Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([N:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:31]2=[O:37])=[N:27][C:26]=1[CH3:38])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([N:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]3[O:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=4)=[N:6][N:7]=3)=[CH:32][C:31]2=[O:37])=[N:27][C:26]=1[CH3:38])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1nnc(-c2ccc(Cl)cc2)o1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCc3nnc(-c4ccc(Cl)cc4)o3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-(chloromethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 32% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.80 (t, J=5.8 Hz, 1H), 8.65 (d, J=7.8 Hz, 1H), 8.0 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 7.32-7.19 (m, 5H), 6.46-6.39 (m, 2H), 5.60 (s, 2H), 4.38 (d, J=5.8 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 534.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]=2[CH2:33][C:34]([CH3:41])([CH3:40])[C:35]([O:37]CC)=[O:36])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]=2[CH2:33][C:34]([CH3:41])([CH3:40])[C:35]([OH:37])=[O:36])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3ccccn3)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)c1c(CC(C)(C)C(=O)O)c(C(=O)c2ccc(Cl)cc2)n2ccc(OCc3ccccn3)cc12
Temperature: 23 °C
Yield: 86 %

Procedure:
A solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(pyridin-2-ylmethoxy)indolizin-2-yl}-2,2-dimethylpropanoate (98 mg, 0.17 mmol) in THF (1 mL), MeOH (1 mL), and 6M aqueous NaOH (0.75 mL) is heated at 50° C. for 3 h then cooled to 23° C. and acidified to pH=1 with concentrated aqueous HCl. The mixture is partitioned between CH2Cl2 and brine then the organics are collected and dried with MgSO4, filtered, and concentrated in vacuo to afford the title compound (80 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[CH:5]=[C:4]([CH3:15])[CH:3]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Cl)nc(NC(=O)C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(N)nc(Cl)c1
Yield: 81.6 %

Procedure:
A solution of N-(6-chloro-4-methylpyridin-2-yl)pivalamide (500 mg, 2.21 mmol) in HCl (40 mL, 6 M) was stirred for 6 hours at 90° C. The mixture was cooled to room temperature and neutralized with NaOH to pH 10. The mixture was extracted with ethyl acetate, evaporated under vacuum, and purified by chromatography on silica gel (5% ethyl acetate in petroleum ether) to afford 6-chloro-4-methylpyridin-2-amine (257 mg, 82%). 1H NMR (CDCl3, 300 MHz) δ 6.52 (s, 1H), 6.26 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:31][CH2:30][N:29](C(OCCCC)=O)[CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.ClCCl>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CCCCOC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Tert-butyl 4-((3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamido)methyl)-4-phenylpiperidine-1-carboxylate (˜1.80 g, ˜2.84 mmol, described in Example 1) was dissolved in trifluoroacetic acid/dichloromethane (1:5, mL). This mixture was stirred at 23° C. for 2 hours, then neutralized with sat. sodium carbonate to pH˜7. The aqueous phase was then extracted with ethyl acetate/THF and the combined organic layers were dried over anhydrous magnesium sulfate to give the title material (1.06 g, 70%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.99-2.09 (2H, m), 2.28 (2H, br s), 2.31 (3H, s), 2.66-2.82 (2H, m), 3.25 (2H, m), 3.45 (2H, br d), 6.86 (1H, d, J=5.31 Hz), 6.93 (1H, s), 7.05 (1H, t, J=5.18 Hz), 7.26-7.34 (1H, m), 7.38-7.46 (4H, m), 7.81 (1H, s), 8.17 (1H, d, J=5.31 Hz), 8.23 (1H, d, J=5.05 Hz), 8.37 (1H, t, J=6.44 Hz), 11.84 (1H, s). LC/MS (M+H)+: 535. HPLC ret. time (Condition C): 4.085 min.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH2:13].[NH:14]1[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[N:15]1>>[S:1]1[C:5]2[CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[N:3]=[C:2]1[NH:13][C:19]([C:17]1[CH:18]=[N:14][NH:15][CH:16]=1)=[O:20]
Reactant: O=C(Cl)c1cn[nH]c1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1cn[nH]c1
Yield: 42.1 %

Procedure:
Acylation 8H-Indeno[1,2-d]thiazol-2-ylamine 1b (Prepared in Example 1, Step 2, 377 mg; 2.00 mmol) with 4-pyrazolecarbonyl chloride 12 (208 mg; 1.6 mmol) in a manner similar to that described in Example 7, provided 190 mg of 1H-Pyrazole-4-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide 13 as a dark powder.
Reaction SMILES: C([N:4]1[C:8]2=[CH:9][C:10]([CH3:12])=[N:11][N:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=[N:5]1)(=O)C.[OH-].[Na+].Cl>CO>[CH3:12][C:10]1[CH:9]=[C:8]2[N:4]=[N:5][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[N:7]2[N:11]=1
Reactant: CC(=O)n1nc(-c2cccc([N+](=O)[O-])c2)n2nc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2n(n1)C(c1cccc([N+](=O)[O-])c1)N=N2

