Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:10]1(O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.S(=O)(=O)(O)O>>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)O
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)Oc1ccccc1
Temperature: 131 °C

Procedure:
Heptanoic acid (180.9 g; 1.39 mol), phenol (180.69 g; 1.92 mol), toluene (216.5; 2.35 mol) and sulfuric acid (5.04 g; 0.0514 mol) were charged to a 2-liter, 3-necked round bottom flask equipped with a thermometer, a magnetic stirrer and an 8" Vigreux column equipped with a Dean-Stark trap. The reaction mixture was heated to 131° C. and maintained at that temperature for five hours to give 74 weight percent phenyl heptanoate. The reaction product was washed once with a solution of 0.08 mol Na2CO3 in 4.5 mol water. Phase separation occurred after approximately 20 minutes. The organic layer was fractionally distilled at atmospheric pressure using a 20-plate Oldershaw column to remove phenol and toluene. The remaining liquid was then distilled through a 10-plate Oldershaw column at 50 torr to give a center cut fraction of 154.4 g (54% yield) of pure phenyl heptanoate.
Reaction SMILES: [CH2:1]1[C:3]([NH:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])([C:4]([OH:6])=O)[CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:51]1[CH:55]=[C:54]([C:56]2([NH2:59])[CH2:58][CH2:57]2)[N:53]=[CH:52]1>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C:3]1([C:4](=[O:6])[NH:59][C:56]2([C:54]3[N:53]=[CH:52][O:51][CH:55]=3)[CH2:58][CH2:57]2)[CH2:2][CH2:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1(c2cocn2)CC1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(C(=O)NC2(c3cocn3)CC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
To a round bottom flask was added Z-1-aminocyclopropane-1-carboxylic acid (150 mg, 0.638 mmol) in DMF (10 ml), followed by the addition of Hunig's base (207 mg, 1.6 mmol) and HATU (270 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 15 min, followed by the addition of 1-Oxazol-4-yl-cyclopropylamine (200 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC to afford 70 mg of [1-(1-oxazol-4-yl-cyclopropylcarbamoyl)-cyclopropyl]-carbamic acid benzyl ester, m/z 343 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH2:11]1[O:21][C:20]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=2[O:12]1.[OH-].[Na+]>CO>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:16][C:15]2[CH:18]=[CH:19][C:20]3[O:21][CH2:11][O:12][C:13]=3[CH:14]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1ccc(O)cc1

Procedure:
4-Hydroxy acetophenone, 1 (2.7 g, 20 mmol), 3,4-methylenedioxy benzaldehyde, 6 (3 g, 20 mmol) and 50% aqueous sodium hydroxide (5 mL) in methanol (40 mL) were reacted under reflux as in 7 to yield 11. Yield 3.5 g (65%); mp 191-193° C.; MS (FAB) 269 (M++1); IR (KBr) 3410, 1646; 1H NMR (200 MHz, CDCl3) δ 9.15 (s, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.72 (d, J=15.5 Hz, 1H), 7.37 (d, J=15.5 Hz, 1H), 7.16 (s, 1H), 7.12 (d, J=8.1 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.82 (d, J=7.9 Hz, 1H), 6.02 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2Cl)n1
Temperature: 150 °C
Yield: 9.5 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2-chloro-5-(trifluoromethyl)benzoyl chloride (0.299 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.015 g (16% yield) of pure product: MS (ES) m/z 512 (M+).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26](C(OCC)=O)[C:27]([O:29]CC)=[O:28].CC(C)=O>CN(C)C=O>[Br:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][CH:15]=1)[CH2:11][O:13][C:26]([C:27]([OH:29])=[O:28])=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)C1=C(c2ccccc2)c2cc(Br)ccc2CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.6 %

