Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH3:17]I.[BH4-].[Na+]>CCOC(C)=O>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH3:17]
Reactant: CI
Reactant: COC(=O)Nc1ccc2c(c1)CCN=C2C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc2c(c1)CCN(C)C2C
Reaction time: 72 h

Procedure:
A mixture of 1.00 g (4.5 mmol) methyl (1-methyl-3,4-dihydro-isoquinolin-6-yl)-carbamate, 2.3 ml (37 mmol) methyl iodide and 25 ml EtOAc is stirred for 72 h. The crystals precipitated are filtered off, taken up in 10 ml of methanol and 140 mg (3.6 mmol) sodium borohydride are added batchwise. After 2 h the mixture is concentrated and purified by chromatography (silica gel; dichloromethane/methanol 90:10).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][C:4](=[S:7])[NH:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[N:17]=[C:18]=[O:19]>CN(C)C=O>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH3:9])[C:11]=1[NH:17][C:18]([N:5]1[CH2:6][C:2]([CH3:8])([CH3:1])[NH:3][C:4]1=[S:7])=[O:19]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CC1(C)CNC(=S)N1
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)N1CC(C)(C)NC1=S
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
A mixture of 39.0 g (0.3 M) 4,4-dimethylimidazolidine-2-thione, 44.2 g (0.3 M) 2,6-dimethylphenyl isocyanate and 100 ml dimethylformamide was refluxed with stirring for 24 hours. After cooling to room temperature, the solution was filtered from a small amount of insoluble solid and poured into 300 ml water with efficient stirring. The precipitated product was filtered, washed well with water, and dried in vacuo. Yield 62.6 g, mp 228°-231° C. Recrystallization from 600 ml of boiling methanol yielded 46 g of N-(2,6-dimethylphenyl)-4,4-dimethyl-2-thioxo-1-imidazolidinecarboxamide as white crystalline product, mp 241.5°-243° C. A small sample was recrystallized from benzene to give an analytical sample, mp 245.5°-246° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][O:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](COc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
Dissolve (R)-(+)-2-(tert-butoxycarbonylamino)-1-propanol (1.75 g, 10 mmol) and phenol (0.95 g, 10 mmol) in anhydrous THF (75 mL). Cool to 0° C., add triphenylphosphine (4.0 g, 15 mmol) and diisopropylazodicarboxylate dropwise and stir at ambient temperature for 18 h. Pour the mixture into water (300 mL), basify to pH 10 with 5N aqueous NaOH, and extract with ethyl ether (3×100 mL). Wash the organic phase with brine, dry over MgSO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as an off-white solid (340 mg, 14%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:40]3[CH2:39][CH2:38][N:37]([C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=4)[CH2:42][CH2:41]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4cccc(F)c4)noc3C)CC2)c1
Yield: 84.2 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (612 mg, 1.55 mmol, 84%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:14]([O-:17])(=[S:16])[CH3:15].[K+]>CC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:16][C:14](=[O:17])[CH3:15])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of 4-bromo-2-trifluoromethylbenzyl bromide (2.4 g) in acetone (20 ml) was added potassium thioacetate (1.04 g). The reaction mixture was heated to reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature and was then filtered through a plug of silica gel. Further acetone (30 ml) was passed through the silica gel (30 ml). The combined filtrate was concentrated to give thioacetic acid S-(4-bromo-2-trifluoromethyl-benzyl) ester as a dark liquid (2.275 g). 1H-NMR (400 MHz, CDCl3): 7.75 (s, 1H), 7.60 (d, 1H), 7.42 (d, 1H), 4.25 (s, 2H), 2.36 (s, 3H) ppm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:18]S(C)=O>>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)C(C)c1cccc2cnccc12
Reactant: CS(C)=O
Product: CCOC(=O)C(C)(C)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 248 using ethyl 2-(5-isoquinolinyl)propanoate instead of ethyl 5-isoquinolinylacetate. MS (ESI+) m/z 244 (M+H)+; MS (ESI−) m/z 242 (M−H)−; 1H NMR (DMSO, 300 MHz) rotamers δ 0.98, 1.08 (t, J 7.1, 3H), 1.67 (s, 6H), 4.58 (q, J 7.1, 1H), 7.53 (m, 1H), 7.82 (m, 1H), 7.97 (m, 1H), 8.05 (m, 1H), 8.55, 8.50 (d, J 6.1, 1H), 9.33 (s, 1H).
