Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[N:18]([CH2:21][C@H:22]([CH3:46])[C@H:23]([C@H:32]1[CH2:36][O:35]C(C)(C)[N:33]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[N+:19]=[N-:20].CCN(C(C)C)C(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CCO>[N:18]([CH2:21][C@H:22]([CH3:46])[C@@H:23]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[C@H:32]([NH:33][C:39](=[O:40])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])[CH2:36][OH:35])=[N+:19]=[N-:20]
Reactant: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
Pyridinium p-toluenesulfonate (1.3 g, 5.2 mmol) was added to a solution of tert-butyl (4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.09 g, 2.6 mmol) in EtOH (15 mL). The mixture was heated under reflux for 2 days. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (25 mL), and DIPEA (0.67 mL, 3.8 mmol) was added followed by Boc2O (0.67 g, 3.1 mmol). The mixture was stirred at room temperature for 5 h, and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with 0-25% EtOAc in hexanes) to provide the sub-title compound (0.56 g, 56%). LCMS calc. for C12H29N4O2Si (M+H-Boc)+: m/z=289.2. found 289.2.
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:11][CH:10]=[C:9]([CH2:30][OH:31])[N:8]=1)([OH:3])=[O:2]>CO.C(Cl)Cl>[C:1]([CH2:4][CH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[CH:11][CH:10]=[C:9]([CH2:30][OH:31])[N:8]=1)([OH:3])=[O:2]
Reactant: COc1ccc(CCCCCCCCOc2ccc(CO)nc2/C=C/CC(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CCCCCCCCOc2ccc(CO)nc2CCCC(=O)O)cc1
Reaction time: 5 h

Procedure:
2-(E-2-Carboxymethyl-ethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (300 mg, 0.702 mmol) was dissolved in MeOH (3 mL) and treated with 5% Pd--C catalyst (30 mg). The reaction was stirred under an atmosphere of H2 (balloon pressure) for 5 hours. The reaction was diluted with CH2Cl2, and filtered through Celite, and concentrated. Purification by flash column chromatography (silica, EtOAc:CH2Cl2 :hexane, 25:50:25) gave a pale yellow oil: 1H NMR (250 MHz, CDCl3) δ 7.09 (m, 4H, phenyl, pyridyl), 6.80 (d, J=8.6 Hz, 2H, phenyl), 4.62 (s, 2H, CH2), 3.93 (t, J=6.5 Hz, 2H, OCH2), 3.77 (s, 3H, OCH3), 3.68 (s, 3H, methyl ester), 3.16 (dd, J=7.3, 7.2 Hz, 2H, CH2), 2.77 (dd, J=7.3, 7.2 Hz, 2H, CH2), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.79 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.44 (m, 2H, CH2), 1.34 (m, 6H, aliphatic); MS (CI): 430.2 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][NH2:31])=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1)#[N:14]>C(O)(=O)C>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][N:31]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:32][CH:33]=1)#[N:14]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: N#Cc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-cyano-N-[4-(hydrazinocarbonyl)phenyl]benzamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 95 mg of the title compound (89%) as a orange powder in 94.7% purity by HPLC (Rt: 4.37, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH:31]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:33])[CH3:32]>CN(C=O)C>[CH:31]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([N:18]2[C:19]3[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16]([CH2:15][CH2:14][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]3[CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:17]2[CH3:27])=[O:40])=[CH:37][CH:36]=1)([CH3:33])[CH3:32]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(OC(C)C)cc1

Procedure:
1-(4-Isopropoxybenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 4-isopropoxybenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[CH:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[K+]>CO.O>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7]/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C(C)=C/C=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 8 h
Yield: 82.2 %

Procedure:
As in the Example 99. a solution of 3,3-diphenyl-2-propenal (2.08 g) in ethanol (25 mL) was reacted with (carbethoxyethylidene)triphenylphosphorane (4.0 g) for 30 minutes at room temperature. The reaction was worked up in the usual manner to give 2.8 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid ethyl ester as the sole product. The crude ester (2.8 g) in methanol (25 mL) was treated with 2N potassium hydroxide (10 mL) and the mixture was heated at reflux until the oil dissolved, then it was cooled and left at ambident temperature overnight. The reaction was diluted with water (20 mL) and most of the methanol was removed under reduced pressure. The solution was acidified with 2N hydrochloric acid (12 mL) and the resulting solid was recovered by filtration, washed with water and dried. The crude acid was triturated with hot hexane to furnish 2.08 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid, mp 184°-186° C. A sample was crystallized from 2-propanol to afford the analytical specimen, mp 185°-186.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[Li].Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Li]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-buryl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with (MgSO4). Solvent was removed in vacuo and the residue further 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:11][S:12][C:13]3[NH:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([CH2:11][S:12]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[N:14]=3)=[O:30])[N:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: Brc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(Cc1nccc2c(Br)csc12)c1nc2ccccc2[nH]1
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of 90 mg (0.239 mmol) of 2-[(3-bromothieno[2,3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-6) in 4 ml of CHCl3 and 1 ml of MeOH was added 52 mg (1.0 equivalent) of 80% m-CPBA at -20° C., and the mixture was stirred for 1 hr. at -20° C. When 10% aqueous sodium sulfite and saturated aqueous NaHCO3 were added to the mixture, crystals separated out and collected by filtration. The extract of the mother liquid with CHCl3 was combined with the crystals and subjected to silica gel column chromatography for purification, whereby 61 mg (Yield : 65.0%) of 2-[(3-bromothieno[2, 3-c]pyridin-7-yl)methylsulfinyl]benzimidazole (Ic-18) was obtained as an objective compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([CH3:23])[C:19]([CH3:24])=[N:18][C:17]=2[C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:25]([C:16]3[C:17]4[N:18]=[C:19]([CH3:24])[C:20]([CH3:23])=[N:21][C:22]=4[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])=[CH:14][CH:15]=3)=[O:27])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3nc(C)c(C)nc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nc(C)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylic acid (Step 122.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture 18 h at rt. Title compound: ESI-MS: 595.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.15 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[K+]>C(O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)cc2)Cc2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 100 g of indanone, 112 g of p-chlorobenzaldehyde and 500 ml of ethanol is stirred, the resulting solution is cooled to -10° and treated rapidly (3 minutes) with a solution of 5.0 g of KOH in 100 ml of ethanol. The solution is allowed to warm and the product begins to crystallize at 17° (cooled to keep under 15°). The resulting slurry is allowed to stir at 20°-25° for 1 hour, and then poured onto 2 liters of icewater. After standing for 3 hours, the solid is filtered, washed with cold water and allowed to air dry; wt., 190 g, m.p. 174°-179°. After crystallization from 400 ml of DMF, the cream-colored solid weighs 164.5 g (86%), m.p. 177°-179°.
Reaction SMILES: Cl.[P:2]([O:14][CH2:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[O:35][CH3:36])[N:31]=[CH:30][N:29]=[C:28]3[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])[CH2:20][CH2:19]1)=[O:17])([O:9]C(C)(C)C)([O:4]C(C)(C)C)=[O:3].C(OCC)C>O1CCOCC1>[P:2]([OH:4])([OH:9])([O:14][CH2:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[O:35][CH3:36])[N:31]=[CH:30][N:29]=[C:28]3[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])[CH2:22][CH2:23]1)=[O:17])=[O:3]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)COP(=O)(OC(C)(C)C)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)COP(=O)(O)O)CC1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
