Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[K+].S(=O)(=O)(O)[OH:15].[OH-].[Ca+2].[OH-]>O>[N+:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[OH:15])([O-:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Ca+2]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1O
Temperature: 55 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
159.1 g (1 mol) of 2,4-difluoronitrobenzene and 550 g of water are initially introduced and are heated to 55° C. With vigorous stirring, 241.2 g (2.15 mol) of 50% strength potassium hydroxide solution are added dropwise over 4 hours and the temperature is maintained at 55° C. (exothermic reaction). Stirring is then continued for another 2 hours at this temperature. The pH is then adjusted to 4.3 (25° C.) using 88 g of sulfuric acid, and 74.1 g of calcium hydroxide are added. The pH is readjusted to 5.0 and the introduction of steam is started. During distillation the pH is decreased from 5 to 1.5 by dropwise addition of sulfuric acid. The product is isolated by cooling and filtering the distillate. After drying, 117.9 g (0.750 mol, 75% of theory) of bright yellow 2-nitro-5-fluorophenol is obtained, which is more than 99.9% pure according to GC and HPLC (solidification point 32.1° C.).
Reaction SMILES: CI.[CH2:3]([O:10]C1C=CC(CCl)=CC=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([CH:27]1[C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:28]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])(=O)C1C=CC=CC=1>>[C:3]([C:27]1([CH3:19])[C:32](=[O:33])[NH:31][CH2:30][CH2:29][N:28]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1C(=O)c1ccccc1
Solvent: CI
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1(C)C(=O)c1ccccc1

Procedure:
When in the procedure of Example 3a, methyl iodide is substituted for p-benzyloxybenzyl chloride and 27d is substituted for 2, the title compound is obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 14, 1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester, according to the procedure of Example 1 as an off-white solid; mp 52-58° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.10-1.20 (m, 6H), 1.20-1.35 (m, 2H), 1.50-2.00 (m, 6H), 2.91 (s, 3H), 2.50-3.00 (m, 7H), 3.70-3.90 (m, 2H), 4.00 (m, 1H), 4.40-4.50 (m, 1H), 4.85-5.00 (m, 1H), 6.77 (d, 1H), 6.98 (d, 1H), 7.03 (d, 2H), 7.18 (d, 1H), 7.57 (d, 2H); MS (ES) m/z: 625.1 (MH+); HRMS Calcd. for C28H40N4O8S2 (MH+): 625.2360. Found: 625.2366.
Reaction SMILES: [IH:1].[CH3:2][N:3]=[C:4](SC)[NH:5][NH2:6].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[IH:1].[NH2:6][NH:5][C:4]([NH:3][CH3:2])=[N:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN=C(NN)SC
Reactant: NCc1ccccc1
Agent: I
Solvent: O
Product: CNC(=NCc1ccccc1)NN
Reaction time: 8 h

Procedure:
A solution of 36.0 g. of methyl N-methylthiocarbazimidate hydroiodide and 16.1 g. of benzylamine in 100 ml. of water is heated on a steam bath for one hour and then allowed to stand at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in ethanol, treated with activated charcoal and filtered. The filtrate is concentrated to a small volume under reduced pressure and the residual solution is diluted with diethyl ether. The resultant crystals are recovered by filtration and recrystallized from a mixture of ethanol and diethyl ether, giving the desired product as pale pink crystals, m.p. 118°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21][CH2:22]I>CCCCCCC.CCOC(C)=O>[Cl:19][CH2:20][CH2:21][CH2:22][N:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: O=C1COc2ccc(F)cc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1COc2ccc(F)cc2N1CCCCl
Yield: 77.5 %

