Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:15]I>CN(C=O)C>[Br:1][C:2]1[C:7]([C:8]2([O:12][CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: OC1(c2cccnc2Br)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cccnc2Br)CCC1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of the above alcohol (410 mg, 1.80 mmol) in DMF (5 mL) was added NaH (60%, 108 mg, 2.70 mmol). After 1 h, MeI (0.23 mL, 3.60 mmol) was added. After 1.5 h, the reaction mixture was filtered and the filtrate was concentrated to afford an orange oil. Purification by flash column chromatography using hexanes/EtOAc (2:1) afforded 2-bromo-3-(1-methoxy-cyclobutyl)-pyridine as a pale yellow solid (308 mg, 71%). 1H NMR (CDCl3) δ 1.61-1.71 (m, 1H), 2.04-2.14 (m, 1H), 2.56 (t, 4H, J=7.5 Hz), 2.96 (s, 3H), 7.25-7.30 (m, 1H), 7.64 (dd, 1H, J=7.5, 2.1 Hz), 8.31 (dd, 1H, J=4.7, 1.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12](COCC[Si](C)(C)C)[C:13]([C:18]([OH:21])([CH3:20])[CH3:19])=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:3]=1.[F-].CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:18]([OH:21])([CH3:20])[CH3:19])=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)[CH:3]=1
Reactant: CC(C)(O)c1c(C#N)nc(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)nc1C#N
Temperature: 50 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of 4-cyano-5-(1-hydroxy-1-methyl-ethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 40.0 mg, 0.0715 mmol) and tetrabutylammomium fluoride (357 μL, 0.357 mmol, 1.0 M in THF) in 2.0 mL of THF was stirred under Ar at 50° C. for 16 h and at reflux for 3 h. After cooling to RT, the mixture was treated with EtOAc (40 mL) and washed with saturated NH4Cl aqueous solution (5 mL), brine (10 mL) and dried (Na2SO4). The organic layer was concentrated in vacuo and residue was purified by flash chromatography on silica gel (5-10% EtOAc/DCM) to give 26 mg (84%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 11.79 (s, 1H), 9.55 (s, 1H), 8.23 (d, 1H, J=8.6 Hz), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.33 (d, 1H, J=2.3 Hz), 5.87 (m, 1H), 5.08 (s, 1H), 2.16-2.34 (m, 4H), 1.83 (s, 6H), 1.71-1.88 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C20H21BrN4O2, 429.1 (M+H), found 428.9.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)C(C)CNCC2
Temperature: 20 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.95 g, 2.59 mmol) in methanol (20 mL) was treated with 15% aqueous NaOH (25 mL), and stirred overnight at 20° C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.687 g of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 6.34 (s, 1H), 3.87 (s, 3H), 3.1-2.9 (m, 6H), 2.75 (m, 1H), 2.60 (bs, 1H), 1.31 (d, J=7 Hz, 3H). MS calculated for C12H16BrNO+H: 270, observed: 270.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1)(=[O:12])=[O:11].[CH2:22](O)[CH2:23][CH2:24][OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:21][CH2:22][CH2:23][CH2:24][OH:25])(=[O:11])=[O:12]
Reactant: OCCCO
Reactant: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To 458 mg (1.49 mmol) 3-(2-methoxy-5-methylphenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 1.08 mL (14.9 mmol) of 1,3-propanediol and 782 mg (2.98 mmol) of triphenylphosphine in 10 mL of anhydrous tetrahydrofuran was added 0.470 mL (2.98 mmol) of diethyl azodicarboxylate dropwise over 15 min. After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to a semisolid. The resulting mixture was flash chromatographed on 50 g of silica gel with 8-10% ethyl acetate-dichloromethane. Impure fractions were re-chromatographed on 40 g of silica gel with 50-100% ethyl acetate-hexane. Material from the two purifications was combined to afford 530 mg (97% yield) of the title compound as a colorless oil: 1H-NMR (300 MHz; CDCl3) δ 7.95 (d, 1 H, J=2.2 Hz), 7.40 (dd, 1 H, J=8.5, 2.3 Hz), 6.97 (d, 1 H, J=8.5 Hz), 6.59 (br s, 1 H), 6.53 (br s, 1 H), 6.47 (t, 1 H, J=2.1 Hz), 4.01 (t, 2 H, J=6.0 Hz), 3.98 (s, 3 H), 3.81 (q, 2 H, J=5.7 Hz), 2.29 (s, 3 H), 2.25 (s, 3 H) and 1.98 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10](=N)[CH:11]([CH3:20])[C:12]2[N:17]=[C:16]([OH:18])[N:15]=CC=2N=1>Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:16](=[O:18])[N:17]([CH3:12])[C:12]2[N:17]=[C:16]([OH:18])[N:15]=[CH:20][C:11]=2[CH:10]=1
Reactant: CC1C(=N)C(c2c(Cl)cccc2Cl)=Nc2cnc(O)nc21
Agent: Cl
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(O)nc21

