[C@@H](C)[C@@H]3O
Temperature: -78 °C
Yield: 83.5 %

Procedure:
To a solution 7a (100 mg, 0.28 mmol) in THF (8 mL) and toluene (8 mL), maintained at -78° C., was added diethyl azodicarboxylate (DEAD, 0.455 mL, 2.88 mmol), PMe3 (2.89 mL, 1.0M solution in THF), and chloroacetic acid24 (220 mg, 2.32 mmol). The reaction mixture was stirred at -78° C. and allowed to warm to -30° C. over a period of 1.5 h (until complete disappearance of starting material was observed by TLC). Ammonium hydroxide (5 mL) was then added, and the solution was concentrated under reduced pressure. The residue obtained was then treated with ammonium hydroxide (5 mL) in CH3CN (10 mL), and the mixture was stirred for 4 h. The mixture was then quickly extracted with ether, the organic layer was dried (MgSO4), concentrated, and submitted for silica gel chromatography (Solvent A) to give 81 mg (81%) of 8a as a colorless syrup: [α]D20 +106° (c 1.1, CHCl3); 1H NMR (CDCl3): δ0.99 (t, 3 H, J=7.3 Hz, --CH2CH2CH3), 1.12 (d, 3 H, J=6.8 Hz, --CHCH3), 1.38 and 1.40 [2d, 6 H, J=5.8 Hz, --CH(CH3)2 ], 1.42 [d, 3 H, J=6.5 Hz, --CH(CH3)], 1.60 (m, 2 H, J=7.48 Hz, --CH2CH2 CH3), 1.93 (m, 1 H, H-9), 2.87 (m, 2 H, --CH2CH2 CH3), 3.59 (bs, 1 H, --OH), 3.91 (m, 1 H, H-8), 4.62 [m, 1 H, J=6.0 Hz, --CH(CH3)2 ], 4.70 (d, 1 H, J=7.6 Hz, H-10), 5.92 (s, 1 H, H-3), 6.21 (s, 1 H, H-6); 13C NMR (CDCl3): δ 13.87, 15.73, 18.95, 21.66, 21.80, 23.19, 39.02, 40.48, 66.66, 70.77, 77.00, 96.92, 104.83, 106.14, 110.02, 155.69, 156.15, 157.75, 159.06, 160.48. Anal. Calcd for C20H26O5.0.03CH2Cl2 : C, 65.50; H, 7.21. Found: C, 65.74; H, 7.39.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:61])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH2:60]>[Cl-].[Na+].O.CN(C=O)C>[CH3:52][O:53][C:54](=[O:61])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCN
Reactant: O=C1Nc2ccc(F)cc2C1=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzoic acid (283 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 6-aminocaproic acid methyl ester hydrochloride (219 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (362 mg, 88% yield) as a brown solid. LC-MS (m/z) 411 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:17]([CH:21]=2)[C:18]([OH:20])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:17]([CH:21]=2)[C:18]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[O:20])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3OC)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3OC)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(2-methoxyphenyl) benzoic acid (66 mg, 0.1563 mmol) was dissolved in methylene chloride (5 ml), then p-anisidine (38 mg, 0.3089 mmol), triethylamine (47 mg, 0.4653 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (53 mg, 0.3136 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:1) to give the title compound (38 mg, 0.0721 mmol, 46%).
Reaction SMILES: O1CCC[CH2:2]1.CO[C:8]([C:10]1[CH:23]=[CH:22][C:13]2[N:14]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:15](=[O:17])[NH:16][C:12]=2[CH:11]=1)=[O:9].[BH4-].[Li+]>CO>[CH:18]1([N:14]2[C:13]3[CH:22]=[CH:23][C:10]([CH2:8][OH:9])=[CH:11][C:12]=3[N:16]([CH3:2])[C:15]2=[O:17])[CH2:19][CH2:20][CH2:21]1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Cn1c(=O)n(C2CCC2)c2ccc(CO)cc21
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran (150 mL) solution of 1-Cyclobutyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester 16.35 g, 62.8 mmol) was added lithium borohydride (63 mL, 2.0 M in tetrahydrofuran). The mixture was heated to 65° C. then methanol (2.5 mL) was added. The reaction was complete after 0.5 hours and was cooled and extracted into ethyl acetate from saturated ammonium chloride. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give 13.79 g of 1-Cyclobutyl-5-hydroxymethyl-3-methyl-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.I(O)(=O)(=O)=O.O>CO>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:3]2[CH:4]=[C:5]3[C:14](=[N:13][C:12]4[C:7]([S:6]3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=[CH:2]2)=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: COc1ccc(N)cc1
Agent: [O-][I+3]([O-])([O-])O
Solvent: CO
Solvent: O
Product: COc1ccc(NC2C=CC3=Nc4ccccc4SC3=C2)cc1
Temperature: 25 °C

Procedure:
Phenothiazine, 0.5 g/0.0025M, and p-anisidine, 0.307 g/0.0025M, were dissolved in 50 ml of methanol and stirred at ambient temperature. Periodic acid, 3.4 g/0.015M, was dissolved in 40 ml of methanol and the solution added in one portion to the stirring phenothiazine mixture. The reaction mixture was stirred for 20 minutes and then poured into 100 ml of water with solid residue being collected by a Buchner funnel. The solid was stirred with 200 ml of a 1:1 mixture of MeOH/H2O and collected. The red-brown solid was dried to yield 0.72 g (91% theory) of the desired product having a melting point of 135°-136° C. (lit. 148°-149° C.).