Procedure:
6-Fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b) (0.090 g, 0.54 mmol), Cs2CO3 (0.263 g, 0.81 mmol) and 3-chloro-1-iodopropane (0.121 g, 0.59 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (8173MF55b) (0.102 g, 78%). 1HNMR(CDCl3) δ 6.95-6.91 (m, 1H), 6.82-6.78 (m, 11H), 6.72-6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.19-2.11 (m, 2H); 13CNMR(CDCl3) δ 164.6, 158.6 (d, J=240.7 Hz), 141.5 (d, J=2.3 Hz), 129.6 (d, J=10.5 Hz), 118.0 (d, J=9.3 Hz), 110.0 (d, J=23.1 Hz), 102.7 (d, J=28.8 Hz), 67.8, 42.3, 39.3, 30.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:17]2[CH:16]=[CH:15][C:14]([Br:13])=[CH:21][C:18]=2[CH:19]=[O:20])[CH:6]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
(3-Hydroxy-phenyl)-acetic acid methyl ester (1.44 g, 8.66 mmol), 5-bromo-2-fluorobenzaldehyde (1.76 g, 8.66 mmol), and potassium carbonate (2.39 g, 17.32 mmol) were combined in 1,4-dioxane (18 mL) and heated to 100° C. overnight. Some starting material was still observed by analytical LCMS, so additional potassium carbonate (0.6 g, 4.3 mmol) was added, and the reaction was stirred at 100° C. for 4 hours. The mixture was cooled to room temperature and partitioned between EtOAc and H2O. Brine was added to facilitate separation, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)#[N:2].[OH-:20].[K+].O>CC(O)(C)C>[N:17]1[CH:18]=[CH:19][C:14]([C:4]2[S:5][C:6]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)=[CH:7][C:3]=2[C:1]([NH2:2])=[O:20])=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: N#Cc1cc(-c2ccncc2)sc1-c1ccncc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: NC(=O)c1cc(-c2ccncc2)sc1-c1ccncc1
Yield: 70.2 %

