Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:13].C1(C)C=CC=C(C)C=1>>[CH3:8][C:7]1[CH:6]=[C:5]([C:9]([CH3:11])([CH3:10])[CH3:12])[CH:4]=[C:3]([CH3:13])[CH:2]=1.[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1Br
Solvent: Cc1cccc(C)c1
Product: Cc1cc(C)cc(C(C)(C)C)c1
Product: Cc1cccc(C)c1Br
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A plastic bottle having a 25 ml. capacity was charged with 2.42 grams (0.01 mole) of 2-bromo-1,3-dimethyl-5-t-butylbenzene, 4.12 grams (0.04 mole) of metaxylene and 4.0 grams of liquid HF. The contents were stirred at 0° C. for 2.5 hours. Analysis of the crude product showed about 10% conversion of 2-bromo-1,3-dimethyl-5-t-butylbenzene to give equal molar amounts of 1,3-dimethyl-5-t-butylbenzene and 2-bromo-1,3-dimethylbenzene.
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].NCCC1C=CC([S:17]([NH2:20])(=[O:19])=[O:18])=CC=1.C(Cl)(Cl)Cl.C1(N=C=[N:33][CH:34]2CCCCC2)CCCCC1>C(#N)C.C(=S)=S>[S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].[S:17]([N:33]=[C:34]=[S:1])(=[O:19])(=[O:18])[NH2:20]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(=O)N=S(=O)=O
Solvent: S=C=S
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: NS(=O)(=O)N=C=S

Procedure:
A sulfonylurea derivative (SUNCS) is synthesized in preparation for making another sulfonylurea-containing initiator polymer. The preparation of SUNCS is achieved according to the synthetic scheme as illustrated in FIG. 3. 4-(2-Amino-ethyl)benzenesulfonamide (AEBS) is first dissolved in acetonitrile (or chloroform). In step 1 the AEBS solution is reacted with carbon disulfide (CS2) and dicyclohexylcarbodiimide (DCC). Dicyclohexylurea (DCU) product is removed from sulfamoyl-isothiocyanate (S-NCS) by filtration. The solvents are then removed to give the S-NCS intermediate. In step 2 the S-NCS, cyclohexyl isocyanate, and tetrabutylammonium bromide (TBAB) are placed in a glass vessel with tetrahydrofuran (THF) and the mixture is stirred under an inert dry atmosphere during the slow addition of sodium hydride (NaH). The SUNCS product (Compound IV, also shown in Table I) is then isolated and purified by flash chromatography.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15])[CH:7]=O.[Cl-].[NH4+:17].[CH3:18]O.C1COCC1>>[F:3][C:4]1[CH:5]=[C:6]([CH2:7][C:18]#[N:17])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15]
Reactant: [NH4+]
Reactant: CO
Reactant: COCOc1ccc(C=O)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(CC#N)cc1F

Procedure:
Sodium borohydride (2.15 g) was added to a methanol-THF (20 ml-100 ml) solution of the compound 321-1 (17.4 g), while the solution was stirred under cooling on ice. The obtained mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (100 ml). Triethylamine (19.8 ml) and methanesulfonyl chloride (8.05 ml) were added to the solution, while the solution was stirred under cooling on ice. The obtained mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (100 ml). Sodium iodide (2.83 g) and sodium cyanide (6.95 g) were added to the solution, and the obtained mixture was stirred at 80° C. for 3 hours. Thereafter, sodium cyanide (9.27 g) and dimethyl sulfoxide (30 ml) were added to the reaction solution, and the obtained mixture was stirred at 100° C. for 5 hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride aqueous solution, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:0 to 1:1), so as to obtain the title compound (11.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:22]2[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1c(F)cccc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,6-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]Br.O.[OH-].[K+]>C(O)(=O)C>[Br:12][C:9]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]([CH3:11])[C:8]=1[NH2:10]
Reactant: BrBr
