Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH:55][C:56]([CH3:62])([CH3:61])[CH2:57][C:58](O)=[O:59]>CN(C)C=O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:58](=[O:59])[CH2:57][C:56]([CH3:62])([OH:55])[CH3:61])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)=[CH:27][N:28]=1
Reactant: CC(C)(O)CC(=O)O
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)CC(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 16 h
Yield: 67.5 %

Procedure:
5-(9-Isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (150 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (128 mg, 0.67 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and 3-hydroxy-3-methylbutanoic acid (79 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (120 mg, 67%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C@@H:3]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[N:19](C(OC(C)(C)C)=O)[CH:20]=[C:21]([C:22]([O:24]C)=[O:23])[C:14]=12)[C:4](=[O:10])[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:33])[C@@H:3]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:14]=12)[C:4](=[O:10])[N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)N3CCCC3)C(C)C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-1-tert-butyl 3-methyl 4-((3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (134 mg, 0.292 mmol). Aqueous NaOH (12N, 2 mL) and MeOH (1 mL) were added and the solution was stirred at 53° C. for 48 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: C[O-].[Na+].O1CCCC1.[CH:9]1([CH2:13][N:14]([CH2:33][CH3:34])[C:15]2[C:24]([CH2:25][NH:26][C:27]3[CH:31]=[C:30]([CH3:32])[O:29][N:28]=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:12][CH2:11][CH2:10]1.[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br>O.C(OCC)(=O)C>[F:35][C:36]([F:49])([F:50])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:44]=1)[CH2:40][N:26]([CH2:25][C:24]1[C:15]([N:14]([CH2:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH2:33][CH3:34])=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:27]1[CH:31]=[C:30]([CH3:32])[O:29][N:28]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCC1)c1nc2ccccc2cc1CNc1cc(C)on1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC1CCC1)c1nc2ccccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
Sodium methoxide (0.108 g, 2.0 mmol) was added to an anhydrous tetrahydrofuran (6 mL) solution of cyclobutylmethyl-ethyl-{3-[(5-methyl-isoxazol-3-ylamino)-methyl]-quinolin-2-yl}-amine (0.14 g, 0.4 mmol), with stirring, at ambient temperature. After this mixture was stirred for 15 minutes, 3,5-bis-trifluoromethybenzyl bromide (0.08 mL, 0.4 mmol) was added slowly, and stirring was continued overnight. Ethyl acetate (30 mL) and water (30 mL) were added, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2×30 mL), and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by chromatography on silica gel and eluted with 10-70% hexane in ethyl acetate to afford the title compound (0.045 g), yield: 20%.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)[CH2:7][CH3:8].II.[I:33](O)(=O)=O>O.C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([I:33])=[CH:29][CH:30]=3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)[CH2:7][CH3:8]
Reactant: [O-][I+2]([O-])O
Reactant: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccc(I)cc3)CC2)cc1
Yield: 46.8 %

Procedure:
To a mixed solution comprising 250 ml of acetic acid, 25 ml of carbon tetrachloride, 25 ml of concentrated sulfuric acid, and 50 ml of water were added 26 g of the (2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)benzene mentioned above, 10 g of iodine, and 8.4 g of iodic acid, and they were stirred under a reflux for 2 hours. After cooled, they were washed with a saturated aqueous solution of sodium thiosulfate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain a yellow-brown oily product. This product was purified by a column chromatography over an alumina by using heptane as an eluent, and then recrystallized from heptane to obtain 10.3 g of 4-(2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)iodobenzene.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[C:11](=[O:16])([O:14][CH3:15])OC.C[O-].[Na+].Cl>O.C(OCC)(=O)C>[O:8]1[CH2:9][CH2:10][CH:5]([C:1](=[O:4])[CH:2]([CH3:3])[C:11]([O:14][CH3:15])=[O:16])[CH2:6][CH2:7]1
Reactant: CCC(=O)C1CCOCC1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)C(=O)C1CCOCC1
Temperature: 7.5 °C
Yield: 33.3 %

