Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][CH:4]([NH:12][C:13]([C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[CH2:29][CH2:30][C:31](O)=[O:32])=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.B#B.O>O1CCCC1>[CH3:1][CH:2]([CH3:34])[CH2:3][CH:4]([NH:12][C:13]([C:15]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17][C:16]=1[CH2:29][CH2:30][CH2:31][OH:32])=[O:14])[C:5]1[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCC(=O)O)c1ccc(F)cc1
Agent: B#B
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)c1cc(COc2ccccc2)ccc1CCCO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of the compound prepared in Example 6(40) (2.00 g) in tetrahydrofuran (5 ml) was added dropwise diborane (1M solution in tetrahydrofuran, 8.6 ml) at 0° C. under an atmosphere of argon. The mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane-ethyl acetate to give the title compound (1.67 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[C:43]1([S:49]([N:52]2[C:56]3=[N:57][CH:58]=[CH:59][C:60](Cl)=[C:55]3[CH:54]=[CH:53]2)(=[O:51])=[O:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:60]2[CH:59]=[CH:58][N:57]=[C:56]3[N:52]([S:49]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)(=[O:50])=[O:51])[CH:53]=[CH:54][C:55]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ccnc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C
Yield: 45 %

Procedure:
To a nitrogen flushed flask containing 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl-4-oxopiperidine-1-carboxylate according to the literature: Eastwood, P. R. (2000), Tetrahedron Lett., 3705-3708. 127 mg, 0.410 mmol), K2CO3 (142 mg, 1.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(H)dichloromethane adduct (17 mg, 0.020 mmol) was added a solution of 1-Benzenesulfonyl-4-chloro-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.342 mmol) in DMF (3 mL). The mixture was heated at 80° C. for 36 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexanes:EtOAc (2:1) to give 4-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.068 g, 45%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.37 (d, J=5.2 Hz, 1H), 8.20 (d, J=8.0 Hz, 2H), 7.73 (d, J=4.0 Hz, 1H), 7.56 (m, 1H), 7.49 (m, 2H), 7.03 (d, J=5.2 Hz, 1H), 6.73 (d, J=4.0 Hz, 1H), 6.14 (br s, 1H), 4.12 (m, 2H), 3.65 (m, 2H), 2.55 (m, 2H), 1.50 (s, 9H). LCMS (APCI+) m/z 440 [M+H]+; Rt=3.84 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]([CH3:25])[C:17](N1CCOCC1)=[O:18].[Mg].[Cl-].[NH4+]>O1CCCC1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:18])[C@@H:16]([O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)[CH3:25]
Reactant: Fc1ccccc1Br
Reactant: C[C@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](OC1CCCCO1)C(=O)c1ccccc1F
Yield: 103.6 %

Procedure:
1-Bromo-2-fluorobenzene (15 g) and 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (40 g) were dissolved in tetrahydrofuran (200 ml), to which magnesium (turnings: 4.4 g) was added. The mixture was stirred vigorously. The reaction flask was cooled when the temperature of the reaction solution reached to 35° C., and 1-bromo-2-fluorobenzene (16.7 g) was added thereto over the period of 10 minutes while the temperature of the reaction solution was kept at 35 to 37° C. After the reaction solution was stirred at 30 to 35° C. for 2 hours, it was cooled in an icebath. A saturated aqueous solution of ammonium chloride (100 ml) was added thereto and the mixture was extracted with ethyl acetate (200 ml×2,100 ml). The extract was washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=10/1 to 5/1) to give (2S)-2′-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (22.4 g) as a pale yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:8])=[O:7].Cl.CN([CH:25]=[C:26]1[C:37]2[C:29](=[CH:30][CH:31]=[C:32]3[C:36]=2[S:35][CH:34]=[N:33]3)[NH:28][C:27]1=[O:38])C>CO.[Pd]>[OH:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:25]=[C:26]2[C:37]3[C:29](=[CH:30][CH:31]=[C:32]4[C:36]=3[S:35][CH:34]=[N:33]4)[NH:28][C:27]2=[O:38])=[CH:12][CH:11]=1)(=[O:8])=[O:7]
Reactant: CN(C)C=C1C(=O)Nc2ccc3ncsc3c21
Reactant: CC(C)(CO)CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(CO)CNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.5 %

Procedure:
A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472-7; Macor, et al., Tetrahedron Letters 1992, 33, 8011-4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI−MS: m/z 301 (M−H)−. A mixture of 0.66 g (2.2 mmol) of N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitro-phenyl)-methanesulfonamide and ˜0.06 g Pd/C 10% in 50 mL of MeOH was shaken on a Parr hydrogenator for 3.5 h. The catalyst was removed via filtration, and 0.273 mL (3.28 mmol) of conc. HCl was added. The solvent was removed in vacuo, and the solid residue was redissolved in 20 mL of EtOH and added to 0.486 g (1.98 mmol) of 8-dimethylaminomethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. The mixture was heated to reflux for 4.5 h and cooled to ambient temperature. The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven at 70° C. to afford the title compound as a yellow solid (0.66 g, 70%): mp 229-230° C. (dec); 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.73 (d, J=6.4 Hz, 2H), 3.08 (d, J=5.3 Hz, 2H), 4.27 (s, 2H), 4.43 (t, J=5.3 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 8.03 (d, J=12.3 Hz, 1H), 9.24 (s,1 H), 10.84 (s, 1H), 11.04 (d, J=12.3 Hz, 1H); ESI−MS: m/z 471 (M−H)−. Anal. Calcd for C22H24N4O4S2.0.5 H2O: C, 54.87; H, 5.23; N, 11.63; S, 13.32. Found: C, 54.90; H, 5.26; N, 11.68; S, 13.25.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:18].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3]
Reactant: COC(=O)c1c(C)cccc1N
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.4 %

Procedure:
Add isopropyl chloroformate (19.8 mL, 19.8 mmol, 1.0 M in toluene) dropwise to a solution of 2-Amino-6-methyl-benzoic acid methyl ester (3.27 g, 19.8 mmol) and pyridine (4.0 mL, 50 mmol) in dichloromethane (39 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 14 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (3.80 g, 76%): 1H NMR (CDCl3) δ 1.29 (d, J=6.5 Hz, 6H), 2.43 (s, 3H), 3.94 (s, 3H), 5.00 (septuplet, J=6.5 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.86 (brs, 1H). MS (ES+): 252 (M+H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=1)[CH3:10].C([C:21]([O:23][CH2:24][CH3:25])=[O:22])#N>C1COCC1>[CH2:24]([O:23][C:21]([CH:15]1[CH2:16][CH2:17][C:12]([O:11][CH2:9][CH3:10])=[CH:13][C:14]1=[O:18])=[O:22])[CH3:25]
Reactant: CCOC(=O)C#N
Reactant: CCOC1=CC(=O)CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(OCC)=CC1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of LDA (192 mmol) in THF (200 mL) was added 3-ethoxy-cyclohex-2-enone (23 mL) dropwise. After stirring for 1 h at −78° C., ethyl cyanoformate (16 mL) was added. The mixture was stirred at −78° C. for 4 h and then was warmed to rt and stirred for 1 h. The mixture was concentrated, diluted with aq. NH4Cl (300 mL), and poured into water. The resulting solids were collected by suction filtration and washed with hexanes followed by water, then was dried and concentrated to provide 17.1 g of a brown solid. TLC (SiO2, 33% EtOAc/hexanes): Rf=0.43.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′((S)-Indan-1-ylaminomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].CI.[C:16](OCC)(=O)C>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CO)cc1Br
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COCc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a solution of (3-bromo-4-methoxy-phenyl)-methanol (500 mg, 2.304 mmol, example 28) in tetrahydrofuran (5 mL) cooled to 0° C. was added sodium hydride (70 mg, 2.765 mmol). After 5 min, methyl iodide (287 μL, 4.608 mmol) was added. The reaction was then stirred at room temperature for 30 min. Thin layer chromatography (KP-Sil™ 32-63 μm, 60 Å silica gel, 40% ethyl acetate in hexanes) showed a mixture of starting material and product (higher Rf spot). Additional sodium hydride (58 mg) and methyl iodide (0.287 μL) were added and the reaction mixture was stirred at room temperature for 12 h. Water (5 mL) was added to quench the excess sodium hydride and the product was extracted with diethyl ether (2×50 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 2-bromo-1-methoxy-4-methoxymethyl-benzene (467 mg, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1)[CH2:6][CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[CH3:2].[CH2:33]([SH:36])[CH2:34][SH:35].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>CC(O)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=1)[CH2:6][CH2:7][C:8]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[S:36][CH2:33][CH2:34][S:35]1)[CH3:2]
Reactant: SCCS
Reactant: CCOC(=O)C(CCC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc(OC)nc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(CCC1(CCCCc2ccc3c(n2)NCCC3)SCCS1)c1cnc(OC)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 3-3a (7.6 g, 17.4 mmol) and 1,2-ethanedithiol (17.5 mL, 208.6 mmol) in 25 mL AcOH was added BF3.OEt2 (17.5 mL, 138.1 mmol) dropwise at 0° C. under nitrogen. The reaction mixture was stirred at 0 C for 0.5 hr, then at rt for 3.5 hr. The reaction mixture was slowly poured into ice-cooled 300 mL NaHCO3 (sat.) and extracted with diethyl ether (2×200 mL). The organic layers were combined and washed with brine and dried over Na2SO4. After removal of the solvent, the residue was purified by flash chromatography on silica gel (100% EtOAc) to afford the desired product 4-1a as an oil.
