Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3].C(OCC)(=O)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH3:3][CH:2]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of tert-butyl 9-(1-methylethyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (330 mg, 1.13 mmol), ethyl acetate (6 ml) and 4N hydrogen chloride-ethyl acetate solution (3 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (106 mg, 97.2%) as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].C([N-]C1CCCCC1)(C)C.[Li+].[I:25]I>C1COCC1>[I:25][C:5]1[O:1][C:2]([P:6]([O:7][CH2:8][CH3:9])(=[O:10])[O:11][CH2:12][CH3:13])=[CH:3][CH:4]=1
Reactant: II
Reactant: CCOP(=O)(OCC)c1ccco1
Agent: CC(C)[N-]C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(I)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of diethyl 2-furanphosphonate (prepared as described in Step A, Example 13) (1 mmol) in 2 mL THF was cooled to −78° C. and added to a solution of lithium isopropylcyclohexylamide (LICA) (1 m mol) in 2 mL THF at −78° C. over 20 min. The resulting mixture was stirred −78° C. for 20 min and added into a solution of iodine (1 mmole) in 1 mL THF at −78° C. over 20 min. The mixture was then stirred at −78° C. for 20 min. Extraction and chromatography provided diethyl 5-iodo-2-furanphosphonate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:17](C(OCC)=O)(C(OCC)=O)[C:18]([O:20]CC)=[O:19])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:33]([CH3:35])[CH3:34])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:33]([CH3:35])[CH3:34])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC(=O)O)CC2
Yield: 20 %

Procedure:
Intermediate 20 (250 mg) was dissolved in ethanol (10 ml) and the resulting soln was treated with sodium hydroxide, 3M aq (4 ml). The resulting suspension was heated to reflux for 4 h. The reaction mixture was allowed to cool and concentrated in vacuo. The crude residue was taken up in Acetic Acid (10.00 ml) and heated to reflux for 2 h. Reaction mixture concentrated in vacuo and was purified by Reverse Phase chromatography using a 5->80% gradient of Acetonitrile/water with an ammonium carbonate modifier over 12 column volumes. The desired fractions were combined and concentrated under vacuum to give material that was repurified by Reverse Phase chromatography using a 5->80% gradient of acetonitrile water with 0.1% formic acid. The desired fractions were combined and concentrated under vacuum to give the title compound (33 mg). MH+=333 LC/MS MH+333, Rt 1.84 min (5 min run).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH3:16][CH:17]([SiH:19]([CH:21]([CH3:23])[CH3:22])Cl)[CH3:18]>CCCCCC>[CH3:16][CH:17]([SiH:19]([CH:21]([CH3:23])[CH3:22])[O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:18]
Reactant: CCCCCCCCO
Reactant: CC(C)[SiH](Cl)C(C)C
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCCCCCO[SiH](C(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Di(2-propyl)octyloxysilane was prepared in the following manner. Dry octanol (52.5 g, 0.40 mole) and dry pyridine (32.9 g, 0.42 mole) were added to a 500 ml round-bottom flask. The solution was cooled to -5° C. with stirring. Di(2-propyl)chlorosilane (67.1 g, 0.44 mole) was added in a dropwise fashion over 60 minutes. After this addition, the temperature of the reaction mixture was maintained at -5° C. for another 30 minutes, then allowed to come to room temperature overnight. Hexane (100 ml) was then added to this reaction mixture. The organic phase was extracted with 500 ml 0.1N aq. HCl and 500 ml water. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled to produce di(2-propyl)octyloxysilane.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.CCN(C(C)C)C(C)C.[N:21]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[C:22]=[O:23]>C(Cl)Cl>[CH:24]1([NH:21][C:22]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCC1
Reactant: Nc1cccc2cnccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2cnccc12)NC1CCCC1
Reaction time: 24 h

