Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(N)CC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNC1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.1 %

Procedure:
Under an argon atmosphere, to a mixed liquid of 1.06 g of 1-isopropylpiperidin-4-amine, 1.00 g of potassium carbonate, and 5.0 mL of DMF was added dropwise a mixture of 0.70 g of ethyl 4-bromobutyrate and 2.0 mL of DMF under ice-cooling, followed by washing with 3.0 mL of DMF. After stirring at room temperature for 96 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (aqueous ammonia-methanol-chloroform) to obtain 0.47 g of ethyl 4-[(1-isopropylpiperidin-4-yl)amino]butyrate as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C>C(Cl)CCl.ClCCl>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([O:12][C:7]1[C:6]2[C:11](=[C:2]([NH:1][C:26](=[O:27])[C:25]3[C:24]([Cl:23])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:33])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1)=[O:22]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cccc2c(OC(=O)c3c(Cl)cccc3Cl)ccnc12
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2c(OC(=O)c3c(Cl)cccc3Cl)ccnc12)c1c(Cl)cccc1Cl
Temperature: 70 °C
Reaction time: 24 h
Yield: 90.9 %

Procedure:
A mixture of 8-amino-4-(2,6-dichlorobenzoyloxy)quinoline (210 mg), 2,6-dichlorobenzoyl chloride (145 mg) and triethylamine (191 mg) in ethylene chloride (3 ml) was stirred for 24 hours at 70° C. The mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diethyl ether to give 4-(2,6-dichlorobenzoyloxy)-8-(2,6-dichlorobenzoylamino)quinoline (290 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:32][CH2:31]1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2-c2ccccc2)cc1

Procedure:
105 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(2-fluorophenyl)piperazine (50 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:21][CH2:22][CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1.Cl>O1CCOCC1>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:10]([O:12][CH2:21][CH2:22][CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClCCCC1OCCO1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)OCCCC1OCCO1

Procedure:
The title compound was prepared in two steps. Boc-Phe-OH was reacted with 2-(3-chloropropyl)-1,3-dioxolane according to Example 10 Step 1, and the subsequent product reacted with hydrogen chloride in dioxan according to Example 79 Step 5.
Reaction SMILES: [N:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:15]=3)[C:10](=[O:24])[C:9]([C:25](OCC)=[O:26])=[CH:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:25]([C:9]2[C:10](=[O:24])[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[CH:12]=3)[N:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:8]=2)=[O:26])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cn(N2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(N2CCOCC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 190 °C
Yield: 79 %

