Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH:16]=O.O.OOS([O-])=O.[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:16]([C:15]3[C:14]([Cl:13])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:22])[NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,4-diaminobenzoic acid methyl ester (3.32 g, 20 mmol) and 2,6-dichlorobenzaldehyde (3.5 g, 20 mmol) in DMF (20 mL)+water (2 mL) was added oxone (2.46 g, 4 mmol). The mixture was stirred at RT for 18 h then EtOAc was added. The mixture was washed with water and brine then was dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:47]=[CH:46][O:45][CH:44]=1>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:47]=[CH:46][O:45][CH:44]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccoc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccoc3)cc12
Yield: 39.3 %

Procedure:
11 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 800 mg of N-[6-chloro-5-(3-furyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate and 50 cm3 of saturated sodium hydrogen carbonate solution. The organic phase is separated out after settling of the phases has taken place, washed with 50 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 25 cm3 of diethyl ether, filtered off, washed with 2×10 cm3 of diethyl ether and dried under reduced pressure (90 Pa; 45° C.) to give 220 mg of N-[6-chloro-5-(3-furyl)-1H-indazol-3-yl]butanamide in the form of white crystals melting at 250° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:4](/[CH:5]=[CH:6]\[CH3:7])[C@H:3]1[C:8]([OH:10])=[O:9].[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:14]=1[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:11][C:2]1([CH3:1])[C@H:4](/[CH:5]=[CH:6]\[CH3:7])[C@H:3]1[C:8]([O:10][CH2:22][C:14]1[C:15]([F:21])=[C:16]([F:20])[CH:17]=[C:18]([F:19])[C:13]=1[F:12])=[O:9]
Reactant: C/C=C\[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: OCc1c(F)c(F)cc(F)c1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C/C=C\[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)cc(F)c2F)C1(C)C
Reaction time: 24 h
Yield: 93 %

Procedure:
To a mixture solution of 0.42 g of (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylic acid, 0.49 g of (2,3,5,6-tetrafluorophenyl)methanol, 0.93 g of triphenylphosphine and 20 ml of tetrahydrofuran, 2.0 ml of 40% toluene solution containing diisopropyl azodicarboxylate was added. After one day, the reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give 0.80 g of (2,3,5,6-tetrafluorophenyl)methyl (1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[S:34][CH:35]=[C:36]([CH3:38])[N:37]=1>CCCCCC.C(OCC)(=O)C>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[S:34][CH:35]=[C:36]([CH3:38])[N:37]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1csc(Br)n1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1csc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)n1
Yield: 62 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromo-4-methyl-1,3-thiazole, the title compound was synthesized in the same manner as in Example 107. Yield: 62%. Melting point: 240-241° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>N#[Zr]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: N#[Zr]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated with 14.1 g of a powdered zirconium nitride from H. C. Starck at 140° C. After 2 hours' reaction time, phenol conversion was 9.4%, wherein 2.2 g of phenyl chloroformate and 12.5 g of diphenyl carbonate were formed. Selectivity for carbonates was 92.4%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]=[CH:7][CH:6]=[CH:5]2.C([O:19]C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[CH:1]=[O:19])([O-:14])=[O:13]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc2cccnc2cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=Cc1cc2cccnc2cc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 63.5 %