Procedure:
500 mg (1.75 mmol) of 1-acetyl-6-methyl-3-(3-nitro-phenyl)pyrazolo[5,1-c][1,2,4]triazole are mixed with 7 ml of methanol and 3 ml of 2N sodium hydroxide solution and heated at boiling point until a clear solution is produced, then cooled down and acidified with 2N hydrochloric acid. The precipitate formed is filtered off under suction, washed neutral with water and then washed with a little methanol and a little ethyl acetate. After recrystallisation from DMSO, 400 mg (94%) of 6-methyl-3-(3-nitro-phenyl)pyrazolo[5,1-c][1,2,4]triazole with a m. pt. of 269°-275° C. (decomposes from 247° C.) are obtained.
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[NH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O>[N:11]1([N:10]2[CH:7]=[CH:6][C:4](=[O:5])[C:3]([OH:9])=[C:2]2[CH3:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1occc(=O)c1O
Reactant: NN1CCCCC1
Solvent: O
Product: Cc1c(O)c(=O)ccn1N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Maltol (3.6 g, 30 mmol) and 1-aminopiperidine (4.5 g, 45 mmol) were suspended in 100 mL of water. The mixture was heated to reflux for 2 days. The mixture was cooled to room temperature, and the solvent was removed under vacuum to give a dark brown liquid. The residue was allowed to stand overnight, a solid was formed. The solid was collected by filtration and was then recrystallized in water to give brownish microcrystals. The product was collected by filtration, washed with water, and dried under vacuum overnight. The yield was 0.64 g (˜10.2%). LC-MS: M/z=209.3 for [C11H16N2O2]+. 1H NMR (600 MHz, in CD3OD, chemical shift in ppm relative to TMS): 1.34 (m, 1H, CH2); 1.81 (m, 5H, CH2); 2.40 (s, 3H, CH3); 3.00 (m, 4H, CH2); 6.43 (d, 1H, JHH=7.5 mHz, CH2/pyridinone); and 7.99 (d, 1H, JHH=7.5 mHz, CH/pyridinone).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:25]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Reaction time: 6 h
Yield: 49.6 %

Procedure:
(4-Bromo-phenyl)-tert-butoxycarbonylamino-acetic acid (780 mg, 2.4 mmol) was dissolved in N,N-dimethylformamide (15 mL) and to this was added potassium hydrogen carbonate (260 mg, 2.6 mmol) followed by benzyl bromide (281 μL, 2.4 mmol) and stirring continued at ambient temperature for 6 hours. The reaction was poured into water (50 mL) and extracted with ethyl acetate (2×60 mL). The organic extracts were washed with water (2×20 mL), brine, dried over sodium sulfate and filtered through a layer of silica gel. The filtrate was concentrated in vacuo and the residue crystallized from 100% hexane to give (4-bromo-phenyl)-tert-butoxycarbonylamino-acetic acid benzyl ester (500 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:7]1[N:8]=[CH:9][C:10]([NH:13]C(=O)C(C)(C)C)=[N:11][CH:12]=1)([O:5][CH3:6])[CH3:4].[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)([O:5][CH3:6])[CH3:4]
Reactant: COC(C)(OC)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(C)(OC)c1cnc(N)cn1
Temperature: 25 °C
Reaction time: 63 h

Procedure:
A solution of N-[5-(1,1-dimethoxy-ethyl)-pyrazin-2-yl]-2,2-dimethyl-propionamide (1.73 g, 6.47 mmol) in ethanol (13 mL) was treated with a 2N aqueous sodium hydroxide solution (11 mL, 22 mmol). The reaction was stirred at 25° C. for 63 h and then was heated at 65° C. for 1.5 h. The reaction mixture was then diluted with ethyl acetate (200 mL) and washed with a saturated aqueous sodium chloride solution (75 mL). The aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4% methanol/methylene chloride) afforded impure 5-(1,1-dimethoxy-ethyl)-pyrazin-2-ylamine as a yellow solid. This material was re-purified via Biotage chromatography (FLASH 40L, Silica, 7/3 ethyl acetate/hexanes) to afford still impure 5-(1,1-dimethoxy-ethyl)-pyrazin-2-ylamine as a light yellow solid (880.4 mg, 74%) which used without further purification and characterization.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][CH:12]([CH3:15])[CH:13]=[CH2:14]>>[OH:4][C:3]([C:5]([F:8])([F:7])[F:6])([C:2]([F:10])([F:9])[F:1])[CH2:14][CH:13]=[C:12]([CH3:15])[CH3:11]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=CC(C)C
Product: CC(C)=CCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 125 °C

