Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=O.O.[NH2:18][NH2:19]>O1CCCC1>[F:1][C:2]([F:16])([F:15])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[N:18][NH2:19]
Reactant: NN
Reactant: O=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: C1CCOC1
Product: NN=C(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
3,3,3-Trifluoro-1-(3-nitrophenyl)-1-propanone (Sov. Prog. Chem. (Engl.Transi.), 1966, 32, 745, 1.8 g, 7.72 mmol) was dissolved in tetrahydrofuran (10 ml) and hydrazine monohydrate (0.56 ml, 11.58 mmol) was added dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature then heated under reflux for 40 min. The reaction mixture was concentrated in vacui and the residue treated with water (10 ml) and extracted with dichloromethane (4×10 ml). The organic extracts were concentrated in vacuo and the residue was purified by chromatography on silica gel (100 g), eluting with diciforomethane: hexane (1:1 and then 2:1). The product was obtained as an amber gum (159 mg, 8%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C[Si]([N:33]=[C:34]=[O:35])(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[O:35]
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCNC(N)=O)c1ccccc1
Reaction time: 12 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in CH2Cl2 was added a large excess of trimethylsilyl isocyanate and triethylamine. After stirring for 12 h, the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with MeOH/CHCl3 to provide 23-1 as a white solid. Data for 23-1: 1HNMR (500 MHz, d6-DMSO) δ 7.6 (m, 1H), 7.5-7.1 (m, 7H), 6.2 (s, 1H), 5.95 (m, 1H), 5.3 (s, 2H), 4.95 (m, 1H), 4.7 (m, 1H), 3.0 (m, 2H), 2.7 (s, 6H), 2.1 (m, 1H), 1.3 (m, 3H) ppm. HRMS (ES) calc'd M+H for C23H26ClFN4O2: 445.1801. Found: 445.1805.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]1[C:32]([I:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].O.N>CN(C=O)C.O>[NH2:23][C:24]1[C:32]([I:33])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH2:3])=[O:27]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(I)cccc1C(=O)O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cccc(I)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
EDCI hydrochloride (18.4 g) and 1-hydroxybenzotriazole (9.5 g) were added to a solution of 2-amino-3-iodobenzoic acid (16.4 g) synthesized using the method described in Journal of Medicinal Chemistry, 2004, 47 (6), 1448-1464 in DMF (120 mL), and subsequently ammonia water (21.2 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-iodobenzamide (12.8 g). 60% sodium hydride (2.29 g) was added to a solution of the obtained 2-amino-3-iodobenzamide (5.0 g) in ethanol (95 ml), then ethyl trifluoroacetate (10.8 g) was added thereto, and the mixture was heated to reflux for 15 hours. After cooling, water was added thereto, and the reaction solution was rendered acidic by the addition of 6 N hydrochloric acid. Then, the deposit was filtrated and dried under reduced pressure to obtain compound (4a) (6.4 g, yield based on 2 steps: 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)c1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (2 mL) was added triethylamine (53.8 mg, 0.525 mmol) (Aldrich), followed by the addition of 1-(4-isocyanato-phenyl)-ethanone (41.2 mg, 0.25 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-acetyl-phenyl)-amide as a white solid (Yield 45 mg, 39%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[NH2:4].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.C(OC(C)C)(C)C>[C:19]([O:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[NH2:4])(=[O:21])[CH3:20]
Reactant: NC(=NO)c1ccc(I)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CC(=O)ON=C(N)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of the product obtained in Step A above (8.43 g, 32.17 mmol) in 200 ml of CH2Cl2 there are added 6.72 ml (48.2 mmol) of triethylamine. 3.34 ml (35.4 mmol) of acetic anhydride are added dropwise and the solution is stirred overnight at ambient temperature. After washing 3 times with water and then with brine, the organic phase is dried over MgSO4 and evaporated. The solid obtained is taken up in isopropyl ether and then filtered to yield the title product.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:11]([O:13][CH3:14])=[O:12].[CH2:22]=O>ClC(Cl)C.O>[CH3:14][O:13][C:11](=[O:12])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:9]1[CH2:8][CH2:7][C:3]2[S:2][CH:6]=[CH:5][C:4]=2[CH2:22]1
