Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.[OH-].[K+]>O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:6]=2)[CH:13]=1
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Yield: 99.8 %

Procedure:
To 2.60 g (8.14 mmol) of 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid methyl ester, prepared as in Example 187B, was added 15 mL of methanol, and a solution of 0.79 g (12 mmol) of 85% KOH in 3 mL of water. The mixture was stirred at reflux for 3 hours, then concentrated in vacuo. The residue was taken up in 5 mL of water and treated with 12 mL of 1M aqueous HCl. The precipitated product was filtered and washed with a small amount of water. The combined washings and filtrate were adjusted to pH 4 with 1M HCl, and additional precipitate was collected, then washed with water. The combined precipitates were dried in vacuo to give 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid (2.48 g, 99%) as an off-white powder. 1H NMR (300 MHz, d6-DMSO) δ 5.31 (s, 2H), 7.31-7.56 (m, 9H), 7.76 (d, J=7.5 Hz, 1H), 8.19 (dd, J=1.0, 6.0 Hz, 1H), 8.39 (d, J=3.0 Hz, 1H), 12.8 (br s, 1H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH3:34][NH:35][S:36]([CH:39]=[CH2:40])(=[O:38])=[O:37]>>[CH3:34][NH:35][S:36]([CH2:39][CH2:40][N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)(=[O:38])=[O:37]
Reactant: C=CS(=O)(=O)NC
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)CCN1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and N-methyl ethene sulfonamide were reacted to give 465. LCMS: RT=7.25 min, [M+H]+=489. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, t, J=8.17 Hz), 7.89 (1H, s), 7.06 (1H, dd, J=8.21, 1.88 Hz), 6.97 (1H, d, J=1.83 Hz), 5.93-5.83 (1H, m), 4.91 (1H, s), 4.38 (2H, t, J=5.03 Hz), 3.76 (2H, t, J=7.01 Hz), 3.72-3.62 (1H, m), 3.41-3.34 (2H, m), 3.25 (2H, t, J=6.71 Hz), 3.08-3.02 (2H, m), 2.99-2.91 (2H, m), 2.80 (3H, s), 1.60 (6H, d, J=6.78 Hz)
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[CH2:31]([O:30][C:28]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][CH2:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:16]=2)[CH2:20][CH2:21]1)=[O:29])[CH3:32]
Reactant: c1ccc(-c2cc(CCC3CCNCC3)c3ccccc3n2)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CCc2cc(-c3ccccc3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.4 %

Procedure:
A solution of 15.6 g of 2-phenyl-4-[2-(4-piperidyl)-ethyl]quinoline, prepared as indicated in Example 16, in 200 ml of chloroform is treated with stirring with 200 ml of a 1N aqueous solution of sodium hydroxide. Then 21.7 g of ethyl chloroformate are added, drop by drop, and the suspension obtained is stirred for 17 hours at the ambient temperature. After separation, the organic phase is washed with water, dried over magnesium sulphate, then evaporated under reduced pressure. 20 g of 4-[2-(1-ethoxycarbonyl-4-piperidyl)-ethyl]-2-phenyl-quinoline in the form of an oil are obtained.
Reaction SMILES: COC(CCC/C=[C:9]1/[C:10](=[O:17])[CH:11]2[CH:15]([CH2:16]/1)[CH2:14][CH2:13][CH2:12]2)=O.[OH-].[Li+].O>CO>[CH:11]12[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:9][C:10]2=[O:17]
Reactant: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CCC2CCCC12
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A stirred solution of 6-[(E)-3-cyclohexyl-(mixture of 3α and 3β)-hydroxyprop-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (20 mg), prepared as described in Example 8 and predominantly in the 6β-configuration, otherwise known as (±)-methyl(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoate, in methanol (3.2 ml) was treated with lithium hydroxide (33.8 mg) and water (1.1 ml) at 20° C. and stirred for 2 hours. The mixture was then concentrated in vacuo. The resulting residue was diluted with water (5 ml) and then acidified to pH 3 by treatment with dilute hydrochloric acid (2N). The aqueous layer was then extracted with ethyl acetate (5×5 ml). The combined organic extracts were dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting residue was subjected to chromatography on a silica gel column, using a mixture of ethyl acetate, hexane and formic acid (50:50:1 by volume) as eluant, to give 3-[(E)-4-carboxybutylidene]-6-[(E)-3-cyclohexyl-(mixture of 3α and 3β)-hydroxyprop-1-enyl]bicyclo[3,3,0]octan-2-one (10 mg), predominantly in the 6β-configuration, otherwise known as (±)-(5E,13E)-(9S),[mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-cyclohexyl-15-hydroxy-16,17,18,19,20-pentanorprosta-5,13-dienoic acid [NMR in deuterochloroform: multiplets at 6.5, 5.5, 4.2-3.5, 3.0-0.7 p.p.m⟧
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][OH:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:15])[CH3:14]>>[C:13]([O:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: O=C(NO)OCc1ccccc1
Product: CC(=O)ONC(=O)OCc1ccccc1