Procedure:
A mixture of 2-benzoyl-4-bromobenzoic acid (25 g, 82 mmol), potassium carbonate (12 g, 87 mmol), diethyl bromomalonate (22 g, 92 mmol), acetone (450 mL) and N,N-dimethylformamide (8 mL) was stirred at room temperature for 15 h. The solvent was evaporated under reduced pressure. The residue was poured into water and extracted with ethyl acetate. The residue was crystallized from hexane and the crystals were collected by filtration. The obtained crystals were added to a mixture of acetic acid (235 mL) and concentrated hydrochloric acid (360 mL) and the mixture was stirred at 120° C. for 8 h. The reaction mixture was cooled and concentrated. The residue was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with diisopropyl ether and dried to give 6-bromo-4-phenyl-1H-isochromene-3-carboxylic acid (17 g, 60%) as crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][NH:28][CH3:29])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]([CH3:29])[C:45](=[O:46])[CH2:44][O:43][CH3:42])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN(C)C(=O)COC)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 188, 230 mg, 0.490 mmol) in DCM (4 ml) at 0° C. was added NEt3 (0.100 ml, 0.721 mmol) and 2-methoxyacetyl chloride (50 μl, 0.548 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (2-5%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a colorless resin. (UPLC-MS 3) tR 0.91 min, ESI-MS 542.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=O.[NH2:15][C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=[N:15][C:16]1[C:17]([CH3:23])=[CH:18][CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: Cc1cccc(O)c1N
Reactant: COCOc1ccc(OC)cc1C=O
Solvent: c1ccccc1
Product: COCOc1ccc(OC)cc1C=Nc1c(C)cccc1O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) (2.77 g, 16.5 mmol) and 2-amino-m-cresol (2.03 g, 16.5 mmol) in benzene (70 mL) was refluxed for 15 h using an additional funnel to remove water. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the resulting residue was washed with ethanol to afford the objective compound as a orange solid (84%), which was used for next reaction without further purification: 1H-NMR (400 MHz, DMSO-d6) δ2.31 (s, 3H), 3.45 (s, 3H), 3.85 (s, 3H), 5.18 (s, 2H), 6.59 (s, 1H), 6.77 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.03 (dd, 1H, J=9.0, 2.5 Hz), 7.14 (d, 1H, J=9.0 Hz), 7.68 (s, 1H), 8.95 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13]([CH:16]=[N:17][O:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:42][Si:43]([C:46]#[CH:47])([CH3:45])[CH3:44]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:1][C:2]1[C:3]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:47]#[C:46][Si:43]([CH3:45])([CH3:44])[CH3:42])=[CH:27][C:26]=2[F:32])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)(O)CON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(O)CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)c(F)c1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-2-methyl-propoxyimino)-methyl]-benzamide (14.6 mg, 0.025 mmol) prepared in Example 12 was dissolved in anhydrous tetrahydrofuran (2.0 ml). Next, (PPh3)2PdCl2 (20,867-1, Sigma-Aldrich, Inc.) (1.0 mg, 0.00127 mmol), copper iodide (2.0 mg, 0.0094 mmol), N,N-diisopropylethylamine (10 μL, 0.057 mmol), and trimethylsilylacetylene (35 μL, 0.25 mmol) were added thereto at room temperature, and the mixture was stirred at 50° C. overnight.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH2:35][CH2:36][S:37][CH3:38])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:48])C=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[C:24]([O:34][CH2:35][CH2:36][S:37]([CH3:38])=[O:48])=[CH:23][N:22]=3)[C:5]=2[CH3:39])[CH2:3][CH2:2]1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCSC)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCS(C)=O)c(Nc4ccncc4)n3)c(C)c2C2CC2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
180 mg 2-[5-cyclopropyl-1-(4-ethoxy-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-[2-(methylsulfanyl)ethoxy]-N-(pyridin-4-yl)pyrimidin-4-amine (0.326 mmol, 1.0 eq.) were dissolved in 1.7 mL chloroform and cooled to 0° C. 80.3 mg 3-chlorobenzenecarboperoxoic acid and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with DCM and a solution of sodium thiosulfate (10% in water) was added and stirred for 5 minutes. The layers were separated and the aqueous layer was washed with DCM twice. The combined organic layers were washed with saturated sodium hydrogencarbonate solution, was dried over a silicon filter and concentrated in vacuo. The crude product was purified by flash chromatography to provide 136 mg of the analytically pure target compound as a racemate.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].CCN(CC)CC>C(Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(Br)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
2,2-dimethylpropanoyl chloride (28 g, 232.2 mmol) was added to a stirred solution of 4-bromo-3-nitro-aniline (42 g, 193.5 mmol) and Et3N (51 mL, 366 mmol) in anhydrous DCM (200 mL) at 0° C. under an atmosphere of N2. The cooling bath was removed and the stirring was continued at room temperature for 2 h. The reaction mixture was poured into ice (500 g) and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to afford crude product N-(4-bromo-3-nitrophenyl)pivalamide (55 g, 94%) which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ: 8.18-8.17 (m, 1H), 7.64-7.63 (m, 2H), 7.50 (br s, 1H), 1.32 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].S(Cl)([Cl:12])(=O)=O>>[Cl:12][CH:4]([CH2:3][CH:2]([CH3:8])[CH3:1])[C:5](=[O:7])[CH3:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)CCC(C)C
Product: CC(=O)C(Cl)CC(C)C