Procedure:
In a flask made of glass having an inner volume of 100 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 1.28 g (9 mmol) of 4-propionyltetrahydropyran synthesized in the same manner as in Example 5, 16.0 g (180 mmol) of dimethyl carbonate and 1.2 g (22 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10° C., to the reaction mixture were added 50 ml of ethyl acetate, 3.4 g (24 mmol) of 6 mol/l hydrochloric acid and 15 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Eluent; hexane/ethyl acetate=3/1 (volume ratio)) to give 0.60 g (Isolation yield: 33%) of methyl 3-(4-tetrahydropyranyl)-2-methyl-3-oxopropanoate as a colorless liquid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[NH:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>>[NH:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:21]=[C:13]1[CH2:12][CH:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(Cc2nc3ncccc3[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CCC(Cc2nc3ncccc3[nH]2)CC1
Temperature: 65 °C

Procedure:
The cis/trans mixture of 4-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-cyclohexanecarboxylic acid ethyl ester (Compound AAA) (1 g) was dissolved in a minimal amount of TBF (10 mL) and mixed with concentrated aqueous LiOH (5 mL). The resulting reaction mixture was stirred vigorously and heated at 65° C. for 3 h. After cooling and concentration, the reaction was acidified to pH 4 with dilute HCl and concentrated to dryness: mass spectrum m/z 260 [(M+H)+; calcd for C14H 18N3O2: 259].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>O.[Na].[Hg]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1ccc2sccc2c1
Agent: [Hg]
Agent: [Na]
Solvent: O
Product: c1ccc2c(c1)CCS2

Procedure:
The dihydrobenzothiophenes are prepared as depicted in Chart D. A solution of a formula LX benzothiophene in water is stirred with excess sodium amalgam (NaHg) for 24 hr. After workup there is obtained the corresponding Formula LXI dihydrobenzothiophene. (See, e.g., D. T. Witiak, et al., J. Med. Chem. 14, 754 (1971).)
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.FC1(F)C(F)=CC=C(OCC2C3C=NC(C(OCC)=O)=CC=3N(CC)C=2)C1.[F:59][C:60]1[C:61]([OH:85])=[C:62]([CH:80]=[C:81]([F:84])[C:82]=1[F:83])[CH2:63][C:64]1[C:68]2[CH:69]=[N:70][C:71]([C:73]([O:75]CC)=O)=[CH:72][C:67]=2[N:66]([CH2:78][CH3:79])[CH:65]=1>>[CH2:78]([N:66]1[C:67]2[CH:72]=[C:71]([C:73]([NH:21][OH:22])=[O:75])[N:70]=[CH:69][C:68]=2[C:64]([CH2:63][C:62]2[CH:80]=[C:81]([F:84])[C:82]([F:83])=[C:60]([F:59])[C:61]=2[OH:85])=[CH:65]1)[CH3:79]
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOC(=O)c1cc2c(cn1)c(Cc1cc(F)c(F)c(F)c1O)cn2CC
Agent: CCOC(=O)c1cc2c(cn1)c(COC1=CC=C(F)C(F)(F)C1)cn2CC
Product: CCn1cc(Cc2cc(F)c(F)c(F)c2O)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(3,4,5-trifluoro-2-hydroxybenzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 2,3,4-trifluorophenol using a methods similar to that set forth in Example 55. (b) 1-Ethyl-N-hydroxy 3-(3,4,5-trifluoro-2-hydroxybenzyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from a mixture of ethyl 3-(3,3,4-trifluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(3,4,5-trifluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: C1COCC1.[NH:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:17]([OH:19])=O)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:37][O:38][C:39]([C@@H:41]([NH2:51])[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:40].Cl>CN(C=O)C>[NH:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:17]([NH:51][C@H:41]([C:39]([O:38][CH3:37])=[O:40])[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:19])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H](N)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 875.5 %

Procedure:
THF (700 ml) and BOC-Ser(Bzl)-OH (23.6 g, 0.8 M) and HOBT (108 g, 0.8 M) were added to H-Ser(Bzl)-Ome.HCl (196.57 g, 0.8 M); and DMF (200 ml) was added to prepare a solution. WSCI (146 ml, 0.8 M) was added dropwise thereto at 0° C. and the mixture was stirred at 0° C. for one hour and at room temperature overnight. The reaction mixture was concentrated in vacuo, and ethyl acetate (1 l.) was added to the residue, which was then washed with 5% sodium bicarbonate solution, 1 N HCl and water, each three times, in that order. Hexane was added to the oily product, which was then crystallized by adding crystalline seed. The material was then recrystallized from ether-hexane to obtain the substance [28] (340.4 g, yield: 87.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6](Br)[CH:7]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>O.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([S:11]([CH3:10])(=[O:13])=[O:12])[CH:7]=1
Reactant: CS(=O)[O-]
Reactant: Cc1cc(Br)cc(Br)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cc(S(C)(=O)=O)c1
Temperature: 210 °C
Yield: 60.2 %