Reaction SMILES: [Na].[CH2:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([CH2:34][O:35][CH3:36])[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:14](=[O:37])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:38])[CH:12]=2)[N:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:39]O>C1COCC1>[CH2:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([CH2:34][O:35][CH3:36])[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=2)[C:14](=[O:37])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:38][CH3:39])[CH:12]=2)[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc2ccc(O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Reactant: CO
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(OC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of sodium (28 mg) in methanol (3 ml) was added a solution of 2-butyl-6-hydroxy-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-4(3H)-quinazolinone (0.6 g) in methanol (5 ml) and THF (5 ml) at 0° C. The solution was stirred at room temperature for 1 hour and evaporated to dryness. The residue was dissolved in DMF (5 ml) and methyl iodide (0.15 ml) was added to the solution. The mixture was stirred at room temperature for 17 hours, poured into water and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give a crystalline product. Recrystallization from ether-hexane gave colorless crystals (0.48 g, 78%).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH2:32][CH2:33][CH3:34]>>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]5[O:29][N:30]=[C:31]([CH2:32][CH2:33][CH3:34])[N:28]=5)[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 6): tR=1.46 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]=[CH2:19])[C:13](=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:28]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:30]=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:39]([N:28]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@@H:29]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:30]([CH:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([CH2:17][CH:18]=[CH2:19])[C:13]1=[O:20])[OH:31])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C=CCN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: O=CC(Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCN1CCN(C(=O)OCc2ccccc2)C(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
Add to a solution of 4-benzyloxycarbonyl-1-allylpiperazin-2-one (1.1 g, 4.0 mmol) in dry THF (4 mL/mmol) at −78° C. under nitrogen lithium bis(trimethylsilyl)amide (1.OM solution in THF, 4.0 mL, 4.0 mmol) dropwise and stir 30 min. Add 2-(dibenzylamino)-3-phenylpropanal (732 mg, 2.2 mmol) in dry THF (2 mL/mmol) and stir at −78° C. for 45 min. Quench with saturated aqueous ammonium chloride solution. Separate organic layer and wash with water, saturated aqueous sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 100% hexanes to 1:1 hexanes:ethyl acetate) to give a mixture of four diastereoisomers (836 mg, 62%). Separate the isomers by normal phase HPLC (95:5 hexanes:isopropanol 95/5) to provide:
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[I-].[NH4+].B(Cl)(Cl)Cl>ClCCl>[OH:2][C:3]1[C:4]([CH3:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: COc1cccc(C#N)c1C
Agent: ClB(Cl)Cl
Agent: [I-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1c(O)cccc1C#N
Temperature: -78 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of 3-methoxy-2-methylbenzonitrile [(1 g, 6.79 mmol) U.S. Pat. No. 5,965,766, p6] and tetra nbutyl ammonium iodide (4.12 g, 17 mmol) in dichloromethane (15 mL) was cooled to −78° C. and purged with nitrogen. Boron trichloride (1M in dichloromethane, 17 mL, 17 mmol) was added dropwise and the mixture was stirred for 15 minutes at −78° C. and at room temperature for 3 hours. The reaction mixture was quenched with water, stirred for 30 minutes and concentrated in vacuo. The aqueous residue was extracted with diethyl ether and the organic solution was washed with water (×5), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown solid in 91% yield, 826 mg. 1H NMR (400 MHz, CDCl3) δ: 2.20 (s, 3H), 7.10 (m, 1H), 7.20 (d, 1H), 10.10 (s, 1H); LRMS APCI m/z 132 [M−H]−