Procedure:
The process for preparing the α-hydroxyketones of the invention starts from inexpensive 5-methyl-2-hexanone which is reacted with sulfuryl chloride in a first step to give 3-chloro-5-methyl-2-hexanone with high selectivity, as set forth below:
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]=[CH2:11])[CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:24][C:25]1[CH:26]=[CH:27][C:28]2[N:34]3[CH:35]=[N:36][C:37]([C:38](=[N:40]O)[NH2:39])=[C:33]3[C@@H:32]3[CH2:42][CH2:43][N:31]3[C:30](=[O:44])[C:29]=2[CH:45]=1>CN(C)C=O>[CH2:9]([N:4]([CH2:5][C:6]1[O:8][N:40]=[C:38]([C:37]2[N:36]=[CH:35][N:34]3[C:28]4[CH:27]=[CH:26][C:25]([F:24])=[CH:45][C:29]=4[C:30](=[O:44])[N:31]4[CH2:43][CH2:42][C@H:32]4[C:33]=23)[N:39]=1)[CH2:1][CH:2]=[CH2:3])[CH:10]=[CH2:11]
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reactant: C=CCN(CC=C)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Reaction time: 2 h
Yield: 37 %

Procedure:
2.32 g (15 mmol) of diallylglycine were dissolved in 15 ml of N,N-dimethylformamide and treated with 2.75 g (17 mmol) of 1,1'-carbonyldiimidazole. After stirring at 50° C. for 20 minutes 3.01 (10 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° for 16 hours and at 120° for 2 hours. The solution was concentrated and the residue was purified by chromatography on 320 g of silica gel while eluting with ethyl acetate. There were obtained 1.54 g (37%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 100°-105°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 90 °C
Reaction time: 17 h
Yield: 65.2 %

Procedure:
Step 1 A mixture of 6-bromo-1H-indole (0.25 g, 1.275 mmol), 4-fluorophenylboronic acid (0.178 g, 1.275 mmol), and 2 M aqueous sodium carbonate (2.0 mL, 4.00 mmol) in toluene (10 mL) and ethanol (2.500 mL) was purged with argon and treated with tetrakis(triphenylphosphine)palladium (0.074 g, 0.064 mmol). The mixture was heated at 90° C. After 17 h, the mixture was cooled to rt and partitioned between water and EtOAc. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 60:40 hexane-EtOAc) to provide 6-(4-fluorophenyl)-1H-indole as a white solid (175.5 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 11.17 (1H, br. s.), 7.65-7.71 (2H, m), 7.56-7.62 (2H, m), 7.37 (1H, t, J=2.9 Hz), 7.22-7.31 (3H, m), 6.44 (1H, t, J=2.0 Hz). Mass spectrum m/z 212.2 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[NH:19][C:20]2=[O:23])=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.C(Cl)Cl>C1COCC1>[OH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[NH:19][C:20]2=[O:23])=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCCO)cc12
Reaction time: 5 h
Yield: 101.9 %

