Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Br:5][C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12](Cl)=[O:13])=[CH:8][CH:7]=1>O.CC(C)=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH:10]=[CH:11][C:12]([N:1]=[N+:2]=[N-:3])=[O:13])=[CH:15][CH:16]=1
Reactant: O=C(Cl)C=Cc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A solution of sodium azide (NaN3) (2.2 g, 33.8 mmol) in water (7.5 mL) was added dropwise over 5 min to a stirred solution of 4-bromocinnamoyl chloride (22.2 mmol) in acetone (22 mL) at −10° C. The heterogeneous mixture was stirred at 0° C. for 1 h and diluted with water (25 mL). The precipitate was collected by filtration and dried in vacuo over phosphorus pentoxide (P2O5) to give 4-bromocinnamoyl azide (5.22 g, 20.7 mmol) as a golden-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1.C(OCC)(=O)C>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccncc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(N)=O)(c4ccncc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using (S)-2-[3(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (4 mmol) and 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide hydrochloride (4.4 mmol). Chromatograph on silica gel eluting sequentially with ethyl acetate, 3% methanol/dichloromethane, 6% methanol/dichloromethane, and then 10% methanol/dichloromethane to give the title compound: Rf =0.3 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([N:40]1[C:36](=[O:46])[C:37]2[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:39]1=[O:41])[CH3:15]
Reactant: Cc1cccc2nc(C(C)O)c(Br)c(=O)n12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(Br)c(=O)n12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.909 g, 3.21 mmol), triphenylphosphine (1.010 g, 3.85 mmol), phthalimide (0.567 g, 3.85 mmol), and THF (21.39 mL) was stirred at rt for 5 min to dissolve all reactants. The mixture was then cooled to 0° C. and to the cooled homogenous mixture was added dropwise over 3 min to diisopropyl azodicarboxylate (0.758 mL, 3.85 mmol) at 0° C. After stirring at 0° C. for 30 min, the cooling bath was removed and the mixture was stirred at rt. After 1.5 h, the mixture was partitioned between EtOAc (50 mL) and water (50 mL) and the organic layer was separated, dried over Na2SO4, filtered and concd under reduced pressure to give the crude material as a yellow solid. The yellow solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc in hexane for 25 min to give the desired product 2-(1-(3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethypisoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.82-7.92 (4 H, m), 7.70 (1 H, dd, J=9.0, 7.0 Hz), 7.32 (1 H, dd, J=8.6, 0.8 Hz), 7.04 (1 H, ddd, J=6.8, 1.4, 1.2 Hz), 5.47-5.57 (1 H, m), 2.94 (3 H, s), 1.82 (3 H, d, J=7.0 Hz); Mass Spectrum (ESI) m/e=412.0 [M+1 (79Br)] and 414.0 [M+1 (81Br)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH2:19])[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:34]([C:37]1[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH:19][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[CH:47][C:37]([CH:34]([CH3:35])[CH3:36])=[CH:38][CH:39]=3)[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(OCC(=O)O)cc1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(OCC(=O)NCc2nc(C(=O)NCCc3cccc(Cl)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
2-Aminomethyl-thiazole-4-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide (50 mg, 0.17 mmol) was dissolved in DMF (1 mL). EDC (38 mg, 0.2 mmol) and HOBt (27 mg, 0.2 mmol) where added and the mixture was stirred at ambient temperature for 10 minutes. (4-Isopropyl-phenoxy)-acetic acid (33 mg, 0.17 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. DI water was added and the mixture was extracted with ethyl acetate ×3. The combined organic layers were washed with 1 N hydrochloric acid ×2, 2 N sodium hydroxide ×2, 1 N sodium bicarbonate ×2, DI water ×2 and brine ×1, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography using silica (1:1 Ethyl acetate:Hexanes) to give the title compound as a semi-solid (16.8 mg, 21%). 1H NMR (400 MHz, d6-DMSO): 9.02 (t, 1H), 8.41 (t, 1H), 8.11 (s, 1H), 7.27 (m, 3H), 7.16 (m, 3H), 6.88 (d, 2H), 4.61 (d, 2H), 4.56 (s, 2H), 3.48 (q, 2H), 2.83 (m, 3H), 1.17 (d, 6H); MS (ESI-LCMS) for C24H27ClN3O3S: 472 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C.O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:15]1[CH:16]=[C:11]([C:9]2[N:8]=[C:5]3[N:4]([CH:10]=2)[N:3]=[C:2]([C:32]2[C:27]([C:26]([F:37])([F:36])[F:25])=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:7]=[CH:6]3)[CH:12]=[CH:13][C:14]=1[CH3:24])=[O:23]
Reactant: OB(O)c1cccnc1C(F)(F)F
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Yield: 33.1 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.034 g, 0.0001 mol), [2-(trifluoromethyl)-3-pyridyl]boronic acid (Combi-Blocks, 0.038 g), bis(triphenylphosphine)palladium(II) dichloride (0.007 g), Na2CO3 (0.032 g), and isopropanol-water (1 mL, 3:1). The mixture is heated at 80° C. for 16 hr. The mixture is concentrated, taken up in EtOAc and CH2Cl2 (1:1), filtered, concentrated onto celite, and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.015 g, 33% yield). LCMS m/z=454.6 [M+H]+, tR=2.52 min. (compound same as Example 284)
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.C([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)C1C=CC=CC=1>C(Cl)Cl>[O:26]=[C:23]1[CH2:24][CH2:25][N:20]([C:7]([Cl:10])=[O:6])[CH2:21][CH2:22]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 251.4 %