Procedure:
6-Methyl-7-nitroquinoline (Achylediani,R. et al. Izvestiya Akademii Nauk Gruzii, Seriya Khimicheskaya (1996), 22(1-4), 43-47) (14 g; 74 mmol) was dissolved in DMF (200 ml) and treated with tert.butoxy-bis(dimethylamino)methan (64.5 ml; 313 mmol) at 160° C. for 30 min. The reaction mixture was evaporated and purified by dissolving in THF (30 ml ), adding TBME (1.5 l) and filtering from the brown precipitate. The filtrate was evaporated to dryness and dissolved in THF (300 ml). NalO4 (95.6 g; 446 mmol) dissolved in water (5 l) was added under stirring within 45 min. The reaction mixture was extracted with EtOAc three times, the combined organic phases were dried over Na2SO4, evaporated to dryness and purified via chromatography (SiO2, toluene/TBME 96/10) to yield the title compound as yellowish crystals (9.5 g; 63%), which were used in the following step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([C:20]([OH:22])=O)[S:19][C:11]1=2)([O-:3])=[O:2].C(N1C=CN=C1)([N:31]1C=CN=C1)=O.N>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]2[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([C:20]([NH2:31])=[O:22])[S:19][C:11]1=2)([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2[N+](=O)[O-])c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
A mixture of the compound of Example 123 (105 mg, 0.268 mmol) and 1,1′-carbonyldiimidazole (65 mg, 0.40 mmol) in DMF (3 mL) was stirred at r.t. for 45 min. Concentrated ammonia solution (1 mL) was added and the mixture stirred overnight at r.t. Volatiles were removed in vacuo, the residue taken up in DCM, washed 2M HCl(aq), dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography on silica (4% MeOH in DCM) gave the title compound as a yellow solid (42 mg). δH (DMSO-d6) 8.28 (1H, dd, J 1.3, 8.2 Hz), 7.99 (1H, dt, J 1.4, 7.8 Hz), 7.92 (1H, dd, J 1.4, 7.8 Hz), 7.87–7.82 (1H, m), 7.54–7.47 (3H, m), 7.46–7.37 (3H, m), 6.44 (1H, d, J 9.7 Hz), 6.21 (2H, v br). LCMS (ES+) RT 2.997 minutes, 392.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8](O)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](O)c1cccc(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H](c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of (R)-tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)carbamate (8.12 g, 29.9 mmol) in THF (100 mL) was added phthalimide (6.16 g, 41.8 mmol) and polymer-bound triphenylphosphine (3 mmol of PPh3/1 g of resin, 9.8 g). DTBAD (7.09 g, 30.8 mmol) in THF (20 mL) was added slowly at room temperature to the reaction mixture, which was then stirred at room temperature overnight. The reaction mixture was filtered through Celite and washed with EtOAc. The resulting filtrate was washed with Na2CO3 solution, water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude material was purified by flash chromatography (0-30% EtOAc/heptane) yielding (S)-tert-butyl (2-(3-chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)carbamate (58.4%). LCMS (m/z): 301.1 (MH+-Boc), 1.06 min.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1C(O)C)[CH2:8]2.CC1(C)N([O])C(C)(C)CCC1.[C:25](O)(=[O:27])[CH3:26].C(O)(=O)C.IC1C=CC=CC=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[C:1]12([CH2:26][CH:25]=[O:27])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(=O)O
Reactant: CC(O)C1C2CC3CC(C2)CC1C3
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: O=CCC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
To a flask containing 2-adamantyl-1-ethanol (5 g, 27.7 mmol) in CH2Cl2 (28 mL) was added TEMPO (433 mg, 2.77 mmol) followed by iodobenzene diacetate (9.8 g, 30.5 mmol). The reaction was stirred 1 hour and then diluted with CH2Cl2 (100 mL). Saturated aqueous solution of Na2S2O3 (100 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organics were washed with saturated aqueous NaHCO3 (150 mL) and brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5% Et2O/pentanes) to provide the title compound, which was identical to the reported literature compound (see Luly et al. (1987) J. Org. Chem. 52: 1487).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([Cl:18])[CH:12]=2)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH2:19][CH2:20][CH2:21][SH:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([Cl:18])[CH:12]=2)[S:22][CH2:21][CH2:20][NH2:19])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(B(O)c2ccc(C)c(Cl)c2)cc1Cl
Reactant: NCCS
Solvent: CCO
Product: Cc1ccc(B(SCCN)c2ccc(C)c(Cl)c2)cc1Cl
Yield: 97.5 %

