Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](N[C@@H]3CCNC[C@H]3CC)=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1.OC(C)(C)C(O)=O.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>ClCCl>[N:6]1[N:5]2[CH:22]=[CH:2][CH:3]=[C:4]2[CH:9]=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=1
Reactant: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CC(C)(O)C(=O)O
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: ClCCl
Product: NC(=O)c1cnn2cccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.8 %

Procedure:
To a solution of 6-bromo-4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (275 mg, 0.75 mmol) and 2-hydroxy-2-methylpropanoic acid (156 mg, 1.501 mmol) in dichloromethane (3.8 ml) were added DIEA (1.3 ml, 7.5 mmol) and HATU (571 mg, 1.501 mmol). The reaction was stirred at room temperature for 14 hrs. The product mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution) to yield 6-bromo-4-((3R,4R)-3-ethyl-1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)amino)pyrrolo-[1,2-b]pyridazine-3-carboxamide (240 mg, 0.531 mmol, 70.7% yield) as a white solid. LCMS (Method K) m/z 454.4 ([M+H]+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:18][CH:17]3[N:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[CH2:23]([O:22][C:20]([N:19]1[CH:14]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH2:13]2)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1CCN(C2CC3CCC(C2)N3C(=O)OCC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1C2CCC1CC(N1CCC(C(=O)O)CC1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Isomer 1 of ethyl 3-[4-(ethoxycarbonyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate (0.549 g, 1.62 mmol) was dissolved in THF (10 mL) at rt and 1 M LiOH sol. (1.62 mL) was added. The reaction mixture was stirred at rt for 2 days. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 1-[8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxylic acid
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH2:17][CH3:18])[C:14](O)=[O:15]>>[CH2:17]([CH:13]1[S:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11][C:14]1=[O:15])[CH3:18]
Reactant: CCC(Br)C(=O)O
Reactant: Cc1ccccc1NC(N)=S
Product: CCC1SC(Nc2ccccc2C)=NC1=O

Procedure:
Synthesis was performed from N-(2-methylphenyl)thiourea and 2-bromo-butyric acid according to Method C1.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:18](=[O:22])([O:20][CH3:21])[NH2:19]>C(OCC)C>[CH:5]([NH:19][C:18](=[O:22])[O:20][CH3:21])=[CH:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC=O
Reactant: COC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCC=CNC(=O)OC
Yield: 78.2 %

Procedure:
430 parts of n-valeraldehyde and 5 parts of p-toluenesulfonic acid are added in succession to a solution of 750 parts of methyl carbamate in 2,000 parts by volume of diethyl ether at 25° C. After a reaction time of one hour, in which the temperature rises to 40° C., filtration with suction and subsequent fractional distillation of the solid in the presence of 15 parts of potassium carbonate and 2 parts of hydroquinone give 559.1 parts of methyl N-(1-pentenyl)-carbamate (78.2% yield, based on n-valeraldehyde employed) as a cis/trans isomer mixture of boiling point 97°-102° C./16 mbar, and 352.5 parts of methyl carbamate, which can be re-used.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@@H:15]([CH3:16])[C@@H:14]([O:17][Si](C(C)(C)C)(C)C)[CH2:13][C:12]2=[O:25])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@@H:15]([CH3:16])[C@@H:14]([OH:17])[CH2:13][C:12]2=[O:25])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)C[C@H](O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-4-[(4S,5S)-4-(tert-butyldimethylsilyloxy)-5-methyl-2-oxopyrrolidin-1-yl]-3-methylbenzonitrile (500 mg) and tetrabutylammonium fluoride-THF solution (1.4 mL, 1 mol/L), and in the same manner as in Example 15, the title compound was obtained as a colorless solid (yield: 210 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:42](=[CH:43][CH:44]=1)[C:7]1=[CH:8][C:9]3[C:10]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:33]=4)(O)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)(O)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:46])[CH3:45].[I-].[K+].[PH2]([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:42](=[CH:43][CH:44]=1)[C:7]1=[CH:8][C:9]3[C:10]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:33]=4)=[C:11]4[C:16](=[C:17]([C:21]5[CH:30]=[CH:29][C:28]6[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=6)[CH:22]=5)[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:46])[CH3:45])[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(O)(c1ccc2ccccc2c1)c1ccccc1C3(O)c1ccc2ccccc2c1
Agent: O=[PH2][O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)c2cc(Br)ccc2-c2cc3c(-c4ccc5ccccc5c4)c4ccccc4c(-c4ccc5ccccc5c4)c3cc21
Reaction time: 5 h
Yield: 75.9 %

