Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH3:14][CH:15]([CH3:21])[CH2:16][CH:17]([NH:19][OH:20])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:19]([CH:17]([CH2:16][CH:15]([CH3:21])[CH3:14])[CH3:18])[O-:20])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CC(C)CC(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOc1cc(C=[N+]([O-])C(C)CC(C)C)ccc1OC

Procedure:
3-Ethoxy-4-methoxybenzaldehyde (12.0 g, 0.0666 mol) and N-(4-methylpent-2-yl)hydroxylamine (9.36 g, 0.0799 mol) were mixed into benzene (200 mL) with p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mol.). The mixture was refluxed for 16 hours under an argon atmosphere with a Dean-Stark trap to remove the generated water. The solution was rotary evaporated, dissolved in ethyl acetate, washed with 5% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated. The title compound was obtained as a white solid (17.07 g, 91.8% yield). m.p. 87.2° C. (Rf=0.31 on a silica gel plate using hexanes;EtOAc,, 1:1, v/v, as an eluant). The N-(4-methyl-2-pentyl)hydroxylamine precursor was obtained by sodium cyanoborohydride reduction of 4-methyl-2-pentanone oxime in methanol, with hydrochloric acid catalysis.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]([NH:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[C:23]([CH:38]3[CH2:40][CH2:39]3)=[N:24][N:25]4[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[O:19])=[CH:16][N:17]=[C:11]2[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH:38]1([C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[CH:29][C:21]=3[NH:20][C:18]([C:15]3[N:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]4=[N:17][CH:16]=3)=[O:19])[N:25]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)[N:24]=2)[CH2:40][CH2:39]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCc6ccccc6)ccn45)cccc32)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(O)ccn45)cccc32)n1
Temperature: 55 °C
Yield: 39.1 %

Procedure:
A mixture of 7-(benzyloxy)-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (0.75 g, 1.4 mmol; prepared as in Example 157) and 10% Pd/C (Degussa type, 0.75 g, 0.35 mmol) was treated with THF (12 mL). The reaction vessel was heated at 55° C. with stirring while maintaining 100 psi of hydrogen in the headspace of the reaction vessel for 20 hours. The reaction mixture was cooled to ambient temperature and filtered to remove the catalyst. The filtrate was diluted with EtOAc (75 mL) and extracted with 2.5 N sodium hydroxide (2×50 mL). The pH of the combined aqueous extracts was adjusted to approximately 5 using 0.5 M monobasic potassium phosphate solution and 6 N HCl to induce precipitation. The resulting solid was collected by vacuum filtration and dried under vacuum to give the product (0.24 g). MS (ES+APCI) m/z=439.4 (M+H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])=[CH:6][C:5]=1[N:24]=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][C:27]=1[N+:38]([O-])=O>O>[C:32]1([C:29]2[CH:30]=[CH:31][C:26]3=[N:25][N:24]([C:5]4[CH:6]=[C:7]([C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH:8]=[C:9]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:4]=4[OH:3])[N:38]=[C:27]3[CH:28]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(-c4ccccc4)cc3n2)c1

