Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1ccc(CCN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(2-bromoethyl)-4-methoxybenzene. MS 438 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.12 μM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:19][C:20]1[C:28]([NH2:29])=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:30])[CH:21]=1.O>CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:29][C:28]3[C:20](=[CH:21][C:22]([OH:30])=[C:23]([C:24]([OH:26])=[O:25])[CH:27]=3)[N:19]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(O)c(C(=O)O)cc1N
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)nc2cc1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
A mixture of 1,2-bis(4-fluorophenyl)ethane-1,2-dione (175 mg, 0.71 mmol, 1.00 equiv) and 4,5-diamino-2-hydroxybenzoic acid (120 mg, 0.71 mmol, 1.00 equiv) in HOAc (3 mL) was allowed to react, with stifling, for 3 hrs while the temperature was maintained at 130° C. in an oil bath. The reaction solution was poured into 10 ml of H2O. The resulting solid was filtered and purified by prep-HPLC, yielding 50 mg (19%) of 2,3-bis(4-fluorophenyl)-7-hydroxyquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:27])[C@@H:12]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[C:32]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:34][C:29]([CH2:28][C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][N:8]([C:11](=[O:27])[C@@H:12]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH2:7][CH2:6]2)=[CH:30][CH:31]=1
Reactant: COC(=O)C1(Cc2ccc(-c3ccccc3)cc2)CCN(C(=O)[C@H](Cc2cccs2)NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid methyl ester (5.63 mmol; 3.17 g) in THF (30 mL) and methanol (20 mL) was added a 1M solution of sodium hydroxide (16.9 mmol; 16.9 mL) and the resulting mixture was heated to reflux for 48 hours. The resulting mixture was then evaporated and a 1N hydrochloric acid solution (200 mL) was added to the residue. A white precipitate formed that was separated via filtration to yield 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid. MS (ESI) m/z 547.44 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH2:22][CH2:21][N:20]3[C:13](=[CH:14][C:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]=43)[C:12]2=[O:25])[C:3]=1[CH:4]=[O:5].C([OH:30])(C)(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>O.ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH2:22][CH2:21][N:20]3[C:13](=[CH:14][C:15]4[CH2:16][C:17]([CH3:23])([CH3:24])[CH2:18][C:19]=43)[C:12]2=[O:25])[C:3]=1[C:4]([OH:30])=[O:5]
Reactant: CC(C)(C)O
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C=O)C3=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C(=O)O)C3=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of 2-bromo-6-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluorobenzaldehyde 128a (810 mg, 2.0 mmol), tert-butyl alcohol (50 mL), and dichloromethane (3 mL) was added 2-methyl-2-butene (22 mL, 262 mmol). An aqueous solution (20 mL) of NaClO2 (1.8 g, 20.0 mmol) and NaH2PO4 dihydrate (2.2 g, 14.0 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. It was then treated with water (30 mL) and extracted with ethyl acetate (4×90 mL). The combined organic extract was dried over MgSO4 and concentrated under reduced pressure to afford 129a (930 mg, 84%) as a yellow solid. MS-ESI: [M+H]+ 421.1
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[C:11]([CH3:29])=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[NH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>O1CCCC1>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([NH:38][CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:13]=[CH:12][C:11]=3[CH3:29])=[O:8])=[CH:5][CH:4]=2)[CH2:40][CH2:41]1
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CCl)cc1
Reactant: CN1CCN(N)CC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1NC(=O)c1ccc(CNN2CCN(C)CC2)cc1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
N-(5-(4-chloromethylbenzoylamino)-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (1.5 g, 3.49 mmol) was dissolved in tetrahydrofuran (30 ml), pyridine (560 μl, 6.98 mmol) was added, and the mixture was stirred for 30 minutes. 1-Amino-4-methylpiperazine (580 μl, 5.23 mmol) was added thereto, and the resulting mixture was refluxed for 12 hours and then filtered. The filtrate was concentrated and crystallized from dimethylether to give 4-(4-methylpiperazin-1-ylaminomethyl)-N-[2-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (1.7 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](O)=[O:30]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][N:27]([CH3:32])[CH3:26])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CN(C)CC(=O)O
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CN(C)C)cs2)c(C(=O)C2CCCC2)c1
Yield: 77.6 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-2-dimethylamino-acetamide (86 mg, 78%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and N,-N-dimethyl glycine (0.30 mg, 0.30 mmol) following the general procedure K.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11].[CH3:23][C:24]1[C:32]2[CH2:31][O:30][C:29](=[O:33])[C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]1[CH2:36][O:35]1>CS(C)=O.O>[CH:1]12[CH2:8][CH2:7][CH:4]([N:5]([CH2:36][CH:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:29](=[O:33])[O:30][CH2:31][C:32]=4[C:24]=3[CH3:23])[OH:35])[CH2:6]1)[CH2:3][N:2]2[CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11]
Reactant: Cc1c(C(O)CN2CC3CCC2CN3)ccc2c1COC2=O
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(O)CN2CC3CCC2CN3CC(O)c2ccc3c(c2C)COC3=O)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
In four separate reactions, isomers A-D of 5-[2-(2,5-diazabicyclo[2.2.2]oct-2-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one (about 100 mg, 0.33 mmol) and 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (95 mg, 0.50 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to it, the mixtures were diluted with water (20 mL), extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residues were purified by preparative TLC (MeOH/DCM=1:15) to obtain 5,5′-[2,5-diazabicyclo[2.2.2]octane-2,5-diylbis(1-hydroxyethane-2,1-diyl)]bis(4-methyl-2-benzofuran-1(3H)-one) as 4 mixtures of two isomers, which were separated by SFC chiral chromatography to obtain two single isomers for each (eight total).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH:16](O)=[O:17]>>[CH:16]([NH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]=2[C:12]=1[CH3:13])=[O:17]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Reactant: O=CO
Product: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(C)O2
Yield: 93.3 %