Procedure:
[(Benzyloxy)carbonyl]amino acetate is prepared from N-(benzyloxycarbonyl) hydroxylamine and acetyl chloride according to Scheme 1. (1.24 g, 33%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.18 (1H, br. s.), 7.32-7.45 (5H, m), 5.22 (2H, s), 2.22 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]2[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4].C1C(=O)N([Cl:30])C(=O)C1>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:30])=[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]2[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4]
Reactant: COC(=O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Yield: 48.1 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid methyl ester (576 mg, 1.40 mmol) in DCM (10 mL) was added NCS (206 mg, 1.54 mmol) and the reaction heated at reflux for 3 hours. More NCS (37 mg, 0.28 mmol) was added and the reaction heated at reflux for 2 hours. The reaction mixture was diluted with water and the product extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-40% ethylacetate in cyclohexane) to yield the title compound as an off-white solid (300 mg, 48%). LCMS (Method B): RT=4.11 min, M+H+=446.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[CH3:9][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:9][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CC1CCSCC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CCSCC1
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
A solution of tetrahydro-thiopyran-4-carbonitrile (3.05 g, 24 mmol) in anhydrous tetrahydrofuran (60 ml) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 26.4 ml, 26.4 mmol) dropwise. After 30 minutes of stirring, iodomethane (1.8 ml, 29 mmol) was added dropwise. The cooling bath was removed, and the reaction mixture was allowed to slowly rise to room temperature and stir overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving an orange oil. The oil was purified by silica gel chromatography using 5-50% EtOAc in hexanes as eluant to provide 1.81 g (53%) of 4-methyl-tetrahydro-thiopyran-4-carbonitrile as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CO>[CH3:12][N:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CNCCc1ccccn1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCc1ccccn1)Cc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
6.8 g of 3-nitrobenzyl chloride in 25 ml of methanol are slowly added dropwise to a solution of 5.4 g of 2-(2-methylaminoethyl)pyridine in 20 ml of methanol at 40° C. 15 ml of triethylamine in 15 ml of methanol are subsequently added, and the mixture is stirred for 15 hours at 40° C. After removal of the solvent by evaporation in vacuo, the residue is taken up in 300 ml of water and extracted three times with dichloromethane. After drying over sodium sulphate, the dichloromethane is evaporated in vacuo and the residue is chromatographed on silica gel (eluent:dichloromethane/methanol 100:5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[O:17]=[C:18]([C:27]1[CH:32]=[CH:31][N:30]=[N:29][CH:28]=1)[CH2:19][C:20](OC(C)(C)C)=[O:21]>>[I:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:18](=[O:17])[C:27]2[CH:32]=[CH:31][N:30]=[N:29][CH:28]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnnc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1NC(=O)CC(=O)c1ccnnc1

Procedure:
The title compound was prepared from the reaction of tert-butyl 2-amino-4-iodophenylcarbamate (Example B3; 1 mmol) and tert-butyl 3-oxo-3-(pyridazin-4-yl)propanoate (Example C1; 1 mmol) according to the general procedure D. Obtained as a yellow solid (87%), MS (EI) 483 [(M+1)+].
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:23]1([CH3:30])[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][CH:24]=1.OS(O)(=O)=O.[OH-].[Na+]>C(O)(=O)C.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:2]2([C:25]3[CH:26]=[CH:27][C:28]([OH:29])=[C:23]([CH3:30])[CH:24]=3)[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][CH:19]=1
Reactant: Cc1ccccc1O
Reactant: COc1ccc(C2(O)c3ccccc3-c3ccccc32)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2(c3ccc(O)c(C)c3)c3ccccc3-c3ccccc32)cc1
Reaction time: 0.01 h
Yield: 95.2 %

