Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg])C.[F:15][C:16]1[C:25]([CH:26]=[O:27])=[C:24]([F:28])[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:26]([C:25]3[C:16]([F:15])=[C:17]4[C:22](=[CH:23][C:24]=3[F:28])[N:21]=[CH:20][CH:19]=[CH:18]4)[OH:27])=[CH:3][N:4]=2)[N:7]=1
Reactant: O=Cc1c(F)cc2ncccc2c1F
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: CC[Mg]
Solvent: C1CCOC1
Product: OC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-6-chloro-imidazo[1,2-b]pyridazine (4.40 g, 18.95 mmol) was suspended in THF (189 mL) and the ethylmagnesium solution (3 M, 6.32 mL) was added slowly under nitrogen condition. The RM was stirred at rt for 15 min and the solution of 5,7-difluoro-quinoline-6-carbaldehyde (Intermediate F, 3.66 g, 18.95 mmol) was added. After 30 min, the reaction was quenched with 10% ammonium chloride. The precipitate was filtered off and a first part of the title compound was obtained as a white solid. The filtrate was concentrated and was taken up with 10% NH4Cl. The precipitate was filtered off and was washed with EtOAc. A second part of the title compound was obtained as a brown solid (tR 0.8 min (conditions 2), MH+=347).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[N:8]3[C:9](=[N:14][C:15]([CH3:16])=[C:7]3[C:6]1=[O:17])[CH:10]=[CH:11][CH:12]=2.C(N(CC)CC)C.[F:25][C:26]([F:33])([F:32])[CH2:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:16][C:15]1[N:14]=[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[N:8]2[C:7]=1[C:6](=[O:17])[N:5]3[CH2:4][CH2:3][CH2:2][NH:1][S:28]([CH2:27][C:26]([F:33])([F:32])[F:25])(=[O:30])=[O:29]
Reactant: Cc1nc2cccc3n(CCCN)c(=O)c1n23
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2cccc3n(CCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 58.5 %

Procedure:
To a solution of 0.43 g (1.87 mmol) of 1-[3-(amino)propan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.39 ml (2.80 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.41 g (2.26 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 412 mg of the desired compound (58.6%, white powdery).
Reaction SMILES: COC[N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([CH:15]1[CH2:18][CH:17]([NH:19][C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16]1)=[O:14].Cl>O1CCCC1>[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([CH:15]1[CH2:18][CH:17]([NH:19][C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16]1)=[O:14]
Reactant: COCn1c(C(=O)C2CC(Nc3ncccc3[N+](=O)[O-])C2)nc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1nc2ccccc2[nH]1)C1CC(Nc2ncccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of (1-(methoxymethyl)-1H-benzo[d]imidazol-2-yl)(3-((3-nitropyridin-2-yl)amino)-cyclobutyl)methanone (534 mg, 1.40 mmol) in tetrahydrofuran (20 mL) at room temperature was added concentrated hydrochloric acid (20 mL). The reaction mixture was stirred at room temperature for 1 hour and then heated at 60° C. for 6 hours. The mixture was partially concentrated, neutralized with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×40 mL) and the combined organic extracts were washed with brine (20 mL). The organic was dried over magnesium sulfate and concentrated to get a residue, which was purified by flash column chromatography on silica gel (10% to 40% ethyl acetate in petroleum ether) to give (1H-benzo[d]imidazol-2-yl)(3-((3-nitropyridin-2-yl)amino)cyclobutyl)methanone (0.57 g, 1.30 mmol, 92% yield) as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13]/[N:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+]([C:26]([CH2:53][CH2:54][CH2:55][CH3:56])=[CH:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][C:29]=1[C:41]([N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])([O-])=O>>[C:35]([O:34][C:32]([C:31]1[CH:39]=[CH:40][C:28]([C:27]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=4)=[CH:12][CH:11]=3)[C:26]=2[CH2:53][CH2:54][CH2:55][CH3:56])=[C:29]([C:41]([N:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[CH:30]=1)=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccc(Oc2ccc(Cl)cc2)cc1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 46.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-(4-chlorophenoxy)phenyl)hydrazono)acetate (41 mg, 0.13 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (60 mg, 0.13 mmol) were converted to the title compound (44 mg, 46%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.09 (dd, J=8, 2 Hz, 1H), 8.04-8.03 (m, 1H), 7.43-6.81 (m, 13H), 5.02-4.98 (m, 1H), 4.48-4.38 (m, 1H), 4.33-4.27 (m, 2H), 4.18-3.98 (m, 1H), 3.58-3.32 (m, 1H), 2.85-2.48 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.20 (t, J=8 Hz, 1.5H), 1.15-0.91 (m, 4H), 0.63-0.59 (m, 3H); MS(ESI+) m/z 734.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2O.P(Br)(Br)([Br:20])=O>C1(C)C=CC=CC=1.CC#N>[Br:20][C:7]1[C:6]2[C:11](=[C:2]([F:1])[C:3]([CH3:17])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=1
Reactant: COC(=O)c1cc(O)c2ccc(C)c(F)c2n1
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)c2ccc(C)c(F)c2n1
Temperature: 75 °C
Yield: 66.5 %