Procedure:
A stirred mixture of hexafluoroacetone (235 g) and 3-methylbut-1-ene (100 g) was heated at 125° C. under a pressure of 17 atmospheres for a period of 20 hours. Distillation of the product mixture under reduced pressure yielded 5-hydroxy-2-methyl-6,6,6-trifluoro-5-trifluoromethylhex-2-ene as a mobile colourless liquid, b.p. 43° C./15 mm Hg.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH:17]=[CH:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][S:12][CH:11]2[CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(O)c1cccc(C=CCC2SCC(=O)N2CCC2(O)CCCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)c1

Procedure:
3-{3-[3-[2-(1-Hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propenyl}benzoic acid (7.8 g., 0.02 mole) (the compound of Example 11) in ethanol (125 ml.) is hydrogenated over 2.5 g. of a 5% Pd on charcoal catalyst at 1 atmosphere pressure and 27° C. When the theoretical amount (0.02 mole) of hydrogen has been absorbed, the catalyst is filtered off, the solvent evaporated, and the residue chromatographed on silica gel with 4% methanol in chloroform as the eluant. The title compound is obtained as a colorless, viscous oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:9][CH:8]=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].O>CN(C)C=O>[CH2:35]([O:34][C:33]([N:15]([CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=1)[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:37])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: COCOc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(CC(Cc1cccnc1)c1ccc(OCOC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 19 h
Yield: 79.1 %

Procedure:
The portion of 120 mg of 60% sodium hydride were suspended in 10 ml of dimethylformamide, and cooled to 0° C., followed by dropwise addition of 1.22 g of N-[2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide, and then followed by addition of 326 mg of ethyl chlorocarbonate. After stirring at room temperature for 19 hours, the reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from the fraction eluted with methylene chloride was obtained 1.12 g of N-ethoxycarbonyl-N-[2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(O)CCC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CCC(=O)O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3-piperidin-4-yl-propionic acid (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C37H45Cl2N4O4 [(M+H)+] 679.2813, observed 679.2814.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([O:11][CH2:12]/[C:13](/[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)=[C:14](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)\[C:15]([OH:17])=[O:16])=[O:10].[CH2:34](I)[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([O:11][CH2:12]/[C:13](/[C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1)=[C:14](/[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)\[C:15]([O:17][CH2:34][CH3:35])=[O:16])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCCCCBr)=C(/C(=O)O)c2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C(\COC(=O)OCCCCCCBr)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2.6 g of (2Z)-4-({[(6-bromohexyl)oxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of DMF at rt was added 3.8 mL of ethyl iodide and 670 mg of potassium carbonate under nitrogen. The reaction was stirred for 1 h, quenched by saturated aqueous NH4Cl, extracted with EtOAc, washed with water (3×), brine, and dried over sodium sulfate. Purification by flash chromatography afforded 1.86 g of the titled compound as a brownish oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>O.C(Cl)Cl>[CH3:16][C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[O:20]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cccc(C(=O)Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C(=O)NNC(=O)OC(C)(C)C)c1C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
T-butylcarbazate (35.15 g, 266 mmol) and 200 mL of CH2Cl2 were added to a round bottom flask. Potassium carbonate (55.2 g, 0.4 moles) dissolved in 350 mL of water was added to the flask, and the mixture was stirred for 15 minutes with ice chilling. 2,3 dimethylbenzoyl chloride (44.9 g, 266 mmol) in ca. 200 mL of CH2Cl2 was added drop-wise from a 500 mL separatory funnel over 30 minutes. The reaction was allowed to stir overnight and then the reaction mixture was poured into a 1 L separatory funnel and the CH2Cl2 phase was separated. Then ca. 150 mL of water was added, and the mixture was extracted twice with 150 mL of CHCl3. The combined organic phase was back-extracted with 100 mL of water, then with 1N HCl (250 mL), to remove the hydrazide. The organic phase was dried, stirred with charcoal, and the solvent removed in vacuo to yield a light tan solid (71.5 g) of N′-(2,3-dimethyl-benzoyl)-hydrazinecarboxylic acid, tert-butyl ester. 1H NMR (300 MHz, CHCl3) δ (ppm): 7.7 (br, 1H), 7.22 (m, 2H), 7.1 (t, 1H), 7.85 (br, 1H), 2.35 (s, 3H), 2.3 (s, 3H), 1.5 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:21][CH:22]([CH2:28][CH3:29])[C:23]([O:25]CC)=[O:24]>>[CH3:34][O:33][C:32]1[CH:31]=[CH:30][C:20]([CH2:21][CH:22]([CH2:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:19][C:18]=1[CH2:17][NH:16][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Product: CCC(Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2OC)c1)C(=O)O
Yield: 62.6 %