Procedure:
5-Amino-2,2,4,6,7- pentamethyl-2,3-dihydrobenzofuran (1.00 g, 4.87 mmol) was dissolved in formic acid (20 ml) and the solution was heated under reflux for 48 hours. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate solution was added to the residue and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-methanol, 97:3) to obtain the desired compound (1.06 g, yield: 93.3%). A part of it was recrystallized from dichloromethan-isopropyl ether to obtain white prisms, m.p. 177°-179° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[CH:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15].C(=O)([O-])[O-].[Na+:29].[Na+]>CN(C)C=O.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>[NH2:1][C:2]1[C:3]([S:10]([O-:13])(=[O:12])=[O:11])=[CH:4][C:5]([Br:9])=[CH:6][C:7]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:14]=[O:15])[CH:21]=1.[Na+:29]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(-c2cccc(C=O)c2)cc(Br)cc1S(=O)(=O)[O-]
Temperature: 70 °C

Procedure:
A mixture of 11.34 g (30 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid, 4.5 g (30 mmol) of 3-formylbenzeneboronic acid, 10.5 g (99 mmol) of sodium carbonate and 1.73 g (1.5 mmol) of tetrakis(triphenylphosphine)palladium (0) in 40 ml of dimethylformamide and 20 ml of water is heated at 70° C. under argon for 5 hours. The reaction medium is then concentrated under reduced pressure and the residue is purified by chromatography on an RP 18 column, eluting with a water-acetonitrile mixture (8:2).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[CH:15]1([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[CH2:17][CH2:16]1.Cl.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>CCCCCC.O1CCCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]([CH:15]2[CH2:16][CH2:17]2)([OH:19])[CH2:29][C:28]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
13.8 ml (22.14 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 4.7 ml (22.14 mmol) of hexamethyldisilazane in 17 ml of tetrahydrofuran at −20° C., and the mixture was stirred at 0° C. for 30 min and then cooled again to −78° C. 2.17 ml (22.14 mmol) of ethyl acetate were added, and the mixture was stirred for 30 min and, after addition of 2.00 g (11.07 mmol) of 4-chlorophenyl cyclopropyl ketone, dissolved in 17 ml of tetrahydrofuran, stirred at −78° C. for a further hour. The reaction solution was mixed with 1N hydrochloric acid and ethyl acetate, and the phases were separated. The organic phase was washed successively with 0.5N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) the acetonitrile was removed in a rotary evaporator, and the aqueous phase was extracted several times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 2.54 g (99% of theory) of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[N:16]=2)=[C:25]2[CH2:26][CH2:27][CH2:28][N:24]2[N:23]=1
Reactant: CC(C)c1nnc2ccc(CC(=NN3CCCC3=O)c3ccc(F)cc3F)nn12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nn4c3CCC4)nn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.3 %

