Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:40])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)[N:12]=[C:11]([N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Yield: 100.9 %

Procedure:
A solution of 2-[2-[isobutyl-(4-trifluoromethyl-phenyl)-amino]-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-4-methyl-pent-4-enoic acid methyl ester (40 mg, 0.07 mmol), Pd/C (10%, 5 mg) in methanol (10 mL) was hydrogenated for 4 h. The mixture was filtered through Celite, washed with methanol, evaporated. The residue was dissolved in CH2Cl2, filtered and evaporated to give the product as colorless oil (40 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=8.29 Hz, 2H), 7.70 (d, J=8.29 Hz, 2H), 7.64 (d, J=8.67 Hz, 2H), 7.38 (d, J=8.67 Hz, 2H), 7.18 (s, 1H), 6.57 (s, 1H), 3.96 (d, J=7.16 Hz, 2H), 3.66 (s, 3H), 2.10-2.23 (m, 1H), 1.90 (dt, J=7.72, 13.56 Hz, 1H), 1.62 (dt, J=6.92, 13.66 Hz, 1H), 1.40-1.52 (m, 1H), 0.97 (d, J=6.78 Hz, 6H), 0.89 (dd, J=4.33, 6.59 Hz, 5H). MS m/e 567.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[CH2:22]([NH:25][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[C:7]3[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=3[O:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:10][CH:11]=1)=[O:17])[CH2:23][CH3:24]
Reactant: O=C=Nc1ccc(-c2c([N+](=O)[O-])oc3ccccc23)cc1
Reactant: CCCN
Product: CCCNC(=O)Nc1ccc(-c2c([N+](=O)[O-])oc3ccccc23)cc1

Procedure:
Using the method of Example 25, 4-(2-nitro-3-benzofuranyl)phenyl isocyanate is reacted with n-propylamine to provide 1-(1-propyl)-3-[4-(2-nitro-3-benzofuranyl)phenyl]urea having the structure ##STR23##
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.O.[CH:23](O)=[O:24]>>[CH:23]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)=[O:24]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=CO
Solvent: O
Product: C[C@]12CC[C@H](OC=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 60 °C

Procedure:
Following the procedure described by Ringold (H. J. Ringold, et al., J. Am. Chem. Soc. 78, 816, 1956), dehydroepiandrosterone (2.88 g, 10 mmol) dissolved in 85% formic acid (100 mL) is heated at 60° C. for 1 h. After cooling, the mixture is poured into iced water and after 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:33])(=[O:32])[NH2:34])=[O:14])=[CH:18][CH:19]=1
Reactant: COc1ccc(COc2cccc(C(=O)O)c2)cc1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (15.5 mmol) of 3-(4-methoxybenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.93 g (17.0 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained residue was purified by a silica gel chromatography to obtain 1.5 g (yield: 31.0%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:39])[C:8]2[O:14][C:13]3[C:15]([Cl:35])=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=5)[CH2:21][CH2:20]4)=[CH:18][C:12]=3[CH2:11][S:10](=[O:37])(=[O:36])[C:9]=2[CH:38]=1)=[O:4]>CN(C=O)C.[Ni]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:39])[C:8]2[O:14][C:13]3[C:15]([Cl:35])=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=5)[CH2:21][CH2:20]4)=[CH:18][C:12]=3[CH2:11][S:10](=[O:36])(=[O:37])[C:9]=2[CH:38]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4cccc([N+](=O)[O-])c4)CC3)cc(Cl)c1O2
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4cccc(N)c4)CC3)cc(Cl)c1O2
Reaction time: 2 h

Procedure:
Activated Raney-Ni (0.54 g) in DMF (10 mL) was added to a solution of Example 126k (0.73 g, 1.276 mmol) in DMF (25 mL) and the reaction mixture was subjected to hydrogenation at 30 psi for 2 h. It was filtered through celite, concentrated and purified using flash chromatography (silica gel, 1.5% methanol/chloroform) to obtain the title compound. Yield: 0.54 g, (75.5%); 1H NMR (CDCl3): δ 2.5 (t, 4H, 2CH2), 2.7 (s, 3H, CH3), 3.22 (t, 4H, 2CH2), 3.5 (s, 2H, CH2), 3.7 (bs, 2H, NH2), 3.9 (s, 3H, OCH3), 4.65 (s, 2H, CH2), 6.6 (d, 1H, Ar), 6.7 (s, 1H, Ar), 6.72 (d, 1H, Ar), 6.77 (s, 1H, Ar), 6.9 (s, 1H, Ar), 7.1 (t, 1H, Ar), 8.08 (s, 1H, Ar), 8.5 (s, 1H, Ar); MS: m/e (CI+) 542 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([NH:22][OH:23])([CH3:21])([CH3:20])[CH3:19]>>[C:1]([C:5]1[C:6]([OH:17])=[C:7]([CH:8]=[N+:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[O-:23])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C=[N+]([O-])C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 3,5-di-tert-butyl-2-hydroxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 82.1% yield as a crystalline solid, m.p. 234.7-235.2° C. (Rf=0.66 on a silica gel plate using 1:4 EtOAc/hexanes as an eluant).