Procedure:
To isoquinolin-5-amine (0.23 g, 1.595 mmol) in DCM (5 mL) was added DIEA (0.557 mL, 3.19 mmol) and isocyanatocyclopentane (0.180 mL, 1.595 mmol). After 24 h, the reaction was quenched with H2O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (10 mL) and dried (MgSO4). The impure yellow solid was collected and was carried onto the next step. MS (ESI) m/z: 256 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([N-]C(C)C)(C)C.[Li+].S(OC)(OC)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[CH3:12][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cn1ccnc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of 40 mL tetrahydro furan containing 1.0 g of 2-phenylimidazole was cooled to 0° C. and 4 mL of 2M lithium diisopropylamide was added dropwise which resulted in the formation of a white suspension. The mixture was stirred for 10 min at 0 C and then 0.7 mL of dimethyl sulfate was added/The reaction was allowed to stir at room temperaturee for an additional 30 min by which time the solution became homogeneous. Aqueous ammonium chloride was added and the tetrahydrofuran was removed by evaporation under reduced pressure. The aqueous phase was extracted with 2×100 mL aliquots of clichloromethane. The combined organic extracts were washed with dilute ammonium hydroxide and brine. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1 g of 1-methyl-2-phenylimidazole which was used in the next step without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5](/[CH:6]=[N:18]/[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1cc(C=O)cc(C)c1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)cc(C)c1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 4-chloro-3,5-dimethyl-benzaldehyde (6.04 g, 35.8 mmol) and (R)-2-methylpropane-2-sulfinamide (4.78 g, 39.4 mmol) in toluene (110 mL) was treated with titanium(IV) isopropoxide (15.74 mL, 53.7 mmol). The mixture was stirred at 50° C. for 24 hours. It was then quenched with 10% aqueous sodium bicarbonate solution (100 mL) and filtered through Celite. The filter cake was washed with Et2O (250 mL). The organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.N1C=CC=CC=1>[CH:26]1([C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:25][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)c4ccccn4)ncc3[nH]2)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCC4)cc3)[nH]c2cn1)c1ccccn1
Yield: 49 %

Procedure:
A solution of amine 22 (0.040 g, 0.12 mmol) and cyclohexane carbonyl chloride (0.100 ml, 0.68 mmol) in dry THF-Pyridine (10 ml/0.300 ml) was stirred at room temperature overnight. A usual work-up as described earlier afforded the diamide 23 (0.025 g, 47%). M.p. 258° C.; 1H NMR (DMSO-d6, 500 MHz): δ 13.5 (1H, brs, NH), 10.60 (1H, brs, NH), 10.13 (1H, brs, NH), 8.78 (1H, d, J=5.0 Hz), 8.74 (1H, brs), 8.46 (1H, brs), 8.24 (1H, d, J=12.5 Hz), 8.115 (2H, d, J=8.0 Hz), 7.81 (2H, d, J=8.0 Hz), 7.74 (1H, dt, J=10.0 and 13.5 Hz), 2.37 (1H, m), 1.84-1.18 (10H, m); EIMS m/z: 441.4 (M+1), 439.6 (M−1); Anal (C25H24N6O2×1.10 H2O) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=O.[CH3:18][O:19][C:20](=[O:27])[CH2:21][C:22]([CH:24]1[CH2:26][CH2:25]1)=O>>[CH3:18][O:19][C:20]([C:21]1[C:22]([CH:24]([CH3:26])[CH3:25])=[N:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[CH:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)=[O:27]
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1F
Product: COC(=O)c1c(C(C)C)nc2cc(Cl)ccc2c1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 6 step A from a mixture of (2-amino-4-chloro-phenyl)-(2-fluoro-phenyl)-methanone and 3-cyclopropyl-3-oxo-propionic acid methyl ester. White solid. MS (ESI): 356.1 (M+H)+.
Reaction SMILES: C([N+](C[CH2:15][CH2:16][CH3:17])(CCCC)CCCC)CCC.[C:18]([NH:25][C@@H:26]([CH2:30][C:31]1[CH:38]=[C:36]([OH:37])[C:34]([OH:35])=[CH:33][CH:32]=1)[C:27]([OH:29])=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CC(N(C)C)=O.C(OC)(C)(C)C>[OH:37][C:36]1[CH:38]=[C:31]([CH2:30][C@H:26]([NH:25][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:27]([O:29][CH2:17][C@H:16]([O:29][C:27](=[O:28])[CH3:26])[CH3:15])=[O:28])[CH:32]=[CH:33][C:34]=1[OH:35]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: COC(C)(C)C
Product: CC(=O)O[C@H](C)COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Yield: 7.3 %

Procedure:
A solution of Boc-L-Dopa tetrabutyl ammonium salt (5.6 g, 104.0 mmol) and crude (1R)-2-bromomethylethyl acetate (46) (2.6 g, 11.6 mmol) in 50-mL dimethylacetamide was stirred overnight at 65° C. The reaction mixture was diluted with methyl tert-butyl ether (500 mL), washed with saturated aqueous NaHCO3 (3×250 mL), brined, dried over Na2SO4, and concentrated to an oil. Chromatography eluting with EtOAc/hexane (2:3) gave 1.5 g (36.7% yield) of the title compound (47). 1H NMR (400 MHz, CDCl3): δ 1.23 (d, J=6.8 Hz, 3H), 1.43 (s, 9H), 2.10 (s, 3H), 2.98 (m, 2H), 4.02 (dd, J=7.2, 6.8 Hz, 1H), 4.30 (dd, J=6.8, 2.8 Hz, 1H), 4.54 (m, 1H), 4.97 (d, 1H, NH), 5.10 (m, 1H). MS (ESI) m/z 398.1 (M+H)+ and 396.1 (M−H)−.
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@@H:9]1[C:13](O)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O.CCOC(C)=O>[Si:1]([N:8]1[C@@H:9]([CH2:13][OH:14])[CH2:10][C:11]1=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CO
Reaction time: 0.75 h
Yield: 60.1 %