Procedure:
A mixture of (methyl 8-fluoro-4-hydroxy-7-methylquinoline-2-carboxylate (7-15, 842.1 mg, 3.58 mmol) and POBr3 (1129 mg, 3.94 mmol) in Toluene (8.14 mL) and CH3CN (0.81 mL) was heated at 75° C. for 1 h. After cooling to room temperature, the mixture was poured to a mixture of ice-H2O, followed by CH2Cl2 extraction (twice). The combined organic fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient 0-50% EtOAc/Hexanes) to afford methyl 4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16, 710 mg). LRMS m/z (M+H)+ 298.1 found, 298.0 required.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:18]Br)=[C:7]2[C:14]([O:16][CH3:17])=[O:15].[Na+].[C:21]1([S:27]([O-:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CC(N(C)C)=O.O>[C:21]1([S:27]([CH2:18][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:2]=3[Br:1])[C:7]=2[C:14]([O:16][CH3:17])=[O:15])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1c(CBr)ccc2c(Br)ccc(OC)c12
Reactant: O=S([O-])c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c(Br)ccc(OC)c12
Temperature: 50 °C
Yield: 28.5 %

Procedure:
A mixture of methyl 5-bromo-2-bromomethyl-8-methoxynapthalene-1-carboxylate (Intermediate 189, 0.716 g), benzenesulphinic acid sodium salt (0.68 g) and sodium hydrogen carbonate (0.35 g) in DMA (15 ml) and water (3 ml) was heated at 50° C. for 2 hours. After cooling, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl 2-(benzenesulphonylmethyl)-5-bromo-8-methoxynaphthalene-1-carboxylate (0.236 g) as an oil which crystallised on standing.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:20]#[N:21])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([Cl:19])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C[O-].[Na+].CO>[Cl:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:20]#[N:21])=[N:9][C:8]([C:6]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:7])=[C:17]2[OH:18]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Cl)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Cl)ccc12
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of 6-chloro-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (99 mg, 0.33 mmol) and glycine (1.84 g, 24.49 mmol) in 0.5 M sodium methoxide/methanol (32.6 mL) was refluxed for twenty-one hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (40 mL) and the solution washed with dichloromethane (3×50 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl. The suspension was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a white solid (84 mg): MS: (+) m/z 306.27 (M+1); (−) m/z 304.26 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][N:6]1[S:14]([CH3:17])(=[O:16])=[O:15])=[O:4].B>O1CCCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][N:6]1[S:14]([CH3:17])(=[O:15])=[O:16])=[O:4]
Reactant: COC(=O)C1CCC(C(=O)O)CN1S(C)(=O)=O
Agent: B
Solvent: C1CCOC1
Product: COC(=O)C1CCC(CO)CN1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution of (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid 2-methyl ester (10.7 g) in tetrahydrofuran was added a 1 M borane solution in tetrahydrofuran (215 ml) within 0.5 h at 0° C. The reaction mixture was stirred for 4 h at 0° C., poured onto ice/saturated sodium bicarbonate solution and concentrated. The aqueous residue was extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:1 and 3:2 as eluents to obtain (2RS,5RS)-5-hydroxymethyl-1-methanesulfonyl-piperidine-2-carboxylic acid methyl ester (8.1 g) as a colourless solid, MS: 206 (100%, M+-59).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[N:10]=1)[CH2:2]2.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[N:12]=2)=[CH:26][CH:25]=1
Reactant: O=C1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: Nc1ccc(B(O)O)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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nc(N3CCC(=O)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
A suspension of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one (1.0 g, 3.1 mmol), 4-aminophenylboronic acid, pinacol ester (1.0 g, 4.7 mmol), and tetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound as a golden yellow foam.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][N:7]=1.[C:16]([Cu])#[N:17]>CN1CCCC1=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([C:16]#[N:17])[C:3]2=[O:15])=[CH:9][CH:10]=1
Reactant: O=c1c(Cl)nccn1-c1ccc(F)cc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1nccn(-c2ccc(F)cc2)c1=O
Temperature: 150 °C
Yield: 23.1 %