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[N:7][C:6]([O:11][CH3:12])=[CH:5][N:4]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:13][C:14]1[N:15]=[C:16]([C:20]2[N:24]([CH2:2][C:3]3[C:8]([O:9][CH3:10])=[N:7][C:6]([O:11][CH3:12])=[CH:5][N:4]=3)[CH:23]=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cnc(CCl)c(OC)n1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(OC)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A mixture of 2-chloromethyl-3,5-dimethoxy-pyrazine (115 mg, 0.61 mmol), 2-fluoro-6-(1H-imidazol-2-yl)-pyridine (98 mg, 0.60 mmol) and K2CO3 (250 mg, 1.81 mmol) in DMF (7 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (3 mL) and extracted with DCM (3×15 mL). The combined organic layers are dried and solvent removed. PTLC (silica gel) separation (10% MeOH in DCM) gives 123 mg of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-3,5-dimethoxy-pyrazine as an oil. LRMS calcd 315.30, found 316.20 (MH+). D. 3,5-Dimethoxy-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-pyrazinel (Compound 5)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1.[NH2:20][C:21]1[C:22](=[O:34])[N:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:24]([CH3:27])[C:25]=1[CH3:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:28]1([N:23]2[C:22](=[O:34])[C:21]([NH:20][C:17]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]4[CH2:16][CH2:15][C:10]5([CH2:14][O:13][CH2:12][CH2:11]5)[CH2:9][CH:8]=4)[O:5][N:4]=3)=[O:19])=[C:25]([CH3:26])[N:24]2[CH3:27])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1c(C(=O)O)noc1C1=CCC2(CCOC2)CC1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC2(CCOC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [4-methyl-5-(2-oxaspiro[4.5]dec-7-en-8-yl)isoxazole-3-carboxylic acid] (40 mg, 0.152 mmol) in DMF (3 mL) was treated with 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (38.2 mg, 0.182 mmol), DIPEA (0.106 mL, 0.608 mmol) and HATU (75 mg, 0.198 mmol). The resulting mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the aqueous was extracted with EtOAc (×2). The combined organic extracts were washed with 0.5M lithium chloride (aq), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-5% MeOH in EtOAc afforded the title compound;
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)/[C:7](=[CH:15]\[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)/[C:6]=1[CH3:24])#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:36]>C1(C)C=CC=CC=1>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)/[C:6]([CH3:24])=[C:5]2[CH2:4][CH2:3][CH:1]=[O:36]
Reactant: CO
Reactant: CSc1ccc(/C=C2/C(C)=C(CCC#N)c3cc(F)ccc32)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CSc1ccc(/C=C2/C(C)=C(CCC=O)c3cc(F)ccc32)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of the nitrile from Step 2 (415 mg, 1.24 mmol) in toluene (4.5 mL) at -78° C. there was added diisobutyl aluminum hydride (1M) in toluene (1.9 mL, 1.9 mmol) and the mixture was stirred at -78° C. for 2 hours; methanol (2 mL) was added and the mixture allowed to warm to room temperature. After partition between ether and water, the residue from evaporation of the organic fraction was chromatographed on silica gel eluting with a 1:2 mixture of ether:hexane to afford the pure title compound as an oil which solidified on standing.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH2:12][C@H:13]2[C@@H:18]([OH:19])[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH2:12][C@H:13]2[C@@H:18]([OH:19])[CH2:17][CH2:16][N:15]([CH3:35])[CH2:14]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC[C@@H]2CNCC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@@H]2CN(C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-4-ol (0.27 mmol, 0.14 g) in DCM (1 mL) was added formaldehyde solution (1 mL) followed by sodium triacetoxyborohydride (0.5 g) and continued stirring the reaction mixture for 2 h at room temperature. The reaction mixture was diluted with DCM, separated the organic layer, dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with DCM (300 mL) followed 10% methanolic solution of ammonia (2 M solution of NH3 in methanol) in DCM to provide (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol which was converted to dihydrochloride salt by treating with 4 N HCl in dioxane. The volatiles were removed under educed pressure, salt was washed with anhydrous ether and solid was dried under high vacuum to provide the title compound (0.121 g). LCMS: m/z 455 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.78 (1H, s), 7.46 (2H, d), 7.12 (2H, d), 4.6-4.73 (1H, m), 4.5-4.58 (2H, m), 4.19 (1H, bs), 3.11-3.53 (6H, m), 2.93 (3H, s), 2.58 (1H, m), 1.99-2.05 (3H, m), 1.8 (2H, m), 1.24-1.60 (11H, m), 0.82 (3H, t).