Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[Li][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].C(OCC)(=O)C.CCCCCC>C(OCC)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:9]=[CH:8]2
Reactant: [Li]c1ccccc1OC
Reactant: COc1cccc2cccnc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccccc1-c1ccc2cccc(OC)c2n1
Reaction time: 2 h

Procedure:
A solution of 8-methoxyquinoline (5.54 g, 34.8 mmol, 1.0 eq) in 55 ml diethyl ether was slowly dropped (within about 30 min) into a solution of o-lithioanisole (4.37 g, 38.4 mmol, 1.1 eq) in 55 ml diethyl ether (each 55 mL). A yellow green fluorescing solution was formed. At the conclusion of the addition, stirring was continued at room temperature for a further 2 hours, after which no more educt could be detected by thin layer chromatography. During the reaction, the color of the reaction mixture changed from fluorescent yellow to green to green-brown. The reaction mixture was worked up by adding it to ice and subsequent extraction with diethyl ether (3×40 ml). The combined organic phases (yellow) were dried over MgSO4 and the solvent was removed in a rotary evaporator. The residue was dissolved in 200 ml dichloromethane and stirred with ca. 40 equivalents of activated manganese dioxide (Merck) until the thin layer chromatographic control (ethyl acetate/hexane=4/6) showed that all of the crude product had reacted. The manganese dioxide was filtered off and the solvent removed in the rotary evaporator. The product was dried under vacuum.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[O:13]=[C:14]([CH3:23])[CH2:15][C:16]([O:18][CH2:19][CH2:20][C:21]#[N:22])=[O:17].C(O)(=O)C.N1CCCCC1>ClCCl>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[C:15]([C:14](=[O:13])[CH3:23])[C:16]([O:18][CH2:19][CH2:20][C:21]#[N:22])=[O:17])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CC(=O)CC(=O)OCCC#N
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C=C(C(C)=O)C(=O)OCCC#N

Procedure:
3.00 g (18.62 mmol) of the compound from Example 10A, 3.18 g (20.48 mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)], 213 μl (3.72 mmol) of acetic acid and 368 μl (3.72 mmol) of piperidine are dissolved in 50 ml of anhydrous dichloromethane and stirred under reflux with a water trap overnight. The volatile components are then removed in a rotary evaporator, and the residue is purified by column chromatography (silica gel; mobile phase: gradient cyclohexane/ethyl acetate 7:3→1:1). 2.77 g (48% of theory) of the title compound are obtained as a mixture of the E/Z isomers.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[C:3]1=[O:14].Cl.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[C:3]1=[O:14]
Reactant: COc1ccc2c(c1)CCC(C)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1CCc2cc(O)ccc2C1=O
Reaction time: 2 h
Yield: 84 %

Procedure:
2-Methyl-6-Methoxy-1-Tetralone (19 g, 0.1 mole) and pyridine hydrochloride (53.1 g, 0.46 mole) were heated neet, under a nitrogen sweep at about 220° for about 2 hours. The melt was cooled, acidified with 1N HCl and dissolved in ethyl acetate. The organic layers were dried (brine, MgSO4) and concentrated in vacuo. Purification by flash chromatography [gradient 7:1 to 5:1 EtOAc:Hexanes] yielded the title compound as a light yellow solid (14.8 g, 0.084 mole, 84% yield), [Lit. Buchta et al., Ann. 576, 7-19 (1952)].
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2](OC)=[O:3].CCOCC.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.Cl>C1COCC1.CCCCCC>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]([C:1]([O:7][CH3:8])=[O:6])=[O:3])=[CH:17][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(F)cc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Dimethyl oxalate (5.90 g, 50 mmol) was dissolved in THF (50 mL) and ether (50 mL) in a 3-neck round bottom flask fitted with a mechanical stirrer. The solution was stirred vigorously at −65° C. as a 1.0 M THF solution of 4-fluorophenylmagnesium bromide (60 mL, 60 mmol) was added dropwise over 40 min. The mixture was stirred 30 min. at −65° C. and allowed to warm to −20° C. over 30 min. before being poured into 2 N HCl (50 mL) with stirring. The layers were separated and the aq. layer was extracted with ether (3×50 mL). The combined organic layers were washed with saturated aq. NaCl (2×50 mL), dried (Na2SO4), decanted, and evaporated. The residue was dissolved in EtOAc, dried (Na2SO4), filtered, and evaporated to give a yellow solid. The crude product was dissolved in warm hexane (25 mL), filtered, and cooled to −20° C. Filtration followed by washing with cold hexane (15 mL) gave 4.95 g of the title compound as light tan crystals. 1H NMR (500 MHz) δ 8.11 (dd, J=9.0,5.0,2H), 7.21 (t, J=9,22H), 4.00 (s, 3H); HPLC A: 2.59 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1.BrC1C=C[C:22]([S:25]C)=CC=1>>[CH3:22][S:25][C:10]1[CH:17]=[CH:16][C:13](/[CH:14]=[CH:15]/[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=2)=[CH:12][CH:11]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: CSc1ccc(Br)cc1
Reactant: Fc1cccc(Br)c1
Product: CSc1ccc(/C=C/c2cccc(F)c2)cc1