Procedure:
To a solution of sodium hydroxide (6 g, 0.15 mol) in 8 mL of water is added 2-hydroxy-2′nitro-3,4′-diphenyl-5-tert-octylazobenzene (6.56 g), prepared in (D) above. The reaction mixture is heated to reflux and then formadine sulfinic acid (10.8 g, 0.1 mol) is added portionwise over 20 minutes. The reaction mixture is heated at reflux for 1.5 hours. To the cooled reaction mixture is added 200 mL of water and the ethanol is removed under vacuum. The reaction mixture is adjusted to pH 4 with hydrochloric acid. The resultant mixture is extracted twice with methylene chloride and the combined organic phases are extracted with water. The organic phase is dried ovdr anhydrous magnesium sulfate, and the solvent is then removed under vacuum. The residue is recrystallized sequentially from a mixture of water and methanol, and petroleum ether to give the title compound as a white solid melting at 123-125° C.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH:11]=[CH:12][CH2+:13]2[C:18]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=3[CH:16]=[C:15]([CH3:27])O2)=[CH:9][CH:8]=1.O.[NH2:31][NH2:32]>C(O)C>[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH:11]=[CH:12][C:13]2[C:18]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=3[CH2:16][C:15]([CH3:27])=[N:32][N:31]=2)=[CH:9][CH:8]=1
Reactant: COc1cc2c(cc1OC)[CH2+](C=Cc1ccc(O)cc1)OC(C)=C2
Reactant: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C=Cc1ccc(O)cc1)=NN=C(C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.5 g (10.6 mM) of 1-(4-hydroxystyryl)-3-methyl-6,7-dimethoxy-2-benzopyrylium perchlorate (m.p. 298° to 300° C. d.) are suspended in 90 ml of 99.5% ethanol, 1.6 ml (31.8 mM) of 100% hydrazine hydrate are added, and the solution is stirred for 2 hours at room temperature. After evaporation at reduced pressure the residue is suspended in 100 ml of water, filtered, washed with 3×5 ml of water, the crude product is resuspended in hot water, filtered, washed with 3×5 ml of water and dried at 80° to 100° C. Yield 2.65g, m.p. 205° to 207° C. (decomp.). This crude product is purified by refluxing in 12 ml of ethanol and subsequent drying. Yield 2.37 g (66.4%), m.p. 209° to 211° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C:10]([CH3:12])=[CH2:11].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[C:10](\[CH3:12])/[C:9]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:7]=1
Reactant: C=C(C)C(=O)OCC
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)/C(C)=C/c1ccc(N)nc1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a stirred solution of 2-amino-5-bromopyridine (25 g, 140 mmole) in propionitrile (150 mL) was added ethyl methacrylate (50 mL, 400 mmole), DIEA (50 mL, 287 mmole), palladium(II) acetate (1.57 g, 7 mmole), and tri-o-tolylphosphine (4.3 g, 14 mmole). The reaction was purged with argon and heated at reflux for 6 hr, then was cooled to RT and concentrated to dryness under vacuum. The residue was taken up in 80% ethyl acetate/hexanes (100 mL), and the solution was filtered through a pad of silica gel, eluting with 80% ethyl acetatelhexanes (400 mL) until all the product was eluted off. The yellowish filtrate was concentrated under vacuum, and the residue was taken up in a small volume of 1:1 Et2O/petroleum ether. The precipitate which formed was collected and dried under vacuum to give ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (10.77 g, 37%) as a pale yellow solid: LCMS (ES) m/e 207.0 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.7 Hz,1H), 7.63 (dd,1H), 7.48 (s,1H), 6.75 (d, J=8.8 Hz,1H), 5.79 (br s, 2H), 4.26 (q, 2H), 2.10 (s, 3H), 1.34 (t, 3H). The filtrate was concentrated to dryness and purified by flash chromatography on silica gel (4:1 ethyl acetate/hexanes) to give additional ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (0.87 g, 3%) and ethyl 2-(6-aminopyridin-3-ylmethyl)acrylate (5.77 g, 20%) as a yellow oil: LCMS (ES) m/e 207.0 (M+H)+; 1H NMR (300.MHz, CDCl3) δ 7.86 (d, J=2.1 Hz,1H), 7.32 (dd,1H), 6.53 (d, J=8.5 Hz,1H), 6.21 (d, J=1.8 Hz,1H), 5.48 (d, J=1.4 Hz,1H), 4.17 (q, 2H), 3.47 (s, 2H), 1.27 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([Li])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:11][Si:12](Cl)([Cl:14])[Cl:13]>C1COCC1>[CH3:1][C:2]1[CH:3]([Si:12]([Cl:14])([Cl:13])[CH3:11])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: C[Si](Cl)(Cl)Cl
Reactant: [Li]C1C(C)=C(C)C(C)=C1C
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(Cl)Cl)C(C)=C1C
Temperature: -78 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
(2,3,4,5-Tetramethylcyclopentadienyl)lithium (1.33 g, 10.37 mmol) was dissolved in 80 mL THF and cooled to -78° C., and MeSiCl3 (1.70 g, 11.4 mmol) was added via a syringe. After addition, the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. Volatiles were removed under vacuum at room temperature, and the residue was extracted twice with hexanes (2×20 mL). The hexane fractions were combined and the solvent was removed under vacuum to give a pale yellow oil (tetramethylcyclopentadienyl methyl silicon dichloride); 2.0 g, 82% yield. 1H-NMR (C6D6): δ(ppm): 2.95 (broad s, 1 H; Me4CpH), 1.92 (s, 6H;), 1.63 (s, 6H; Me4Cp), 0.19 (s, 3 H; MeSi).
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[CH:8][N:9]([CH3:11])[CH:10]=1.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH3:11][N:9]1[CH:10]=[C:6]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])[N:7]=[CH:8]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1cnc(I)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reaction time: 2 h