Procedure:
A mixture of 3-cyano-2,5-di(4-pyridyl)thiophene (40 mg, 0.152 mmol), potassium hydroxide (25 mg, 0.446 mmol) in 2-methyl-2-propanol (2 mL) was heated at reflux temperature for 2 hours. After cooling, the mixture was poured into water. The precipitates were collected by filtration, and dried under reduced pressure to give the title compound (30 mg, 70% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[CH3:15][C:10]1[C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Cc1ncccc1Oc1ccc(N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncccc1Oc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
5-Amino-2-(2-methylpyridin-3-yloxy)pyridine (D9, 60.3 g, 0.3 mole) in dry CH2Cl2 (2.5L) was cooled to −20° C. under argon. Triethylamine (46 ml, 0.33 mole) was added, followed dropwise by phenyl chloroformate (41 ml, 0.33 mole) and the mixture was stirred at −20° C. for 1 hour. After warming to ambient temperature, the mixture was washed with dil. aq. NaHCO3, dried (Na2SO4) and evaporated in vacuo. The residue was recrystallised from ethyl acetate/60-80° petroleum ether to afford the title compound (53.7 g, 56%) as a pink solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)([O-:8])=[O:7].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=2)[CH:12]=[N:13]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)n1ncc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
Methanesulfonyl chloride (887 μl, 7.20 mmol) was added to a suspension of 5-nitroindazole (979 mg, 6.00 mmol) and triethylamine (2.0 ml, 14.3 mmol) in dichloromethane (20 ml) at 0° C., and the resulting mixture was stirred at room temperature for 3 hours. Methanesulfonyl chloride (222 μl, 1.80 mmol) was further added thereto, followed by stirring for another 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution to terminate the reaction, followed by extraction with chloroform. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by washing with methanol to obtain 1-(methylsulfonyl)-5-nitro-1H-indazole (1.16 g, 80%).
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:45][CH2:46][CH:47]2[CH2:54][CH2:53][C:50]3([CH2:52][CH2:51]3)[CH2:49][CH2:48]2)=[CH:31][C:32]([F:44])=[C:33]([CH:43]=1)[C:34]([NH:36][S:37]([CH:40]1[CH2:42][CH2:41]1)(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:45][CH2:46][CH:47]3[CH2:54][CH2:53][C:50]4([CH2:52][CH2:51]4)[CH2:49][CH2:48]3)=[CH:31][C:32]([F:44])=[C:33]([CH:43]=2)[C:34]([NH:36][S:37]([CH:40]2[CH2:41][CH2:42]2)(=[O:39])=[O:38])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro- N-(methylsulfonyl)benzamide with 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(spiro[2.5]octan-6-ylmethoxy)benzamide, the title compound was obtained as a colorless solid (0.024 g, 18%): 1H NMR (300 MHz, CDCl3) δ8.76-8.62 (m, 1H), 7.63-7.54 (m, 1H), 6.63-6.53 (m, 1H), 3.96-3.78 (m, 2H), 3.20-3.02 (m, 1H), 2.12-1.72 (m, 6H), 1.50-1.41 (m, 2H), 1.40-1.22 (m, 2H), 1.20-1.10 (m, 2H), 1.02-0.88 (m, 4H), 0.72-0.61 (m, 2H), 0.38-0.15 (m, 4H); MS (ES+) m/z 422.2 (M+1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([OH:14])=[O:13].[OH-].[Na+].O.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>CC(C)=O>[CH2:34]([O:33][C:31]([N:18]1[CH2:17][CH2:16][C:15]([C:12]([OH:14])=[O:13])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A mixture of 37.7 g of 4-carboxy-4-phenylpiperidine p-toluenesulphonate, 53.3 g of 30% aqueous NaOH solution and 250 ml of water is cooled to 5° C. A solution of 18 g of benzyl chloroformate in 60 ml of acetone is added rapidly at 5° C., and the mixture is left stirring overnight while allowing the temperature to rise to RT. The reaction mixture is washed twice with ether and, after settling has taken place, the aqueous phase is separated and acidified to pH 1 by adding concentrated HCl and then 2N HCl. The precipitate formed is drained, dried, taken up in ether and drained again. 30.6 g of the expected product are obtained, m.p.=142°-144° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C@@H:4]([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[C:36]([NH:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C@@H:4]([N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:3]1)(=[O:38])[CH3:37]
Reactant: N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
Compound 31 (0.10 g, 0.213 mmol) was suspended in DCM (5 ml), and to this was added acetic anhydride (0.047 g, 0.044 ml, 0.469 mmol) and triethylamine (0.065 ml, 0.469 mmol). The mixture was stirred at room temperature for 3 hours. After this time the solvent was evaporated to give a white solid. The product was purified by column chromatography (MeOH/DCM 2%→6%), and evaporation of the solvent gave the title compound as a white solid (0.103 g, 95%).
Reaction SMILES: [NH:1]1[C@H:4]([C:5]([NH:7][C@H:8]([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][CH:11]=2)=[O:6])[CH2:3][C:2]1=[O:25].C1C=CC2N(O)N=[N:32][C:30]=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CN>CN(C=O)C.CO>[NH:1]1[C@H:4]([C:5]([NH:7][C@H:8]([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([NH:32][CH3:30])=[O:20])=[O:16])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][CH:11]=2)=[O:6])[CH2:3][C:2]1=[O:25]
Reactant: On1nnc2ccccc21
Reactant: O=C1C[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CC(=O)N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In 2 ml of DMF were dissolved 300 mg of Nα -[(S)-2-azetidinone-4-carbonyl]-L-histidyl-L-proline (13) (obtained in Example 3), 116 mg of HOBT, and 177 mg of DCC and after stirring for 7 hours at room temperature, the solution was cooled in an ice bath. Then 0.6 ml of a methanol solution of 30% methylamine was added to the solution and the mixture was reacted overnight with stirring at 2° to 6° C. Insoluble matters were filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue thus formed was purified by column chromatography using LiChroprep Si 60 (size B). By using chloroform-methanol-aqueous ammonia (40:10:1) as the eluant. Nα -[(S)-2-azetidinone-4-carbonyl]-L-histidyl-N-methyl-L-prolinamide (46) was obtained. The product was dissolved in water and then lyophilized. The amount of the product thus obtained was 149 mg.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O[C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:36])[C:23]3[C:24](=[C:26]([CH2:33][CH2:34][CH3:35])[N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:37]([N:40]2[CH2:45][CH2:44][N:43]([CH2:46][CH3:47])[CH2:42][CH2:41]2)(=[O:39])=[O:38])=[CH:16][N:15]=1)C.[CH3:48][CH:49]([CH3:52])[CH2:50][OH:51]>>[CH2:50]([O:51][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:36])[C:23]3[C:24](=[C:26]([CH2:33][CH2:34][CH3:35])[N:27]([CH2:29][CH2:30][O:31][CH3:32])[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:37]([N:40]2[CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH2:45]2)(=[O:38])=[O:39])=[CH:16][N:15]=1)[CH:49]([CH3:52])[CH3:48]
Reactant: CC(C)CO
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1CCOC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC(C)C)[nH]c(=O)c2nn1CCOC
Temperature: 120 °C
Reaction time: 18 h