Procedure:
A solution of triphosgene (2.84 g, 9.6 mmol) in methylene chloride (100 mL) at 0° C. was treated with a solution of 1-benzyl-piperidin-4-one (6.0 g, 31.7 mmol) in methylene chloride (100 mL). The reaction mixture was allowed to warm to 25° C. and was stirred at 25° C. overnight. At this time, the mixture was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, gradient elution 60/40 ethyl acetate/hexanes) afforded 4-oxo-piperidine-1-carbonyl chloride (3.9 g, 76%) as a brown oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [N:1]1([CH:6]([CH3:10])[CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)([O-])=O>>[N:1]1([CH:6]([CH3:10])[CH2:7][CH2:8][O:9][C:17]2[CH:18]=[CH:19][C:14]([NH2:11])=[CH:15][CH:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCO)N1CCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(CCOc1ccc(N)cc1)N1CCCC1

Procedure:
The target compound was obtained by the method according to Example 18, using 3-pyrrolidin-1-yl-butan -1-ol (racemic mixture) manufactured by the method described in the literature (J. Org. Chem., 1949, Vol. 14, p. 862) and 4-nitrofluorobenzene as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[CH2:10][OH:11].N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([O:11][CH2:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[Br:9])(=[O:20])[CH3:19]
Reactant: OCc1c(Br)cc(F)cc1Br
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cc(F)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
To a solution of 101i (20 g, 71 mmol) in CH2Cl2 (500 mL) at 0° C. was added pyridine (8.4 g, 107 mmol) and acetyl chloride (8.3 g, 107 mmol). The mixture was stirred at room temperature for 5 h. TLC showed the start material disappeared. The reaction was evaporated in vacuum and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (from 50:1 to 20:1) to give 101j as a white solid (20 g, 87%). MS: [M−Oac]+ 267. 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J=7.5, 2H), 5.38 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccs2)c1Br
Yield: 34 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-thiophenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-thiophenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 125°-127° C., yield 34%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[NH:5][CH2:6][C:7]#[N:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26]>ClC1C=CC=CC=1Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[NH:5][CH2:6][C:7]1[NH:26][CH2:25][CH2:24][N:8]=1
Reactant: N#CCNc1ccc(Cl)c(Cl)c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: Cl
Product: Clc1ccc(NCC2=NCCN2)cc1Cl
Yield: 61.8 %