Procedure:
Following the procedure describe in Method 3, but substituting4-methylthiostyrene and 1-bromo-3-fluorobenzene for 4-fluorostyrene and 4-bromothioanisole, the title product was obtained as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCOCC1
Reactant: O=C1CCc2cc(O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCc2cc(OCCN3CCOCC3)ccc21

Procedure:
To a solution of 5-hydroxy-1-indanone (610 mg, 4.1 mmol) in acetonitrile (30 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (3.8 g, 20.5 mmol) and potassium carbonate (680 mg 4.9 mmol) and the mixture was heated to reflux for about 3 days. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel using ethyl acetate as the mobile phase to provide the desired product. MS (ESI): m/z 262 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]=O)[N:3]=1.Cl[CH2:12]C=O.Cl.C(OCC)(=O)C>C(O)C>[F:1][C:2]1[N:3]2[CH:12]=[CH:9][N:8]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCl
Reactant: O=CNc1cccc(F)n1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Fluoro-6-formylaminopyridine (5 g) was dissolved in 50 mL of ethanol. To the solution was added 23.5 mL (4 equivalents) of 40% chloroacetaldehyde. The mixture was stirred for one hour under reflux. The reaction mixture was gradually cooled to room temperature, to which were added a 1N—HCl aqueous solution (100 mL) and ethyl acetate (100 mL). The ethyl acetate solution was subjected to extraction with a 1N—HCl aqueous solution (100 mL×2). The aqueous solutions were combined, to which was added NaHCO3 for neutralization (pH 0.35-7.30). To the neutralized aqueous solution was added ethyl acetate (100 mL×3) to extract the product. The extract solutions were combined and dried over magnesium sulfate, which was concentrated under reduced pressure to afford 5-fluoroimidazo[1,2-a]pyridine as a black liquid product (1.5 g, yield 31%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl-].[NH2:11][CH:12]([CH2:26][C:27]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]2[C:28]=1[CH:29]=[CH:30][N:31]2[S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14].[C:47]1([S:53](Cl)(=[O:55])=[O:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl.CCOCC>[C:47]1([S:53]([NH:11][CH:12]([CH2:26][C:27]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]3[C:28]=2[CH:29]=[CH:30][N:31]3[S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:40])=[O:39])[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:14])(=[O:55])=[O:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1ccc(CC(N)C(=O)NCCCCc2ccccc2)c2ccn(S(=O)(=O)c3ccccc3)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COc1ccc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2ccn(S(=O)(=O)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Hunig's base (2.1 g, 16 mmol) is added to a suspension of 2-amino-3-(1-benzenesulfonyl-7-methoxy-1H-indol-4-yl)-N-(4-phenyl-butyl)-propionamide, hydrogen chloride salt (3.0 g, 5.6 mmol) in CH2Cl2. The resulting solution is cooled to 0° C. and benzenesulfonyl chloride (1.2 g, 6.9 mmol) is added. After being warmed to rt and stirred 2 h, the reaction mixture is diluted with Et2O and washed sequentially with 0.5 M HCl and saturated NaHCO3 solutions. The aqueous phases are extracted once with Et2O. The desired compound crystallizes at this point. The volatiles are removed in vacuo and the remaining residue is azeotroped sequentially with dioxane and toluene to provide 2-benzenesulfonylamino-3-(1-benzenesulfonyl-7-methoxy-1H-indol-4-yl)-N-(4-phenyl-butyl)-propionamide as a solid which is used as is without further purification.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[OH:36]>>[OH:36][C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]1[NH:29][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[C:3]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COCCOc1ncc(C(=O)O)cc1Br
Reactant: N[C@@H]1CCCC[C@H]1O
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31b to c, using 5-bromo-6-(2-methoxy-ethoxy)-nicotinic acid, 4-trifluoromethylphenyl-boronic acid (commercially available) and (1R,2R)-2-amino-cyclohexanol (commercially available) as starting materials. MS (ISP): 439.0 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:23][CH:24]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:25]([OH:27])=[O:26])[CH:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].CS(O)(=O)=O>C(O)C.[Pd]>[N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]3[N:15]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[N:14]=[C:13]([CH2:23][CH:24]([C:28]4[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=4)[C:25]([OH:27])=[O:26])[CH:12]=3)=[CH:7][CH:6]=2)[CH:3]=[CH:2][CH:1]=1.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[N:14]=[C:13]([CH2:23][CH:24]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:25]([OH:27])=[O:26])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: C=CCNc1ccc(-c2cc(CC(C(=O)O)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(N)cc2)cc1
Product: Cc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc3ncccc3c2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 35 %
Yield: 35 %

