Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:23]([O:26][CH2:27][CH3:28])([CH3:25])[CH3:24])[C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:10][O:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:23]([O:26][CH2:27][CH3:28])([CH3:24])[CH3:25])[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: [H][H]
Reactant: CCOC(C)(C)C(Oc1nc(OC)nc(OC)n1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(C)(C)C(Oc1nc(OC)nc(OC)n1)C(=O)O
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
That is, in 200 ml of ethanol were dissolved 39.2 g (0.1 mol) of Compound 155 prepared in the above (6), and 0.5 g of palladium carbon was added thereto as a catalyst. The mixture was stirred at room temperature (20° C.) for 1 hour while blowing hydrogen therein. Subsequently, the catalyst was removed by filtration, and the mother liquor was concentrated to obtain 28.6 g (yield: 95%) of the title compound as a colorless oily product.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][N:16]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:17][CH2:18][CH2:19][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:48](Br)[CH:49]=[CH2:50]>CN(C=O)C>[CH2:50]([N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:23][CH2:22][CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:49]=[CH2:48]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCN(CCC1CCCCN1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCCN(CCCN(CCC1CCCCN1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 1.13 g (1.758 mmol) of 1-[2-[(N-BOC)-2-piperidyl]-ethyl]-1,5,9-tri-BOC-1,5,9-triazanonane in 11.3 ml of DMF there are added, with stirring, 0.14 g (3.5 mmol) of sodium hydride dispersion (approximately 60%) and, after 10 minutes, 0.296 ml (3.5 mmol) of allyl bromide (Fluka, Buchs, Switzerland). The reaction mixture is stirred at room temperature for 15 hours and then a further 1/3 of the original amount of sodium hydride dispersion (approximately 60%) and a further 1/3 of the original amount of allyl bromide are added, the reaction mixture is stirred at room temperature for a further 24 hours and is then concentrated by evaporation in vacuo. The residue is partitioned between water and methylene chloride, and the organic phase is washed with brine, dried over sodium sulfate and concentrated by evaporation. After purification of the residue by flash chromatography on silica gel having a particle size of 0.04-0.063 mm using a hexane/tert-butyl methyl ether mixture (7:3), the title compound is obtained in the form of a resin, Rf value=0.34 (silica gel/methylene chloride:methanol (30:1)).
Reaction SMILES: 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.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][CH2:41]O.[C:43]([OH:51])(=[S:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.C(OCC)(=O)C>[C:43]([S:50][CH2:41][CH2:40][C:36]1[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=1)(=[O:51])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: OC(=S)c1ccccc1
Reactant: Cn1ccnc1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1ccnc1CCSC(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (10.48 g) was dissolved in tetrahydrofuran (120 ml). To the solution were added diisopropyl azodicarboxylate (8.07 g) at 0° C. The mixture was stirred for 15 minutes at the same temperature. To the mixture were added a solution of 2-(1-methyl-2-imidazolyl)ethanol (2.52 g) in tetrahydrofuran (10 ml) and thiobenzoic acid (4.7 ml) in the order mentioned. The mixture was stirred for 2.5 hours at 0° C. and then for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, then washed with saturated solution of sodium hydrogencarbonate in water and saturated solution of sodium chloride in water in the order mentioned. The residue was dried over anhydrous sodium sulfate and concentrated under reduced pressure, which was then subjected to column chloromatography on silica gel (developing solvent: ethyl acetate-methanol: 100:0→93:7) to give the title compound (3.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CSc1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
To 10 ml of an ethanol solution of 1.5 g of 4,6-dichloropyrimidine was slowly added 0.78 g of sodium thiomethoxide at 0° C., followed by stirring at 0° C. for 7 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture and concentrated under reduced pressure. The residue was extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.1 g of 4-chloro-6-methylthiopyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[C:9]=2[O:16][CH3:17])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[O:15])[C:9]=2[O:16][CH3:17])=[CH:6][CH:7]=1
Reactant: COc1c(CO)cccc1-c1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1c(C=O)cccc1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a solution of (4′-chloro-2-methoxybiphenyl-3-yl)methanol (800 mg, 3.21 mmol, 1.0 eq) in dry DCM at 0° C. was added pyridinium chlorochromate (3.0 g, 3.91 mmol, 4.3 eq). The reaction mixture was stirred for 1 h, filtered on a silica pad and washed with DCM. The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to afford the desired product (0.430 g, 54%). 1H NMR (400 MHz, CD3OD) δ 3.83-3.94 (s, 3H), 7.02-7.05 (t, 1H), 7.14-7.16 (d, 1H), 7.46-7.48 (t, 1H), 7.57-7.59 (t, 1H), 7.61-7.63 (m, 2H), 7.74-7.76 (d, 1H). MS (ESI): 248.0 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]([C:20]1[S:21][CH2:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][C@:24]2([C:29]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[C:31]([Cl:44])[CH:30]=2)[N:25]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.[Cl-].[Na+].O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:5]([O:9][C:10]([N:12]([C:20]1[S:21][CH2:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][C@:24]2([C:29]2[CH:30]=[C:31]([Cl:44])[CH:32]=[C:33]([N:1]=[N+:2]=[N-:3])[CH:34]=2)[N:25]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Cl)cc(B4OC(C)(C)C(C)(C)O4)c3)CCC[C@H]2CS1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Cl)cc(N=[N+]=[N-])c3)CCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 144 h
Yield: 14 %