Procedure:
di(3-Chloro-4-methylphenyl)borinic acid (44 mg) and 2-aminoethanethiol (35 mg) were reacted in ethanol (1 mL) to give the title compound (52 mg).
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[C:8]([F:9])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([O:19][CH3:20])[CH:4]=1.[Br:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](Cl)=[N:28][C:29]([CH3:33])=[N:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([C:6]3[CH:7]=[C:8]([F:9])[C:3]([CH:2]([F:1])[F:21])=[CH:4][C:5]=3[O:19][CH3:20])=[N:28][C:29]([CH3:33])=[N:30]2)=[CH:25][CH:24]=1
Reactant: COc1cc(C(F)F)c(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(Cl)c2ccc(Br)cc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(F)F)c(F)cc1-c1nc(C)nc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.095 g, 0.116 mmol), 2-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate SSSSS; 1.290 g, 4.27 mmol), 7-bromo-4-chloro-2-methylquinazoline (ACES Pharma, 1.000 g, 3.88 mmol), and potassium carbonate (2.147 g, 15.53 mmol) in 12 mL dioxane was treated with 4 mL water and was allowed to stir at room temperature overnight. LC/MS showed mostly product, so the reaction mixture was diluted with DCM and filtered through a plug of Celite. The aqueous layer was removed and the organics concentrated. The crude residue was carried on to step 2 without purification. (M+H)+=399.0.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
2-Fluoro-5-nitrobenzaldehyde (0.055 g, 0.33 mmol) was dissolved in N,N-dimethyl-formamide (2.8 mL), and phenol (0.077 g, 0.82 mmol) and potassium carbonate (0.11 g, 0.82 mmol) were added thereto, followed by stirring at 25° C. for 1 hour. After a conventional treatment, the residue was purified by silica gel chromatography (eluted with chloroform), to obtain 5-nitro-2-phenoxybenzaldehyde (77 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[CH:9]1>C(O)=O.[Zn]>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Agent: [Zn]
Solvent: O=CO
Product: CC1=C(c2ccncc2)SCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 3.7 %

Procedure:
To a solution of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (1 g) in formic acid (14 ml), zinc powder (1 g) was added and the reaction mixture was stirred at room temperature for 3 hours. The insoluble solid was removed by filtration. The filtrate was evaporated to dryness and the residue was dissolved in water (30 ml). The solution was adjusted to pH 7.0 by 1N aqueous sodium hydroxide. The precipitates were extracted with chloroform (although the solution was converted into an emulsion at this extracting step, the operation was facilitated by using a filter aid such as "Avicel"). The extract was dried over anhydrous magnesium sulfate and chloroform was removed under reduced pressure. The crude product was purified by the preparative thin layer chromatography [Merck TLC plate, silica gel 60F254 (particles average porous diameter 60A, Fluorescent substance Zn2SiO4 /Mn), 20×20 cm, t=1 mm, chloroform/methanol=20/1] to give 20 mg of 5-methyl-6-(4-pyridinyl)- 2H-1,4thiazin-3(4H)-one. The physical properties were as described above. The aqueous layer left after the chloroform extraction was adjusted to pH 12.5 by 1N aqueous sodium hydroxide and extracted with chloroform (50 ml×3 times). The extract was dried over anhydrous magnesium sulfate and chloroform was removed under reduced pressure. The residual solid was washed with ether and collected by filtration to give 5-methyl-6-(4-piperidinyl)-2H-1,4-thiazin-3(4H)-one (200 mg) as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH3:11])[CH:7]=[CH:8][CH:9]=1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[Cl:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([C:10](=[N:16][OH:17])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: NO
Reactant: CC(=O)c1cccc(OC(F)(F)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1cccc(OC(F)(F)Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 106.4 %

Procedure:
A mixture of 3.3 g of 1-(3-(chloro-difluoro-methoxy)-phenyl)-ethanone, 1.4 g of hydroxylamine hydrochloride and 10 ml of pyridine is stirred at 50° C. for 2 hours. It is then poured into ice-water, extracted with diethyl ether and concentrated using a rotary evaporator, and any pyridine still present is removed azeotropically by means of toluene. Drying under reduced pressure at 60° C. yields 3.75 g of the desired oxime in the form of an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C@H:11]([CH2:16][OH:17])[C@H:12]([CH2:14][CH3:15])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:17][CH2:16][C@@H:11]([NH:10][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])[C@@H:12]([CH3:13])[CH2:14][CH3:15]
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-thiophenesulfonyl chloride (1 g, 5.48 mmol) in CH2Cl2 (5 mL) and (S)-isoleucinol (642 mg, 5.48 mmol) was added Hunig's base (1.05 mL, 6.02 mmol). The reaction mixture was stirred at 25° C. for 24 h. The solvent was removed and the oil was dissolved in EtOAc (100 mL). The solution was washed with water (2×100 mL), brine (1×100 mL), and dried over Na2SO4. The desired sulfonamide (m/z=264.0(M+H), rt=0.79 min) was isolated by semi-preparative RP-HPLC using the conditions outlined for example 195.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[C:14]3=[O:17])=[CH:10][CH:9]=2)[CH2:3]1.CO.[B-][N+](C)(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[F:1][C:2]1([F:24])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][C:13]4([CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]4)[C:14]3=[O:17])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: O=C1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [B-][N+](C)(C)C
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1c2cc(OCC3CC(F)(F)C3)ccc2CC12CCC(O)CC2
Reaction time: 8 h
Yield: 84.4 %