Procedure:
To a solution of 3-[5-(4-allylamino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (Example 94, Step A; 70 mg, 0.15 mmol) in ethanol (1 mL) was added 10% Pd/C (26 mg) and methanesulfonic acid (0.01 mL, 0.15 mmol, 1 equiv). The mixture was stirred at 65° C. for 2 h. The catalyst was removed by filtering the reaction mixture through a CELITE® pad, and the pad was rinsed with EtOH (1.5 mL). The combined filtrates were concentrated under reduced pressure. The crude residue was dissolved in 1:1 THF/H2O (1.5 mL), and LiOH was added (10 mg, 0.45 mmol, 3 equiv). After 3 h at 45° C., the mixture was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the title compound (26 mg, 35%) along with 3-[5-(4-amino-phenyl)-1-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid (20 mg, 35%). HPLC: Rt=3.18 (Method A). MS (ESI): mass calculated for C29H25N3O2, 447.19; m/z found, 448.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.43 (d, J=8.5 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.85 (d, J=1.7 Hz, 1H), 7.68 (dd, J=8.3, 4.8 Hz, 1H), 7.59 (dd, J=8.8, 1.7 Hz, 1H), 7.26-7.23 (m, 2H), 7.12 (s, 4H), 6.42 (s, 1H), 4.17 (dd, J=9.8, 5.3 Hz, 1H), 3.58 (dd, J=14.9, 9.8 Hz, 1H), 3.17 (dd, J=14.9, 5.3 Hz, 1H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:7]2[C:6]3[CH:11]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C1COc2ccc(F)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2coc3ccc(F)cc23)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of TiCl4 (1M solution in CH2Cl2, 7 ml) and 5-fluoro-benzofuran -3-one (Cagniant, et al., Comptus Rendus des Seances Acad. de Sci., Ser. C, 282:993 (1976), 3.0 g) (3.0 g, 19.7 mmol) in methylene chloride (200 ml) at −10° C., ethyl-1-piperizine carboxylate (commercially available) (3.9 g, 35 mmol) was slowly added. After the addition, the reaction mixture was warmed to room temperature and slowly refluxed for 24 hours. After cooling to room temperature, the reaction was quenched with 2 N aqueous HCl. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were washed well with water and dried over anhydrous MgSO4, then filtered and concentrated resulting in a brown oil. Yield: 3.5 g, (60%); MS (ESI) m/z 293 [M+−H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Pd].C([O-])([O-])=O.[Ca+2]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C=CCCC(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: N#Cc1ccc(CCCCC(=O)O)cc1