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:14][C:15]1[C:16](Cl)=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1>CN(C)C=O.ClCCl.CO>[Br:14][C:15]1[C:16]([O:11][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: Clc1ncc(Br)c(Oc2ccc3cccnc3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial was charged with quinolin-7-ol (0.200 g, 1.378 mmol) and sodium hydride (0.066 g, 1.653 mmol) in N,N-dimethylformamide (13.78 ml) to give a brown solution. The reaction was stirred at room temperature for 30 minutes and then 5-bromo-2,4-dichloropyrimidine (0.176 mL, 1.378 mmol) was added. The mixture was stirred at room temperature overnight. Diluted with 9:1 dichloromethane/methanol; washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to afford a tan residue. (ESI(+)) m/e 337.7 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Cl:22])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(CO)ccc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1cc(CCl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under agitation, 58.3 g of 4-benzyloxy-3-nitrobenzyl alcohol is introduced in incremental portions into 250 ml of thionyl chloride, stirred for 30 minutes at room temperature, and concentrated under vacuum. The residue is recrystallized from diisopropyl ether while decolorizing with active carbon, thus producing 50.9 g of 4-benzyloxy-3-nitrobenzyl chloride, mp 60°-61° C.
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].[CH2:17]([O:19][C:20](OCC)=[CH:21][C:22](OCC)=[O:23])[CH3:18].CS(C)=O>[OH-].[Na+]>[CH2:17]([O:19][C:20]1[N:11]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:10][C:22](=[O:23])[CH:21]=1)[CH3:18]
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C=C(OCC)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(=O)[nH]c(-c2ccccc2)n1
Temperature: 120 °C
Yield: 52.7 %

Procedure:
A mixture of 3.14 g (20.0 mmol) of benzamidine hydrochloride hydrate, 1.65 g (20.1 mmol) of powdered anhydrous sodium acetate, 4.17 g (22.2 mmol) of ethyl 3,3-diethoxyacrylate and 10 mL of DMSO was heated at 120° C. for 8 h. The mixture was cooled, diluted with 50 mL of 5% aqueous NaOH and washed with two 100 mL portions of ether. The aqueous layer was acidified with concentrated hydrochloric acid and the precipitate was collected by filtration and dried under vacuum at 50° C. to furnish 2.28 g (57%) of crude 6-ethoxy-2-phenyl-4(3H)-pyrimidinone as a yellow solid 1 H-NMR (d6-DMSO) δ 1.35(3H,t), 4.33(2H,q), 5.60(1H,s), 7.50(3H,m), 8.2(2H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[O:22])[N:20]=2)[CH:17]=1
Reactant: NCc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1c(Cl)cccc1Cl)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2,6-dichlorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH:3]1[F:10].N1C=CC=CC=1.[N+:18]([C:21]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])([O-:20])=[O:19]>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[CH:3]([F:10])[C:4](=[O:9])[CH:5]=[C:6]([O:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:21]=2[N+:18]([O-:20])=[O:19])[CH2:7]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC1(C)CC(=O)CC(=O)C1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])=CC(=O)C1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5,5-Dimethyl-4-fluoro-1,3-cyclohexanedione [0.5 grams (g), 0.0032 mole, prepared according to the teaching of Liebigs Ann. Chem., 679, 9 (1964)] and 0.25 g (0.0032 mole) pyridine were dissolved in 20 milliliters (ml) methylene chloride at room temperature. 