Procedure:
2-Bromo-13,13-dimethyl-6,11-di(naphthalen-2-yl)-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (5 g, 1 eq, 0.0075 mol), potassium iodide (12.45 g, 10 eq, 0.075 mol), and sodium hypophosphite (6 g, 5 eq, 0.037 mol) were placed in a flask, and acetic acid (200 ml) was added thereto. The reaction mixture was stirred for five hours while heating. After the reaction was terminated, the reaction solution was added to an excess of distilled water. The resultant solid was washed, filtered, and purified by column chromatography to give a target compound (3.56 g, yield=76%).
Reaction SMILES: C([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][CH:14]2[NH:19][C:20]([NH:22][CH2:23][CH2:24][F:25])=[O:21])(=O)C1C=CC=CC=1.[OH-].[Li+]>CO>[F:25][CH2:24][CH2:23][NH:22][C:20]([NH:19][CH:14]1[C:15]2[C:11](=[C:10]([OH:9])[CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:21]
Reactant: O=C(NCCF)NC1CCc2c(OC(=O)c3ccccc3)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCCF)NC1CCc2c(O)cccc21
Temperature: 25 °C

Procedure:
1-({[(2-fluoroethyl)amino]carbonyl} amino)-2,3-dihydro-1H-inden-4-yl benzoate (reported earlier, 230 mg, 0.67 mmol) was dissolved in MeOH (20 mL) and lithium hydroxide (900.00 mg, 37.58 mmol) was added. The resulting reaction mixture was refluxed for 4 hours and then cooled to room temperature. Concentration followed by the addition of HCl (10%, 10.00 mL) gave a precipitate. The solid was then washed with water, ether and then vacuum-dried to afford the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.53-1.68 (m, 1H) 2.27-2.41 (m, 1H) 2.47-2.61 (m, 1H) 2.70-2.85 (m, 1H) 3.24-3.39 (m, 2H) 4.31 (t, J=5.13 Hz, 1H) 4.47 (t, J=4.98 Hz, 1H) 4.97-5.10 (m, 1H) 6.03 (t, J=5.57 Hz, 1H) 6.25 (d, J=8.21 Hz, 1H) 6.58-6.72 (m, 2H) 6.97 (t, J=7.77 Hz, 1H) 9.24 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[CH:27][C:28](=[O:37])[N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=1>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:26]=[CH:27][C:28](=[O:37])[N:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1ccc(=O)n(-c2ccccc2)c1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc(=O)n(-c5ccccc5)c4)ncnc3[nH]2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (75 mg, 0.22 mmol) and 5-amino-1-phenyl-1H-pyridin-2-one (50 mg, 0.27 mmol) in 1-butanol (3 mL) was heated at 120° C. overnight, LC-MS showed the desired product together with some de-Boc product. After the mixture was cooled to rt, it was diluted with methylene chloride (3 mL), then N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) and di-tert-butyldicarbonate (49 mg, 0.22 mmol) were added. The resulting mixture was stirred at rt for 30 min. The mixture was diluted with EtOAc (30 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized with EtOAc/Hexane to give the title compound as a green solid. LC-MS (ES, Pos.): 485 [MH+], and 1H NMR (DMSO-d6, 400 MHz): δ 1.43 (s, 9H), 2.50 (m, 2H), 3.56 (m, 2H), 4.04 (m, 2H), 6.39 (s, 1H), 6.56 (d, J=9.7 Hz, 1H), 6.66 (s, 1H), 7.39-7.57 (m, 5H), 7.81 (dd, J=9.7, 2.7 Hz, 1H), 8.17 (s, 1H), 8.34 (d, J=2.7 Hz, 1H), 9.17 (s, 1H), 11.94 (br s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([S:11][CH2:12]C)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:12][S:11][C:9]1[O:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(SCC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(C(=O)O)o1
Temperature: 80 °C