Reactant: Cn1nc(C(C)(C)C)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(C(C)(C)C)c(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (10 g, 65.3 mmol) in acetic acid (90 mL) was added bromine (10.4 g, 65.26 mmol) in acetic acid (10 mL). The solution was stirred at rt for 30 min, and then water (100 mL) was added. The reaction mixture was basified to pH 9 using KOH (1.0 M ice cold solution). The resulting brown solid was filtered, collected, and purified by silica gel flash chromatography using 10 to 30% ethyl acetate in hexanes to afford 13.2 g (87%) of the title compound (white solid).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:19][CH:20]=C)[C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[O:22]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[CH2:19][CH:20]=[O:22])[O:3][CH2:4][CH2:5][O:6]1
Reactant: O=[O+][O-]
Reactant: C=CCC(CCCC1(C)OCCO1)C(=O)N1CCOC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(CCCC(CC=O)C(=O)N2CCOC2=O)OCCO1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-4 (4.0 g, 13.5 mmol), sudan III (10 mg) and CH2Cl2 (350 mL) at −78° C. under argon was bubbled ozone until red solution changed to yellow-orange. The solution was purged with argon for 30 minutes. PPh3 (5.28 g, 20.3 mmol) was added followed by the removal of the cooling bath. After 3.0 h, the reaction was concentrated. Flash chromatography (silica, 20%-50% EtOAc/hexanes) gave 2-5 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1OC.OCCC1C=C(F)C=C([Cl:45])C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:45][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F
Reactant: OCCc1cc(F)cc(Cl)c1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cc(F)cc(Cl)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-{2-[3-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 1-(2-hydroxy-ethyl)-3-chloro-5-fluoro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) in dichloromethane (1.5 ml) was added at room temperature triethylamine (113 mg, 156 μl, 1.12 mmol) and methanesulfonyl chloride (42.8 mg, 29 μl, 374 μmol). The mixture was allowed to stir at room temperature for 18 h, and was afterwards evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as an off-white solid (96 mg, 95%), MS (ISP) m/z=407.4 [(M+H)+], mp 152° C.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2>CN1CCCC1=O.O.Cl.[Fe](Cl)(Cl)Cl>[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)#[N:3]
Reactant: N#C[Cu]
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2cc(O)ccc2c1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
Copper (I) cyanide (2.73 g, 0.03 mol) was added to a solution containing 5 g (0.022 mol) 6-bromo-2-hydroxynaphthalene in 25 ml of dry N-methyl-2-pyrrolidinone and refluxed at 200° C. under nitrogen for 1.5 h. The reaction mixture was cooled to 100° C., poured into a solution of iron(III) chloride (5.9 g) in water (91 ml) and concentrated hydrochloric acid (3.18 ml), and stirred at 60° C. for 30 min. The obtained mixture was extracted with ethyl ether. The ether layer was treated with charcoal, dried over anhydrous sodium sulfate, and then evaporated to dryness. The obtained solid was recrystallized from water to yield 2.04 g (54%) white solid. 1H-NMR (CDCl3, TMS, δ in ppm): 5.60 (s, 1H, --OH), 7.10-8.07 (m, 6, aromatic protons).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C[Si](Cl)(C)C.C(N(C(C)C)C(C)C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-azetidine carboxylic acid (0.50 g, 4.9 mmol), trimethylsilyl chloride (1.25 ml, 9.8 mmol) and N-ethyldiisopropylamine (2.20 ml, 12.6 mmol) was heated under reflux in dichloromethane (20 ml) for 20 minutes. The reaction mixture was cooled in an ice bath and benzyl chloroformate (0.92 ml, 6.4 mmol) added. The mixture was stirred at room temperature for 72 hours before quenching with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase was acidified to pH2 with 2N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a brown oil, 1.01 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[OH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])[CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(O)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(O)ccn1)C1CC1
Yield: 32.1 %

Procedure:
Dissolve 2-amino-pyridin-4-ol (5 g, 45.4 mmol) in DCM (30 mL), add Et3N (13.8 g, 136 mmol) and then cyclopropanecarbonyl chloride (14.2 g, 136 mmol) dropwise while keeping the temperature below 10° C. After addition, stir the reaction at room temperature for 16 hrs. Remove the solvent under reduced pressure, dissolve the residue in THF (40 mL), adjust pH=12 with 1N NaOH solution. Stir the mixture for 3 hrs. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:MeOH=9:1) affords the title compound (2.6 g, 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Br-].O=[C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[N+]1CCCC1>CO.C(#N)C>[C:7]([C:6]1[CH:10]=[C:2]([N:1]2[C:17]3[CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[CH:15]=[C:14]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=[CH:4][C:5]=1[OH:11])([OH:9])=[O:8]
Reactant: O=C(CC1C(=[N+]2CCCC2)CCc2ccccc21)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: [Br-]
Solvent: CC#N
Solvent: CO
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A mixture of 1.92 g of 5-aminosalicylic acid and 5.0 g of tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide (Example 1a), in 75 ml of methanol is refluxed under nitrogen for 9 hours. The solution is allowed to reach ambient temperature before being filtered. The methanol is removed under a vacuum to give a viscous oil which is dissolved in acetonitrile. This solution immediately crystallizes to give a yellow crystalline solid which is collected by filtration and washed with acetonitrile to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:21])[C:19]#[N:20]>C1C(O)=CC=CC=1C>[ClH:1].[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:19]([N:18]([CH3:21])[CH3:17])=[NH:20])=[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=1
Reactant: CN(C)C#N
Reactant: COc1ccc(N)c(-c2ccccc2)c1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: COc1ccc(NC(=N)N(C)C)c(-c2ccccc2)c1

Procedure:
2-Amino-5-methoxybiphenyl hydrochloride (0.4 g) was heated with N,N-dimethylcyanamide (0.3 ml) in m-cresol (0.5 ml) at 110° C. for 8 hours to give a residue which was triturated with ether and crystallised from a 1:1 mixture of acetone and ether to give N-(5-methoxy-2-biphenylyl)-N',N'-dimethyl guanidine hydrochloride (m.p. 160° C.).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[OH:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1.N1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([O:8][C@@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:25]2[C:24](=[O:30])[CH2:23][C@@:22]2([CH3:31])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C(Cl)(Cl)Cl)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of trichloroacetyl chloride (0.5 ml.) in dry tetrahydrofuran (8 ml.) was added dropwise to a cooled (-80°) and stirred solution of 3α-hydroxy-5α-pregnane-11,20-dione (0.75 g.) and pyridine (0.35 ml.) in dry tetrahydrofuran (15 ml.). After 30 min. the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N-hydrochloric acid, aqueous sodium hydrogen carbonate, then water. The solution was dried and concentrated to leave a residue which was crystallised from benzene then benzene-petrol to afford the title compound (0.21 g.), m.p. 126°-127°, [α]D + 86°.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.[OH-].[Na+]>O>[C:14]([C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])[N:1]([C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cc(Nc2ccccc2)cc(C(C)(C)C)c1O
Reactant: O=C1CCCC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1cc(N(C(=O)CCCC(=O)O)c2ccccc2)cc(C(C)(C)C)c1O
Temperature: 90 °C
Yield: 56.9 %

Procedure:
12.0 g (0.038 mole) of 4-anilino-2,6-di-t-butylphenol was added to a 55° C. melt of 12.0 g (0.105 mole) of glutaric anhydride. The reaction warmed to 90° C. during the addition. The reaction was allowed to cool to 50° C., and was then maintained at that temperature for 3 hours. Thereafter, the mixture was heated briefly to 80° C. and allowed to cool to room temperature. The reaction mass was ground to a powder and the powder was heated in water. This cloudy solution was allowed to cool, and was then basified with dilute sodium hydroxide, extracted twice with diethyl ether, and acidified with dilute hydrochloric acid. The resulting precipitate was collected, dried and recrystallized from a mixture of ethanol and water to give 8.9 g of white crystalline 5-(3,5-di-t-butyl-4-hydroxy-N-phenylanilino)-5-oxopentanoic acid, m.p. 168.5°-169° C. Analysis: Calculated for C25H33NO4 :% C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 73.6; % H, 8.1; % N, 3.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[C:15]1([CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[C:24]1([CH:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][NH:23][C:11](=[O:12])[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:14])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(NCC(c1ccccc1)c1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
N-(2,2-Diphenylethyl)-2-(1H-indol-3-yl)-2-oxo-acetamide was synthesized following the scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and 2,2-diphenyl-ethylamine. Yield (48%). HPLC ret. time 3.55 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.70 (t, J=5.9 Hz, 1H), 8.50 (s, 1H), 8.17 (m, 1H), 7.52 (m, 1H), 7.36-7.18 (m, 12H), 4.43 (t, J=8.0 Hz, 1H), 3.90 (dd, J=8.0, 6.0 Hz, 2H); ESI-MS 369.3 m/z (MH+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:35][CH:34]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-nitrobenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][CH3:10])=[O:8])=[O:3]
Reactant: BrBr
Reactant: CNC(=O)c1cccc(C(C)=O)c1
Solvent: CC(=O)O
Product: CNC(=O)c1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To an acetic acid (2.4 mL) solution of 3-acetyl-N-methylbenzamide (0.33 g), at room temperature, an acetic acid (0.30 mL) solution of bromine (95 μL) was added dropwise, and the resultant was stirred at room temperature for 3.5 hours and then stirred at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure and then dried to obtain the title compound (0.50 g) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C([N+]([O-])=O)=CC=C([Cl-:25][C:26]([O-])=[O:27])C=1.[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1.C(N(CC)CC)C>O1CCCC1.ClCCl>[ClH:25].[F:45][C:42]1[CH:41]=[CH:40][C:39]([CH:36]2[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][CH2:30][NH:29][C:26]([N:12]3[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][CH2:10][C:11]3=[O:13])=[O:27])[CH2:38][CH2:37]2)=[CH:44][CH:43]=1
Reactant: NCCCN1CCC(c2ccc(F)cc2)CC1
Reactant: O=C1CCCC(c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CCCC(c2ccccc2)N1C(=O)NCCCN1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution 6-phenylpiperidin-2-one (132 mg, 0.753 mmol) in tetrahydrofuran (3 mL) was added to a suspension of 95% sodium hydride (40 mg, 1.67 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at ambient temperature for 30 minutes. The resulting solution was transferred via syringe to a solution of 4-nitrophenylchloroformate (152 mg, 0.754 mmol) in tetrahydrofuran (3 mL) which had previously been chilled to −78° C. The mixture was stirred at −78° C. for 2 hours, then evaporated to dryness. The residue was dissolved in 6 mL of dichloromethane and treated with a solution of 1-(3-aminopropyl)-4-(4-fluorophenyl)piperidine (220 mg, 0.931 mmol) in dichloromethane (4 mL) and triethylamine (209 mL, 1.50 mmol). The yellow reaction mixture was stirred at ambient temperature for 18 hours, and then evaporated to dryness. The resulting solid was purified by “flash” chromatography (98:2 dichloromethane : methanol), and the product fractions were evaporated to dryness. The resulting oil was dissolved in dichloromethane and washed six times with saturated sodium bicarbonate and once with brine. The organic phase was then dried over sodium sulfate, filtered, and the filtrate was evaporated to an oil. This residue was treated with HCl-saturated ethyl acetate, evaporated to dryness, and reconcentrated from diethyl ether twice to give the title compound as a solid.