Procedure:
3 M Ethyl magnesium bromide in THF (11.0 ml, 33.0 mmol) was added dropwise to a solution of 4-iodo-1-methyl-1H-imidazole (5.61 g, 27.0 mmol) in THF (50 ml) at −78° C. After stirring for 2 h, tributyltin chloride (8.0 ml, 29.5 mmol) was added. After stirring for an additional 2 h, the solution was concentrated under reduced pressure. The residue was flash chromatographed (hexane:ethyl acetate) to yield 1-methyl-4-(tributylstannyl)-1H-imidazole. Method [7] Retention time 7.34 min by HPLC (MH+ 373).
Reaction SMILES: COC(=O)C(N1C(=O)CC[N:11]([C:16](=O)/[CH:17]=[CH:18]/[C:19]2C=CC(Cl)=C(Cl)C=2)CC1)CCO.[Cl:29][C:30]1[CH:31]=[C:32](/[CH:37]=[CH:38]/[C:39]([N:41]2[CH2:47][CH2:46][C:45](=[O:48])[N:44]([CH:49]3[CH2:53][CH2:52][O:51][C:50]3=[O:54])[CH2:43][CH2:42]2)=[O:40])[CH:33]=[CH:34][C:35]=1[Cl:36].N1CCCC1>CCO>[Cl:29][C:30]1[CH:31]=[C:32](/[CH:37]=[CH:38]/[C:39]([N:41]2[CH2:47][CH2:46][C:45](=[O:48])[N:44]([CH:49]([C:50]([N:11]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[O:54])[CH2:53][CH2:52][OH:51])[CH2:43][CH2:42]2)=[O:40])[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=C1OCCC1N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Solvent: CCO
Solvent: C1CCNC1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(C(CCO)C(=O)N2CCCC2)CC1
Yield: 88 %

Procedure:
In analogy to the procedure described in example 3, treatment of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid methyl ester (with 50% of the lactone, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) (intermediate 6) in EtOH with pyrrolidine over night at RT gave 88% of the titled compound as white foam. MS: 468.1 (MH+, 2Cl).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:13]=[CH:14][C:15]=1[N+]([O-])=O)[C:9]([O:11][CH3:12])=[O:10].[CH3:20][S-:21].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:13]=[CH:14][C:15]=1[S:21][CH3:20])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COCCOc1c([N+](=O)[O-])ccc(C(=O)OC)c1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1c(SC)ccc(C(=O)OC)c1C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
Methyl 3-(2-methoxyethoxy)-2-methyl-4-nitrobenzoate (31 g) was dissolved in anhydrous DMF (300 mL), and sodium thiomethoxide (purity: 95%, 8.92 g) was added at room temperature, followed by stirring for 45 minutes. To the reaction mixture, ethyl acetate (400 mL) was added and washed once with 1 N hydrochloric acid (150 mL) and washed twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain methyl 3-(2-methoxyethoxy)-2-methyl-4-(methylthio)benzoate (30 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][NH:19]2)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:21]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: FC(F)(F)c1ccc2c(c1)NCCC2
Reactant: BrCc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)N(Cc1cccc(Br)c1)CCC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Under a nitrogen atmosphere, a solution of bromo-3-bromomethyl-benzene (3.47 g, 13.p mmol) and 7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.93 g, 14.6 mmol) in ethanol (15 mL, 1 M) was treated with sodium acetate (5.69 g, 69.3 mmol) and heated to 80° C. After stirring 2 h, the solution was cooled to room temperature, diluted with water, extracted with ethyl acetate and washed with saturated aq sodium chloride. The organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography (10% ethyl acetate in heptane) provided 1-(3-bromo-benzyl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline 4.21 g (82%) as a colorless oil.
Reaction SMILES: [NH:1]([N])C1C=CC=CC=1.NN.[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[C:15]([N+:22]([O-:24])=[O:23])=[CH:14][C:13]=1C(F)(F)F>>[Cl:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([C:15]([N+:22]([O-:24])=[O:23])=[CH:14][CH:13]=1)[NH2:1]
Reactant: [N]Nc1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: NN
Product: Nc1c([N+](=O)[O-])ccc(Cl)c1[N+](=O)[O-]

Procedure:
The 3-chloro starting materials for the preparation of the azido compounds of my invention are prepared by reacting the appropriate amine or appropriate hydrazine with 2,4-dichloro-3,5-dinitrobenzotrifluoride as described in U.S. Pat. No. 3,617,252. The amine or hydrazine is chosen to give the desired substitution pattern on the anilino nitrogen of the final product. The amine or hydrazine reacts preferentially with the chlorine atom between the two nitro groups of the 2,4-dichloro-3,5-dinitrobenzotrifluoride to give the 3-chloro-2,6-dinitroaniline starting material for use in preparing the compounds of my invention.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 74 %