Procedure:
A mixture of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.20 g, 0.63 mmol, Preparation #K.1), 1-aminopyrrolidin-2-one hydrochloride (0.13 g, 0.95 mmol, prepared according to WO02/094833 Preparation #38), pyridine (0.15 mL, 1.9 mmol), and HOAc (1.2 mL) was sonicated to give a solution in a sealed vial. After stirring for about 16 h, additional 1-aminopyrrolidin-2-one hydrochloride (0.086 g, 0.632 mmol) was added and the resulting solution was stirred at ambient temperature for about 2 d. The reaction was then concentrated under reduced pressure and purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give impure 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.16 g) as an oil that was carried on without further purification. A 10 mL round-bottomed flask equipped with reflux condenser and outfitted with a nitrogen inlet adapter was charged with 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.060 g, 0.15 mmol) in toluene (1.5 L) to give a yellow solution. Sodium ethoxide (0.020 g, 0.30 mmol) was added in one portion to give a yellow suspension. The reaction mixture was heated to reflux for about 5 h. The reaction mixture was allowed to cool to ambient temperature and continued stirring for about 2 d. The reaction mixture was diluted with water (5 mL) adjusted to about pH 2 with 6 N HCl. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried with MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. The product-containing fractions were concentrated under reduced pressure and the resulting material was crystallized from EtOAc/heptane to give the title compound (0.031 g, 54%) as orange needles: LC/MS (Table 1, Method b) Rt=2.44 min; MS m/z: 381.4 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:13]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:31])[CH2:26][CH2:25]4)[CH:12]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CN(C)C=O>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:5]2[N:10]=[CH:9][C:8]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[C:13]([C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[C:27](=[O:31])[CH2:26][CH2:25]5)[CH:12]=3)=[CH:7][N:6]=2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)c1ncc(-c2cc(-c3ccc4c(c3)CCC4=O)c(-c3ccncc3)o2)cn1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(-c3cc(-c4ccc5c(c4)CCC5=O)c(-c4ccncc4)o3)cn2)CC1
Temperature: 90 °C
Yield: 57 %

Procedure:
A solution of the product from Step 6 (0.15 g, 0.35 mmol) in dry dimethylformamide (2 ml) was treated with N-methylpiperazine (0.077 ml, 0.70 mmol) and heated at 90° C. for 2 hours. After cooling to room temperature the reaction mixture was applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and chromatographed on silica gel eluting with 0.880 ammonia/methanol/dichloromethane solution (0.5:4.5:95) to afford the title compound (0.09 g, 57%); MS(ES+) m/e 452 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.C([Li])CCC.CCCCCC.Cl[Si:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C>[Br:9][C:4]1[CH:3]=[C:2]([Si:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:7]=[C:6]([Br:8])[CH:5]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
Into a solution of 1,3,5-tribromobenzene (9.0 g, 28.6 mmol) in diethyl ether (200 mL) was added n-butyllithium solution in hexane (2.5 M, 12 mL, 30.6 mmol) dropwise at −78° C. The reaction was stirred at this temperature for 30 minutes before a solution of chlorotriphenylsilane (9.27 g, 31.4 mmol) in diethyl ether (90 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour, and then allowed to warm to room temperature and continue to stir overnight, and finally refluxed for 2 hours. After cooling to room temperature, the solid was filtered off. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (9/1, v/v) as eluent to yield (3,5-dibromophenyl)triphenylsilane (4.0 g, 28%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:29][CH3:30])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:32]([CH3:47])[CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46]>CCN(CC)CC>[CH3:30][O:29][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:32]([CH3:47])[CH2:33][CH2:34][CH2:35][N:36]3[C:40](=[O:41])[C:39]4=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]4[C:37]3=[O:46])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Reaction time: 2 h
Yield: 72.4 %

