Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([OH:30])=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH3:39]>>[OH:1][C:2]([CH3:37])([CH3:38])[CH2:3][C@@:4]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([NH2:39])=[O:30])[CH2:26][CH2:27]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N
Reactant: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 50 %

Procedure:
The title compound was prepared from 1-[6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazin-3-yl]-cyclopropanecarboxylic acid and ammonia (32% in water) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 50% of theory; LC (method 1): tR=1.72 min; Mass spectrum (ESI+): m/z=515 [M+H]+.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:26])[C@:15]3([OH:25])C(=O)CO)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[O-][Bi](=O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:26])[C:15]3=[O:25])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: O=[Bi](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)C1=O
Yield: 81.6 %

Procedure:
A solution of 33 g (84.09 mmole) of 9-fluoro-16α-methyl-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione in 50% acetic acid (3 liters) was stirred with 320 g of sodium bismuthate at room temperature for 20 hours. The resulting brown suspension was filtered through a bed of deactivated silica powder and washed with 300 ml of 50% acetic acid. The filtrate was concentrated in vacuo to 500 ml, diluted with 250 ml of 20% hydrochloric acid and extracted with chloroform. The chloroform solution was washed with 20% hydrochloric acid and water, dried over anhydrous Na2SO4 and evaporated in vacuo to give a solid. This was dissolved in chloroform and chromatographed on a 250 g-silica gel column, eluting successively with chloroform and 1:4 ethyl acetate-chloroform to give 22.8 g (81.6%) of tlc-homogeneous title compound, melting point 240°-242° with consistent spectral data.
Reaction SMILES: [CH3:1][C:2](=[O:10])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>CC(O)C>[CH3:1][CH:2]([OH:10])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCCCC/C=C/C(C)=O
Solvent: CC(C)O
Product: CCCCC/C=C/C(C)O
Reaction time: 16 h
Yield: 95 %

Procedure:
Chiral hydrogenation of (E)-3-nonene-2-one was carried out(see formula (14) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using (E)-3-nonene-2-one (701 mg; 5.0 mmol) (made by Tokyo Kasei Kogyo Co., Ltd.)as the substrate and 2-propanol (2.5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 16 hours. As a result, (E)-3-nonene-2-ol was obtained at a GC yield of 95%, isolation yield of 93% (668 mg; 4.65 mmol), and enantiomeric excess of 99%. GC (column: Chirasil-DEX CB; column temperature: 65° C.; injection and detection temperature: 200° C.; helium pressure: 41 kPa; tR of (R)-(E)-3-nonene-2-ol: 70.5 minutes(99.6%); tR of (S)-(E)-3-nonene-2-ol:80.7 minutes (0.4%)); [α]26D+21.16° (c:1.042; CHCl3); absolute structure: R; literature value: [α]25D+10.68° (c:1.03; CHCl3), 97% ee (R).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:22][F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.C(Cl)Cl.[C:27]1([CH3:40])[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[S:35]([NH:38]O)(=[O:37])=[O:36]>CCOCC>[C:27]1([CH3:40])[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[S:35]([O-:4])(=[O:37])=[O:36].[NH2:38][N+:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH2:22][F:23])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1ccccc1C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Yield: 143.2 %

Procedure:
To a mixture of 200 mg of 2,2-bisfluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran and 2 ml of methylene chloride was added dropwise a mixture of 135 mg of (0-mesitylenesulfonyl)hydroxylamine and 3 ml of methylene chloride at room temperature with stirring. The mixture was stirred for 1 hour and ether was added thereto. The separated crystal was collected by filtration to obtain 240 mg of N-amino-2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridinium mesitylenesulfonate. To a mixture of 60 mg of the above-obtained N-amino-2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridinium mesitylenesulfonate and 1 ml of dimethylformamide was added 5 mg of sodium hydride and 36 mg of cyano bromide under ice-cooling with stirring. The mixture was stirred under ice-cooling for 1 hour. Water was added thereto and the mixture was extracted with ether. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =5:95) to obtain 11 mg of 2-(2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridine N-cyanoimine represented by the following formula having a melting point of 212-214° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])#[N:2].CI.[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([CH:3]([C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:25])#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1CC#N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)C#N
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(cyanomethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-B) (1.2 g, 4.00 mmol) was dissolved in THF (40.0 ml), MeI (0.300 ml, 4.79 mmol) was then added at −78° C. At this point, lithium bis(trimethylsilyl)amide (4.39 ml, 4.39 mmol) was added and the reaction stirred for 10 minutes. The reaction was then quenched at −78° C. with a saturated aq. solution of ammonium chloride, diluted with water and EtOAc and the layers were separated. The organic layer was dried over Na2SO4 and concentrated and purified via FCC (0-50% EtOAc:heptanes) to obtain the title compound. MS (ESI+) m/z 313.5 (M−H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[C:29]1([CH2:28][S:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:2]3[O:3][C:4]([C:7]4[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=4)=[CH:5][N:6]=3)[CH:19]=2)(=[O:26])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Solvent: CC(C)O
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.651 g, 2.63 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 26 (0.69 g, 2.63 mmol) in 2-propanol (50 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 1-phenyl-N-(3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)phenyl)methane sulfonamide. 34 (0.407 g, 33% yield) as a solid. MS (ES) m/z 474 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH2:23])C1C=CC=CC=1>CO.S1C=CC=C1.[Pd]>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([NH2:23])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: NC1CCN(CCc2ccccc2)CC1
Reaction time: 72 h

