Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>O1CCOCC1>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Nc2ccc(Cl)cc2Cl)nc1C(F)(F)F

Procedure:
To a solution of methyl 2-chloro-4-trifluoromethylpyrimidine-5-carboxylate (70 g, ex Maybridge 22 g, ex Fluorochem 48 g) in 1,4-dioxan (100 n−1) was added 2,4-dichloroaniline (142 g) and the solution stirred under reflux for 10.5 h. 1,4-Dioxan was partially removed (approx 50 ml) under reduced pressure and 2N HCl (800 ml) added. The mixture was stirred with overhead stirring for 3 h and the resulting solid filtered onto a sinter. The solid was washed with 2N HCl (2×300 ml) and water (4×400 ml) then dried over sodium hydroxide in vacuo at 50° C. to afford methyl 2-(2,4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylate. The solid contained approximately 5% 2,4-dichloroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[NH2:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([NH:5][C:4]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(Nc2ccc(Cl)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCN1CCC(Nc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The product from step (iii) above (1.2 g) was dissolved in dichloromethane (30 ml) and trifluoroacetic acid (10 ml) added. After 72 hours at room temperature the reaction mixture was evaporated and residue triturated under ether to give the sub-titled product as a solid (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:23])([F:22])[S:20]Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][C:12]=2[S:20][C:19]([F:23])([F:22])[F:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c(SC(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
A solution of ethyl 4-(p-chlorophenyl)pyrrole-3-carboxylate (9.0 g, 0.036 mol) in methylene chloride (180 mi) is treated with trifluoromethylsulfenyl chloride (4.9 g, 0.036 mol) with stirring for 45 minutes at -30° C. The reaction mixture is warmed to room temperature and stirred for several hours. Since a TLC shows some starting material present, the reaction mixture is cooled to -30° C., treated with additional trifluoromethylsulfenyl chloride (1.3 g, 0.0095 mol), warmed to room temperature overnight with stirring, washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an off-white solid (12.0 g, mp 161.5°-164.00° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: O=C(Cc1ccc(Cl)cc1)c1cccs1

Procedure:
A mixture of 85.3 g of p-chlorophenylacetic acid and 200 ml of thiophene was stirred at 40° C. as 105 g of trifluoroacetic anhydride was added. The mixture was then refluxed for 4 hrs. It was poured into ice and water and made basic with sodium carbonate. The mixture was extracted with dichloromethane, dried over potassium carbonate and concentrated. The crude yield was 126.4 g. This was recrystallized from 300 ml of methanol to give 103 g, m.p. 98°-99° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:10](=[O:11])[O:9][CH:8]1[CH2:12][CH:13]([O:25][C:26]([CH:28]([NH:33][C:34]([CH3:36])=[O:35])[CH2:29][C:30]([NH2:32])=[O:31])=[O:27])[CH2:14][CH:15]=[CH:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H][H]>[Pt]=O.CO>[CH3:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]([O:25][C:26]([C@@H:28]([NH:33][C:34]([CH3:36])=[O:35])[CH2:29][C:30]([NH2:32])=[O:31])=[O:27])[CH2:12][C@@H:8]1[O:9][C:10](=[O:11])[C@H:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCC=CCC=CCC(CC1OC(=O)C1CCCCCC)OC(=O)C(CC(N)=O)NC(C)=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CCCCCCCCCCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(N)=O)NC(C)=O
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Esterastin (95 mg) was taken up into 10 ml of methanol, and this methanolic solution of esterastin was admixed with 20 mg of platinum oxide as the hydrogenation catalyst. The mixture was subjected to hydrogenation with hydrogen gas at 20 lbs. per square inch at ambient temperature for 2 hours. After the reduction was completed, the reaction mixture was filtered to remove the platinum oxide. The filtrate (the reaction solution) was concentrated to dryness to yield 96 mg of a colorless powder of tetrahydroesterastin which gave a single spot in a silica gel thin layer chromatography.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][C@@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[C@@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]
Reactant: CCOC(=O)N1CCN[C@@H](C)C1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)[C@@H](C)C1
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 63 mg HATU and 28 mg (S)-3-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 360 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([F:38])[CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:27][C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([F:38])[CH:29]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(CBr)cc1F
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: COC(=O)c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F

Procedure:
Use a method similar to the Example 428, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and methyl 4-bromomethyl-2-fluorobenzoate, to give the desired intermediate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@@H:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: C[C@@H]1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1ccc(O)cc1