Reaction SMILES: C([Mg]Br)C.C1COCC1.[CH2:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:11]#[CH:12].[CH2:20]([O:22][CH:23](OCC)[O:24][CH2:25][CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][CH:23]([O:24][CH2:25][CH3:26])[C:12]#[C:11][CH2:10][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH3:21]
Reactant: C#CCOC1CCCCO1
Reactant: CCOC(OCC)OCC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(C#CCOC1CCCCO1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A 1 M solution of ethylmagnesium bromide in THF (200 ml, 0.2 mol) was treated with 29 ml (0.2 mol) of a solution of 3,4,5,6-tetrahydro-2-(2-propynyloxy)-2H-pyran in toluene, while maintaining ambient temperature through use of a cool water bath. The resulting solution was stirred for 4 h and treated with 47 ml (0.28 mol) of a solution of triethylorthoformate in toluene, while maintaining ambient temperature with a cool water bath. The resulting solution was heated to 85° C. for 8 h, allowing the removal of THF by distillation. After being allowed to cool, the resulting solution was poured into 500 ml of ice-water containing 29 g of NH4OAc, extracted with two portions of ether, dried over K2CO3, and concentrated in vacuo. The residue was distilled at ca. 0.5 mm Hg pressure (b.p. 103-108° C.) to provide 39.5 g (79%) of the desired compound. 1H NMR (CDCl3) δ 1.24 (t, J=7 Hz, 6H), 1.5-1.9 (m, 6H), 3.5-3.65 (m, 3H), 3.7-3.9 (m, 3H), 4.32 (AA′, 2H), 4.82 (m, 1H), 5.31 (m, 1H). Mass spectrum: (M+NH4)+=260.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([NH:17][C@H:18]([CH2:28][OH:29])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:16])[CH:12]=[CH2:13].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:11]([O:14][C:15]([NH:17][C@H:18]([CH:28]=[O:29])[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N[C@H](CO)CCC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](C=O)CCC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of DMSO (1.51 g, 19.3 mmol) in CH2Cl2 (25 ml) at -70° C. was added oxalyl chloride (1.34 g, 19.3 mmol). After 10 minutes at -70° C., a solution of (206a) (2.4 g, 8.8 mmol) in CH2Cl2 (10 ml) was added dropwise and the mixture stirred for 15 minutes at -70° C. Diisopropylethylamine (3.4 g, 26.3 mmol) was added and the mixture stirred at -25° C. for 15 minutes then diluting with EtOAc (50 ml) washed with a solution of sodium hydrogensulfate 2M, concentrated to give an oil which was used immediately without purification: 1H NMR (CDCl3) δ 9.5 (1H, s), 6.0-5.5 (2H, m), 5.5-5.1 (2H, m), 4.5 (2H, m), 4.2 (1H, m), 2.4-2.10 (2H, m), 2.05 (2H, m), 1.36 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>ClCCl>[F:29][C:28]([F:31])([F:30])[S:25]([O:17][C:6]1[CH:7]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=[C:2]([F:1])[C:3]=1[CH:4]=[O:5])(=[O:26])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1c(F)cc(OC2CCCCO2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a mixture of 2-fluoro-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (3.60 g, 15.0 mmol) and pyridine (5.93 g, 75.0 mmol) in dichloromethane (50 mL) was added dropwise Tf2O (6.35 g, 22.5 mmol) at −15° C. After stirring at room temperature for 3 h, the reaction was quenched by addition of iced-brine (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/8) on silica gel to give the title compound as a white solid (3.77 g, Yield: 67.5%). 1H NMR (400 MHz, DMSO-d) δ 10.12 (s, 1H), 7.26-7.30 (m, 1H), 7.04 (s, 1H), 5.78 (s, 1H), 3.62-3.71 (m, 2H), 1.80-1.87 (m, 3H), 1.56-1.64 (m, 3H). MS (ESI) m/z=373 [M+H]+.