Procedure:
A solution of 1.47 g (7.32 mmol) of (3) in 90 mL of methanol was hydrogenated over 200 mg of 5% Pd/CaCO3 at 5 psi hydrogen over a 1.2 hour period. After removing the catalyst by filtration and evaporation of the solvent in vacuo, the residue was triturated with ether followed by hexane which afforded a white solid: m.p. 101°-102° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc(O)cc1

Procedure:
To a solution of 4-hydroxyphenylacetic acid (10 g) in methylene chloride (66 mL) and methanol (26 mL) was added p-toluenesulfonic acid (1.25 g), and the resulting solution was heated at reflux overnight. The solvent was evaporated, the residue dissolved in ethyl acetate, and the the solution washed (H2O), dried (MgSO4), and evaporated to give crude methyl 4-hydroxyphenylacetate (10.4 TLC: Rf =0.72, ethyl acetate:dichloromethane (10:90); MS: m/z=167(M+1).
Reaction SMILES: Cl[CH:2]([Cl:4])C.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](Cl)=[O:10].[O:16]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([O:16][CH2:2][Cl:4])=[O:10]
Reactant: CC(Cl)Cl
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: C1COOOC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 10 ml of dichloroethane were added 1.2 g of zirconium tetrachloride and 1 g of 3,4-difluorobenzoyl chloride, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C., 0.19 g of trioxane was added, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour. Water was added slowly at 0° C., the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 1.1 g of chloromethyl 3,4-difluorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: Cc1cc(Cl)cnc1CCCCN
Product: Cc1ccc(Cc2cnc(NCCCCc3ncc(Cl)cc3C)[nH]c2=O)cn1
Yield: 28.3 %

Procedure:
Reaction of 5-chloro-2-(4-aminobutyl)-3-methyl-pyridine [from Example 5(a)] (1.0 g) with 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.23 g) under conditions analogous to those described in Example 1(f) gave 2-[4-(5-chloro-3-methylpyrid-2-yl)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (0.53 g) m.p. 140°-141° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([C:14]3[O:15][C:16](=[O:28])[C:17]4[C:23]([CH2:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[CH:20][C:18]=4[N:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:4]1.[CH3:30]I>ClCCl>[C:16]([O-:28])(=[O:15])[CH3:17].[CH2:24]([C:23]1[C:17]2[C:16](=[O:28])[O:15][C:14]([C:13]3[C:8]([N:5]4[CH2:6][CH2:7][CH:3]([N+:2]([CH3:30])([CH3:1])[CH3:29])[CH2:4]4)=[N:9][CH:10]=[CH:11][CH:12]=3)=[N:19][C:18]=2[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=1)[CH3:25]
Reactant: CI
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3N3CC[C@H](N(C)C)C3)oc(=O)c12
Solvent: ClCCl
Product: CC(=O)[O-]
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CCC([N+](C)(C)C)C3)oc(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 156.1 %

Procedure:
To a solution of compound 132 (30 mg, 0.076 mmol) in dichloromethane (380 μL) was added methyl iodide (14.2 μL, 0.228 mmol) and the resulting mixture was stirred at ambient temperature for 2 hours. The solution was concentrated, and the residue was purified using preparative HPLC. The fractions containing the desired compound were lyophilized to yield compound 232 (27.8 mg, 89%) as a yellow powder. 1H NMR (CDCl3, 400 MHz) δ: 8.30 (dd, 1H, J=4.5 Hz), 8.11 (dd, 1H, J=1.6 Hz), 6.95 (d, 1H, J=2.4 Hz), 6.89 (m, 2H), 4.74 (m, 1H), 4.13 (m, 1H), 3.94 (s, 3H), 3.91 (m, 1H), 3.52 (m, 2H), 3.43 (s, 9H), 3.19 (m, 2H), 2.52 (m, 1H), 2.33 (m, 1H), 1.92 (s, 3H), 1.29 (t, 3H, J=7.5 Hz). ESMS m/z: 409.1 [M+]
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[C:3](=O)[CH2:4][C:5]#[N:6].[OH-:21].[Na+].S(O)(O)(=O)=O.[NH2:28]O>O>[CH3:1][C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[O:21][N:28]=1)([CH3:20])[CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12]
Reactant: NO
Reactant: [OH-]
Reactant: CC(C)[Si](OCC(C)(C)C(=O)CC#N)(C(C)C)C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)[Si](OCC(C)(C)c1cc(N)on1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 17.7 %