Procedure:
A mixture of 3-chloro-1-(4-fluorophenyl)pyrazin-2(1H)-one (3.52 g, 15.7 mmol), CuCN (2.81 g, 31.3 mmol) and N-methylpyrrolidone (30 mL) was heated for 5.5 hours at 150° C. while being stirred. The residue was triturated with hot CHCl3 and filtered over charcoal. The filtrate was evaporated and concentrated under reduced pressure. The residue was triturated with CH2Cl2 and the solution was concentrated. The crude was purified by silica gel flash column chromatography (3:1=CH2Cl2:Hexane then CH2Cl2) to afford 0.78 g (23%) of the desired product. LRMS (ESI pos) m/e 215.9 (M+1).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26][NH2:27].[OH-].[Na+]>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.Cl[Ti](Cl)(Cl)Cl.C1COCC1>[F:21][C:22]1[CH:23]=[C:24]([CH2:25][CH2:26][NH:27][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:28]=[CH:29][CH:30]=1
Reactant: NCCc1cccc(F)c1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2cccc(F)c2)cc1
Yield: 5.9 %

Procedure:
In a round bottom flask, combine 4-(1-Oxo-indan-5-yloxy)-benzamide (Intermediate 24, 45.0 mg, 0.17 mmol), m-Fluorophenethylamine (33 uL, 0.25 mmol), THF (5 mL), and Ti(OiPr)4 (0.1 mL, 0.27 mmol) at 0° C. under nitrogen atmosphere. Stir the reaction for 3 hours then add TiCl4 (0.3 mL, 0.27 mmol) at 0° C. For the next 2 hours, warm the reaction to room temperature and then add BH3SMe2 (0.09 mL, 0.17 mmol). Stir the reaction at room temperature for 12 hours, then add 1N NaOH (aq) and stir for 2 hours. Centrifuge and decant the reaction into a separatory funnel and wash the organic phase with water and dry over Na2SO4. Concentrate the reaction under reduced pressure and purify using reverse phase chromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) to afford 3.5 mg, 0.01 mmol (6% yield) of the title compound:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:26]=[CH:25][C:24]5[O:27][CH2:28][O:29][C:23]=5[CH:22]=4)[CH2:17][CH2:16]3)[O:11][C:10]2=[O:30])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:26]=[CH:25][C:24]5[O:27][CH2:28][O:29][C:23]=5[CH:22]=4)[CH2:17][CH2:16]3)[O:11][C:10]2=[O:30])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CC(CN3CCC(c4ccc5c(c4)OCO5)CC3)OC2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1OC(CN2CCC(c3ccc4c(c3)OCO4)CC2)CN1c1ccc(O)cc1
Reaction time: 3 h

Procedure:
A mixture of 10 g of 3-p-methoxyphenyl-5-[4-(3,4-methylenedioxyphenyl)piperidinomethyl]oxazolidin-2-one and 10 g of pyridine hydrochloride is stirred at 160° for 3 hours. Usual workup gives 3-p-hydroxyphenyl-5-[4-(3,4-methylenedioxyphenyl)piperidinomethyl]oxazolidin-2-one.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[C:4]2[C:13]3[CH:12]=[C:11]([O:14][CH3:15])[C:10]([C:16]4[C:17]([CH3:22])=[N:18][O:19][C:20]=4[CH3:21])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:23]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN1C(=O)CCC1>[CH3:22][C:17]1[C:16]([C:10]2[C:11]([O:14][CH3:15])=[CH:12][C:13]3[C:4]4[N:3]([C@@H:24]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH3:25])[C:2]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[N:23][C:5]=4[CH:6]=[N:7][C:8]=3[CH:9]=2)=[C:20]([CH3:21])[O:19][N:18]=1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n([C@H](C)c3ccccc3)c12
Reactant: C1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N3CCCCC3)n([C@H](C)c3ccccc3)c12
Temperature: 150 °C
Yield: 53.6 %

Procedure:
2-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (30 mg, 0.069 mmol) (for a preparation see Intermediate 12) was dissolved in NMP (0.5 ml), piperidine (0.2 ml, 2.020 mmol) was added and the mixture was heated at 150° C. for 30 min, then cooled, added to water (10 ml) and extracted with EtOAc (10 ml). The solvent was washed with water (2×10 ml), dried and evaporated. The residue was dissolved in DCM (2 ml), loaded onto a 10 g silica column, eluted with 2M methanolic ammonia/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-2-(1-piperidinyl)-1H-imidazo[4,5-c]quinoline (18 mg, 0.037 mmol, 53.9% yield) as a amber solid. LCMS (formate) Rt 1.05 min, MH+ 482
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:9]=2[O:18][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(=O)=O.C(OCC)C>[Br:22][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:9]=2[O:18][C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(C)cc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(CBr)cc2)c1