4M Hydrogen chloride in 1,4 dioxane (1.95 ml) was added to a stirred solution of di-tert-butyl 2-[4-(4-[3-chloro-2-fluoroanilino]-7-methoxyquinazolin-6-yloxy)piperidin-1-yl]-2-oxoethyl phosphate (0.951 g) in 1,4-dioxane (16 ml). The mixture was stirred overnight and diethyl ether (50 ml) was then added. The resulting precipitate was collected by filtration and dried to give the title product as a white solid (0.77 g); NMR Spectrum: (DMSO d6) 1.60–1.76 (m, 2H), 2.11 (m, 2H), 3.38 (m, 2H), 3.69 (m, 1H), 3.91 (m, 1H), 4.02 (s, 3H), 4.53 (m, 2H), 5.02 (m, 1H), 7.37 (m, 2H), 7.55 (m, 1H), 7.65 (m, 1H), 8.53 (s, 1H), 8.81 (s, 1H), 11.86 (br s, 1H); Mass Spectrum: (M+H)+ 541.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][CH2:22][O:23][CH3:24])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][CH2:22][O:23][CH3:24])=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOCCc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOCCc1ccc(OCc2ccccc2)c(C(=O)O)c1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
To a solution of methyl 2-benzyloxy-5-(2-methoxymethoxyethyl)benzoate (1.34 g) in methanol (15 ml) was added 2N aqueous sodium hydroxide solution (4.0 ml), and the mixture was heated under reflux for 40 minutes with stirring. After the reaction mixture was cooled to 0° C. 2N hydrochloric acid (5.0 ml) was added and the resulting mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, crystallization of the residue from hexane and diethyl ether (1/1) gave 2-benzyloxy-5-(2methoxymethoxyethyl)benzoic acid (1.23 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+].[NH2:21][C:22]1[C:39]([CH2:40][N:41]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH3:43])=[CH:38][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH2:32][CH2:33]Cl)=[O:27])=[CH:24][C:23]=1[Br:50]>>[NH2:21][C:22]1[C:39]([CH2:40][N:41]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH3:43])=[CH:38][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH:35]([CH3:36])[CH3:37])[CH2:32][CH2:33][O:18][C:17](=[O:19])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[O:27])=[CH:24][C:23]=1[Br:50]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CCN(Cc1cc(C(=O)OCCN(CCCl)C(C)C)cc(Br)c1N)C1CCCCC1
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)OCCN(CCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)C(C)C)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from sodium 2-[(2,6-dichlorophenyl)-amino]-phenyl-acetate and N-{2-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyloxy]-ethyl}-N-(2-chloroethyl)-isopropylamine analogous to Example 8. Oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1[O:34][C:35]([CH:38](O)[CH2:39][CH3:40])=[CH:36][CH:37]=1.[OH:42][C:43]1[C:50]([CH3:51])=[CH:49][C:46]([C:47]#[N:48])=[CH:45][C:44]=1[CH3:52]>C(Cl)Cl>[CH3:32][C:33]1[O:34][C:35]([CH2:38][CH2:39][CH2:40][O:42][C:43]2[C:50]([CH3:51])=[CH:49][C:46]([C:47]#[N:48])=[CH:45][C:44]=2[CH3:52])=[CH:36][CH:37]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: CCC(O)c1ccc(C)o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCCOc2c(C)cc(C#N)cc2C)o1
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
Diethyl azodicarboxylate (DEAD, 11.9 mL; 75.6 mmol) was added dropwise over a 10 min period to a solution of triphenylphosphine (19.8 g; 75.6 mmol), (2-methyl-5-furanyl)propanol (ex 1a, 9c and 12a) (10.6 g; 75.6 mmol), and 4-hydroxy-3,5-dimethyl-benzonitrile (12.2 g; 83.2 mmol) in methylene chloride cooled in an ice-bath under nitrogen with stirring. After 10 min, a solid formed. Additional methylene chloride (50 mL) was added to the mixture and the resulting suspension was filtered. The filtrate was washed with water (2×100 mL) and brine (1×100 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield a brown oil which crystallized on standing. The solid product was chromatographed on silica gel eluting with ethyl acetate/hexane (2:8), and the appropriate fractions were concentrated in vacuo to afford 16.43 g (81%) of 2-methyl-5-[3-(2,6-dimethyl-4-cyanophenoxy)-propyl) furan. The cyano moiety is then elaborated to a suitably substituted 5-tetrazolyl moiety as in the preparation of Intermediates 5-6 or oxadiazolyl as in Intermediates 7-8, giving a compound of formula II wherein R3 is methyl, R4 is hydrogen, R1, R2 is 3,5-dimethyl Y is 1,3-propylene and R5 is as described.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:22])[N:14]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:64]([NH2:69])[CH2:65][CH:66]([CH3:68])[CH3:67]>CN(C=O)C>[CH2:64]([NH:69][C:19](=[O:21])[CH2:18][N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:22])[CH2:65][CH:66]([CH3:68])[CH3:67]