Procedure:
Ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (5.0 g) from Preparation No. 56 and 4-chlorobenzylamine (7.6 mL) are combined and heated to 190° C. for 7 hours. After cooling to room temperature, the mixture solidifies. The solid is triturated with a 10:1 mixture of EtOAc/MTBE (30 mL) and filtered on a frit. The crude solid is triturated again, this time with a hot mixture of 10:1 EtOAc/MTBE (110 mL). The suspension is cooled to room temperature and filtered on a frit to afford 4.9 g (79%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][NH2:2].C(O)(=O)C.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([Cl:17])[N:11]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[N:9]=1.O>O1CCCC1>[Cl:17][C:12]1[C:13]([N+:14]([O-:16])=[O:15])=[C:8]([NH:2][CH3:1])[N:9]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[N:11]=1
Reactant: CC(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CN
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(NC(C)=O)nc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixed solution (reagent A) of 2 liters of a 40% aqueous solution of methylamine and 1.5 liters of acetic acid previously prepared at not higher than 10° C. was weighed and taken out in an amount of 1.8 liters and added dropwise into a solution of 1.5 kg of N1-(4,6-dichloro-5-nitro-2-pyrimidinyl)acetamide in 15 liters of tetrahydrofuran with stirring under ice-cooling over 1 hour. The addition was carried out keeping the bulk temperature at 4° C. or lower. After the mixture was stirred for 30 minutes under ice-cooling, 450 ml of the reagent A was further added. After further 30 minutes, 450 ml of the reagent A was added again followed by stirring for 40 minutes. Ice (4.5 kg) was added to the reaction mixture followed by adding 10 liters of cold water. The resulting crystals were collected by filtration and washed with 1 liter of water twice and with 1 liter of ether twice. Then it was dried at 50° C. for 6 hours to give 1253 g of N1-(4-Chloro-6-methylamino-5-nitro-2-pyrimidinyl)acetamide. The yield was 85%.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].[H-].[Na+].[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>C1COCC1>[C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH:14][C:37](=[O:38])[CH2:36][O:35][CH3:34])=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of the product from Example 2 (100 mg) in THF (3 mL), under nitrogen, was treated with sodium hydride (60% in mineral oil) (10 mg). The suspension was stirred for 5 min were upon methoxyacetyl chloride (40 uL) was added. The reaction was allowed to warm to room temperature and was stirred 30 min. The reaction mixture was quenched with aqueous NaHCO3 (saturated) and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluted with 0-30% EtOAc in hexane afforded the title compound. HPLC/MS: 543.8 (M+1), 545.8 (M+3); Rt=4.19 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[O:26])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Product: CCN(CC)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with diethylamine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)[C:8](=O)[CH2:7][CH2:6]2.[NH2:23][C:24]1[CH:32]=[C:28]([C:29]([OH:31])=[O:30])[C:27]([OH:33])=[CH:26][CH:25]=1>C(O)(=O)C>[C:29]([C:28]1[CH:32]=[C:24]([N:23]2[C:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=4[C:9]=3[CH:13]=[C:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:25]=[CH:26][C:27]=1[OH:33])([OH:31])=[O:30]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: COc1ccc2c(c1)CCC(=O)C2CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCc1c-2cc(-c2ccccc2)n1-c1ccc(O)c(C(=O)O)c1
Yield: 64.4 %

Procedure:
A mixture of 5.8 g. (0.02 mole) of 6-methoxy-1-phenacyl-2-tetralone, 3.02 g. (0.02 mole) of 5-aminosalicylic acid, and 20 ml. of glacial acetic acid was heated under reflux for 1 hour, cooled, and filtered. The collected solid was washed with acetic acid and petroleum ether and recrystallized from acetonitrile to provide 5.3 g (67%) of pale yellow crystals, m.p. 233°-234°.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1nnc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)[C@H](CO)C3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1nnc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of crude (R)-t-butyl 2-((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)-2-(hydroxymethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.065 g, 0.11 mol) in dichloromethane (1.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 5-20% methanol in dichloromethane) to give the title compound as a white solid (0.032, 0.064 mol, 59%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=9.2 Hz, 1 H), 7.41 (s, 1 H), 7.16-7.15 (m, 2 H), 7.03 (dd, J=2.0, 8.8 Hz, 1 H), 6.57 (s, 1 H), 6.24 (q, J=6.8 Hz, 1H), 4.78-4.74 (m, 1 H), 4.02-3.76 (m, 4 H), 3.62-3.54 (m, 2 H), 3.22-3.16 (m, 1 H), 2.98-2.87 (m, 3 H), 2.14 (d, J=6.8 Hz, 3 H), 1.96-1.73 (m, 6 H); MS: (ES) m/z calculated for C24H29Cl2N6O2 [M+H]+503.2, found 503.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([N:23]([CH3:36])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32]CC=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:39]([CH:44]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:41][CH2:42][CH3:43])=[O:40].O1CC[CH2:66][CH2:65]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([N:23]([CH3:36])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:65][CH:66]=[CH:44][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCC=O)cc2)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=CCCCOc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(3-formylprop-1-yloxy)phenyl]benzamide (507 mg) and (carbethoxymethylene)triphenylphosphorane (418 mg) in tetrahydrofuran (20 ml) was stirred at ambient temperature overnight and the solvent was evaporated in vacuo. The oily residue was purified by silica gel column (chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-ethoxycarbonyl-4-penten-1-yloxy)phenyl]benzamide (435 mg) as a colorless amorphous.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([NH:29][C:30](=O)[CH:31]=[CH2:32])[CH:4]=1.O.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1COCC1>[CH:31]([C:30]1[NH:29][C:5]2[C:6]([CH:9]=1)=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)=[CH2:32]
Reactant: C=CC(=O)Nc1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cc2ccc(F)cc2[nH]1
Yield: 50 %