Procedure:
A mixture of 3,5-dibromotoluene (2.0 g, 8.0 mmol), sodium methanesulfinate (0.92 g, 9.0 mmol), copper(I) iodide (152 mg, 0.8 mmol), proline (0.18 g, 1.6 mmol) and sodium hydroxide (64 mg, 1.6 mmol) in DSMO (15 mL, anhyd) was heated in a microwave unit (Biotage Initiator™) at 210° C. for min. The reaction was repeated two more times and the reaction mixtures were combined, diluted with H2O and extracted with EtOAc. The combined extracts were washed with H2O and brine, then dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 40:60) to give the title compound (1.2 g, 20% combined yield) as a white solid. GC-MS (EI): 248, 250.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([O:8]CC)=O)[N:3]=[CH:2]1.[CH2:11]([CH2:13][NH2:14])[OH:12]>>[OH:12][CH2:11][CH2:13][NH:14][C:6]([C:4]1[N:3]=[CH:2][S:1][CH:5]=1)=[O:8]
Reactant: CCOC(=O)c1cscn1
Reactant: NCCO
Product: O=C(NCCO)c1cscn1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 4-thiazolecarboxylate (24.49 g) and monoethanolamine (28.0 ml) was heated at 100° C. with stirring for 1 hour 20 minutes. After being cooled, the mixture was subjected to column chromatography on silica gel (245 g) and eluted with chloroform. The fractions containing the objective compound were combined and concentrated under reduced pressure to give a light brown oil of N-(2-hydroxyethyl)-4-thiazolecarboxamide (25.93 g).
Reaction SMILES: C([Li])CCC.[CH:6]1([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH:6]1([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH:17]=[C:16]3[CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(OC3CCCCC3)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1cn(S(=O)(=O)c2ccccc2)c2ccc(OC3CCCCC3)cc12
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 16.9 %

Procedure:
n-Butyllithium (0.19 mL, 1.45M in hexane, 0.28 mmol) was added to a solution of (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (Example 3g, 77.1 mg, 0.25 mmol) in THF (1 mL) at -78° C.; the temperature was raised to 0 ° C. and the mixture was stirred for 40 min. After recooling to -78° C., phenylsulfonyl chloride (60 μL, 0.47 mmol) was added and the mixture was allowed to warm to room temperature slowly (overnight). The mixture was quenched with water (5 mL) and extracted into dichloromethane. The organic layer was washed sequentially with water and brine, and dried over sodium sulfate. Purification by flash chromatography (silica gel, 1-4% 2M methanolic ammonia in chloroform) yielded (R)-5-cyclohexyloxy-3-(1-methyl-2-pyrrolidinylmethyl)-1-phenylsulfonylindole (19.1 mg, 17%, HRMS-FAB+ for C26H32N2O3S: calculated MH+ :453.22119; found MH+ :453.22550).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C:8]1([C:33]([O:35]C(C)(C)C)=[O:34])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=3)[CH:16]=[CH:15][C:14]=2[CH3:32])[CH2:9]1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]([O:19][C:17]2[CH:16]=[CH:15][C:14]([CH3:32])=[C:13]([C:10]3[CH2:9][C:8]([CH2:7][C:6]([OH:40])=[O:5])([C:33]([OH:35])=[O:34])[O:12][N:11]=3)[CH:18]=2)=[O:31])=[CH:26][CH:25]=1)[C:28]([NH2:30])=[NH:29]
Reactant: Cc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1C1=NOC(CC(=O)O)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(5-((4-carbamimidamidobenzoyl)oxy)-2-methylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (210 mg) and TFA (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then, the residue was washed with diethyl ether to obtain the title compound (146 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=C1CCC[CH2:28][CH2:27]2.C(I)C.O>C(O)C.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH3:28]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Solvent: O
Solvent: CCI
Solvent: CCO
Product: CCOc1cc(-c2nc(CCC(=O)c3ncccc3C)co2)ccc1OC