Reactant: O=C(O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCNC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 900 mg of 2-(3-(benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)acetic acid (˜2.32 mmol), 744 mg of TBTU (2.32 mmol), 313 mg of HOBt (2.32 mmol) is dissolved in 25 mL of DMF. By addition of 985 μL of DIPEA (5.79 mmol, 2.5 eq) a pH value is adjusted to ˜9. 539 μL of isopentylamine (4.63 mmol) is added and the mixture is stirred at RT for 2.5 h. The solvent is removed in vacuo and the obtained residue is taken up in 100 mL of DCM and subsequently washed with 10% citric acid (3×75 ml), saturated NaHCO3 solution (3×75 ml) and brine (75 mL). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo in dryness. Brown solid is obtained and it is suitable for further processing without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[NH:7][C:6](=[O:8])[CH:5](C(OCC)=O)[C:4](=[O:14])[CH2:3]1>C(#N)C.O>[CH3:1][C:2]1([CH3:15])[NH:7][C:6](=[O:8])[CH2:5][C:4](=[O:14])[CH2:3]1
Reactant: CCOC(=O)C1C(=O)CC(C)(C)NC1=O
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(=O)CC(=O)N1
Yield: 84.9 %

Procedure:
Ethyl 6,6-dimethyl-2,4-dioxopiperidine-3-carboxylate (0.69 g, 3.23 mmol) was dissolved in acetonitrile containing 1% of water (15 mL) and the resulting solution was refluxed for 2 hours. After evaporating to dryness, the crude material was suspended in isopropyl ether, kept under vigorous stirring and filtered to give the title compound (387 mg, Y=85%) as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N1C2C(=CC=CC=2)C=CC=1.O=P(Cl)(Cl)[Cl:24]>O>[Br:1][C:2]1[C:3]([Cl:24])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Br)c1
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a cooled (0-5° C.) mixture of 3-bromo-2-hydroxy-5-nitropyridine (47.0 g, 0.214 mol) and quinoline (13.7 g, 0.107 mol) was added POCl3 (26.0 mL, 0.278 mol) dropwise over ˜10 min (the mixture was difficult to stir initially but became less viscous as the reaction progressed and the mixture warmed). After stirring at 120° C. for 3.5 h, the mixture was cooled to 100° C. and water (90 mL) was added. The resulting mixture was stirred vigorously while cooling to 0-5° C. The product was collected by filtration, washed with water and dried in vacuo at 45° C. to give 3-bromo-2-chloro-5-nitropyridine (42.0 g, 82% yield). 1H NMR (CD3OD) δ 9.19 (d, J=2.4 Hz, 1H), 8.93 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1)Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][C@H:30]1[CH2:35][NH:34][C@H:33]([CH3:36])[CH2:32][NH:31]1>CN(C)C=O>[CH3:29][C@H:30]1[CH2:35][NH:34][C@H:33]([CH3:36])[CH2:32][N:31]1[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:11]1[CH:26]=[CH:27][CH:28]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=1
Reactant: CN(C)S(=O)(=O)c1ccc(C(Cl)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(c2ccc(S(=O)(=O)N(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Temperature: 140 °C
Yield: 26.6 %

Procedure:
The alcohol (88.8 g, 0.21 mol) was treated with thionyl chloride in dichloromethane as described in Example 1 to give 93.7 g of 4-(3-(tert-butyldimethylsilyloxy)-α-chlorobenzyl)-N,N-dimethylbenzenesulfonamide as a brown oil. The crude benzhydryl chloride (93.7 g, 0.21 mol) was combined with trans-2,5-dimethylpiperazine (71.8 g, 0.63 mol) in 400 mL of dimethylformamide and heated to 140° C. for 1 hour. The mixture was cooled to room temperature, poured into ice water and extracted with diethyl ether. The ether extracts were washed with 1M sodium hydroxide, water, and saturated aqueous sodium chloride, and dried over sodium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel with dichloromethane:methanol to give 28.9 g (27%) of trans-4-(α-(2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-dimethylbenzenesulfonamide as a brown oil.