Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH3:19])[C:8]([N+:20]([O-])=O)=[CH:7][C:6]=1[OH:23])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH3:19])[C:8]([NH2:20])=[CH:7][C:6]=1[OH:23])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of 2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (3.0 g, 9.5 mmol) in methanol (30 ml) was added Raney Ni (300 mg). The mixture was stirred under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether—ethyl acetate, 6:1) to afford 2-tert-butyl-4-(2-ethoxyphenyl)-5-aminophenol (C-15) (2.35 g, 92%). 1HNMR (DMSO-d6) δ 8.89 (s, 1H), 7.19 (t, 1H, J=4.2 Hz), 7.10 (d, 1H, J=1.8 Hz), 7.08 (d, 1H, J=1.8 Hz), 6.94 (t, 1H, J=3.6 Hz), 6.67 (s, 1 H), 6.16 (s, 1 H), 4.25 (s, 1 H), 4.00 (q, 2H, J=6.9 Hz), 1.26 (s, 9H), 1.21 (t, 3H, J=6.9 Hz); ESI-MS 286.0 m/z (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([NH:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:29][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:31][CH:30]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CC(=O)Nc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 91.6 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and p-acetylaminoaniline (75 mg, 0.5 mmol) to give 190 mg of the title compound (91%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (s, 1H), 9.94 (s, 1H), 9.87 (s, 1H), 7.44~7.52 (m, 4H), 7.23 (bs, 1H), 7.17 (bs, 1H), 5.18~5.26 (m, 1H), 3.07 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.55~2.64 (m, 2H), 2.10 (dm, 1H, J=13.5 Hz), 2.02 (s, 3H), 1.80~1.96 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][O:16][C:17]=3[CH:18]3[CH2:20][CH2:19]3)=[N:11][N:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:18]1([C:17]2[O:16][N:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]=2[C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:3][C:4]=3[O:27][CH3:28])=[N:12][N:11]=2)[CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Yield: 59 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.53 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using morpholine instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 138 mg, 59%) which was obtained as a white solid. MS: m/e=445.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=O)[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>C(#N)C>[CH2:12]([O:11][C:9]1[O:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])=[N:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOC(=O)CNC(=O)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC#N
Solvent: O
Product: CCCCOc1cnc(C(=O)OCC)o1
Temperature: 60 °C

Procedure:
To a solution of butyl N-[ethoxy(oxo)acetyl]glycinate (783 g, 3.38 mol) in acetonitrile (8 L) in a 50 L glass reactor with overhead stirrer, phosphorus pentoxide (415 g, 2.92 mol) was added in portions. The reaction was heated at 60° C. for 1 hour. The product mixture was cooled, and water (8 L) was added with the mixture maintained at 20° C. The resultant mixture was extracted with dichloromethane (8 L, and 3 times 2 L). The organic extracts were combined, washed twice with saturated aqueous sodium bicarbonate (8 L total), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residual oil was subjected to column chromatography on silica gel eluting with 0-30% heptanes/ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([C:40](=[N:44][OH:45])[C:41]([OH:43])=[O:42])[C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:38]=[CH:37][C:36]6[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=6)[N:30]=5)=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:47]>CCO.C1COCC1>[Na+:47].[Cl:39][C:33]1[CH:32]=[C:31]2[C:36]([CH:37]=[CH:38][C:29]([CH2:28][O:27][C:24]3[CH:23]=[CH:22][C:21]([CH:20]([C:40](=[N:44][OH:45])[C:41]([O-:43])=[O:42])[C:17]4[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]5[CH:7]=[CH:6][C:5]6[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=6)[N:9]=5)=[CH:19][CH:18]=4)=[CH:26][CH:25]=3)=[N:30]2)=[CH:35][CH:34]=1
Reactant: O=C(O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C([O-])C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution in EtOH--THF (3:1, 4 mL) of bis(4-(7-chloro-2-quinolyl-methoxy)phenyl)methyloximinoacetic acid (240 mg, 0.4 mmol), prepared as in Example 5, was added 1N aqueous NaOH (0.5 mL, 0.5 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was slurried in ether (15 mL), filtered, and dried in vacuo to provide bis(4-(7-chloro-2-quinolylmethoxy)phenyl)methyloximinoacetic acid sodium salt (220 mg): mp 181°-183° C.; 1H NMR (300 MHz, DMSO-d6)δ4.15 (s, 2H), 5.41 (m, 4H), 7.07 (dd, 4H, J=12, 3 Hz), 7.28 (d, 2H, J=9 Hz), 7.56 (d, 2H, J=9 Hz), 7.73 (m, 4H), 8.06 (m, 4H), 8.49 (m, 2H); MS (FAB) 660 (M+H)+, 682 (M+Na)+. Anal. Calcd. for C35H24Cl2N3O5Na×2.5 H2O: C, 59.58, H, 4.11; N, 5.96. Found C, 59.61; H, 3.94; N, 5.72.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[CH:16][C:17]([OH:19])=[O:18]
Reactant: Cc1nc(-c2ccccc2)sc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1nc(-c2ccccc2)sc1C=CC(=O)O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 300 mg (1.47 mmol) of 4-methyl-2-phenyl-thiazole-5-carbaldehyde, 169 mg (1.62 mmol) of malonic acid and 880 mg (10.33 mmol) of piperidine in 10 ml of pyridine was stirred at 90° C. for 5 h and at 100° C. for 6 h. After concentration, the residue was treated with a sodium hydrogencarbonate solution and ethyl acetate. The aqueous phase was separated and acidified. The precipitated product was filtered off with suction and dried. Yield: 260 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.B([C:20]1[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>O>[O:11]=[C:6]1[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=3)[CH:3]=2)[NH:7]1
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere was added tetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol%). After 15 min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash columm chromatography on silica gel (eluting with 30% EtOAc/hexane) to give subtitled compound: (3.4 g, 76%) as a white powder, mp 177° C. 1H NMR (CDCl3; 300 MHz) δ 1.38 (s, 9H), 1.59-1.93 (m, 10 H), 6.18 (m, 1H), 6.23 (‘t’, 1H, 3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2Oex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.14 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/heptane) to yield the title compound as an off-white solid (0.087 g, 20%). MS (ISP) 442.4 [(M+H)+]; mp 227° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.CO.[OH-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][CH:23]=1>O>[NH:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:2]1[S:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Reactant: Sc1nc2ncccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCSc2nc3ncccc3[nH]2)cc1
Yield: 32.4 %