Procedure:
A mixture of 30.15 g of 3,4-dichloroanilinoacetonitrile and 35.0 g of ethylenediamine p-toluenesulfonate in 110 ml of 1,2-dichlorobenzene was heated at reflux temperature under a small flow of nitrogen for 1.5 hours. The reaction mixture was then cooled and washed with water. The 1,2-dichlorobenzene was concentrated under vacuum and the remaining residue was put in solution in CH2Cl2 and shaken with dilute sodium hydroxide. The CH2Cl2 layer was separated and treated with diatomaceous earth and activated charcoal and then filtered. The filtrate was concentrated to dryness under vacuum and the black gummy residue which remained put in solution in isopropyl alcohol. Gaseous HCl was bubbled through the solution resulting in crystal formation. The mixture was cooled and filtered to obtain the product. Recrystallization from absolute ethanol gave 13.0 g of purified 2-((3,4-dichloroanilino)methyl)-2-imidazoline hydrochloride as tan crystals, m.p. 221°-223° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.[F:33][C:34]([F:42])([F:41])[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][S:37]([CH2:36][CH2:35][C:34]([F:42])([F:41])[F:33])(=[O:39])=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)CCC(F)(F)F)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 21.3 mg, 0.0474 mmol) was dissolved in methylene dichloride (1 mL), 3,3,3-trifluoropropane-1-sulfonyl chloride (11.6 mg, 0.0590 mmol) and triethylamine (18 μL, 0.13 mmol) were added thereto, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.5 mg) as a colorless amorphous product. (Yield 80%)
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]([OH:14])=O)=[C:5]([F:15])[CH:4]=1)#[N:2].[ClH:16].[N:17]1(C(=O)CC2C=NC(N3C=NN=N3)=CC=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[ClH:16].[F:15][C:5]1[C:6]([CH2:11][C:12](=[O:14])[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: COc1cc(CC(=O)O)c(F)cc1C#N
Reactant: O=C(Cc1ccc(-n2cnnn2)nc1)N1CCNCC1
Agent: Cl
Product: COc1cc(CC(=O)N2CCNCC2)c(F)cc1C#N

Procedure:
5-Fluoro-2-methoxy-4-[2-oxo-2-(piperazin-1-yl)ethyl]benzonitrile hydrochloride was prepared in two steps from (4-cyano-2-fluoro-5-methoxyphenyl) acetic acid in an analogous fashion to that described for the synthesis of 1-(piperazin-1-yl)-2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethanone hydrochloride. MS m/z 278 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[CH:13]=[C:14]([C:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:8][C:9]1[CH:30]=[CH:29][C:12]2[CH:13]=[C:14]([C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([CH3:28])[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(OCc3ccccc3)cc2o1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(OCc3ccccc3)cc2o1
Yield: 86.4 %

Procedure:
4-[1-(6-Benzyloxy-benzofuran-2-yl)-1-ethyl-propyl]-2-methyl-phenol (5.50 g, 13.7 mmol) and 1-bromopinacolone (4.92 g, 27.5 mmol) and K2CO3 (3.80 g, 27.5 mmol) are reacted analogous to Example 1E to give the title compound as a pale yellow oil (5.90 g, 86%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1CSC(=O)N1CCCCOc1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCOc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.71 g (5.6 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-yloxy)butyl]thiazolidine-2,4-dione and 0.51 ml (5.6 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.79 g (88.9%, yellow oily substance) of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.C(NC(C)C)(C)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.[Cu](I)I>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:3][C:4]=1[CH3:10]
Reactant: COc1ccc(Br)cc1C
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(C#C[Si](C)(C)C)cc1C
Temperature: 45 °C