Reaction SMILES: [ClH:1].C[O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1.[CH3:29][NH2:30].CO.C(OCC)(=O)C.C(OCC)C>CO>[ClH:1].[ClH:1].[C:22]1([CH:18]2[CH2:17][N:16]([CH:14]([CH3:15])[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH:30][CH3:29])=[O:3])=[CH:8][CH:9]=3)[CH2:21][CH2:20][O:19]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3ccccc3)C2)cc1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CNC(=O)COc1ccc(CC(C)N2CCOC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(2-phenylmorpholino)propyl]phenoxyacetic acid methyl ester hydrochloride (3.0 g; obtained from the mother liquors of Example 1) in methanol (50 ml) was added a 30% aqueous solution of methylamine (10 ml). This mixture was heated under reflux for 3 hours during which time 3 further 10 ml portions of the methylamine solution were added. The solution was cooled to room temperature, a further 10 ml portion of methylamine solution added, and the reaction mixture allowed to stand at room temperature overnight. The solvent was removed under vacuum, aqueous sodium carbonate added to the residue and extracted with dichloromethane (X2). The combined extracts were washed with brine (X2), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated to dryness. Chromatography of the residue on silica gel in 2% methanol-dichloromethane gave an oil, which, on treatment with an ethereal solution of hydrogen chloride, gave the title compound, m.p. 127°-130° C. (methanol-ethyl acetate-diethyl ether), as a 12:88 mixture of diastereoisomers.
Reaction SMILES: C([S:4][C@@H:5]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:6]([NH:8][CH:9]1[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:19][C:12]=2[N:11]([CH2:26][C:27]([O:29]CC)=[O:28])[C:10]1=[O:32])=[O:7])(=O)C.C(O)C.[OH-].[Na+].Cl>O>[C:27]([CH2:26][N:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:13]=2[CH:14]=[CH:15][CH:9]([NH:8][C:6](=[O:7])[C@@H:5]([SH:4])[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:10]1=[O:32])([OH:29])=[O:28]
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)[C@H](Cc2ccccc2)SC(C)=O)C=Cc2ccc(-c3ccccc3)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1C(=O)C(NC(=O)[C@@H](S)Cc2ccccc2)C=Cc2ccc(-c3ccccc3)cc21
Yield: 86 %

Procedure:
To a mixture of 358 mg (0.657 mmol) of 3-[(S)-2-acetylthio-3-phenylpropionylamino]-1-ethoxycarbonylmethyl-8-phenyl-1H-[1]benzazepin-2-one obtained in the Example A-2 with 10 ml of degassed ethanol was added 3.3 ml of a degassed 1N aqueous solution of sodium hydroxide at 0° C. under a nitrogen atmosphere under stirring. The mixture thus obtained was stirred at room temperature for 2 hours and half. The reaction mixture was cooled and acidified with 1N hydrochloric acid and water was further added thereto. The white crystals thus precipitated were collected by filtration, washed with water and n-hexane and dried under reduced pressure. Thus, 267 mg of the title compound was obtained. Yield 86%.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:7]=1[C:8]([NH:10][C:11]1[C:12]([CH3:17])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])=O.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:8](=[O:9])[C:7]2[C:6](=[CH:21][CH:20]=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=2)[N:5]=1
Reactant: Cc1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Temperature: 0 °C
Yield: 99 %

Procedure:
16.5 g(0.05 mol) of N-(2-fluoroacetamido-5-nitrobenzoyl)-o-toluidine and 25.5 g(0.25 mol) of acetic acid anhydride are dissolved in 250 ml of glacial acetic acid. The solution is refluxed for 2 hours under heating. Then, the reaction solution is evaporated to remove solvent. The residue thus obtained is poured into ice-water, and the aqueous mixture is adjusted to pH 9 with potassium carbonate. The crystalline precipitate is collected by filtration. 15.5 g of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone are obtained.