Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:25]1[N:26]=[N:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)=[CH:29][CH:30]=1.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:25]3[N:26]=[N:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[N:36]4)=[CH:29][CH:30]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: Clc1ccc(CCCCn2ccnn2)nn1
Reactant: OCc1coc(C=Cc2ccc(Cl)cc2F)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)ccc1C=Cc1nc(COc2ccc(CCCCn3ccnn3)nn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.100 g, 0.40 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.043 g, 0.43 mmol). After stirring for 15 min at r.t. 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine (0.075 g, 0.32 mmol) is added slowly and stirred for further 4 h at 60° C. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 98:2) 3-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine is isolated as a colorless solid. Yield 0.105 g (73%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[C:4]=2[CH:3]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:26][C:22](=[O:25])[CH2:23][CH2:24][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:8]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=3[S:6][CH:7]=2)[C:11]1=[O:19])[CH3:28]
Reactant: O=c1[nH]c2ccccc2n1Cc1csc2ccc(Cl)cc12
Reactant: C=CC(=O)OCC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.16 mmol) in DMF (2 mL) were added ethyl acrylate (0.02 mL) and benzyltrimethyl ammonium hydroxide (20 mg, 0.01 mmol). The resulting mixture was stirred at room temperature overnight. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 50 mg of the desired product as a colorless oil. LCMS (ESMS): m/z 415.78 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:27]=[CH:26][C:13]([CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[O:3]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH2:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:6]2[C:5]3[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=3[O:3][C:2]2=[O:1])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22])[CH3:20]
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve the compound obtained in Example 2 (0.5 g) in absolute ethanol (6.5 ml) and add tetrahydrofuran (2 ml). Subsequently, cool the reaction mixture using an ice bath and add 2N sodium hydroxide (0.7 ml). Stir magnetically for 18 hours at ambient temperature. Remove the absolute ethanol/tetrahydrofuran mixture by evaporation under reduced pressure. Take up the resulting residue in water and extract twice with 50 ml of ether each time. Acidify the aqueous phase with a 6N hydrochloric acid solution until a pH of 1 is obtained, then extract twice with 50 ml of ether each time. Dry the organic phase over magnesium sulphate and remove the ether by evaporation under reduced pressure.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:12]([N:16]4[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:31])=[O:5])[CH2:3][CH2:2]1.[Cl-].[NH4+].O1CCCC1.C(O)C>[Fe].O>[NH2:21][C:19]1[CH:18]=[N:17][N:16]([C:12]2[C:11]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[C@@H:7]([CH3:31])[CH2:8][CH2:9]3)[CH:20]=1
Reactant: C[C@H]1CCc2c(ccc(-n3cc([N+](=O)[O-])cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@H]1CCc2c(ccc(-n3cc(N)cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of (S)-cyclopropyl(2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (0.060 g, 0.15 mmol), iron powder (0.040 g, 0.72 mmol), ammonium chloride (0.023 g, 0.43 mmol), tetrahydrofuran (4 mL), ethanol (4 mL), and water (1 mL) stirred overnight at 80° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative thin layer chromatography (eluting with 1:1, ethyl acetate/petroleum ether) to afford (S)-(6-(4-amino-1H-pyrazol-1-yl)-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.045 g, 81%) as a brown solid. MS (ESI, pos. ion) m/z 389 [M+H]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([O:16][C:17]([CH3:56])([CH3:55])[C:18]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]#[N:48])=[CH:37][CH:36]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]3[N:52]=[CH:53][CH:54]=[C:28]23)[CH2:23][CH2:22]1)=[O:19])(=[O:15])[CH3:14]>C(OCC)(=O)C>[C:13]([O:16][C:17]([CH3:55])([CH3:56])[C:18]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[C:32](=[O:33])[C:31]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[C:47]4[NH:3][C:4](=[O:7])[O:5][N:48]=4)=[CH:39][CH:40]=3)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]3[N:52]=[CH:53][CH:54]=[C:28]23)[CH2:23][CH2:22]1)=[O:19])(=[O:15])[CH3:14]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(=O)C(C)(C)OC(C)=O)CC2)c2ccnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(=O)C(C)(C)OC(C)=O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogen carbonate (1.0 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C. for 30 min, trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl 2-(acetyloxy)-2-methylpropanoate (0.67 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.28 g, 55%).