2-Nitro-4-trifluoromethylbenzoyl chloride (1.0 g, 0.0039 mole) dissolved in 20 ml methylene chloride was slowly added with cooling. The reaction mixture was stirred at room temperature for 24 hours and then washed two times with water, one time with saturated sodium bicarbonate aqueous solution and one with with water. The aqueous phases were discarded and the organic phase dried with MgSO4 and then evaporated to yield the intermediate enol ester, 5,5-dimethyl-6-fluoro-3-(2-nitro-4-trifluoromethylbenzoyloxy)cyclohex-2-enone. The 5,5-dimethyl-6-fluoro-3-(2-nitro-4-trifluoromethylbenzoyloxy)cyclohex-2-enone was dissolved in 30 ml acetonitrile and triethylamine (0.7 g, 0.007 mole) which was added all at once, followed by acetonecyanohydrin (0.05 g, 0.0006 mole). The solution was stirred for 24 hours. The solvent was evaporated and the residue washed with diethyl ether to yield the product.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[N:18]1[CH:17]=[CH:16][C:15]([C:14]2[O:21][C:2]3[CH:7]=[CH:6][C:5]([S:8][C:9]([F:10])([F:11])[F:12])=[CH:4][C:3]=3[N:13]=2)=[CH:20][CH:19]=1
Reactant: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)Sc1ccc2oc(-c3ccncc3)nc2c1
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a mixture of 0.69 g of N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide, 9 ml of tetrahydrofuran, and 0.63 g of triphenylphosphine, 1.05 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature and stirred for three hours. To the mixture, 0.21 g of triphenylphosphine and 0.35 g of 40% toluene solution of diethyl azodicarboxylate were added. The reaction mixture was stirred for further two hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and the resultant crystals were washed with methanol to give 0.17 g of 2-(pyridin-4-yl)-5-(trifluoromethylthio)benzoxazole (hereinafter, referred to as “active compound 76”).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:20])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Li+].Cl>O1CCCC1>[OH:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:10]([NH:9][CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:22])=[O:2])=[O:21])[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: COC(=O)C(CC(C)C)NC(=O)CCc1ccc(O)c(O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)CCc1ccc(O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
2-[3-(3,4-dihydroxyphenyl)propionylamino]-4-methyl pentanoic acid methyl ester (200 mg), prepared in Example 13, was dissolved in tetrahydrofuran (5 mL) and treated with 2M lithium hydroxide (1 mL). The resulting mixture was stirred for 18 hours at room temperature. The resulting reaction was neutralized with aqueous hydrochloric acid, extracted with ethylacetate (EtOAc) (100 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexan/EtOAc (1/5)) to obtain 184.5 mg of the title compound. The yield was 97%. The results of analyses of the compound are as follows:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].Cl.[CH2:10]([O:12][C:13](=N)[CH3:14])[CH3:11].C([O-])([O-])=O.[K+].[K+]>C(OCC)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]=[C:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)CN=C(C)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
17.140 g (0.123 mol) of aminoacetic acid ethyl ester hydrochloride and 15.175 g (0.123 mol, 1 eq) of acetimidic acid ethyl ester hydrochloride were stirred in solution in 300 mL ice cold water. 200 mL diethyl ether and then 16.97 g (0.123 mol, 1 eq) K2CO3 were added. The reaction mixture was stirred for 10 minutes. The organic phase was separated and dried over Na2SO4, filtered and evaporated to dryness to yield to 15.229 g (72%) of (1-ethoxy-ethylideneamino)-acetic acid ethyl ester as a light yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[Na].C(O)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=1)[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.9 g (10 mmol) 1,3-dihydro-5(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4 thiadiazin-5-yl)-3,3 dimethyl-2H-indol-2-one (Example 3), 0.4 g (10 mmol) sodium hydroxyde and 100 ml ethanol were refluxed 30mn. After evaporation of the solvent, the residue was dissolved in 50 ml DMF and 1.86 g (10 mmol) p-nitrobenzoyl chloride were added while keeping the temperature under 30° C. The mixture was stirred 2 hrs at room temperature, diluted with 100 ml water, extracted with ethyl acetate. The organic layers were washed with brine and dried over magnesium sulfate. The residue was purified by column chfomatography on silica (eluent:ethylacetate/hexane:1/1) and the major fraction was triturated in isopropyl ether and dried under vacuum.