Procedure:
The enantiomers of 4-[(3-chloro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol (400 mg, 1.14 mmol) were separated by automated, on-column solvent change, preparative, normal phase, chiral chromatography on a Chiralpak AD (20 mm×250 mm) column eluting with 20% ethanol in hexane at a flow rate of 12 mL/min with. After combination of fractions and evaporation of the solvent in vacuo, one peak (99.9%) with a retention time of 3.571 minutes was isolated as a white solid (194 mg, 97% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 200 mg). mp 273.5-276° C.; [α]D25=−321° (c=0.010 g/mL, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.73 Hz, 3 H) 5.67 (q, J=6.90 Hz, 1 H) 6.71 (d, J=8.79 Hz, 2 H) 6.79 (d, J=2.07 Hz, 1 H) 7.17 (m, 2 H) 7.26 (dd, J=8.54, 2.07 Hz, 1 H) 7.41 (m, 3 H) 7.98 (dd, 2 H) 10.04 (s, 1 H); MS (ESI) m/z 350/352 ([M+H]+); MS (ESI) m/z 348/350 ([M−H]−).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18]N[CH2:16][CH2:15]1)(C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:21].[Na+].[Na+]>O1CCCC1>[CH2:15]([N:14]([CH2:19][CH3:18])[C:1](=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of benzhydrylpiperazine epimers (7.6 g, 14.9 mmol) was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL (18.6 mmol) of alkyl bromide and 5.1 g (36.9 mmol) of sodium carbonate and stirred at room temperature under nitrogen for 2 days. The reaction solution was poured into ice water/ethyl acetate and separated. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and placed on a column of silica gel. The diastereomers were separated by elution with a stepwise gradient of ethanol in dichloromethane. The first isomer was eluted with 1.3% ethanol in dichloromethane, and the second isomer was obtained with 1.6% ethanol in dichloromethane. Fractions containing the second isomer were combined and the solvent removed in vacuo to give 1.44 g of 4-(αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[OH:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:14])=[O:15])[CH2:33][C:32]2[CH:35]=[CH:36][C:29]([OH:28])=[CH:30][CH:31]=2)=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=S(=O)(NCCN(CC=Cc1ccc(Cl)cc1)Cc1ccc(O)cc1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.3 %

Procedure:
0.2 g of the product of Example 172 and 0.13 g of p-hydroxybenzaldehyde were dissolved in 10 ml of methanol, to the solution were added 60 mg of sodium cyanoborohydride and two drops of acetic acid, and the mixture was stirred for 2 days at a room temperature. The reaction mixture was concentrated under a reduced pressure, and after adding a saturated sodium chloride aqueous solution, extracted three times with 20 ml of ethyl acetate. The extracts were combined, washed with sodium chloride, dried over magnesium sulfate, filtered and concentrated under a reduced pressure. The resulting residue was purified on a silica gel column (silica gel 10 g, eluant: 2% methanol in chloroform), to obtain 150 mg of the title compound in a colorless amorphous form.
Reaction SMILES: Br[CH2:2][C:3](=[N:8][OH:9])[C:4]([F:7])([F:6])[F:5].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OC)(C)(C)C>[F:5][C:4]([F:7])([F:6])[C:3](=[N:8][OH:9])[CH2:2][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][CH:11]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ON=C(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: ON=C(Cc1c[nH]c2ccccc12)C(F)(F)F
Yield: 89.2 %

Procedure:
To a solution of the 1.64 g (7.96 mmol) of 3-bromo-1,1,1-trifluoropropan-2-one oxime in 250 mL of methyl tert-butyl ether was added 3.74 g (31.92 mmol) of indole followed by 5.0 g (47.62 mmol) of powdered (freshly ground) sodium carbonate. The reaction was monitored by thin layer chromatography (ethyl acetate-hexanes (2:8)) to afford a new more polar product compared to indole (PMA-stained and UV-active). The mixture was then filtered through diatomaceous earth and concentrated in vacuo. The residue was then concentrated in vacuo and diluted first with dichloromethane (1 part) and then hexanes (4 parts) and passed through a pad of silica gel using dichloromethane-hexanes (gradient: 20%-100%) to afford 1.72 g (89.2%) of 1,1,1-trifluoro-3-(1H-indol-3-yl)propan-2-one oxime as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccccc1F
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccccc4F)cc3c2C1
Yield: 71.8 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 5.4 mg (0.051 mMol) 2-fluorobenzoyl chloride, 11.6 mg (74%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:6][CH:7]([CH3:14])[CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:6][CH:7]([CH3:14])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CC(C)Nc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(NC(C)CC(=O)O)cc1OC