Procedure:
To a mixture of 570 mg 2-mercapto-1H-imidazo[4,5-b]pyridine and 18 ml methanol, was added a mixture of 166 mg sodium hydroxide, 6 ml water and 1.8 g ethyl 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanoate. The resulting mixture was heated under reflux for 12 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, affording 610 mg ethyl 6-[p-[5-(1H-imidazo[4,5-b]pyridin-2-ylthio)pentyloxy]phenoxy]-2,2-dimethylhexanoate as waxy solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[S:29][CH:30]=[CH:31][C:32]=1B(O)O)(=[O:27])[CH3:26]>>[C:25]([C:28]1[S:29][CH:30]=[CH:31][C:32]=1[C:5]1[CH:6]=[CH:7][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:24])(=[O:27])[CH3:26]
Reactant: CC(=O)c1sccc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: CC(=O)c1sccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 20 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-acetyl-3-thienylboronic acid (available from Aldrich Chemical Company, Inc.; 68 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(2-acetyl-thiophen-3-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (19 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 13.12 (br s, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.94 (d, J=5.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.10 (d, J=5.0 Hz, 1H), 2.08 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:54])[NH:22][CH:23]([C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][CH:40]=2)=[CH:37][N:38]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:19][O:20][C:21](=[O:54])[NH:22][CH:23]([C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]1[NH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([C:14]3[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:12][CH:13]=3)=[CH:43][CH:44]=2)=[CH:37][N:38]=1)=[O:28])[CH:24]([CH3:26])[CH3:25]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(Br)cc1
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: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CNC(=O)OC(C)(C)C)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
A mixture of [2-(4-Bromo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (1 g, 3.2 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (1.57 g, 3.2 mmol), tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.15 mmol), potassium carbonate (878 mg, 6.5 mmol), 1,2-dimethoxyethane (25 mL) and water (2.5 mL) was stirred at 80° C. for 16 hours. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dichloromethane (100 mL) and washed with water (25 mL) and saturated sodium chloride (25 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide [1-(2-{5-[4′-(2-tert-butoxycarbonylamino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (869 mg, 1.4 mmol, 44%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][OH:8])[C:5](=[O:9])[CH2:4][N:3]1[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][CH:32]([CH:36]([CH3:38])[CH3:37])[C:33](O)=[O:34]>CCOCC>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][CH:32]([CH:36]([CH3:38])[CH3:37])[C:33]([O:8][CH2:7][N:6]1[C:5](=[O:9])[CH2:4][N:3]([CH2:10][C:11]#[CH:12])[C:2]1=[O:1])=[O:34]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C#CCN1CC(=O)N(COC(=O)C(Nc2ccc(C(F)(F)F)cc2Cl)C(C)C)C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2,4-dioxo-1-propargyl-3-imidazolidinyl)methanol (0.99 mmol) and triethylamine (1.38 mmol) in ether (about 15 ml), under nitrogen, is added by syringe a solution of the acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (1.5 mmol) in ether. The mixture is stirred for 30 minutes and then quenched with saturated aqueous sodium bicarbonate. The ether phase is washed with aqueous sodium bicarbonate, water and brine and filtered through silica. Evaporation of solvent, followed by thin layer chromatography using a circular chromatograph, eluting with 20% ether/hexane, gives (2,4-dioxo-1-propargyl-3-imidazolidinyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Ni].[H][H]>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OCCCc2ccccc2)cc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(OCCCc2ccccc2)cc1