Procedure:
The 7-[3-(tert-butyldimethylsilyloxy)propylamino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (435 mg, 0.913 mmol) obtained in step A was dissolved in THF (9 ml). Thereafter, a 1 M tetrabutylammonium fluoride THF solution (1.1 ml, 1.1 mmol) was added to the obtained solution at a room temperature. The obtained mixture was stirred for 5 hours. Thereafter, methylene chloride was added to the reaction solution. An organic layer thereof was washed with a saturated saline solution, and was then dried over magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel chromatography (methylene chloride:methanol=30:1), so as to obtain 7-(3-hydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (337 mg, 95%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1.[NH:20]1[C:24]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=2)=[N:23][N:22]=[N:21]1.Cl.O>CN(C)C=O>[OH:1][C:2]1[C:3]([C:17](=[N:32][NH:31][C:29](=[O:30])[C:28]2[CH:33]=[CH:34][C:25]([C:24]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:26][CH:27]=2)[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CC(=O)c1csc(-c2ccc3c(c2)CCCC3)c1O
Reactant: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(-c2nnn[nH]2)cc1)c1csc(-c2ccc3c(c2)CCCC3)c1O
Yield: 1.9 %

Procedure:
21.6 mg (0.0793 mmol) of 1-[4-hydroxy-5-(5,6,7,8-tetrahydronaphthalen-2-yl)thiophen-3-yl]ethanone and 17.9 mg (0.0877 mmol) of 4-(1H-tetrazol-5-yl)benzohydrazide in N,N-dimethylformamide (1.0 ml) was stirred with a drop of concentrated hydrochloric acid at 60° C. for 3 hours. After completion of the reaction, water was added, and the precipitated solid was collected by filtration, washed with chloroform (2.0 ml) and dried under reduced pressure to obtain the desired product (0.7 mg, yield 2%).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]([CH3:30])[C:27](=[O:29])[CH:28]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]([CH3:30])[C:27](=[O:29])[CH:28]=2)=[C:16]([F:21])[CH:15]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of i-Pr2NH (0.39 mL, 2.80 mmol) in THF (4 mL) at 0° C. was added n-BuLi (1.1 mL, 2.80 mmol, 2.5 M solution in hexanes). After stirring 15 minutes, the mixture was cooled to −78° C. 4-Bromo-2-fluorophenylamine (0.38 g, 2.0 mmol) was added. After vigorous stirring for 10 minutes, a mixture of the 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g, 0.80 mmol) in THF (5 mL) was added. The dry-ice bath was removed after 30 minutes, and the reaction mixture was stirred for 17 hours at room temperature. The reaction mixture was treated with a 10% aqueous HCl solution (15 mL), extracted with EtOAc, dried (MgSO4), and concentrated. Trituration with methylene chloride gave 0.21 g (77%) desired product. MS APCI (−) m/z 339, 341 (M−, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 9.61 (s, 1H), 8.53 (s, 1H), 7.69 (dd, 1H), 7.46 (m, 2H), 3.41 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2].[O:11]=O.[OH-].[Na+:14]>O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([O-:11])=[O:10])(=[O:3])[CH3:2].[Na+:14]
Reactant: O=O
Reactant: CC(=O)NCCOCCO
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCCOCC(=O)[O-]
Temperature: 70 °C
Yield: 85 %

Procedure:
73.5 g of 5-acetylamino-3-oxa-1-pentanol were dissolved in 425 g of water, and 2.90 g of Pd/C (10% by weight) were added. The solution was heated to 70° C. and, while stirring vigorously, about 50 ml/min O2 were passed continuously through the solution under atmospheric pressure for 5 h. Throughout the reaction, the pH was kept at 10 by continuously metering in a total of 116 g of 20% by weight aqueous NaOH. The remaining solution was then extracted with ethyl acetate in a perforator for 3 days. The aqueous phase was then distilled to dryness to leave 77.8 g (corresponding to 85% of theory) of NMR-pure sodium 5-acetylamino-3-oxapentanoate.