Procedure:
6′-((3,3-Difluorocyclobutyl)methoxy)spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (Intermediate 12, 3.51 g, 10.5 mmol) were dissolved in the mixture of THF (50 mL) and methanol (4.25 mL, 105 mmol). Borane-trimethylamine complex (1.69 g, 23.1 mmol) was added and the mixture was stirred overnight. Citric acid monohydrate (30.9 g, 147 mmol) was added in one portion, followed by dropwise addition of water (3.78 mL, 210 mmol). The mixture was stirred for 3 h before being diluted with water and extracted with EtOAc (×2). The combined organic phases were dried and concentrated. The product was purified using column chromatography (0-10% MeOH in DCM), providing 2.98 g (quantitative yield) of the title compound. MS (ES+) m/z 337 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:9].[O:10]=[C:11]1[NH:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.[F-].[Cs+].CN(C)CCN.[Cl-].[NH4+]>C(#N)C.[Cu](I)I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:15]2[C:11](=[O:10])[CH2:12][C@H:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:14]2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(I)ccc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC(=O)C1
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc(N2C[C@@H](NC(=O)OC(C)(C)C)CC2=O)ccc1Br
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A suspension of 2-bromo-5-iodotoluene (1.5 g), tert-butyl ((S)-5-oxopyrrolidin-3-yl)carbamate (2.7 g), copper iodide (95 mg), cesium fluoride (1.9 g), and N,N-dimethylethylenediamine (0.11 ml) in acetonitrile (20 ml) was stirred at 100° C. for 3 hours under a nitrogen atmosphere. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a 10% aqueous sodium thiosulfate solution and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (1.8 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:29][C:28]([CH2:30][NH:38][CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)o1

Procedure:
5-(4-(4-phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde (0.05 g) was reacted with 2-(methanesulphonyl)ethylamine (0.075 g) according to procedure D. Acidification with acetic acid (0.5 ml) followed by purification using a ion-exchange (SCX) Bond Elut™ cartridge, eluting with methanol-ammonia (9:1), concentration and trituration with diethylether afforded an off-white solid; δ H [2H6] DMSO 8.44 (1H, d), 8.41 (1H, d), 8.11 (1H, s), 7.85 (1H, d), 7.44-7.35 (4H, m), 7.18-7.03 (6H, m), 6.79 (1H, d), 6.47 (1H, d), 3.82 (2H, s), 3.01 (2H, t); m/z 514 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]([C:24]#[C:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[F-].[Cs+]>COCCOC.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:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([C:10]2[CH:2]=[C:3]3[C:7](=[CH:8][CH:9]=2)[CH:6]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C@@H:18]([C:24]#[C:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=2)[CH2:5][CH2:4]3)[CH:32]=[CH:33][CH:34]=1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OC2CCc3c(Br)cccc32)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OC2CCc3cc(-c4cccc(C(F)(F)F)c4)ccc32)cc1
Temperature: 95 °C

Procedure:
A mixture of 1.3 (74 mg, 0.18 mmol), 4-(trifluoromethyl)phenylboronic acid (45.8 mg, 0.22 mmol) and CsF (56 mg, 0.37 mmol) in 1,2-dimethoxyethane (2 mL), was degassed with N2 for 3 minutes. Pd(PPh3)4 (21 mg, 0.018 mmol) was added, and the resulting mixture was heated at 95° C. for 8 hours. After cooling, the reaction mixture was quenched with water and extracted with EtOAc providing 1.4 (20 mg), which was directly hydrolyzed in the next step.