Procedure:
To a solution of 1-(tert-butyldimethylsilyl)-4-oxoazetidine-2(R)-carboxylic acid (15.0 g, 65.40 mmol) in THF (367 mL) at 0°, was added N-methylmorpholine (7.2 mL, 65.40 mmol) and isobutyl chloroformate (8.5 mL, 65.40 mmol). After stirring for 1.5 h at 0° a solution of NaBH4 (9.9 g, 261.61 mmol) in H2O (98 mL) was added portionwise. The reaction was stirred for 45 min, then diluted with EtOAc and quenched with aqueous HCl solution (10%) to pH 5-6. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residual oil was purified by flash chromatography (SiO2, eluent:gradient 25% to 50% EtOAc/hexane) to provide 1-(tert-butyldimethylsilyl)-4(R)-(hydroxymethyl)azetidin-2-one (8.46 g, 60% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ3.74-3.69 (m, 1H), 3.65-3.56 (m, 2H), 3.1-2.98 (m, 1H), 2.81-2.76 (m, 1H), 2.01 (s, 1H), 0.89 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H). FAB MS m/z 216.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1I)[C:16]#[N:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[CH:24]=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(C#N)ccc1I
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OCCCNC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4.5 g (11.2 mmol) of 3-[3-(t-butoxycarbonylamino)propoxy]-4-iodobenzonitrile was dissolved in 20 ml of DMF. 6.0 ml (56 mmol) of ethyl acrylate, 6.2 ml (56 mmol) of triethylamine and 56 mg (0.22 mmol) of palladium acetate were added to the obtained solution, and they were stirred at 100° C. overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@@H:15]1[CH2:19][N:18]([C:20](=[O:33])[C:21]2[CH:26]=[C:25]3[O:27][CH2:28][O:29][C:24]3=[CH:23][C:22]=2[N+:30]([O-:32])=[O:31])[C@@H:17]([C:34]([OH:36])=[O:35])[CH2:16]1>CC(C)=O.O>[O:14]=[C:15]1[CH2:19][N:18]([C:20](=[O:33])[C:21]2[CH:26]=[C:25]3[O:27][CH2:28][O:29][C:24]3=[CH:23][C:22]=2[N+:30]([O-:32])=[O:31])[CH:17]([C:34]([OH:36])=[O:35])[CH2:16]1
Reactant: O=C(O)[C@H]1C[C@H](O)CN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC(C(=O)O)N(C(=O)c2cc3c(cc2[N+](=O)[O-])OCO3)C1
Reaction time: 2 h

Procedure:
15 ml of Jones reagent (aqueous chromic and sulfuric acid solution) are added dropwise to a solution of 8 g (0.025 mole) of trans-4-hydroxy-1-(4,5-methylenedioxy-2-nitrobenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 1, in 500 ml of acetone. The reaction mixture is stirred for 2 hours. The acetone is removed under vacuum. The residue obtained is taken up in water. The precipitate is separated, dried and recrystallized in a V/V mixture of methanol and petroleum ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.C(O)C.[OH-].[Na+]>CC(O)C.Cl>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2F)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 68.1 %

Procedure:
To a solution of ethyl 2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.54 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.074 g, 0.50 mmol) in 2-propanol (2.5 mL), 2M hydrochloric acid in ethanol (0.25 mL, 0.50 mmol) was added at ambient temperature then refluxed for 24 h. Cooled with ice bath, aqueous 2M sodium hydroxide solution (0.024 mL, 0.048 mmol) was added dropwise to neutralize and the mixture was refluxed for 1 h. The precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.14 g, y. 69%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.N12CCCN=C1CCCCC2.[C:23]1([CH2:29][SH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:29]([S:30][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1cc(Cl)ccn1
Reactant: SCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(SCc2ccccc2)ccn1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
4-Chloro-2-(trifluoromethyl)pyridine (141 μl, 1.102 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (199 μl, 1.322 mmol), and phenylmethanethiol (129 μl, 1.102 mmol) were dissolved in dry dimethylformamide (2 mL). The reaction mixture was heated at 100° C. in a microwave for 30 minutes, then partitioned between ether (25 mL) and water (25 mL). The aqueous layer was extracted with ether (2×25 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-30% ethyl acetate in isohexane) to afford 4-(benzylthio)-2-(trifluoromethyl)pyridine (224 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.79 min, m+H=270.1.
Reaction SMILES: C1COCC1.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:9]([F:21])[CH:8]=1.[C:22](=[O:24])=[O:23]>Cl>[F:21][C:9]1[CH:8]=[C:7]([C:22]([OH:24])=[O:23])[CH:12]=[CH:11][C:10]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1
Reactant: O=C=O
Reactant: Fc1cc(F)cc(-c2ccc(Br)cc2F)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(F)cc(F)c2)c(F)c1
Temperature: 25 °C