Procedure:
A 71.5 g (0.14 mol) sample of [[4-fluoro-2[(1-oxo-2-propenyl)amino]phenyl]-methyl]triphenylphosphonium bromide was suspended in 1.6 L of toluene and heated under reflux briefly with azeotropic removal of water. A 180 mL (0.18 mol) solution of 1M potassium t-butoxide in THF was added dropwise under Ar. The mixture was heated under reflux for one hour, cooled, washed with dilute HCl and filtered. The organic phase was washed with brine, dried (MgSO4) and concentrated. The residue was crystallized from methyl t-butyl ether (MTBE)/hexane. The precipitated triphenylphosphine oxide was collected and washed with MTBE. The combined filtrates were concentrated and flash chromatographed twice using EtOAc:hexane 1:10 as eluant. There was obtained 11.3 g (50%) of 2-ethenyl-6-fluoro-1H-indole: Cl-MS m/z=162 (M+H). 1H NMR (CDCl3) δ 8.1 (br s, 1H); 7.5 (m, 1H); 7.0 (d, 1H); 6.85 (m, 1H); 6.7 (m, 1H); 6.5 (s, 1H); 5.5 (d, 1H); 5.25 (d, 1H). ##STR19##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2O)[C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C1C[O:28]CC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:18]2[CH:23]=[CH:22][C:21]([OH:28])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)N(c1ccc(F)cc1)c1ccccc1O
Reactant: C1CCOC1
Product: Oc1ccc(CN(c2ccc(O)cc2)c2ccc(F)cc2)cc1
Yield: 92 %

Procedure:
Compound N-(4-fluorophenyl)-4-hydroxy-N-(hydroxyphenyl)benzamide (0.30 g, 0.93 mmol) was dissolved in 20 mL anhydrous THF at room temperature. H3B(SMe2) (1.86 mL of 2M THF solution, 3.71 mmol) was added via a syringe at room temperature under argon. The reaction solution was stirred and heated to reflux for 6 hours. Then, the reaction was quenched by adding 10 mL of MeOH at 0° C. The solvent was removed under reduced pressure. The residue was subjected to flash column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow oil, 0.26 g, 92% yield. 1H NMR (DMSO-d6, 500 MHz) δ 9.29 (s, 1H), 9.24 (s, 1H), 7.09 (d, 2H, J=8.3 Hz), 6.98 (d, 2H, J=9.0 Hz), 6.94-6.91 (m, 2H), 6.73 (d, 2H, J=9.0 Hz), 6.68-6.64 (m, 4H), 4.70 (s, 2H). MS m/z 307.8 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([CH:20]=[CH:21][N:22]=4)[CH:19]=3)([OH:13])C)=[CH:9][N:10]=2)[N:7]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([CH:20]=[CH:21][N:22]=4)[CH:19]=3)=[O:13])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(O)(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CC(C)=O
Product: O=C(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Temperature: 25 °C