Procedure:
Following the procedure of Lobbezoo, J. Med. Chem. 24:777 (1981). N-(β-phenylethyl)-4-piperidinone (15.0 g, 74.0 mmol) dissolved in 200 ml of methanol containing 1 ml of a 4% thiophene in methanol solution is treated with benzyl amine (10.0 g, 93.0 mmol) and 2 g of 10% palladium-on-carbon in a Parr flask and hydrogenated for 18 hours (initial pressure, 26.5 psi, final pressure 22.0 psi). The catalyst is filtered and replaced with 2.0 g of fresh 10% palladium-on-carbon. The catalyst is filtered and replaced again with 4.8 g of fresh 10% palladium-on-carbon. The hydrogenation is followed over 3 days, at which point, hydrogen uptake ceases (initial pressure, 35 psi, final pressure, 29 psi). The catalyst is filtered through Celite and is washed with methanol. GLC analysis (2 ft SE-30, 100 C, 1 minute, programmed 20 C/minute rise to 250 C) indicated that 7% unreacted benzyl amine remained). This material nevertheless was used for subsequent experiments.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[OH:40][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Example 5) according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (m, 2H), 1.95-2.15 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 5H), 3.55-3.70 (m, 2H), 3.80-3.90 (m, 1H), 4.05-4.20 (m, 1H), 5.70 (brs, 1H), 6.67 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 8.97 (s, 1H), 10.37 (s, 1H); MS (ES) m/z: 555.1 (MH+); HRMS Calcd. for C28H35N4O6S(MH+): 555.2277. Found: 555.2267.
Reaction SMILES: Br[C:2]([CH3:14])([CH2:12]Br)[C:3](=[NH:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([O:25][CH:12]=[C:2]([CH3:14])[C:3](=[N:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(O)cc1OC
Reactant: CC(Br)(CBr)C(=N)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC=C(C)C(=Nc2ccccc2)Oc2ccccc2)cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a solution of 1.0 g (2.51 mmol) of phenyl 2,3-dibromo-2-methylpropanimidate and 466 mg (3.02 mmol) of 3,4-dimethoxyphenol in 5 ml of DMF was added 2.05 g (6.29 mmol) of cesium carbonate and stirred at 70° C. for 5 hours. After cooling to room temperature, the reaction solution was poured into water and extracted with tert-butyl methyl ether. The organic layer was washed sequentially with water and a saturated NaCl, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 252 mg of phenyl 3-(3,4-dimethoxyphenyloxy)-2-methyl-N-phenyl-2-propenimidate (hereinafter referred to as the present compound 99) and 145 mg of 3,4-dimethoxyphenyl 3-(3,4-dimethoxyphenyloxy)-2-methyl-N-phenyl-2-propenimidate (hereinafter referred to as the present compound 100).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccnc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Bromopyridine (116 μL, 1.20 mmol) was added slowly dropwise to a stirred suspension of n-butyllithium (480 μL of a 2.5 M hexanes solution, 1.20 mmol) in THF (1.00 mL) at −78° C. After 15 min, tert-butyl 4-formylpiperidine-1-carboxylate (213 mg, 1.00 mmol) was added, and the resulting mixture was allowed to stir at −78° C. After 1 h, the reaction was quenched with 1.0 M HCl, poured into satd. aq. NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-100% EtOAc/DCM as eluent) afforded the title compound i-15a. 1H NMR (500 MHz, CDCl3): δ 8.55 (m, 2H), 7.70 (d, 1H, J=8.0 Hz), 7.32 (dd, 1H, J=4.9, 7.4 Hz), 4.49 (m, 1H), 4.15 (m, 4H), 2.65 (m, 2H), 1.83 (m, 1H), 1.79 (m, 1H), 1.46 (s, 9H), 1.31 (m, 1H).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:13].[Na+]>CN1CCN(C)C1=O>[F:11][C:9]1[CH:10]=[C:2]([OH:13])[C:3](=[CH:7][C:8]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: [OH-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1cc(F)c(F)cc1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
1.76 g (0.01 mole) of 2,4,5-trifluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1,3-dimethyl-2-imidazolidinone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 3 hours to give rise to a reaction. Then, the same post-treatment as in Example 1 was conducted to obtain 0.50 g of 4,5-difluorosalicylic acid. The isolated yield was 28.7% relative to the 2,4,5-trifluorobenzoic acid used.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[C:9](/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)\[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:10]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[CH:8][C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[CH:7]=[CH:6][CH:5]=1)#[N:11]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(C#N)=C/c2cccc(N)c2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(C(C#N)=Cc2cccc(NC(C)=O)c2)cc1OC
Yield: 84 %