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N+:20]=3[O-:29])[CH:17]=[N:16][CH:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C>Br>[OH:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][N+:20]=3[O-:29])[CH:17]=[N:16][CH:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(-c2cncn2-c2ccc(C(F)(F)F)c[n+]2[O-])cc([N+](=O)[O-])c1OC
Agent: Br
Product: O=[N+]([O-])c1cc(-c2cncn2-c2ccc(C(F)(F)F)c[n+]2[O-])cc(O)c1O
Temperature: 25 °C

Procedure:
2-(5-(3,4-Dimethoxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine 1-oxide (0.41 g, 1 mmol) was heated at 140° C. in 48% aqueous hydrogen bromide (6 mL) for 2.5 hours. The dark homogeneous solution was cooled to room temperature and volatiles were removed by evaporation to leave a pale brown crystalline solid that was dried over P2O5 under vacuum. Trituration of the resulting solid with diethyl ether gave 2-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine 1-oxide as a yellow crystalline solid, 0.27 g (71%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.[CH:13]1[C:18]([CH:19]=O)=[CH:17][C:16]2[O:21][CH2:22][O:23][C:15]=2[CH:14]=1.Cl.CO>O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[C:7](=[CH:19][C:18]3[CH:13]=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccc3c(c2)OCO3)COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
After 7-hydroxy-4(4H)-benzopyranone 1.0 g and piperonal 1.0 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for two hours and cooled to room temperature, and water 200 ml was added. The mixture was allowed to stand for one hour and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.266 g.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[N:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:8]=1)C.[Li+].[OH-]>C1COCC1.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:9]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[N:8]=[C:7]([CH2:6][CH:5]([C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[C:4]([OH:33])=[O:3])[CH:11]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Br)cc2)cc1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 3-[5-(4-bromo-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (100 mg, 0.2 mmol) was added LiOH (14 mg, 0.6 mmol, 3 equiv) in 2:1 THF/H2O (1 mL). After 3 h at 45° C., the mixture was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the title compound (66 mg, 79 %). HPLC: Rt=4.25 (Method A). MS (ESI): mass calculated for C26H23BrN2O2, 474.09; m/z found, 475/477 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.40 (d, J=8.5 Hz, 2H), 7.22 (d, J=7.6 Hz, 2H), 7.19-7.05 (m, 7H), 7.01 (d, J=8.5 Hz, 2H), 6.23 (s, 1H), 4.10 (dd, J=9.6, 5.5 Hz, 1H), 3.53 (dd, J=14.8, 9.6 Hz, 1H), 3.13 (dd, J=14.8, 5.5 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)C)=[CH:19][CH:18]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][C:6](=[O:8])[CH:7]=1.[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O.C(O)(=O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:4]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:5][C:6](=[O:8])[C:7]([S:40][C:32]3[CH:33]=[C:34]([CH3:39])[C:35]([CH2:37][OH:38])=[CH:36][C:31]=3[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:2]([OH:1])[CH2:3]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(=O)Nc1ccc(CCC2(c3ccccc3)CC(O)=CC(=O)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(N)cc3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 0.23 g (0.65 mmol) of N-{4-[2-(4-hydroxy-6-oxo-2-phenyl-3,6-dihydro-2H-pyran-2-yl)-ethyl]-phenyl}-acetamide (prepared in Example RR), 0.33 g (0.90 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.54 g (3.9 mmol) of K2CO3, and 5 mL of DMF. The solution was stirred overnight at room temperature and then poured into glacial acetic acid (5 mL) and EtOAc (20 mL). After standard work-up, the residue was triturated with Et2O, and the solids were filtered. The penultimate intermediate was dissolved in H2O (30 mL), 50% NaOH (4 mL), and MeOH (5 mL) and was refluxed for 18 hours. The mixture was cooled to room temperature, concentrated, and suspended in phosphate buffer (pH 7.5). Acidification to pH 6.8 with phosphoric acid was followed by extraction with CH2Cl2. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound, m.p. 218°-221° C. 1H NMR (DMSO-d6) δ 1.44 (s, 9 H), 1.76 (s, 3 H), 2.05-2.22 (m, 3 H), 2.40 (m, 1 H), 3.40 (m, partially obscured by H2O, 2 H), 4.32 (s, 2 H), 4.90 (br s, 1 H), 6.17 (s, 1 H), 6.47 (d, 2 H), 6.75 (d, 2 H), 7.21 (s, 1 H), 7.38-7.43 (m, 5 H).