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(9-phenylnonoxy) quinoline (0.85 g, 0.002 mol) and 4-bromo-1-phthalimidopentane (BPP) (2.4 g, 0.008 mol) was heated at 125°-135° C. while Et3N (1 ml) was added in small portions during 0.5 hr. After 2 h, second portions of BPP (0.6 g) and Et3N (2 drops) were introduced. Identical additions of BPP (0.6 g) and Et3N (2 drops) were made three more times at 1 h intervals. The mixture was allowed to cool, extracted with Et2O and the extract was treated with Darco and evaporated to dryness. The residue was redissolved in Et2O (100 ml) and treated with an excess of ethereal hydrogen chloride. The resulting dark red precipitate was separated by decantation, basified with ethereal Et3N and the solvent was evaporated. The residual brown oil was dissolved in CHCl3, placed on a silica gel column (100 g) and eluted with CHCl3. Concentration of the eluate provided 0.9 g (72%) of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(9-phenylnonoxy) quinoline as a pale brown oil which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:3]([O:5]CC)=[O:4].[ClH:16]>O>[ClH:16].[CH3:1][CH:2]([CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)CCN1CCCCC1
Agent: Cl
Solvent: O
Product: CC(CCN1CCCCC1)C(=O)O

Procedure:
6.5 g. (0.030 mole) of ethyl 2-methyl-4-piperidinobutyrate was combined with a mixture of 45 ml. of water and 45 ml. of concentrated hydrochloric acid and heated at reflux for 16 hours. The solution was concentrated under reduced pressure (water aspirator) to give a residue which crystallized upon addition of 50 ml. of diethyl ether. The ether was decanted, and the solid was triturated with acetone and filtered. Recrystallization from acetic acid/acetone gave 3.38 g. of colorless crystals, m.p. 166°-168°C. and a second crop of 1.27 g. of solid, m.p. 165°-168°C. The total yield for both batches was 69%. Anal. Calcd. for C10H20ClNO2 (MW = 221.72): C, 54.20; H, 9.09; N, 6.32; Found: C, 54.17; H, 9.15; N, 6.36.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[NH4+]>CCO.[Fe]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[C:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1cc(N)c(F)cc1Br
Temperature: 55 °C
Yield: 93.4 %

Procedure:
A solution of ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (2.127 g, 6.95 mmol) in EtOH (70 mL) was treated with iron powder (3.88 g, 69.5 mmol) and satd ammonium chloride (14.48 mL, 69.5 mmol) and heated to 55° C. for 1 h. The mixture was cooled to RT, filtered through a pad of diatomaceous earth, rinsed well with EtOH and the organics concentrated under reduced pressure. The resulting aqueous residue was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with water, dried (MgSO4), and concentrated to afford ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (1.792 g, 93% yield) as an amber oil. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (d, 1H), 6.76 (d, 1H), 5.35 (s, 2H), 4.08 (q, 2H), 3.61 (s, 2H), 1.18 (t, 3H); MS (ESI) m/z: 278.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([CH2:10][O:11][CH3:12])[N:3]=1.[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[CH3:12][O:11][CH2:10][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([N:15]2[CH2:16][CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]2[CH3:13])[C:5]=1[CH3:9]
Reactant: COCc1nc(Cl)nc(Cl)c1C
Reactant: CC1NCCc2ccccc21
Product: COCc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Yield: 59.9 %

Procedure:
The same procedures as in Step 1 of Example 25 were repeated using 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine(1.3 g, 6.3 mmol) and 1-methyl-1,2,3,4-tetrahydroisoquinoline(1.02 g, 6.93 mmol) to afford 1.2 g of the titled compound. (Yield: 60%)