Procedure:
A solution of 76.0 mg (0.19 mmol) of the imino derivative from Example 23 in 5.0 mL of concentrated hydrochloric acid was heated at reflux for 3 days, and the solvent was then removed by evaporation. The residue was triturated with water, filtered, and dried to afford 6-(2,6-dichlorophenyl)-2-hydroxy-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, as a hydrate;
Reaction SMILES: ClC1C=CC=C(Cl)C=1C([O:6][CH2:7][C:8]1[C:17]2[C:12](=[C:13]([NH:18][C:19](=[O:28])[C:20]3[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)=O.[OH-].[Na+]>C(O)C.O1CCOCC1.ClCCl>[Cl:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=1[C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[CH2:7][OH:6])=[O:28]
Reactant: O=C(Nc1cccc2c(COC(=O)c3c(Cl)cccc3Cl)ccnc12)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCO
Product: O=C(Nc1cccc2c(CO)ccnc12)c1c(Cl)cccc1Cl
Yield: 30 %

Procedure:
A mixture of 4-(2,6-dichlorobenzoyloxymethyl)-8-(2,6-dichlorobenzoylamino)quinoline (100 mg), 1N sodium hydroxide solution (0.4 ml) in ethanol (2 ml) and dioxane (1 ml) was refluxed for 5 hours. After cooling, the mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (ethyl acetate-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-4-hydroxymethylquinoline (20 mg).
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:4]1.[NH:38]1[CH:42]=[N:41][N:40]=[CH:39]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@H:7]1[CH2:8][C@@H:3]([CH2:2][N:40]2[CH:39]=[N:38][CH:42]=[N:41]2)[CH2:4][N:5]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:6]1)=[O:15]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: c1nnc[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](Cn3cncn3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 78.8 %

Procedure:
A solution of tert-butyl (3R,5S)-3-(hydroxymethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (208 mg), 1,3,4-triazole (52 mg), triphenylphosphine (262 mg) and diisopropyl azodicarboxylate (40% toluene solution, 632 mg) in THF (5 ml) was stirred at 50° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, diluted with water and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:5-1:0) and ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9 to 3:1) was concentrated under reduced pressure to give the object product (180 mg).
Reaction SMILES: [CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(OC(F)(F)F)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethoxy)phenyl)quinoxaline-6-carboxylate (120 mg, 0.29 mmol, 1.00 equiv) in methanol (15 mL), sodium hydroxide (57 mg, 1.43 mmol, 4.98 equiv), H2O (2 mL). The resulting solution was stirred for 2 hr at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (2.5 mol/L). The resulting solids were collected by filtration. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (65% CH3CN up to 85% in 8 min, up to 100% in 2 min); Detector, UV 220 254 nm. This resulted in 70 mg (60%) of 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethoxy)phenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][C:4]=2[O:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:6]2[C:5]3[CH:9]=[CH:10][C:11]([CH2:13][N:14]([S:22]([CH3:25])(=[O:24])=[O:23])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:12][C:4]=3[O:3][C:2]([CH3:26])([CH3:1])[C:7]2=[O:8])=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OC(C)(C)C(=O)N2)S(C)(=O)=O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OC(C)(C)C(=O)N2c1ccc(F)cc1)S(C)(=O)=O
Yield: 20.1 %