Reaction SMILES: [C:1]([CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2]>C(O)C.[Pd]>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)([OH:3])=[O:2]
Reactant: Cc1c(-c2cccnc2)n(CCCCCC=CC(=O)O)c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2cccnc2)n(CCCCCCCC(=O)O)c2ccccc12
Reaction time: 3.5 h

Procedure:
1-(7-Carboxyhept-6-enyl)-2-(3-pyridyl)-3-methylindole (10 mg) is dissolved in 1 ml of absolute ethanol with a catalytic amount of 10% palladium on charcoal and hydrogenated at 1 atmosphere pressure. After 3.5 hours, the catalyst is removed by filtration and washed with a few milliliters of ethanol. The combined filtrates are concentrated in vacuo to yield a colorless oil which crystallizes to give 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)indole of Example 1 (crude product has m.p. 110°-113°).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.CS(O)(=O)=O.[CH3:38][NH:39][C:40]([N:42]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=1)[NH2:43])=[O:41].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:43][N:42]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[C:47]([CH3:52])[CH:46]=2)[C:40]([NH:39][CH3:38])=[O:41])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: CNC(=O)N(N)Cc1ccc(C)c(C)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2ccc(C)c(C)c2)C(=O)NC)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl] butyric acid (1.46 g, 4.96 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl chloride (474 μL, 5.46 mmol) was added to this solution dropwise in the presence of a catalytic amount of N,N-dimethylformamide (30.6 μL, 0.39 mmol). Completion of acid chloride formation was verified by HPLC. This solution was then added dropwise to a suspension of N-Methyl-1-(3,4-dimethylphenylmethyl)hydrazine carboxamide methanesulfonate (1.50 g, 4.95 mmol) and pyridine (1.00 μL, 12.9 mmol) in ethyl acetate (15 mL) at 0° C. After stirring at 0° C. for 6 h, the solution was warmed to rt and washed with 1N HCl (2×20 mL), 5% aq. NaHCO3 (2×20 mL) and sat'd aq. NaCl. The organic layer was dried (MgSO4), filtered and concentrated to a yellow oil. The oil was purified by column chromatography (SiO2, 9:1 ethyl acetate:hexanes), to afford the title compound as a clear oil (1.48 g, 62%): 1H NMR (DMSO-d6, 60° C.) δ 9.42 (s, 1H), 6.97 (m, 5H), 6.71 (d, 2H, J=8 Hz), 6.23 (s, 1H), 4.46 (s, 2H), 4.15 (q, J=7 Hz), 2.59 (s, 3H), 2.43 (t, 2H, J=8 Hz ), 2.15 (s, 6H), 2.06 (t, 2H, J=8 Hz ), 1.70 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.17 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 172.0, 158.7, 153.8, 136.4, 136.0, 135.9, 135.4, 130.2, 129.9, 129.7, 126.5, 119.5, 79.2, 61.6, 50.6, 34.4, 33.5, 27.6, 27.2, 25.7, 20.0, 19.7, 14.6; IR (CHCl3) 3009, 1669, 1509, 1142 cm−1; Exact Mass Calcd. for C27H38N3O5: 484.2811. Found: 484.2822.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[C:3]1([C:44](=[O:46])[NH2:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=1.O.C([O-])([O-])=O.[K+].[K+]>C(O)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:20])[CH3:21])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[C:3]1([C:44](=[O:46])[NH2:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([OH:41])=[O:40])[CH:34]=1
Reactant: CCOC(=O)c1cccc(C2(C(N)=O)C(=O)N(CC(=O)N(c3ccccc3)C(C)C)c3ccccc3N(c3ccccc3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)N(C(=O)CN1C(=O)C(C(N)=O)(c2cccc(C(=O)O)c2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Yield: 86.4 %

Procedure:
0.12 g of 2-[2,4-dioxo-5-phenyl-3-(3-ethoxycarbonylphenyl)-carbamoyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Example 1, is dissolved in 5 mL of hot ethanol. 2.5 mL of H2O and 0.13 g of K2CO3 are added and the mixture heated at reflux for 4 h and subsequently concentrated in vacuo. The residue is poured into 20 mL of 1N HCl and extracted with ethyl acetate (×3). The organic extract is washed with brine, dried over MgSO4 and concentrated in vacuo to a white solid. Purification by reverse phase C-18 MPLC (70% methanol/TFA-H2O) gave 99 mg of the title compound as a white powder: mp. 165°-170° C.; 1H NMR (CDCl3, 300 MHz) δ8.6 (s, 1H), 8.05 (s, 1H), 7.92 (d, 1H, J=7), 7.75 (d, 1H, J=7), 7.5-7.2 (m, 14H), 7.15 (t, 1H, J=7), 6.97 (d, 1H, J=7), 5.02 (m, 1H), 4.27 (s, 2H), 4.10 (t, 1H, J=7), 3.20 (d, 2H, J=7), 1.08 (d, 3H, J=7), 1.02 (d, 3H, J=7); low resolution MS (FAB) m/e 605 (MH+); Anal. (C35H32N4O6.0.5 TFA.0.5 H2O) Calc. C, 64.5; H, 5.0; N, 8.4; Found: C, 64.5; H, 5.0; N, 8.3.