Procedure:
A 0.23 g quantity of 3-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of ethanol, 0.21 g of ethyl iodide was added thereto, and the mixture was heated and refluxed for 4 hours. After standing to cool, water was added to the reaction mixture, and ethyl acetate extraction was performed. The extract was washed twice with water, the organic layer was then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.17 g of white powdery 3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C>O1CCCC1.O>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH:38][C:9]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=2)=[O:11])=[CH:32][CH:31]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccc(Cl)cc1)c1cc([N+](=O)[O-])[nH]n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.8 %

Procedure:
To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (200 mg, 1.3 mmol, 1 eq) in tetrahydrofuran (5 mL) were added triethylamine (350 μL, 1.9 mmol, 1.5 eq), hydroxybenzotriazole (HOBT) (257 mg, 1.27 mmol, 1 eq), 2-(4-chloro-phenyl)-ethylamine (180 μL, 1.27 mmol, 1 eq) and EDCI (364 mg, 1.9 mmol, 1.5 eq). The mixture was stirred at room temperature during 20 h. Water (10 mL) was then added and the aqueous phase was extracted with ethyl acetate (2×15 mL). The organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography using cyclohexane and ethyl acetate (100/0) to (50/50) to afford 5-nitro-1H-pyrazole-3-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide as white solid (160 mg, 43% yield).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1(Cl)[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][C:5]1([F:17])[F:16]>C(O)C>[Cl:3][C:4]1[C:5]([F:16])([F:17])[CH2:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(C2CC(F)(F)C2(Cl)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=C(Cl)C(F)(F)C2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3.2 g. (0.049 mole) of 85% potassium hydroxide in 60 ml. of absolute ethanol there is added 10.7 g. (0.04 mole) of 2,2-dichloro-1,1-difluoro-3-(p-methoxyphenyl)cyclobutane. The mixture is heated at reflux for 1 hr. and then cooled to room temperature. Precipitated potassium chloride is removed by filtration and the filtrate concentrated to about 20 ml. About 70 ml. of water is added and the mixture is extracted with three 50 ml. portions of ether. The extract is washed (water 70 ml.), dried and the solvent distilled. The residual material constitutes a 96% yield of desired intermediate suitable for use in the next step. A small sample was distilled for analysis, b.p. 67° C. (0.02 mm) ND27 1.5597.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:49][O:50][CH3:51])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH:36]=[CH:37][O:38][S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])=[C:16]3[C:20]([O:22]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:21])=[O:9])[N:6]=1.C(O)=O>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:49][O:50][CH3:51])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH:36]=[CH:37][O:38][S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=2)(=[O:40])=[O:41])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Solvent: O=CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=COS(=O)(=O)c3ccc(C)cc3)CSC12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A mixture of 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.35 g), formic acid (10 cc) and water (3 cc) is stirred at 50° C. for 30 minutes. Water (8 cc) is then added, and the mixture is filtered and concentrated to dryness at 30° C. under 0.05 mm Hg (0.007 kPa). The residue is taken up in ethanol (2×20 cc), and in each case the mixture is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The solid obtained is triturated in diethyl ether (20 cc). After filtration and drying, 7-[2-(2-amino-thiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (syn isomer, E-form) (0.12 g) is obtained in the form of a yellow powder.
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)=[C:8]([F:20])[CH:7]=1.[N-:21]=[N+:22]=[N-].[Na+].C([O-])(=O)C.[Na+]>Cl>[N:5]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[CH2:14][CH2:15][C:16](=[O:19])[CH2:17][CH2:18]2)=[C:8]([F:20])[CH:7]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cc(F)c(N2CCC(=O)CC2)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Product: [N-]=[N+]=Nc1cc(F)c(N2CCC(=O)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Sodium nitrite (2.40 g, 35.30 mmol) was added to an ice cooled solution of 1-(4-amino-2,6-difluorophenyl)-piperidin-4-one (4.00 g, 17.69 mmol), obtained in Preparation 17, in 6 N HCl (10 ml) and the resulting solution was stirred at 0° C. for 0.5 h. The reaction mixture was quenched with an aqueous solution of sodium azide (2.30 g, 35.3 mmol) and sodium acetate (29.0 g, 353 mmol). The reaction mixture was extracted with ethylacetate (100 ml×2) and the combined extract was washed with water followed by brine. The ethylacetate extract was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethylacetate/pet ether; 1:9) to yield the title compound (2.20 g, 55%).