Procedure:
4-Bromoanisole (46.7 g) was added dropwise to a stirred mixture of magnesium (6.0 g) in dry THF (250 mL). When all the magnesium had dissolved, 9-fluorene (40.0 g) in THF (400 mL) was added dropwise. The mixture was then stirred at room temperature for 3 hours and quenched with saturated ammonium chloride solution. The excess solvent was evaporated in vacuo and the residue extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated and recrystallized from hexane/ether to give 9-hydroxy-9-(4-methoxyphenyl)fluorene as a solid (48.2 g) M.P. 91°-93° C. This trityl alcohol (3.2 g) and o-cresol (1.8 g) were dissolved in acetic acid (25 mL) and concentrated H2SO4) (0.5 mL) was added dropwise. A deep red color developed rapidly and the reaction mixture decolorized after 30 seconds. After five minutes, the mixture was poured into water, neutralized with NaOH solution, and extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated in vacuo to give 9-(4-methoxyphenyl)-9-(3-methyl-4-hydroxyphenyl)fluorene (4.0 g) as an oil, which was used in the next step without further purification. Ethanethiol (3.7 g) was added dropwise to a stirred suspension of sodium hydride (2.3 g, 60% in mineral oil) in dry DMF (20mL). After the hydrogen bubbling had ceased, the above-mentioned oil was added and the mixture refluxed for 2 hours under nitrogen. The excess solvent was evaporated in vacuo and the residue extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated in vacuo and the residue recrystallized from chloroform-hexane to give the title compound (2.5 g) as a solid. M.P. 186°-188° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C(O)C>[CH2:14]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 73 %

Procedure:
2.11 g of sodium hydroxide was dissolved in 50 ml of ethyl alcohol and to the solution were added 2.6 g of para-hydroxy benzoic acid and 5.8 ml of 1-bromodecane. After the mixture was refluxed for 15 hours, 25 ml of 10% aqueous sodium hydroxide solution was added and refluxed for another two hours. After cooling, concentrated HCl was dropped into the solution until it was acidic. Filtration and recrystallization from ethyl alcohol gave 3.8 g of pure product (yield 73%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[S:22][CH2:23][C:24]([OH:26])=[O:25])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH3:27]O>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[S:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Product: COC(=O)CS[C@@H]1CCC[C@H]1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The compound of Example 5 (1.0 g, 0.0025 mole) was dissolved in methanol (35 ml) and hydrogen chloride gas was bubble into the solution for 10 minutes. Nitrogen gas was bubbled into the reaction solution to remove most of the dissolved hydrogen chloride, and then the reaction mixture was poured into water (150 ml). The mixture was extracted twice with 100 ml of diethyl ether, and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR, infrared spectroscopy and elemental analysis.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]([CH3:13])=[O:12])=[CH2:10].N(CCO)(CCO)CCO>CN(C)C=O>[C:2]1([C:1](=[O:8])[CH2:10][CH2:9][C:11](=[O:12])[CH3:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC(C)=O
Solvent: CN(C)C=O
Solvent: OCCN(CCO)CCO
Product: CC(=O)CCC(=O)c1ccccc1
Reaction time: 15 h

Procedure:
Following the description in Example 1, 5.1 g (approx. 0.02 mol) of Cat. 3, 21.2 g (0.2 mol) of distilled benzaldehyde, 350 ml of dimethylformamide and 14 g (0.2 mol) of stabilized methyl vinyl ketone are introduced into a 500 ml three-necked flask. After displacing the air by pure nitrogen, the mixture is brought to a temperature of 80° C and 14.9 g (0.1 mol) of triethanolamine are added. The mixture is then stirred for 15 hours at the same temperature. Working up takes place as in Example 11 except that the mixture is filtered after having been taken up in chloroform. 1-Phenyl-pentane-1,4-dione is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1.Cl.Cl.[CH3:25][N:26]([CH3:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([N:26]([CH3:34])[CH3:25])[CH:28]=2)=[O:7])=[CH:4][C:3]=1[NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CCCc1ccc(C(=O)Nc2cc(C(=O)Cl)ccc2Cl)cc1
Agent: Cl
Product: CCCc1ccc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2Cl)cc1