Procedure:
As described for example 125, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (160 mg, 74%), which was obtained as a white solid. MS: m/e=386.5 [M−H]−.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([OH:19])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A combination of (2) (14 g, 0.050 mol), benzyl chloride (6.3 mL, 0.055 mol) and potassium carbonate (20.7 g, 0.15 mol) was heated to 100° C. for 3 h. After cooling to room temperature, water (200 mL) and ethyl acetate (400 mL) were added; the organic layer was separated and washed with water (5×200 mL), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to produce the crude product as a yellow oil. This was used without further purification in the next step.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]2[C:1]([NH:2][C:18]3[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=[CH:16][C:17]=3[S:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[N:12][CH:11]=[N:10][C:4]=2[N:5]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of the product from Example 10B (340 mg, 1.80 mmol), and the product of Example 85A (480 mg, 1.80 mmol) in acetic acid (10 mL) was stirred in an oil bath preheated to 130° C. for 30 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum leaving a brown oil as the title compound (0.65 g, 89%).
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][O:5][C:6](=[O:20])[C:7](=[C:12]([C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH3:13])[C:8]([O:10][CH3:11])=[O:9].[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH3:11][O:10][C:8](=[O:9])[CH:7]([C:12]([CH3:1])([C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[CH3:13])[C:6]([O:5][CH3:4])=[O:20]
Reactant: C[Mg]Cl
Reactant: COC(=O)C(C(=O)OC)=C(C)c1ccc(C)o1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(C)(C)c1ccc(C)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
Step B To a suspension of CuI (7.61 g, 40 mmol) in anhydrous tetrahydrofuran (100 mL) at −50° C. was added methylmagnesium chloride (3 M, 27 mL, 80 mmol) during a period of 15 min. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 20 min. Then the temperature of the mixture was lowered to −50° C., a tetrahydrofuran solution (50 mL) of 2-[1-(5-methyl-furan-2-yl)-ethylidene]-malonic acid dimethyl ester (3.7 g, 15.5 mmol) was added. The reaction mixture was allowed to slowly warmed to room temperature and stirred for 3 h. Aqueous saturated NH4Cl solution was added to quench the reaction. The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran. The residue was extracted with ethyl acetate twice. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20, 1:10) to give 2-[1-methyl-1-(5-methyl-furan-2-yl)-ethyl]-malonic acid dimethyl ester as a colorless oil (2.5 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][O:10][S:13]([CH3:12])(=[O:15])=[O:14])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1c(Cl)ncnc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 2-(4,6-Dichloro-pyrimidin-5-yl)-ethanol (0.46 g, 2.4 mmol) in DCM (40 mL) and was added MsCl (0.50 g, 4.36 mmol), triethylamine (1 mL) and cat. amount of DMAP. After stirring at room temperature overnight, the solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to afford methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-ethyl ester (0.52 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 4.50 (t, J=6.4 Hz, 2H), 3.42 (t, J=6.8 Hz, 2H), 3.02 (s, 3H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:25]1([CH2:31][CH2:32][CH2:33][C:34]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[S:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=4)=[N:17][CH:16]=3)=[CH:23][CH:22]=2)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OC(=O)CCCc4ccccc4)cc3)s2)cc1
Reaction time: 8 h
Yield: 26.9 %

Procedure:
0.675 g of 4-{2-(4-hexylphenyl)thiazole-5-yl}phenol, 0.328 g of 4-phenylbutanoic acid, 0.41 g of DCC (1,3-dicyclohexylcarbodiimide) and 40 mg of 4-(N-pyrrolidino)pyridine were dissolved in 40 ml of dichloromethane, followed by stirring overnight. After the reaction, the reaction mixture was subjected to filtration to remove an insoluble matter, followed by distilling-off of the solvent and purification by silica gel column chromatography to obtain 0.260 g of an objective product (Yield: 26.9%).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>C(O)(C)(C)C>[C:2]([O:4][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1)([CH3:5])([CH3:3])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1ccc([N+](=O)[O-])cn1

Procedure:
To 50 ml. of tert-butanol, there was added potassium tert-butoxide (0.06 mole) and 2-chloro-5-nitropyridine (0.05 mole). A white solid precipitated. The reaction mixture was heated to about 60° for 4 hours. Excess ammonium chloride was added to neutralize excess potassium tert-butoxide. Solvent was removed by evaporation, and the residue was taken up in chloroform, separated, washed with water, dried over magnesium sulfate, and chromatographed on silica gel with a 50:50 mixture of ethyl acetate:toluene. The structure was confirmed by NMR spectroscopy.