Reactant: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Reactant: C=O
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 60 °C
Yield: 90.1 %

Procedure:
6 g (0.017 mol) of dextrorotatory methyl [2-(2-thienyl)ethylamino](2-chlorophenyl)acetate hydrochloride is suspended in 6.7 ml of 38% aqueous formaline solution and heated to 60° C. under stirring. The starting material dissolves at 60° C., the resulting solution is stirred at the temperature for 30 minutes, till the completion of the reaction. The reaction mixture is then diluted with 100 ml of 1.2 dichloroethane and 150 ml of water, and after shaking well, the phases are separated. The aqueous phase is extracted with 2×30 ml of 1,2-dichloroethane, the united organic phase is extracted with 100 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residual 6 g of material is dissolved in 30 ml of diethyl ether, and while cooling the reaction mixture, 0.6 g of dry hdyrogen chloride gas is introduced into the solution, at room temperature. The precipitated crystalline material is filtered off, washed with ether and dried. Weight: 5.5 g. Mp.: 130-132° C., [α]22D=+60°. Yield: 90.1%. Optical purity: 99% (by HPLC investigation).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:24][N:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[N:26]1>>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:29]2[N:25]([CH3:24])[N:26]=[CH:27][CH:28]=2)[N:7]=3)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Product: Cn1nccc1-c1ccc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)sc2n1
Yield: 4 %

Procedure:
The titled compound (yield=4%) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 4.20 (s, 3H) 6.86 (d, J=1.26 Hz, 1H) 7.52 (d, J=1.26 Hz, 1H) 7.67 (d, J=8.08 Hz, 2H) 7.92 (d, J=8.59 Hz, 1H) 8.11 (d, J=8.34 Hz, 2H) 8.23 (d, J=8.34 Hz, 1H) 13.03 (s, 1H);); ESI-MS: m/z 394.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH2:17][C:18]2=[O:21])=[CH:13][CH:12]=1.CC(O)=O>C1COCC1.O>[CH3:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][CH:17]([C:3]([O:6][CH3:7])=[O:8])[C:18]2=[O:21])=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCc2ccc(OC)cc2C1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 9.99 g, 250 nmuol) in THF (100 mL), was added dimethyl carbonate (21.0 mL, 249 mmol). The mixture was heated to 65° C. and a solution of 7-methoxy-1-tetralone (20.00 g, 114 nmuol) in THF (100 mL) was added. The reaction mixture was allowed to stir vigorously at 65° C. for 2 h. After this time the reaction became very vigorous, and gas was evolved. The heating bath was removed for 10 min then heating continued for an additional 1 h. AcOH (18.00 mL, 317 mmol) was added slowly, followed by water (100 mL). The mixture was extracted with Et2O (2×) and the organic solutions were combined, washed with water and saturated NaHCO3 solution, dried over Na2SO4, filtered and evaporated. The residue was purified by filtration through a pad of silica to yield methyl 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate as an oil. (25.2 g, 95%). LCMS: (FA) ES+ 235.0, ES− 233.0.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C1C=CC=CC=1>[CH2:10]([O:9][C:7]([NH:1][CH2:2][C@@H:3]([OH:5])[CH3:4])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](O)CN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccccc1
Product: C[C@H](O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-amino-2-propanol (9.76 g, 130 mmol)in anhydrous benzene (60 mL) at 0° C. was added benzyl chloroformate (10.23 g, 60 mmol) in anhydrous benzene (120 mL) slowly, in portions, over a period of 20 min while vigorously stirring under an atmosphere of nitrogen. The mixture was stirred for 1 hour at 0° C., then allowed to warm to room temperature and stirred for a further 2 hours. The mixture was washed with water (2×) and brine (2×) before the organic layer was dried over anhydrous MgSO4. Evaporation of all solvent gave the title product as an oil. 1H NMR (CDCl3) δ1.22 (d, 3H,) 2.40 (bs, 1H), 3.07 (m, 1H), 3.37 (m, 1H) ), 3.94 (m, 1H), 5.16 (s, 2H), 5.27 (m, 1H), 7.38 (m, 5H). MS m/z (electrospray) 232 [M+23]+ (100%), 166 (96).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[CH:23][NH:24]4)=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:8]=1[O:32][CH3:33])[CH3:5].Cl>C1COCC1.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][NH:24]4)=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:8]=1[O:32][CH3:33])[CH3:3]