Procedure:
To a solution of 2-ethylsulfanyl-oxazole-5-carboxylic acid ethyl ester (4.6 g, 24.57 mmol) in ethanol (100 mL) was added a 2 N solution of sodium hydroxide (37 mL, 74 mmol) in water. The mixture was heated at 80° C. for 4 hours and then concentrated in vacuo to remove the ethanol. The remaining aqueous solution was then acidified with 1 N HCl and extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate and concentrated to afford 2-methylsulfanyl-oxazole-5-carboxylic acid.
Reaction SMILES: [C:1]([C:9]1[C:10](C(=O)C2C=CC=CC=2)=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([NH2:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:9]1[CH:10]=[N:11][C:12](=[N:33][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:13](=[N:33][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:14]=1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)c1ccccc1
Reactant: Nc1cccc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(C1=C(C(=O)c2ccccc2)C(=Nc2cccc3ccccc23)C(=Nc2cccc3ccccc23)N=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TiCl4 (0.4 ml, 3.5 mmol) in toluene (20 ml) was added to a mixture of dibenzoylpyridine (0.91 g, 3.2 mmol) and 1-naphthylamine (2.90 g, 17 mmol) in toluene (50 ml) at 0° C. After the addition was complete, the reaction was stirred at room temperature for 1 hour and then under refluxed for 3 hours. The solid was filtered and washed with toluene. The solvent was removed under vacuum. The ligand was isolated after the column chromatography (hexane/ethyl acetate=5/1) to produce a yield of 0.65 g.
Reaction SMILES: N[C@H](C(NCCC(O)=O)=O)CC1C=CC=CC=1.C1C=CC(C[C@H](N)C(N[C@H](C(N)=O)CC2C=CC=CC=2)=O)=CC=1.[NH2:41][C@H:42]([C:50]([NH:52][C@H:53]([C:58]([OH:60])=[O:59])CC(C)C)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C[C@H](NC([C@@H](N)CC1C=CC=CC=1)=O)C(O)=O.N[C@H](C(N[C@H](C(O)=O)CC(=O)O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)CC1C=CC=CC=1>>[CH:47]1[CH:46]=[CH:45][C:44]([CH2:43][C@H:42]([NH2:41])[C:50]([NH:52][CH2:53][C:58]([OH:60])=[O:59])=[O:51])=[CH:49][CH:48]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Agent: C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Agent: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Agent: N[C@@H](Cc1ccccc1)C(=O)NCCC(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O

Procedure:
Phe-β-Ala (compound 12); Phe-Phe (compound 13); Phe-Leu (compound 14); Phe-Ala (compound 15); and Phe-Asp (compound 16): Phe-Tau (compound 17).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>>[C:12]1(=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccc2cccnc12
Product: O=C1c2ccccc2C(=O)N1c1cccc2cccnc12

Procedure:
Referring to the above equations, the starting 8-aminoquinoline I was treated with phthalic anhydride to give the 8-phthalimidoquinoline II. This was necessary to provide protection for the 8-amino group during peroxidation and introduction of the 2-chloro group. Thus compound II was treated with MCPBA, followed by chromatography over basic alumina to afford the 1-oxide III. Intermediate III was treated directly (preferred procedure) with phosphorus oxychloride to afford the 2-chloro derivative V. However, it was discovered also that treatment of the reaction mixture from the oxidation step with a combination of basic and neutral alumina gave the 2-quinolone IV which was converted also with phosphorus oxychloride to give the 2-chloro derivative V, albeit in lower yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[Cl:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:16]=1[CH2:27][OH:28]>CC(C)=O.C(N(CC)CC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:24]2[CH2:23][CH2:22][N:21]([C:19]3[CH:18]=[CH:17][C:16]([CH2:27][OH:28])=[C:15]([Cl:14])[CH:20]=3)[CH2:26][CH2:25]2)=[CH:8][CH:9]=1
Reactant: OCc1ccc(N2CCNCC2)cc1Cl
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(CCCN1CCN(c2ccc(CO)c(Cl)c2)CC1)c1ccc(Cl)cc1

Procedure:
A solution of 4,4'-dichlorobutyrophenone (4.5 g, 20.7 mmole) in 25 ml of acetone was added to a warm suspension of 2-chloro-4-(1-piperazinyl)benzenemethanol (4.7 g, 20.7 mole) in 50 ml acetone and 2.5 ml of triethylamine. The reaction mixture was refluxed for four days, cooled at -10° for three hours, and then filtered. The product was washed with a little acetone, triturated on the filter with water (four times, 50 ml), and air dried. Recrystallization from acetonitrile (65 ml) gave 3.0 g (35%), mp 137°-139°.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27](O)([CH2:34][C:35]([NH2:37])=[O:36])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:39])(=[O:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27](=[CH:34][C:35]([NH2:37])=[O:36])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:39])(=[O:16])=[O:17])([CH3:14])[CH3:13]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(O)(CC(N)=O)c3ccccc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=CC(N)=O)c3ccccc3)cc21
Yield: 35 %