Procedure:
Tert-butyl [(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) -methyl](methylsulfonyl)carbamate (compound obtained in Reference Example 48(2), 200 mg) and 4-fluorophenylboronic acid (146 mg) were treated in the same manner as described in Reference Example 1(2) to give tert-butyl {[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methyl}(methylsulfonyl)carbamate (50 mg) as a colorless powder.
Reaction SMILES: [NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:2]([C:22](O)=[O:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:21])[NH:8][S:9]([C:12]1[C:19]([CH3:20])=[CH:18][C:16]([CH3:17])=[CH:15][C:13]=1[CH3:14])(=[O:11])=[O:10].CN1CCOCC1.ClC(OCC)=O.S(O)(C1C=CC(C)=CC=1)(=O)=O.[NH2:59][C@H:60]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[CH2:61][CH:62]([CH3:64])[CH3:63]>O1CCCC1.CN(C)C=O>[NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C@H:2]([C:22]([NH:59][C@H:60]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[CH2:61][CH:62]([CH3:64])[CH3:63])=[O:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:21])[NH:8][S:9]([C:12]1[C:13]([CH3:14])=[CH:15][C:16]([CH3:17])=[CH:18][C:19]=1[CH3:20])(=[O:10])=[O:11]
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)c(C)c1
Agent: CCOC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)OCc2ccccc2)c(C)c1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
In 300 ml of tetrahydrofuran is dissolved 49.0 g (100 millimoles) of Z-Arg(Mts)-OH, and 11 ml of N-methylmorpholine is added to the solution and the mixture is stirred at -5° C. for 5 minutes. Then, 9.6 ml of ethyl chloroformate is added to the mixture, and a cooled solution of 39.4 g (100 millimoles) of Tos-OH.H-Leu-OBzl and 11 ml of N-methylmorpholine in dimethylformamide is added to the above mixture. The resulting mixture is stirred at -5° to 0° C. for 4 hours and concentrated under reduced pressure. The residue is dissolved in 700 ml of ethyl acetate, and the solution is washed with 0.1 N aqueous hydrochloric acid, 1 N aqueous NaHCO3 and water and concentrated under a reduced pressure to obtain 52 g of intended Z-Arg(Mts)-Leu-OBzl (the yield being 75%) like oil.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=O)=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.CO.C[O-].[Li+].C(Cl)[Cl:25]>[Ti](Cl)(Cl)(Cl)Cl.O.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[O:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([Cl:25])=[N:16][OH:18])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: O=[N+]([O-])CCc1ccc(Cc2ccc(Cl)o2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: ON=C(Cl)Cc1ccc(Cc2ccc(Cl)o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a mixture of 2-chloro-5-(4-(2-nitro-ethyl)-benzyl)furan (100 mg, 0.38 mmol) described in Manufacturing Example 62-1-5 and methanol (2 mL) was added lithium methoxide (29 mg, 0.75 mmol) at room temperature, which was stirred for 10 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure. Titanium (IV) chloride (91 μL, 0.83 mmol) was added at −78° C. to a mixture of the resulting residue, methylene chloride (2 mL) and tetrahydrofuran (1 mL), and stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., water (1 mL) was added, and the temperature was gradually raised to room temperature. Ethyl acetate and water were added to extract the reaction mixture. The organic layer was washed with water until the pH became roughly 5. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under a reduced pressure to obtain the title compound (110 mg, 84%).
Reaction SMILES: Cl.[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)#[N:30]>>[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:35]([C:34]4[CH:38]=[CH:39][C:31]([C:29]#[N:30])=[CH:32][CH:33]=4)=[O:36])[CH2:27][CH2:28]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(C3CCNCC3)cs2)c1-c1ccc(F)cc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)(C)n1ncc(-c2nc(C3CCN(C(=O)c4ccc(C#N)cc4)CC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 4-{2-[1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}piperidine monohydrochloride and 4-cyanobenzoic acid and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Cl[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:14]([OH:15])[N:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: COc1ccc(C(N)=S)cc1
Product: COc1ccc(-c2nc(O)c(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except 4-methoxythiobenzamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22]([CH:24]1[CH2:26][CH2:25]1)=[O:23])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:24]1([C:22]([NH:21][NH:20][C:18]([C@H:13]2[CH2:12][CH2:11][C@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[OH:8])=[O:19])=[O:23])[CH2:26][CH2:25]1
Reactant: O=C(NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1)C1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O)C1CC1
Yield: 99 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N′-(cyclopropylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 197 (0.27 g, 0.75 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)—N′-(cyclopropylcarbonyl)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 198 (0.20 g, 98%) as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](C)=[N:7]2.[CH3:15]C1C=C2C(C=CC=N2)=CC=1O>>[Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:15])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc2ncccc2cc1O
Reactant: Cc1ccc2c(Br)c(O)c(Cl)cc2n1
Product: Cc1cc2ncccc2c(Br)c1O