Procedure:
Potassium bis(trimethylsilyl)amide (149.7 mg, 0.75 mmol) was added to a solution of the title compound of example 3 (80 mg, 0.15 mmol) in 2-methyl-n-propanol (5 ml) and the reaction stirred at 120° C. for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in water (10 ml), and extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (100:0 to 95:5) to afford the title compound, 67 mg, as a solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[N:8][CH:9]=1.[CH3:13]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[N:8][CH:9]=1
Reactant: N#CCc1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a suspension of NaH (95%, 113 mg, 4.70 mmol) in DMF was added a solution of 2-(5-bromopyridin-3-yl)acetonitrile (from example 199, 0.8 g, 4 mmol) in DMF. Upon completion of addition, the reaction mixture was stirred at RT for 30 min. After this time, methyl iodide (0.3 mL, 4 mmol) was added and the stirring continued for an additional 4 h. At the conclusion of this period, the reaction mixture was quenched by addition of saturated ammonium chloride solution and then extracted into ethyl acetate. The combined organic portions were concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (30% EtOAc in hexanes) to yield racemic 2-(5-bromopyridin-3-yl)propanenitrile (200 mg, 24%). 1H NMR (400 MHz, CDCL3) δ (ppm): 8.67 (d, 1H, J=2 Hz); 8.53 (d, 1H, J=5 Hz); 7.88 (t, 1H, J=5 Hz); 3.94 (q, 1H, J=7.6 Hz); 1.69 (d, 3H, J=7.6 Hz). LCMS Method Y: retention time 1.54 min; [M+1]=212.6.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16](Cl)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1Cl
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1-c1ccccc1

Procedure:
Ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[h][1,4]oxazin-6-yl)-5-phenylthiazole-4-carboxylate (7E) was prepared following a similar procedure as that described in example 1, except ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-chlorothiazole-4-carboxylate (7D) was used instead of ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-chlorothiazole-4-carboxylate (1J) and phenylboronic acid was used instead of 4-methoxyphenylboronic acid in step 11 of example 1. LC/MS (APCI): m/z 409.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:16])=[O:8])=[O:4]
Reactant: COC(=O)c1ncccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ncccc1C(=O)Cl

Procedure:
A mixture of 2-methoxycarbonylnicotinic acid (4.0 g) and thionyl chloride (30 ml) is heated under reflux until homogeneous. The remaining thionyl chloride is distilled off in vacuo to give 2-methoxycarbonylnicotinoyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12](O)=[O:13]>>[O:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:13]
Reactant: C1CNCCN1
Reactant: O=C(O)C1CCCO1
Product: O=C(C1CCCO1)N1CCNCC1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A suspension of piperazine (7.23 g, 0.084 mol) in xylenes (50 mL) was added tetrahydro 2-furanoic acid (4.85 g, 0.042 mol). The mixture was heated to reflux for 28 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to give 3.53 g of product (46% yield).
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)=[CH:25][CH:24]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:34]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: Cc1ccc(C2CNCCN2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2CN(c3cc4nc5c(cc4cc3F)c(=O)c(C(=O)O)cn5C)CCN2)cc1
Temperature: 115 °C
Yield: 29.9 %

Procedure:
A suspension of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.84 g) in pyridine (20 cc), (RS)-2-(4-methylphenyl)piperazine (5.83 g) and triethylamine (1.24 g) is heated to a temperature in the region of 115° C. for 37 hours. After cooling to approximately 20° C., the insoluble matter is drained and washed with ethanol (2×5 cc) and ethyl ether (2×5 cc). After recrystallization in dimethylformamide (25 cc), (RS)-7-fluoro-1-methyl-8-[3-(4-methylphenyl)-1-piperazinyl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (0.8 g) is obtained in the form of a yellow solid, decomposing at 282° C.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])=CC=1)([O-])=O.C[O:44][C:45]([CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:46]>>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:35])([F:36])[F:34])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:15][CH2:14][N:13]([C:11]([N:49]5[CH2:50][CH2:51][CH:47]([C:45]([OH:46])=[O:44])[CH2:48]5)=[O:12])[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C1CCNC1
Reactant: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(C2CCN(C(=O)N3CCC(C(=O)O)C3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to above, 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-pyrrolidine-3-carboxylic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester and pyrrolidine-3-carboxylic acid methyl ester. LCMS calcd for C28H27F3N4O5 (m/e) 556, obsd 557 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.