Procedure:
0.24 g of 2-methoxy-4-(trifluoromethyl)benzoic acid and 0.3 g of ethyl 2-[3-(aminomethyl)-4-methoxybenzyl]butanoate were treated in the same manners as in Example 19d) and then in Example 19e), to give 0.3 g of 2-[4-methoxy-3-({[2-methoxy-4-(trifluoromethyl)benzoyl]amino}methyl)benzyl]butanoic acid as a pale yellow oil.
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH2:20]([NH2:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[F:18][C:13]1[CH:12]=[C:11]([CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[C:3]([NH:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: COC(=O)C(c1ccc(F)c(F)c1)c1ccccn1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)C(c1ccc(F)c(F)c1)c1ccccn1

Procedure:
The title compound, amorphous, MS: m/e=333.3 (M+H+) was prepared in accordance with the general method of example 22(a) from (RS)-2-(3,4-difluoro-phenyl)-2-pyridin-2-yl-acetic acid methyl ester and hexylamine.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](O)=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1.Cl.[CH3:23][O:24][NH2:25]>>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([NH:25][O:24][CH3:23])=[O:15])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: CON
Reactant: O=C(O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Agent: Cl
Product: CONC(=O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1

Procedure:
The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and O-methyl hydroxylamine hydrochloride in analogy to step (c) of example 1. 1H NMR (CD3OD) δ: 8.80 (s, 1H), 8.33 (s, 1H), 7.64 (d, 1H, J=3.0 Hz), 7.24-7.27 (m, 1H), 6.96-7.08 (m, 2H), 6.74 (d, 1H, J=3.0 Hz), 5.62 (s, 2H) 3.85 (s, 3H). LCMS (API-ES, M+H+): 318.0. HRMS calcd for C16H14F2N3O2. (M+H) 318.1054, found 318.1045. Anal. (C16H13F2N3O2) C, H, N. HPLC: 99.6% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][N:12]=[C:13]([C:15]2[C:16]3[CH:17]=[CH:18][NH:19][C:20]=3[CH:21]=[CH:22][CH:23]=2)[NH2:14])=O)[CH:5]=[N:6][C:7]=1[Cl:8]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][N:12]=[C:13]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][NH:19]4)[N:14]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: NC(=NOC(=O)c1cnc(Cl)c(Cl)c1)c1cccc2[nH]ccc12
Solvent: C1COCCO1
Product: Clc1cc(-c2nc(-c3cccc4[nH]ccc34)no2)cnc1Cl
Yield: 79.5 %

Procedure:
N2-{[(5,6-Dichloropyridin-3-yl)carbonyl]oxy}-1H-indole-4-carboxamidine (1.91 g) was added to dioxane (40 ml), followed by heating under reflux for 5 hours. It was concentrated under reduced pressure, and then purified by silica gel column chromatography (EtOAc). To the obtained solid was added acetone, followed by suspension under heating. After being left to be cooled, the insolubles was collected by filtration to obtain 4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-1H-indole (1.44 g) as pale yellow powders.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11]([C:13]2[N:14]=[CH:15][O:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH:7]=[N:6]1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[O:2]=[CH:3][CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11]([C:13]2[N:14]=[CH:15][O:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH:7]=[N:6]1
Reactant: COC(Cn1cc(NC(=O)c2ncoc2-c2cccc(C)c2)cn1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC=O)c2)c1
Temperature: 80 °C

Procedure:
To N-(1-(2,2-dimethoxyethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (800 mg, 2.25 mmol) in THF (11.5 mL), 2 N aq. HCl-solution (10.3 mL, 20.60 mmol) was added dropwise and the resulting solution was refluxed (80° C.) for 1.5 h. The reaction mixture was allowed to reach rt, then neutralized with sat. aq. NaHCO3-solution and the org. solvent was removed under reduced pressure. The remaining aq. layer was extracted with EtOAc (2×) and the combined org. layer were washed with brine, dried (MgSO4), filtered and concentrated to obtain the title compound as a yellow solid which was used immediately in the next step. LC-MS conditions C: tR=0.72 min, [M+H2O+H]+=329.09.