Procedure:
Compound 3D was prepared following the procedure used to prepare compound 1D of Example 1, except that 7-methylquinolin-6-ol (3C) was used instead of compound 1C. LCMS-ESI+ (m/z): 238.1, 240.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:26])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=2)=[O:26])=[CH:19][CH:18]=1
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(COc1ccc(-c2ccccc2)cc1)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 30 h
Yield: 104.9 %

Procedure:
To 4-[2-(biphenyl-4-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (100 mg, 0.259 mmol) in ethanol (6 mL) was added a solution of sodium hydroxide (1N, 0.41 mL, 0.41 mmol) and the reaction was stirred at room temperature for 30 hours. After such time the reaction mixture was filtered through glass wool and the filtrate was then neutralized by addition of a solution of hydrochloric acid (1N, 0.39 mL). The precipitate was filtered, washed with water and dried in vacuo to yield the title compound as a white solid (96 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([O:7][C:8]([N:10]([CH2:22][CH2:23][C@H:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([O:30][CH2:31][C:32]3[N:33]=[C:34]([C:38]4[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=4)[O:35][C:36]=3[CH3:37])[CH2:25]2)[C@@H:11]([CH:19]([CH3:21])[CH3:20])[C:12]([O:14]C(C)(C)C)=[O:13])=[O:9])=[CH:5][CH:4]=1.ClC(Cl)(Cl)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([O:7][C:8]([N:10]([CH2:22][CH2:23][C@H:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([O:30][CH2:31][C:32]3[N:33]=[C:34]([C:38]4[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=4)[O:35][C:36]=3[CH3:37])[CH2:25]2)[C@@H:11]([CH:19]([CH3:20])[CH3:21])[C:12]([OH:14])=[O:13])=[O:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(OC(=O)N(CC[C@H]2CCC[C@@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)[C@H](C(=O)OC(C)(C)C)C(C)C)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(OC(=O)N(CC[C@H]2CCC[C@@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)[C@H](C(=O)O)C(C)C)cc1

Procedure:
0.10 g of tert-butyl (S)-2-((4-methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyrate are dissolved in 2 ml of dichloromethane, and the solution is stirred with 1 ml of trichloroacetic acid at RT overnight. The solvent is then removed completely and the residue is purified by preparative HPLC. This gives 15.6 mg of (S)-2-((4-methoxyphenoxycarbonyl)-{2-[cis-3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyl]ethyl}amino)-3-methylbutyric acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)O1)=[O:5])[CH3:2].[N-:14]=[N+]=[N-].[Na+].[NH4+].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N#N>CO>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1OC1c1cccs1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)[C@@H]1N[C@H]1c1cccs1
Temperature: 65 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
In a round bottom flask equipped with a magnetic stirring bar and a reflux condenser was added 3-thiophen-2-yl-oxirane-2-carboxylic acid ethyl ester (2.2 g, 11 mmol), and NaN3 (2.15 g, 33 mmol) in 25 ml of MeOH. NH4Cl (1.77 g, 33 mmol) was then added and the reaction mixture was heated to 65° C. and stirred for 4 hours. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was then dissolved in 35 ml acetonitrile and heated to 50° C. in a round bottom equipped with a condenser. PPh3 (3.18 g, 12.1 mmol) was added slowly (N2 evolved) and then the flask was fitted with a condenser and heated to 83° C. for 2 hours. The resulting mixture was filtered and the filtrate concentrated under reduced pressure. To the residue was added 5% EtOAc in pentane and the precipitate was filtered off. The filtrate was then subjected to silica gel column chromatography using 10% EtOAC in hexanes to afford the title compound as a purple oil in 62% yield over two steps. The NMR spectra were in accordance with literature (Solladie-Cavallo, A.; Lupattelli, P.; Bonini, C; De Bonis, M. Tetrahedron Lett. 2003, 44, 5075). 1H NMR (CDCl3, 300 MHz) δ: 7.22 (d, J=5.0 Hz, 1H), 7.09 (d, J=3.4 Hz, 1H), 6.99 (dd, J=5.0 Hz, 3.4 Hz, 1H), 4.30 (qd, J=7.0 Hz, 1.6 Hz, 2H), 3.54 (d, J=7.0 Hz, 1H), 2.73 (d, J=6.2 Hz, 1H), 2.2-1.9 (bt, 1H), 1.37 (t, J=7.0 Hz, 3H) ppm. 13C NMR (CDCl3, 50 MHz) δ: 171.3, 142.6, 127.1, 125.3, 124.5, 61.7, 40.4, 37.0, 14.23 ppm. (ESI MS) [MH]+=198.1