Reactant: COc1cc(-c2nc(-c3ccc4c(CCC(=O)[O-])c[nH]c4c3)no2)cnc1OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2nc(-c3ccc4c(CCC(=O)O)c[nH]c4c3)no2)cnc1OC(C)C
Temperature: 90 °C
Yield: 61.1 %

Procedure:
Sodium hydroxide (50 mg) was added to a solution of 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D112) (258 mg) in THF (3 mL) and water (3 mL). The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(6-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E87) (158 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.61 (2H, t), 2.97 (2H, t), 3.94 (3H, s), 5.42 (1H, m), 7.34 (1H, d), 7.72 (2H, m), 7.82 (1H, d), 8.13 (1H, s), 8.54 (1H, d), 11.18 (1H, s), 12.08 (1H, br s). MS (ES): C22H22N4O5 requires 422; found 423.2.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([Br:35])[CH:29]=3)=[CH:24][CH:23]=2)[CH3:20])=[O:18])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:37][C:38]#[N:39])=[C:30]([Br:35])[CH:29]=3)=[CH:24][CH:23]=2)[CH3:20])=[O:18])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccc(-c2ccc(O)c(Br)c2)cc1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A mixture of 1-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-N-methyl-1H-indole-3-carboxamide (1.60 g, 3.05 mmol), prepared in the previous step, bromoacetonitrile (255 μL, 3.66 mmol) and potassium carbonate (2.11 g, 15.30 mmol) in 25 mL of DMF was stirred under nitrogen at room temperature for 16 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 1-benzyl-N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-N-methyl-1H-indole-3-carboxamide (1.69 g, 98%) as a yellow foam, MS (ESI) m/z 564 [M+H]+. Elemental Analysis for C32H26BrN3O2: Calc'd: C, 68.09; H, 4.64; N, 7.44; Found: C, 67.53; H, 4.57; N, 7.14
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH:23]1[CH2:28][N:27]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][NH:24]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:55]1([N:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:62](Cl)=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C)C=O>[C:55]1([N:61]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:62]([N:24]2[CH2:25][CH2:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH:23]2[CH2:22][CH2:21][O:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:63])[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: c1ccc(C(OCCC2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCN2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N(c1ccccc1)c1ccccc1)N1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.2 %

Procedure:
To a suspension of 364 mg (0.59 mmol) of (±) 2-(2-trityloxyethyl)-4-N-tritylpiperazine in 10 ml of N,N-dimethylformamide was added 170 ml (1.22 mmol) of triethylamine in one portion and 140 mg (0.60 mmol) of diphenylcarbamyl chloride in portions and the mixture was allowed to stir under nitrogen at room temperature for 20 hours. The solution was cooled and concentrated in vacuo. Flash chromatography on 40 g of silica gel using 25:75 v/v ethyl acetate/hexane as the eluant afforded 240 mg (50%) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1.Br>C(#N)C>[Br-:10].[C:18]([CH2:17][O:16][C:15]1[CH:21]=[CH:22][C:12]([CH2:11][N:3]2[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:4]2)=[CH:13][CH:14]=1)([OH:20])=[O:19]
Reactant: O=C(O)COc1ccc(CBr)cc1
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccc2ccccc2c1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)COc1ccc(Cn2c[n+](Cc3ccc4ccccc4c3)c(Cl)c2Cl)cc1