Procedure:
To a stirred solution of 15.32 g (51 mmol) of 4,4-dimethyl-3-oxo-5-triisopropylsilanyloxy-pentanenitrile and 8.44 g (211 mmol) of sodium hydroxide in water (150 mL) are added 8.87 g (54 mmol) of hydroxylamine sulfate. The reaction mixture is stirred at reflux for 28 h. After this time, the reaction mixture is cooled to room temperature and extracted with chloroform (3×150 mL). The organic layers are combined and washed with water (30 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residual brown oil is purified by column chromatography (silica, eluent DCM, 0-1% methanol) to afford 2.82 g of 3-(1,1-dimethyl-2-triisopropylsilanyloxy-ethyl)-isoxazol-5-ylamine as a yellow solid. Yield 18%; m/z 313 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.98-1.15 (21H, m), 1.29 (6H, s), 3.68 (2H, s), 4.30 (2H, br. s.), 5.10 (1H, s)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C)P(=O)(N(C)C)N(C)C>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:12][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)Oc1ccc(C(=O)NOCc2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=NOCc2ccccc2)OCc2ccccc2)cc1
Product: CC(=O)Oc1ccc(C(=O)N(Cc2ccccc2)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %
Yield: 66 %

Procedure:
To a solution of 4-{[(benzyloxy)amino]carbonyl}phenyl acetate (18) (2.000 g, 7.0 mmol) and benzyl bromide (3.59 g, 21.0 mmol) in hexamethylphosphoric triamide (10 ml) Cs2CO3 (2.51 g, 7.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 24 hours. The mixture was diluted with benzene (50 ml) and washed successively with water (2×30 ml), 2N HCl (30 ml), water (2×30 ml), brine (30 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel (100 g) with petroleum ether-benzene (1:1) and benzene-ethyl acetate (9:1) as eluents to give 4-{(benzyloxy)[(benzyloxy)imino]methyl}phenyl acetate (19) (1.743 g, 66%) as an oil, Rf 0.83 (toluene-ethyl acetate, 9:1), and 4-{[benzyl(benzyloxy)amino]-carbonyl}phenyl acetate (20) (0.744 g, 28%) as a white solid, Rf 0.48 (toluene-ethyl acetate, 9:1). (19): 1H NMR (DMSO-d6, HMDSO) δ: 2.24 (3H, s); 5.12 (2H, s); 5.32 (2H, s); 7.17 (2H, d, J=8.7 Hz); 7.25-7.54 (10H, m); 7.66 (2H, d, J=8.7 Hz). GC-MS, m/z (%): 375 (0.2), 268 (0.3), 253 (1), 227 (0.6), 211 (1.3), 196 (0.5), 180 (2.3), 163 (19.5), 121 (36), 107 (5.2), 91 (100), 77 (6), 65 (16). IR (film, cm−1): 1758, 1616, 1578, 1507. (20): 1H NMR (DMSO-d6, HMDSO) δ: 2.28 (3H, s); 4.72 (2H, s); 4.99 (2H, s); 6.88-7.10 (2H, m); 7.12-7.50 (8H, m); 7.22 (2H, d, J=8.0 Hz); 7.63 (2H, d, J=8.0 Hz). GC-MS, m/z (%):269 (36), 227 (27), 121 (100), 106 (25), 91 (46), 77 (14), 65 (26). IR (nujol, cm−1): 1756, 1663, 1604, 1578, 1507.