Procedure:
A solution of 4-bromo-1-methoxy-2-methylbenzene (6.702 g) in toluene was treated with tetrakis(triphenylphosphie)palladium (0) (1.15 g), followed by diisopropylamine (23 mL), trimethylsilyl acetylene (4.7 mL) and copper iodide (I) (0.127 g). The reaction was heated at 45° C. in nitrogen atmosphere overnight and evaporated to dryness. The resultant residue was applied on a large silica pad and eluted with hexane:ethyl acetate (2:1). The elute was evaporated to dryness to give the silane intermediate as a brown oil (7.167 g). The compound was characterized by LCMS analysis. LCMS Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% NH4OH in water; Solvent B 0.02% NH4OH in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(benzyloxy)-1-methoxy-4-nitrobenzene (35.35 g, 136 mmol) in 1:1 ethyl acetate: ethanol (640 mL) at 80° C. is added tin(II) chloride hydrate in portions over 25 minutes. The mixture is heated at this temperature for 5 h. The mixture is allowed to cool to room temperature and stirred for 2 days. The mixture is poured into water (1 L) and neutralized with solid sodium bicarbonate. The mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with water and brine, dried (sodium sulfate), filtered and evaporated to yield the title compound as a dark brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([O:32]C(C)C)=[C:28]([O:36][CH3:37])[CH:27]=1.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC(C)C)c(OC)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(O)c(OC)c1
Reaction time: 6 h
Yield: 48.1 %

Procedure:
Titanium tetrachloride (TiCl4)(125 mg) was added at 0° C. to a solution of ethyl 6,7-dimethoxy-4-(4-isopropoxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (55.6 mg) in dichloromethane (2 ml), and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with a saturated aqueous sodium carbonate solution and water, and dried over magnesium sulfate. The solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/chloroform(3/2, v/v) gave ethyl 6,7-dimethoxy-4-(4-hydroxy-3-methoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (24.5 mg, 48%) which was then recrystallized from ethyl acetate-hexane. mp. 176°-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CC(Cc1ccccn1)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Product: CC(Cc1ccccn1)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
2-(p-Bromophenyl)-1-(2-pyridyl)propane (11.5 g., 0.043 mole) is heated in 80 ml. of concentrated nitric acid (specific gravity 1.42, 69-71%) for 4.5 hr. at 80°C. The solution is cooled, quenched in 300 g. of ice, made alkaline with sodium hydroxide, and extracted with ethyl acetate. The extract washed with water and brine, dried over sodium sulfate, and evaporated affords 12.2 g. (88%) of oily nitrated product of sufficient purity to be used in following "step d". Distillation provides analytically pure 2-(4-bromo-2-nitrophenyl)-1-(2-pyridyl)propane, b.p. 172°-176°C. (0.2 mm. Hg.), nD 29 1.5968.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12](/[C:13](=[CH:22]\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[O:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cc2ccccc2cc1O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)/C(=C/c1ccccc1)C(=O)c1cc2ccccc2cc1O
Yield: 56.9 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(3-hydroxynaphthalen-2-yl)-3-oxopropanoate (286 mg, 1.0 mmol), benzaldehyde (100 μL, 1.00 mmol), 15.0 mL benzene, piperidine (10 μL, 0.10 mmol) and glacial acetic acid (5.7 μL, 0.10 mmol), refluxed for 4 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 213 mg (57%) of yellow solid. mp=132-135° C.; IR (film) 2977.6; 1716.6; 1639.5; 1154.5 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.20 (bs, 1H), 8.19 (s, 1H); 7.96 (s, 1H), 7.70 (t, J=7.3 Hz, 2H), 7.51 (t, J=8.0 Hz, 1H), 7.40-7.25 (m, 7H), 1.38 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.9, 163.9, 157.1, 142.8, 138.7, 135.1, 132.8, 131.6, 130.8, 130.4, 130.2, 129.8, 129.2, 127.3, 126.6, 124.4, 121.7, 112.6, 83.0, 28.1; LRMS (electrospray): Mass calculated for C24H22O4 [M]+, 374.15. Found [M+23]+, 397.0.