Reaction SMILES: C1C2C(COC([CH2:18][C:19]([N:21]3[CH2:25][C:24]([F:27])([F:26])[CH2:23][C@@H:22]3[C:28]([O:30]C)=O)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:32]1CCCCC1>CO>[F:26][C:24]1([F:27])[CH2:25][N:21]2[C:19](=[O:20])[CH2:18][NH:32][C:28](=[O:30])[C@@H:22]2[CH2:23]1
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H]1CC(F)(F)CN1C(=O)CC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CO
Product: O=C1NCC(=O)N2CC(F)(F)C[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate (1.10 g, 2475 μmol) and 25 mL MeOH. Piperidine (1225 μl, 12375 μmol) was added, and the mixture was stirred at RT overnight. The mixture was concentrated and purified by silica gel chromatography, DCM in 90/10 DCM/MeOH to provide (S)-7,7-difluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione as a white solid. GC/MS: [M+H]=191.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:18])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])C.[Li+].[OH-].O>C1COCC1.CO>[CH3:18][N:9]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(C(=O)O)c1Oc1ccccc1

Procedure:
1-Methyl-5-phenoxy-1H-pyrazole-4-carboxylic acid ethyl ester (22.55 g; 91.37 mmol) was dissolved in THF/MeOH (1/1) and LiOH in water (7.67 g; 182.73 mmol) was added. After 16 hours at ambient temperature the reaction mixture was washed with EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with EtOAc which was dried and evaporated afterwards.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:28])=[O:17])=[CH:14][C:13]=1[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1C(C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3.0 g of product from Example 131 in 30 ml of methylene chloride plus 2 drops of dimethylformamide is added 2.0 ml of oxalyl chloride via syringe. The reaction is stirred at room temperature for 18 hours, concentrated in vacuo, dissolved in diethyl ether and filtered through a pad of diatomaceous earth. The diethyl ether is concentrated in vacuo to give 3.15 g of the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][OH:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[H-].[Na+].Br[CH2:30][C:31](OC(C)(C)C)=[O:32].CC(C[AlH]CC(C)C)C>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][O:26][CH2:30][CH2:31][OH:32])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(COCCO)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.28 mmol) of 1-9 in 3 mL of DMF at 0° C. was added 20 mg of NaH (0.6 mmol of a 60% suspension in oil), followed by 80 μL (0.6 mmol) of tert-butyl bromoacetate. After stirring for 2 h at 0° C., the reaction was quenched with a saturated NH4Cl solution, and extracted twice with EtOAc. The combined organic layers were then washed with brine, dried over Na2SO4, concentrated, and the residue purified by silica gel chromatography with EtOAc/hexanes to provide a colorless oil. This residue was dissolved in 10 mL of CH2Cl2, cooled to −78° C., and 900 μL of a 1M DIBAL-H solution in CH2Cl2 was added dropwise. After stirring for 45 min, the reaction was quenched with 500 μL of acetone, the cooling bath was removed, 15 mL of a 0.5 M tartaric acid solution was added, and the biphasic mixture was stirred for 1 h. The layers were separated, the organic was washed with water, dried over Na2SO4, and concentrated: The residue was then dissolved in 5 mL of THF and 1 mL of MeOH, and a small amount of NaBH4 was added. After stirring for 15 min, the reaction was quenched with 1M HCl, extracted twice with EtOAc, washed with brine, dried over Na2SO4, concentrated, and the residue purified by silica gel chromatography with EtOAc/hexanes to provide 2-2 as a sticky white taffy. Data for 2-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.4 (s, 1H), 4.8-4.6 (m, 3H), 4.2 (d, 1H), 3.8-3.7 (m, 2H), 3.7-3.5 (m, 2H), 2.85 (s, 6H) ppm. HRMS (ES) calc'd M+H for C22H24F2N2O3: 403.1828. Found: 403.1824.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:12]C1C=CC(C(O)=O)=NC=1.FC1N=C(C(O)=O)C=CC=1>>[CH3:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([NH:10][NH2:11])=[O:9])=[N:7][CH:2]=1