Procedure:
A solution of 3.0 g. of p-toluenesulfonic acid and 3.0 g. of 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-aminocarbonylmethylbenzyl)benzimidazole (prepared as described in Example 23) in 100 ml. of chloroform was heated at reflux for four hours. The reaction mixture then was cooled, washed with aqueous sodium bicarbonate solution and with water, dried, and the solvent was removed by evaporation under reduced pressure. Crystallization of the product thus formed from tetrahydrofuran afforded 1.1 g. of trans-1-isopropylsulfonyl-2-amino-6-(α-aminocarbonylmethylenebenzyl)benzimidazole, M.P. 218°-219° C. Yield 35%, and 1.0 g. of the corresponding cis-isomer, M.P. 211°-212° C., yield 32%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C:23](N5CCOCC5)=[O:24])[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:31])[CH2:3][CH2:2]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][CH:23]([OH:24])[CH3:32])[CH2:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:31])[CH2:3][CH2:2]1
Reactant: O=C(COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1)N1CCOCC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)COC1CCc2oc(-c3ccc(OCC4CC4)c(F)c3)nc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-5-yl)oxy)-1-(morpholin-4-yl)ethanone (4.36 g) in THF (25 mL) was added methylmagnesium bromide (1 M THF solution, 15.2 mL), and the reaction mixture was stirred at room temperature for 10 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in a mixed solvent of THF (10 mL)-methanol (10 mL) was added sodium tetrahydroborate (383 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.48 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][CH:6]=1.[ClH:22]>>[ClH:22].[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1
Agent: Cl
Product: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1

Procedure:
N-[4-(2-fluoro-4-nitrophenoxy)phenyl]-acetamide (1.00 g, 3.45 mmol) was added to 6 M hydrochloric acid (10 mL), and the resulting solution was refluxed for 2 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 0.910 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@H:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1>[C:26]([O:30][C:31](=[O:32])[NH:33][C@H:34]([CH:38]([CH3:39])[CH3:40])[C:35]([NH:23][NH:22][C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]1[CH:16]=[N:17][C:13]([C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)=[N:14]1)=[O:36])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.05 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.038 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.16 mL, 2 eq.) was added dropwise followed by DIPEA (0.095 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (R,Z)-tert-butyl(1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.017 g, yield: 26%). In a 10 mL round-bottom flask, (R,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.2 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.02 g), which was triturated with petroleum ether and dried under reduced pressure to yield (R,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.007 g, yield: 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3ccc(Cl)cc3)s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(-c3ccc(Cl)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 59.8 %

Procedure:
A mixture of ethyl 4-[5-(4-chlorophenyl)-2-thienyl]benzoate (1.03 g), 1 M aqueous sodium hydroxide solution (4.5 ml), tetrahydrofuran (30 ml) and ethanol (30 ml) was stirred at 60° C. for 1.5 hrs. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (15 ml) was added. The crystals were collected by filtration and recrystallized from ethanol to give 4-[5-(4-chlorophenyl)-2-thienyl]benzoic acid (0.566 g, yield 60%) as a pale-green crystalline powder. melting point: 285–286° C.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][O:14]C2CCCCO2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O1CCCC1.O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[C:1]1([O:11][CH2:12][CH2:13][OH:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cc2c(c(OCCOC3CCCCO3)c1)CCCC2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OCCOc1cccc2c1CCCC2
Reaction time: 3.5 h
Yield: 44.2 %

Procedure:
A solution of 700 mg (2.54 mmol) of the title product of Example 58 in a mixture of 9 ml of acetic acid, 3 ml of tetrahydrofuran, and 3 ml of water was stirred at 85°-90° C. After 3.5 hours, 4 drops of concentrated sulfuric acid were added and stirring continued for an additional one-half hour. The mixture was permitted to cool, and 4 g of sodium carbonate monohydrate was added. The resulting mixture was partitioned between diethyl ether and water. The organic layer was washed repeatedly with saturated aqueous sodium bicarbonate, with water, and then with brine. The solution was dried over magnesium sulfate, the drying agent was removed by filtration, and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel, using 15% ethyl acetate/toluene as eluent, gave 216 mg of the title compound.