Procedure:
99 g of 4-(3'-phenyl-propoxy)-nitrobenzene is dissolved in 2000 ml of methanol and hydrogenated with Raney nickel until the absorption of hydrogen is completed. The catalyst is filtered off and the filtrate is concentrated by evaporation to obtain, as a crystalline residue, 4-(3'-phenylpropoxy)-aniline having a melting point of 55°- 57°. -
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([OH:35])=[C:27]([C:32](O)=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:32]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[OH:35])=[CH:24][CH:23]=[C:22]([Cl:21])[CH:31]=2)=[O:33]
Reactant: O=C(O)c1cnc2cc(Cl)ccc2c1O
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1cnc2cc(Cl)ccc2c1O

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 7-chloro-4-hydroxy-quinoline-3-carboxylic acid. MS: 479.2 (M+H).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][NH:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]1[C@@H:19]2[C@@H:14]([NH:15][C:16]([NH:18]2)=[O:17])[CH2:13][S:12]1.Cl>CO>[O:2]=[CH:3][CH2:4][NH:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]1[C@@H:19]2[C@@H:14]([NH:15][C:16]([NH:18]2)=[O:17])[CH2:13][S:12]1
Reactant: COC(CNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)OC
Agent: Cl
Solvent: CO
Product: O=CCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2,2-Dimethoxyethyl)biotinamide (9, 280 mg, 850 μmol) was dissolved in MeOH (2 mL) and conc. HCl (0.5 mL) was added to the solution, which was allowed to stir for 1 h at 25° C. The reaction mixture was evaporated to dryness under reduced pressure to yield the aldehyde, the total amount of which was used without further purification in the preparation of 10.
Reaction SMILES: [CH2:1]1[CH2:21][O:20][C:19]2[C:3](=[C:4]([CH:16]=[CH:17][CH:18]=2)[CH2:5][CH:6]([CH2:14][OH:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:1]1[CH2:21][O:20][C:19]2[C:3](=[C:4]([CH:16]=[CH:17][CH:18]=2)[CH2:5][CH:6]([CH2:14][O:15][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CO)Cc1cccc2c1OCCO2
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(Cc2cccc3c2OCCO3)C(=O)OC(C)(C)C)cc1
Yield: 70.9 %

Procedure:
238 mg of tert-butyl 2-(2,3-ethylenedioxybenzyl)-3-hydroxypropionate was dissolved in 4 ml of dry pyridine, and 170 mg of p-toluenesulfonyl chloride was added thereto. The mixture was reacted at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate and washed sequentially with 50 ml of a 5% potassium hydrogensulfate aqueous solution, with 50 ml of a 4% sodium hydrogencarbonate aqueous solution and with 50 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to obtain 257 mg of tert-butyl 2-(2,3-ethylenedioxybenzyl)-3-p-toluenesulfonyloxypropionate as colorless transparent syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>>[CH3:27][CH:28]([CH3:32])[C:29]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:30]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C(C)C)c4)CC3)cccc2n1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-methylpropanoyl chloride.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.C(N(C(C)C)C(C)C)C.[CH2:21]([O:23][C:24]([C:26]1[C:27]([OH:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]>O1CCOCC1>[CH2:21]([O:23][C:24]([C:26]1[C:27]([OH:33])=[N:28][C:29]2[N:30]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:32]=2)[CH:31]=1)=[O:25])[CH3:22]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCOC(=O)c1cnc(N)nc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2cc(-c3ccc(F)cc3)nc2nc1O
Yield: 4 %

Procedure:
2-Bromo-1-(4-fluoro-phenyl)ethanone (200.1 mg, 0.922 mmol), ethyl-diisopropylamine (160.6 μl, 0.922 mmol) and 2-amino-4-hydroxy-pyrimidine-5-carboxylic acid ethyl ester (168.9 mg, 0.922 mmol) were heated under reflux in 50 ml dioxane for 8.5 hours. The mixture was evaporated. Ethyl acetate and water were added, the organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 11 mg (4%) of the desired product. MS (mass spectrum): M+H+=302.11.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:10]
Reactant: O=Cc1cccnc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cccnc1

Procedure:
prepared by reaction of the commercially available pyridin-3-carbaldehyde with 2M ethylamine in THF.