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 2-(4-(bromomethyl)phenoxy)acetic acid (1.80 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 2-(bromomethyl)naphthalene (1.63 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting white precipitate was collected and analyzed. 1H NMR (300 MHz, DMSO-d6): δ 4.70, 5.45, 5.76, 7.12, 7.61, 8.05, 9.74, 12.32.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[CH3:34]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[C:26]([CH3:34])[CH:27]=3)[C:32]2=[O:33])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(N=C=O)ccc1F
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(F)c(C)c3)c(=O)n(C3CCCC3)c12
Yield: 59.6 %

Procedure:
1-Cyclopentyl-3-(4-fluoro-3-methyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (25 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-fluoro-4-isocyanato-2-methyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 420 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[In].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[NH2:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-benzyloxy-4-phenoxy-1-nitrobenzene (1.0 g, 3.12 mmol) and indium powder (1.0 g, 8.7 mmol) in THF (8 mL) is added concentrated HCl (1.5 mL) dropwise. The mixture is stirred at ambient temperature for 2.5 h. The solution is decanted from unreacted indium and 2N NaOH is added, which results in the formation of a gummy precipitate. The residue is triturated with EtOAc and centrifuged. The solution is decanted and the solvent removed under reduced pressure to afford a dark oil. The residue is purified by flash chromatography using DCM to elute 2-benzyloxy-4-phenoxyphenylamine as an oil: 1H NMR (CDCl3) δ 7.43-7.23 (m, 8H), 7.00 (t, 1H), 6.92-6.88 (m, 1H), 6.69 (d, J=8.33 Hz, 1H), 6.63 (d, J=2.52 Hz, 1H), 6.51 (dd, J=8.34, 2.52 Hz, 1H), 5.00 (s, 2H), 3.71 (br s, 2H); MS (M+H)+=292.
Reaction SMILES: [CH3:1][C:2]1([C:5]2[NH:6][CH:7]=[CH:8][C:9](=O)[CH:10]=2)[CH2:4][CH2:3]1.P(Br)(Br)([Br:14])=O.C([O-])(O)=O.[Na+]>>[Br:14][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)[CH:10]=1
Reactant: CC1(c2cc(=O)cc[nH]2)CC1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(c2cc(Br)ccn2)CC1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(1-methyl-cyclopropyl)-1H-pyridin-4-one (Step 1.5) (13.4 mmol) and POBr3 (14.74 mmol) was stirred for 15 min at 85° C. and then 15 min at 120° C. After cooling slightly, the reaction mixture was poured into a saturated solution of NaHCO3 and extracted with CH2Cl2 (2×). The combined organic phases were washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a brown oil. HPLC: tR=4.11 min (method B); LC-MS: tR=2.39 min, [M+H]+ 212/214; TLC: Rf=0.31 (CH2Cl2).
Reaction SMILES: [I-].CC(OC([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)C.[H-].[Na+].[I:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[C:40]2=O.CC(C)=O>CN(C=O)C>[I:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])/[C:40]/2=[CH:14]\[C:10]1[NH:9][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)n1cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=C1Nc2ccc(I)cc2/C1=C/c1ccc[nH]1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of [[1-[[(1,1-dimethylethyl)oxy]carbonyl]-1H-pyrrol-2-yl]methyl]triphenylphosphonium iodide (2.3 g, 4.0 mmol) (prepared according to the procedure of: V. H. Rawal et. al., J. Org. Chem. 1987, 52(1), 19-28) in 36 mL DMF at 0° C. under argon, was added slowly NaH (0.13 g, 5.4 mmol). The mixture was stirred at 0° C. for 45 min. The solution was then allowed to warm to room temperature and 5-iodoisatin (1.0 g, 3.66 mmol) was added. The solution was heated at reflux for 15 h, at which time acetone (1 mL) was added and the solvent mixture was evaporated. The residue was then purified via flash column chromatography (25% EtOAc/hex) to yield (Z)-1,3-dihydro-5-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 1.05 g, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=1)[CH3:2].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]C>C(OCC)C>[Br-:15].[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]2[CH:14]=[CH:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCCCCCBr
Reactant: CCOc1ccc(-n2ccnc2)cc1
Solvent: CCOCC
Product: CCCCCCn1cc[n+](-c2ccc(OCC)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 10.00 mmol (1,883 g) 1-(4-ethoxyphenyl)imidazole and 11.00 mmol (1,816 g, 1.59 ml) 1-bromoheptane are dissolved in 3 ml diethylether and heated for 12 h to 60° C.