Procedure:
In a reactor under an N2-atmosphere, 100 ml of a 1.3M THF solution of isopropyl magnesium chloride/lithium chloride complex (130 mmol) was added and then stirred at room temperature, 28.7 g (100 mmol) of 4-bromo-2,3′,5′-trifluoro-1,1′-biphenyl was slowly added, and then the mixture was stirred at room temperature for 2 hours. Next, while the mixture was cooled to 5-15° C. by an ice bath, dried CO2 gas was blown in without heat generation. The reaction solution was poured in 200 ml of 2N HCl(aq) and extracted by diethyl ether. After the organic layer was collected, washed by saturated saline and dried by anhydrous magnesium sulfate, it was filtered to remove the insoluble substance and concentrated under a reduced pressure. The residue was purified by a fractionation operation utilizing column chromatography, with ethyl acetate as an eluent solvent and silica gel as a filler. The product was further purified by recrystallization using heptane/ethanol in a volume ratio of 30/70, so that 10.3 g of 2,3′,5′-trifluoro-1,1′-biphenyl-4-carboxylic acid was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:10]/[OH:11])/[CH3:9].Cl[CH2:13][CH2:14][CH2:15][OH:16]>>[OH:16][CH2:15][CH2:14][CH2:13][O:11]/[N:10]=[C:8](/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])\[CH3:9]
Reactant: C/C(=N\O)c1ccccc1N
Reactant: OCCCCl
Product: C/C(=N\OCCCO)c1ccccc1N

Procedure:
In Scheme 3, Compound (α1) is reacted with hydroxylamine hydrochloride to obtain (E)-1-(2-aminophenyl)ethanone oxime (Compound (a4)). Compound (a4) is reacted with 3-chloropropan-1-ol to obtain (E)-1-(2-aminophenyl)ethanone O-3-hydroxypropyl oxime (Compound (a5)). Compound (a5) is then reacted with p-pivaloyloxybenzenesulfonyl chloride to obtain the compound of formula (I). The following Compound (7) in Preparation Examples 6 was prepared using Scheme 3.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=O)=[O:12].[C:35]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:16][CH2:17][C:18]([N:45]1[CH2:44][CH2:43][N:42]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:47][CH2:46]1)=[O:20])=[O:12]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1nc2ccccc2s1
Reaction time: 8 h

Procedure:
To a solution of (S)-5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoic acid (˜4.41 mmol) in DMF (8 mL) at RT were added N-Boc-piperazine (820 mg, 1 equiv.), DIEA (1.2 mL, 1.5 equiv.), and HBTU (2.00 g, 1.2 equiv.) The reaction was allowed to stir overnight, and the crude was purified by RP-HPLC (5-100% ACN in H2O) to give (S)-tert-butyl 4-(5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate as a white solid (801 mg, 27% over 2 steps). LRMS (M+Na+)=699.4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34]>CC(O)C>[OH:37][C:32]1([C:33]([F:36])([F:35])[F:34])[CH2:31][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)=[N:13]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(-c3cccs3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(-c3cccs3)cc2)cc1
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a mixture of N-[4-(methylsulfonyl)phenyl]-4-(2-thienyl)benzenecarboximidamide (0.7 g. 1.96 mmol) and sodium bicarbonate (0.33 g, 3.93 mmol) in 2-propanol (30 mL) was added 3-bromo-1,1,1-trifluoroacetone (0.449 g, 2.35 mmol). After the reaction mixture was heated to 80° C. for 21 hours, the solvent was removed. The residue was redissolved in CH2Cl2 (50 mL) and washed with water (30 mL×2). The organic fractions were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (2/1) to give the subtitle compound (0.351 g, 30.1% yield, via 2 steps).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:11]([NH2:14])(=[O:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][CH2:12][C:11]([NH2:14])=[O:13])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(N)=O
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)COc1cccnc1Br
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 2-bromo-3-pyridinol (1.5 g, 8.49 mmol) in tetrahydrofuran (15 mL) at 0° C. is added 60% sodium hydride in mineral oil (509.44 mg, 12.74 mmol) and the mixture is stirred at that temperature for 30 min. Then acetamide, 2-chloro-(16.98 mmol) is added and the mixture is stirred at room temperature over the weekend. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is separated dried on magnesium sulfate and the solvent evaporated in vacuo to give the title compound in a 75% yield. The compound is used without any further purification. MS (m/z): 231 (M+1), 233 (M+3).