Procedure:
A mixture of 28.4 g. (0.1 mole) of 4'-methyl-2,5-diacetoxy-1,1'-biphenyl prepared in section (a) of this Example, 18.7 g. (0.105 mole) of N-bromosuccinimide, and 0.25 g. (0.001 mole) of dibenzoyl peroxide in 250 ml. of carbon tetrachloride was heated at reflux for about 6 hours. The mixture was cooled and the precipitated succinimide was removed by filtration. The filtrate solvent was removed on a rotary evaporator yielding about 42 g. of a syrupy residue. The residue was mixed with 80 ml. of low boiling petroleum ether, the mixture heated to reflux with stirring, and the petroleum ether decanted. This extraction process was repeated twice more yielding 35.5 g. of a syrupy residue. This residue was then dissolved in 180 ml. of diethylether and the solution diluted with 120 ml. of n-hexanes. Cooling of the solution in dry-ice and scratching the sides of the container induced crystallization of the product. A first crop of 17.2 g. of 4'-bromomethyl-2,5-diacetoxy-1,1'-biphenyl was obtained. The mother liquor was concentrated and crystallization induced as above to yield an additional 6.5 g. of product. The procedure was repeated once again to yield a third crop of 8.3 g. Total yield was thus 32.0 g. Nuclear magnetic resonance analysis of the combined product in deuterochloroform was consistent with the structure of 4'-bromomethyl-2,5-diacetoxy-1,1'-biphenyl. The melting range of the product was 51°-53° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[C:4]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[CH:14][CH:13]=3)[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl.CCOC(C)=O>[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]3[C:10](=[O:20])[N:11]([CH3:19])[C:12]4[C:17]([CH:18]=3)=[CH:16][N:15]=[CH:14][CH:13]=4)[C:3]=2[Cl:21])=[O:29])=[CH:26][CH:25]=1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc(N)c2Cl)cc2cnccc21
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(=O)c(-c2c(Cl)ccc(NC(=O)c3ccc(CCl)cc3)c2Cl)cc2cnccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
To a solution of 3-(3-amino-2,6-dichloro-phenyl)-1-methyl-1H-[1,6]-naphthyridin-2-one (30 mg, 0.0937 mmol) in the dichloromethane (7 mL) is added 4-(chloromethyl)benzoyl chloride (53.2 mg, 0.28 mmol). After the mixture is stirred 24 hours at room temperature, it is diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column elute with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (NH3, 2N)(95/5%) to give the titled intermediate as a solid (32.4 mg, 73.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][C@H:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]1)[CH:8]=[CH:7]2)([O-])=O>C(O)C.O.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH:14][C@H:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(6-Nitro-quinolin-2-yl)-(R)-indan-1-yl-amine (0.37 g, 1.2 mmol) was dissolved in ethanol (15 mL). Platinum oxide hydrate (9 mg) was added and the mixture stirred for 4 h at ambient temperature under an atmosphere of hydrogen. The reaction mixture was filtered and evaporated and the residue was subjected to column chromatography (silica gel, heptane, ethyl acetate 1:0=>6:4). (6-Amino-quinolin-2-yl)-(R)-indan-1-yl-amine was isolated as a yellow foam (0.22 g, 66%); MS 276.5 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[CH2:12][N:11]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](Cl)[N:14]=3)[CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)CO>[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:24]=1[NH:25][C:15]1[N:14]=[C:13]([N:11]2[CH2:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH2:9][CH2:10]2)[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: Cc1cc(N2CCC=C(c3ccccc3)C2)nc(Cl)n1
Reactant: CC(C)c1ccc(N)c(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: Cc1cc(N2CCC=C(c3ccccc3)C2)nc(Nc2ccc(C(C)C)cc2Br)n1
Yield: 74 %

Procedure:
4-(5-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-2-chloro-6-methylpyrimidine (1.10 g), 2-bromo-4-isopropylaniline hydrochloride (0.97 g), and diisopropylethylamine (0.50 g) were heated at reflux in 5 ml of ethylene glycol for 1 hour. The reaction solution was poured into a saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The extract was washed with water and then with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give 1.32 g of 2-[N-(2-bromo-4-isopropylphenyl)amino]-4-(5-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine as an amorphous substance.