Reactant: Cc1ccc(C(=O)O)nc1
Reactant: NNC(=O)c1cccc(F)n1
Agent: O=C(O)c1cccc(F)n1
Product: Cc1ccc(C(=O)NN)nc1

Procedure:
5-Methyl-2-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 5-methyl-2-pyridinecarboxylic acid (5-methylpicolinic acid, CAS [4434-13-3], commercially available e.g. from Allichem or Ryan Scientific) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C:4]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[CH:3]1.[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[C@@H:29]1[CH2:31][O:30]1>C(O)C>[OH:30][C@H:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:28])[O:25][CH2:26][C:27]=2[C:19]=1[CH3:18])[CH2:31][N:14]1[CH2:13][CH2:12][C:9]2([C:8](=[O:17])[N:7]([C:4]3[CH2:5][O:6][C:2](=[O:1])[CH:3]=3)[CH2:11][CH2:10]2)[CH2:16][CH2:15]1
Reactant: O=C1C=C(N2CCC3(CCNCC3)C2=O)CO1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCC3(CC2)CCN(C2=CC(=O)OC2)C3=O)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-16, 200 mg, 0.846 mmol) was combined with 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4B) (177 mg, 0.931 mmol) in ethanol (5 mL) and heated in a microwave apparatus at 145° C. for 3 hours. The solvent was removed and the residue was purified by preparative TLC, eluting with 25% methanol/EtOAc to afford the title compound. LC-MS (IE, m/z): 427 (M+1)+.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[C:9]1[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)([OH:24])=[O:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: Cc1c(-n2ccnc2)n(CCCCCC=O)c2ccccc12
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1c(-n2ccnc2)n(CCCCCC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Formylpentyl)-3-methyl-2-(1-imidazolyl)indole (115 mg) is dissolved in dimethylformamide (1.0 ml) and pyridinium dichromate (300 mg) added all at once. The mixture is stirred overnight at room temperature, then diluted with chloroform, and the combined filtrate is extracted with 0.1N aqueous sodium hydroxide (2 ml). The aqueous extract is acidified to about pH 5.5-6.0 and extracted with chloroform. The chloroform extract is dried and concentrated in vacuo. Purification by chromatography on silica gel yields 1-(5-carboxypentyl)-2-(1-imidazolyl)-3-methylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][C@H:15]1[NH:23][C:24]([C:26]1[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=1)=[O:25])=[O:12])=[CH:5]2.Cl.[CH3:37][NH:38][CH3:39].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([N:38]([CH3:39])[CH3:37])=[O:22])[CH2:16][C@H:15]1[NH:23][C:24]([C:26]1[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=1)=[O:25])=[O:12])=[CH:5]2
Reactant: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 153.7 %

Procedure:
The compound (900 mg) obtained in Example 58 was dissolved in N,N-dimethylformamide (50 ml), to which dimethylamine hydrochloride (304 mg), 1-hydroxybenzotriazole monohydrate (262 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (369 mg) and diisopropylethylamine (1.83 ml) were added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to conduct extraction with methylene chloride. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (methylene chloride:methanol=47:3). The thus-obtained white solids were dissolved in methylene chloride, to which 1N ethanol solution (1.49 ml) of hydrochloric acid was added. The solvent was distilled off under reduced pressure, and methanol and diethyl ether were added to the residue to collect precipitate formed by filtration, thereby obtaining the title compound (777 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>C1COCC1.O>[F:25][C:24]1[C:23]([F:26])=[CH:22][CH:21]=[C:20]([N+:27]([O-:29])=[O:28])[C:19]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To a solution of aniline (1.6 g, 16.9 mmol) in THF (40 mL) at −78° C. was added LiHMDS (34 mL, 1M, 33.9 mmol) and the reaction mixture stirred at −78° C. for 10 min. This solution was added via cannula to a solution of 2,3,4-trifluoronitrobenzene (3 g, 16.9 mmol) in THF (10 mL) at −78° C. and the dark purple reaction mixture stirred at −78° C. for 30 min. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo to give the title compound as a dark orange solid (4.2 g, 100%). 1H NMR 400 MHz δ (CDCl3): 8.95 (1H, br s), 8.00 (1H, ddd, J=9.7, 5.4, 2.3 Hz), 7.31-7.25 (2H, m), 7.13-7.08 (1H, m), 7.04-6.99 (2H, m), 6.75-6.67 (1H, m).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@H:8]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][C:13]3=[O:21])[CH2:9][CH2:10][C@@H:2]12.Cl[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.Cl>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@H:8]([CH2:11][N:12]4[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=5[O:14][C:13]4=[O:21])[CH2:9][CH2:10][C@H:2]3[CH2:1]2)=[N:24][CH:25]=1
Reactant: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Agent: Cl
Product: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1

Procedure:
The title compound was synthesized according to Preparation 11 from 3-[(7R,9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]-pyrazin-7-ylmethyl]-3H-benzoxazol-2-one (Preparation 12) and 2,5-dichloropyridine. mp (.HCl) 247–248° C. HRMS calcd for C21H23ClN4O2: 398.1510, found: 398.1484.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:21]([S:23]([C:26]1[CH:27]=[CH:28][C:29]2[O:33][C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:31][C:30]=2[CH:40]=1)(=[O:25])=[O:24])[CH3:22]>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:37]2[CH2:38][CH2:39][N:34]([C:32]3[O:33][C:29]4[CH:28]=[CH:27][C:26]([S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:40][C:30]=4[N:31]=3)[CH2:35][CH2:36]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: CCS(=O)(=O)c1ccc2oc(N3CCNCC3)nc2c1
Agent: Cl
Product: CCS(=O)(=O)c1ccc2oc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC4CCCC4)CC3)nc2c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example 2.3) and 5-ethanesulfonyl-2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate) to yield the title compound as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[C:30]([Cl:47])(=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[ClH:47].[C:30]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:16]([CH3:22])[CH:17]=1)(=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: Cc1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(OC2CCNCC2)c(C)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-4-(4-amino-2-methylphenyloxy)piperidine (1.5 g) in methylene chloride (30 ml) were added triethylamine (1.3 g) and palmitoyl chloride (1.2 g) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Aqueous saturated solution of sodium bicarbonate was added to the reaction mixture and the organic layer was separated. The aqueous layer was further extracted with methyene chloride (50 ml×2) and the combined orgnaic layer was dried over sodium sulfate and concentrated under reduced pressure. To the solidified residue was added trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 30 minutes. After concentration of the reaction mixture under reduced pressure, the resulting residue was dissolved in ethanol and conc. hydrochloric acid (0.37 ml) was added. The resulting solution was concentrated under reduced pressure and the residue was washed with hexane to obtain 4-(4-palmitoylamino-2-methylphenyloxy)piperidine hydrochloride (1.8 g) as white crystals, m.p. 125°-137° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=O)C.[CH3:21][NH:22][CH3:23]>>[CH3:21][N:22]([CH3:23])[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[N:7]=1)=[O:3]
Reactant: CNC
Reactant: CCOC(=O)c1nc(-c2cccc3ccccc23)no1
Product: CN(C)C(=O)c1nc(-c2cccc3ccccc23)no1
Reaction time: 1 h

Procedure:
5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (618 mg.) was dissolved in an ethanolic solution of dimethylamine (10 ml., 33% v/v). After 1 hr. The solution was evaporated leaving a residue that was recrystallised from methanol (3.5 ml.) to give title compound (424 mg.,) m.p. 109°-110°, λmax. (EtOH) 302.5 nm (ε 9,400) νmax. (CHBr3) 1660 cm.-1 (CONMe2).