Procedure:
Compound 57 (50 mg) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (48 mg, yield: 84%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CN=C1>CO.CC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[O:21])[CH2:14][S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[CH3:20]
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: CCOC(=O)C(=O)CBr
Agent: c1c[nH]cn1
Solvent: CC(C)=O
Solvent: CO
Product: CCOC(=O)C(=O)CSc1nnc(-c2ccccc2)o1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 5-phenyl-1,3,4-oxadiazole-2-thiol (178 mg, 1.0 mmol) and ethyl 3-bromopyruvate (0.150 mL, 1.19 mmol) in methanol (2 mL) and acetone (2 mL) was added imidazole (68 mg, 1.0 mmol). The resulted solution was shaken at 20° C. for 4 hour. After the removal of solvents under vacuum, the residue was triturated with ethyl ether. The ether phase was discarded. The residue was treated with sodium bicarbonate aqueous solution and ethyl ether. The ether phase was washed successively with sodium bicarbonate aqueous solution, water, and dried over magnesium sulfate. Evaporation to dryness under vacuum gave 209 mg (72% of yield) of the expected product, 2-oxo-3-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-propionic acid ethyl ester. Proton NMR showed the product was sufficiently pure to be used without further purification. 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.90-7.80 (m, 2H), 7.60-7.35 (m, 3H), 4.41 (q, J=7.1 Hz, 2H), 3.44 (br. s, 2H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCNCC4)c(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To 170 mg of N,N-dimethylformamide were added 50 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of piperazine, and the mixture was stirred at 90° C. for 1 hour. After adding about 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 33 mg of the title compound as a colorless powder.
Reaction SMILES: Br[CH:2]1[CH2:4][C:3]1([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Mg].II.Cl[P:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23].[CH3:28]CCCCC>[Cu](I)I.C1COCC1>[C:5]1([C:3]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][C:2]2([P:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH3:28])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)P(Cl)C(C)C
Reactant: BrC1CC1(c1ccccc1)c1ccccc1
Reactant: CCCCCC
Agent: I[Cu]I
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)P(C(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
Under a nitrogen atmosphere, 1-bromo-2,2-diphenylcyclopropane (1.43 g, 5.0 mmol), magnesium (0.133 g, 5.5 mmol) and THF (10 ml) were placed in a reaction flask, followed by addition of a trace amount of iodine and stirring at 40° C. for 1.5 hours. After cooling, copper iodide (0.952 g, 5.0 mmol) and chlorodiisopropylphosphine (0.80 ml, 5.0 mmol) were added and the resulting mixture was stirred at 40° C. for 5 hours, followed by cooling to room temperature. The resulting mixture was diluted with hexane (20 ml) and crystal separated was collected by filtration. The crystal was dissolved in toluene, and the toluene solution was washed with a 28% aqueous ammonia and a brine, and dried over anhydrous magnesium sulfate. Then, the solvent was removed under reduced pressure to give the title compound (1.06 g, 66%) as white crystal.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@@H]1CCC(=O)O1

Procedure:
Hydrogenating 3.0 g (7.29 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl]dihydrofuran-2-(3H)-one [preparation, see Example 1g)] in 100 ml of methanol with 0.6 g of 10% Pd/C results in the title compound, after filtering off the catalyst and evaporating the filtrate: tRet (II)=10.6 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1oc2cc(Br)ccc2n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-bromo-3H-benzoxazol-2-one (15 g; ca. 0.07 mol, containing 8-9% 3H-benzooxazol-2-one) and triethylamine (11.1 mL, 0.08 mol) in DCM (250 mL) was added trityl chloride (21.5 g, 0.08 mol). The solution was stirred at room temperature for 18 h and was then washed with distilled water (3×250 mL), brine (250 mL) and dried (MgSO4), filtered and evaporated to give an off-white colored solid. The product was dissolved in refluxing EtOAc then allowed to cool to room temperature with constant stirring for several hours. The solids were collected (21.16 g) and the filtrate was concentrated until precipitation occurred, re-heated (reflux) for several hours and allowed to cool with stirring to encourage a second crystallization (7.88 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[H][H].[C:18]([O:22][C:23]([NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N[C@H]1CCNC1)=O)(C)(C)C>>[C:18]([O:22][C:23]([NH:25][CH2:26][CH:27]1[CH2:28][CH2:29][N:30]([S:12]([C:10]2[C:11]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH2:31][CH2:32]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2cncc(Cl)c12
Reactant: [H][H]
Agent: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)CC1

Procedure:
4-Chloro-5-isoquinolinesulfonyl chloride obtained in Reference Example 7 (131 mg) and 4-(tert-butoxycarbonylaminomethyl)piperidine (129 mg, Acros) were used in the method of Example 1-1, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-(tert-butoxycarbonylamino)pyrrolidine, respectively, to obtain the title compound (209 mg).