Procedure:
(rac)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(imidazo[1,2-a]pyridin-6-yl)ethanol (Stage 9.1, 5 g, 16.68 mmol) was suspended in acetone (334 mL) with 2-iodoxybenzoic acid (45%, 14.01 g, 22.5 mmol). It was refluxed for 2 h. The RM was then cooled down to rt and the solvent was removed. The residue was triturated with 2.5 N NaOH solution and the precipitated was filtered off and dried to give the title compound as a beige solid (tR 0.6 min (conditions 2), MH+=298).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[C:28]1([CH:34]2[CH2:38][CH2:37][NH:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:27][N:24]1[CH2:23][CH2:22][N:21]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:18]([N:36]5[CH2:37][CH2:38][CH:34]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH2:35]5)=[O:20])=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:26][CH2:25]1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)N5CCC(c6ccccc6)C5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and 3-Phenyl-pyrrolidine (Matrix Scientific, Cat. No. 018619).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: O=C([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of 2-chloro-3-nitrobenzoate (1.0 g, 5.0 mmol) in anhydrous methanol (10 mL) at 0° C. was added thionyl chloride (0.5 mL, 7.4 mmol) dropwise and the reaction mixture was stirred overnight at reflux. The mixture was diluted with methanol and concentrated under reduced pressure to remove the excess thionyl chloride and then re-dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, re-extracted with ethyl acetate, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-chloro-3-nitrobenzoate (1.1 g, 98%) as a white foam that was used in the next step without further purification: 1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J=1.5 Hz, 1H), 8.07 (dd, J=7.8, 1.5 Hz, 1H), 7.73 (t, J=8.1 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1
Reactant: NCC1CCNCC1
Reactant: Clc1ccc(Br)cc1
Product: Clc1ccc(NCC2CCNCC2)cc1
Yield: 59.6 %

Procedure:
Using the general procedure, 4-bromochlorobenzene (192 mg, 1.0 mmol) was coupled with 4-aminomethylpiperidine (171 mg, 1.5 mmol) at 100° C. for 20 h. Purification of the crude product by column chromatography on silica gel using methanol/dichloromethane (saturated with ammonia) (1:20) as eluent afforded the desired product as a light yellow solid (134 mg, 60% yield). Rf=0.3 (methanol/dichloromethane (saturated with ammonia)=1:20).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[O:15][C:16]([CH3:19])=[CH:17][N:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]([C:14]2[O:15][C:16]([CH3:19])=[CH:17][N:18]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(Cc2ccc(OCc3ccccc3)cc2)o1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccc(OCc2ccccc2)cc1)c1ncc(C)o1
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
To a solution of 2-(4-(benzyloxy)benzyl)-5-methyloxazole (M5.2) (3.23 mmol) in THF (25 mL) at −78° C., was added dropwise LDA (4.5 mmol). The mixture was stirred for 18 minutes, followed by addition of ethyl bromoacetate (4.5 mmol). It was allowed to warm to room temperature for 3 hours, followed by addition of water, which was extracted with EtOAc. The extract was washed with brine and dried over Na2SO4 using standard work up conditions. Column chromatography (1/3 EtOAc/hexane) of the residue afforded compound M5.3. MS ESI (pos.) m/e: 366 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O.[H][H]>ClCCl.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19][OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: CC(C)Cn1c(CO)nc2c(N)nc3ccccc3c21
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1c(CO)nc2c(N)nc3c(c21)CCCC3

Procedure:
A mixture of [4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methanol (15.2 g, 56.2 mmol, U.S. Pat. No. 5,389,640 Example 9), platinum(IV) oxide (7.6 g), and trifluoroacetic acid (75 mL) was hydrogenated at 50 psi (3.5×105 Pa) of hydrogen on a Parr apparatus for 2 days. The mixture was diluted with dichloromethane and filtered through CELITE filter agent, which was rinsed afterwards with dichloromethane and methanol. The filtrate was concentrated under reduced pressure and the residue was partitioned between dichloromethane (250 mL) and 1:1 saturated aqueous sodium bicarbonate/water (250 mL). Some solid formed that was isolated by filtration. The aqueous layer was extracted with dichloromethane (2×200 mL). The solid was dissolved in methanol and the resulting solution was combined with the organic layers, concentrated under reduced pressure, and purified by chromatography using a HORIZON HPFC system (silica gel, elution with 10% 1 M NH3 in methanol/dichloromethane) to afford 4.98 g of [4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methanol as a grey solid.