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-3-(4-propylbenzamido)benzoyl chloride was reacted with 3-dimethylamino aniline dihydrochloride to give the title compound; NMR Spectrum: DMSOd6) 0.9 (t, 3H), 1.18 (t, 2H), 1.69 (m, 2H), 2.99 (s, 6H), 7.0 (d, 1H), 7.2-7.5 (m, 4H) 7.64-7.8 (m, 3H), 7.84 (d, 1H), 8.0 (m, 2H), 8.19 (s, 1H); Mass Spectrum: M+H+ 436 and 438.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([N:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2>>[CH2:12]([C@H:3]([NH:2][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=2)=[O:30])[C:4](=[O:5])[N:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(=O)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
(S)-1-(2-Amino-3-phenyl-propionyl)-pyrrolidin-3-one hydrochloride (0.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.6 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first, then base) and the product purified by chromatography on silica gel eluted with 40 and 50% ethyl acetate in hexanes, followed by trituration of the resulting foam with ether. Yield 112 mg, 45%; HPLC (60/40) 5.13 minutes (>99%); PBMS 410/412 (MH+, 100%);
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:24])=[C:7]([CH:23]=1)[C:8]([NH:10][CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:9].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[Cl:24][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:35]2[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37][CH2:36]2)=[CH:23][C:7]=1[C:8]([NH:10][CH2:11][CH2:12][C:13]12[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2)=[O:9]
Reactant: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 87.1 %

Procedure:
A mixture 5-(bromomethyl)-2-chloro-N-(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)-benzamide (Example 18a, 0.35 g), 1-tertbutyloxycarbonylpiperazine (0.213 g), potassium carbonate (0.20 g) and potassium iodide (10 mg) in acetone (5 ml) was heated at 60° C. for 2 h. The acetone was removed under vacuum, the residue taken into dichlorometane and the solid removed by filtration. The crude material was purified on a silica gel eluting with dichloromethane/ethanol (0-10% gradient) to afford the subtitle compound as a white foam (0.383 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4]1.CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CS(Cl)(=O)=O.CCOC(C)=O>[CH3:41][S:42]([O:1][CH2:2][C@@H:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4]1)(=[O:44])=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A 150-mL round-bottomed flask was charged with tert-butyl (3R)-3-(hydroxymethyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.393 g, 0.857 mmol), DIPEA (0.450 mL, 2.58 mmol) and EtOAc (5 mL). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (0.095 mL, 1.2 mmol, Sigma-Aldrich, St. Louis, Mo.) was added dropwise. The mixture was stirred at 0° C. for 1 h. At that time, 4 drops of methanesulfonyl chloride was added and stirring at 0° C. resumed for 10 min. The material was directly purified by column chromatography (25 g of silica, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((methylsulfonyl)oxy)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.311 g) as a white foam.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][C:2]([Br:1])=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)[CH:20]=1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc2ccc3c(-c4cccc(-c5ccccc5)c4)ccc4ccc1c2c43
Yield: 69.2 %

Procedure:
To a solution of 1,6-dibromopyrene (5.4 g, 15.0 mmol), [1,1′-biphenyl]-3-ylboronic acid (3.3 g, 16.5 mmol), and K2CO3 (10.4 g, 75.0 mmol) in 1,4-dioxane (320 mL) and water (50 mL) was bubbled with nitrogen for 15 min. Pd(PPh3)4 (0.87 g, 0.75 mmol) was then added to the mixture. The mixture was bubbled with nitrogen for 15 min. The resultant mixture was refluxed for 19 h. The reaction mixture was then extracted by DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography using 15% DCM/hexane (containing 0.25% triethylamine) to yield 1-([1,1′-biphenyl]-3-yl)-6-bromopyrene (4.5 g, 70% yield) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+].ClCCl>O>[C:16]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CNc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of 2.7 parts of ethyl 2-[(4-aminophenyl)amino]acetate hydrochloride, 1.1 parts of acetic acid anhydride, 0.98 parts of sodium hydrogen carbonate, 65 parts of dichloromethane and 50 parts of water was stirred for 30 minutes at room temperature. The organic phase was separated, washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 1.9 parts (68%) of ethyl 2-[[4-(acetylamino)phenyl]amino]acetate; mp. 119.5° C. (12).