Procedure:
A 54-g sample of the unpurified ester product of Example 2 was combined with 17.5 g of sodium hydroxide, 550 ml of methanol and 130 ml of water, and refluxed for 1.5 hrs. The reaction mixture was cooled, concentrated under reduced pressure, diluted with water and neutralized with 6N hydrochloric acid to give an oily mixture which was extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 48 g of an oily product. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][N:8]([CH2:20][C:21](=[O:22])[NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:7]2[CH2:6][C:5]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13]=1[O:18][CH3:19])[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Product: CCOC(=O)COc1cc2c(cc1OC)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl bromoacetate
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:13]=2)[C:8]=1[Br:35])C.[OH-].[K+].Cl>C1COCC1.O>[Br:35][C:8]1[C:9]2[C:14](=[CH:13][C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][CH2:5][C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)COc1ccc2cc(-c3sc4ccccc4c3C(=O)Cc3ccccc3)ccc2c1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3sc4ccccc4c3C(=O)Cc3ccccc3)ccc2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
A mixture of [1-bromo-6-(3-phenylacetyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.427 g, 0.764 mmol) and potassium hydroxide (0.162 g 2.89 mmol) in THF (125 mL) and water (125 mL) was stirred at ambient temperature for two hours. It was then poured in excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate and washed with water and brine. The organic phase was dried with anhydrous magnesium sulfate, filtered, solvent evaporated and purified by HPLC using 65% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for 25 minutes to yield [1-bromo-6-(3-phenylacetyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid as a yellow solid (0.100 g, 24.6%): MP: 170–2° C.; mass spectrum (+EI, [M+H]+) m/z 531/533. 1H NMR (500 MHz, DMSO-d6): δ13.0–13.3 (br, 1H), 8.27 (d, 1H, J=8.86 Hz), 8.16 (d, 1H, J=1.52 Hz), 8.06–8.12 (m, 2H), 7.89–7.92 (m, 1H), 7.81 (dd, 1H, J=8.86 Hz and 1.83 Hz), 7.44–7.52 (m, 3H), 7.13–7.19 (m, 3H), 6.92–6.94 (m, 2H), 5.02 (s, 2H), 3.81 ppm (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[H][H]>[Pd].C(O)CCC>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CCCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
0.07 Gram of 5% palladium on carbon catalyst was added to a mixture of 7.7 grams of 5-nitrotetrahydroanthraquinone and 240 grams of butanol, which was then heated up to 50° C. Hydrogen was then fed into the solution under normal pressure to absorb hydrogen in an amount of 2 mols per mol of the starting 5-nitro compound. After separation of the catalyst by filtration, 4.0 grams of crystal sodium carbonate was added to the reaction solution while agitating at a temperature of 100° C. for 1 hour. Thereafter, hydrochloric acid was added to the reaction solution for neutralization, then butanol was distilled off from the solution until crystals began to precipitate. After allowing to cool, the reaction solution was filtered and the crystals were washed with water and dried to obtain 6.0 grams of 1-aminoanthraquinone having a purity of 97.2%.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16](O)=[O:17])=[CH:12][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[CH:10][CH:9]=2)(=O)C.[OH-].[K+].Cl>>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)=[CH:10][CH:9]=3)[C:14]3[C:15](=[O:19])[C:16](=[O:17])[O:4][CH2:5][C:6]2=3)=[CH:29][CH:30]=1
Reactant: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(Cn2c3c(c4cc(-c5cccc(C)c5)ccc42)C(=O)C(=O)OC3)cc1

Procedure:
The title compound was prepared from [2-[(acetyloxy)methyl]-1-(4-methylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetic acid and aqueous potassium hydroxide in substantially the same manner, as described in step 6 of Example 1 followed by the treatment with aqueous HCl in substantially the same manner, as described in step 7 of Example 1. The product was obtained as a white solid; mp: 216–217° C. Mass spectrum (ESI, [M+H]+) m/z 396. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.71 (d, 1H, J=8.56 Hz), 7.64 (dd, 1H, J=8.75 and 1.28 Hz), 7.49 (s, 1H), 7.46 (d, 1H, J=8.09 Hz), 7.36 (t, 1H, J=7.63 Hz), 7.19–7.14 (m, 5H,), 5.91 (s, 2H), and 5.49 (s, 2H), 2.39 (s, 3H), 2.26 ppm (s, 3H),
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g. 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=2[CH3:40])=[C:19]([CH3:41])[CH:18]=1>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=2[CH3:40])=[C:19]([CH3:41])[CH:18]=1)(=[O:5])=[O:4]
Reactant: Cc1cc(O)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoromethanesulfonic anhydride (1.3 g, 4.6 mmol) was slowly added to a 0° C. solution of C5 (600 mg, 1.6 mmol) in pyridine (15 mL), and the reaction mixture was stirred at room temperature for 3 hours. After solvent had been removed under reduced pressure, the residue was purified by silica gel chromatography (Gradient: 5% to 17% ethyl acetate in petroleum ether) to afford the product as a yellow oil. Yield: 790 mg, 1.55 mmol, 97%. 1H NMR (400 MHz, CDCl3) δ 7.27-7.33 (m, 2H), 7.21-7.25 (m, 1H), 5.50 (AB quartet, JAB=9.2 Hz, ΔνAB=4.1 Hz, 2H), 3.73-3.79 (m, 2H), 3.02 (s, 3H), 2.26 (br s, 3H), 1.63 (s, 3H), 1.00-1.06 (m, 2H), 0.03 (s, 9H).