Procedure:
Sodium azide (53 mg) and copper (II)acetate (19.9 mg) were added to a solution of (±)-N,N-bis(t-butoxycarbonyl){(4aR*,7aS*)-7a-[3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl}amine (1.16 g) in methanol (20 mL). The mixture was stirred at room temperature for six days. Brine was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (58.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[O:33]C)[CH2:5][N:6]1[C:14]2[CH:13]=[C:12]3[NH:15][C:16]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17][C:11]3=[CH:10][C:9]=2[C:8]([CH3:28])([CH3:27])[C:7]1=[O:29].B(Br)(Br)Br.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:5][N:6]1[C:14]2[CH:13]=[C:12]3[NH:15][C:16]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17][C:11]3=[CH:10][C:9]=2[C:8]([CH3:28])([CH3:27])[C:7]1=[O:29]
Reactant: COc1ccc(CN2C(=O)C(C)(C)c3cc4nc(NC(=O)c5ccccc5)[nH]c4cc32)cc1F
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC1(C)C(=O)N(Cc2ccc(O)c(F)c2)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
N-[5-(3-Fluoro-4-methoxy-benzyl)-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (105 mg) is suspended in a BBr3 solution in CH2Cl2 (1 M; 700 μl) and stirred at RT for 18 h. After addition of hydrochloric acid (400 μl; 1 N) the mixture is stirred at RT for another 1 h and then evaporated to dryness. The crude material is purified by preparative RP-HPLC, eluted with MeCN/water to yield the desired compound (25 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:11]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:17]=2B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[CH:11]1([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:17]=2[C:2]2[CH:3]=[C:4]([OH:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH2:12][CH2:13]1
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1cc(Br)cc(O)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(O)c(=O)n(C)c2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a mixture of 5-bromo-3-hydroxy-1-methylpyridin-2-one (1.00 g, 4.9 mmol), 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.80 g, 4.9 mmol) in dioxane (30 mL) and H2O (5 mL) was added K3PO4 (3.12 g, 14.7 mmol), Pd(dppf)Cl2 (358 mg, 0.49 mmol). After purging the mixture with nitrogen, the mixture was stirred at 90° C. under microwave irradiation for 1 h. After the mixture was filtered, the filtrate was concentrated to dryness. The resulting residue was purified by prep-HPLC to give the title compound (0.9 g, 51%) as a purple solid. 1H NMR (CDCl3, 400 MHz) δ 7.81 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.16-7.15 (m, 2H), 3.95 (d, J=6.8 Hz, 2H), 3.70 (s, 3H), 3.12 (q, J=7.6 Hz, 2H), 1.32-1.27 (m, 4H), 0.70-0.67 (m, 2H), 0.39-0.36 (m, 2H). LCMS (M+H)+=364.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.C(#N)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>O.ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CCc1ncnc(Cl)c1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCc1ncnc(Sc2ccc(Cl)cc2)c1F
Temperature: 25 °C
Yield: 83.8 %

Procedure:
61.0 g of 4-chloro-6-ethyl-5-fluoropyrimidine was added to 600 ml of acetonitrile, and 60.4 g of 4-chlorothiophenol was added thereto followed by lowering the temperature to 10° C. 66.1 ml of diisopropylethylamine was added to the resulting solution, and reacted for 2 hours while maintaining the temperature at room temperature. 100 ml of dichloromethane and 300 ml of water were added to the resulting mixture to separate layer, and the resulting aqueous mixture was extracted with 300 ml of dichloromethane. The organic layer was dried over magnesium sulfate, concentrated under a reduced pressure, and crystallized at 5° C. in 305 ml of isopropanol and 122 ml of water to obtain the white title compound (85.6 g). Then, the filtrate was additionally concentrated under a reduced pressure, and crystallized at 5° C. in 30 ml of isopropanol to obtain 12.3 g of the title compound (total: 97.9 g, total yield: 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[C:12]3[C:17]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:16][CH:15]=[N:14][C:13]=3[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Nc4ccc(F)cc4OC4CCOCC4)c23)C1
Temperature: 120 °C
Yield: 19.5 %

Procedure:
A solution of 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (prepared according to WO2007/109279, 0.141 g, 0.43 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.092 g, 0.44 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and then heated at 120° C. for 5 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc) followed by trituration with MeOH afforded the title compound as white solid (0.042 g, 20%).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([C:15]3[CH:24]=[CH:23][C:22]4[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=4[CH:16]=3)=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42]([C:44]3[CH:53]=[CH:52][C:51]4[C:50]([CH3:55])([CH3:54])[CH2:49][CH2:48][C:47]([CH3:57])([CH3:56])[C:46]=4[CH:45]=3)=O)[CH:38]=2)[C:33]=1[CH2:58][CH3:59])(=[O:31])=[O:30])[CH3:2].Cl>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH2:1]([C:3]1[C:12]2[CH:11]=[CH:10][C:9](=[CH:13][C:15]3[CH:24]=[CH:23][C:22]4[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:27])([CH3:28])[C:17]=4[CH:16]=3)[CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[CH2:38][C:37](=[CH:42][C:44]3[CH:53]=[CH:52][C:51]4[C:50]([CH3:55])([CH3:54])[CH2:49][CH2:48][C:47]([CH3:57])([CH3:56])[C:46]=4[CH:45]=3)[CH:36]=[CH:35][C:34]=2[C:33]=1[CH2:58][CH3:59])(=[O:31])=[O:30])[CH3:2]
Reactant: CCc1c(S(=O)(=O)c2ccc3cc(C(=O)c4ccc5c(c4)C(C)(C)CCC5(C)C)ccc3c2CC)ccc2cc(C(=O)c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(S(=O)(=O)c2ccc3c(c2CC)C=CC(=Cc2ccc4c(c2)C(C)(C)CCC4(C)C)C3)ccc2c1C=CC(=Cc1ccc3c(c1)C(C)(C)CCC3(C)C)C2
Reaction time: 1 h

Procedure:
A suspension of 0.50 g of ethyl 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbonyl]-2-naphthylsulfone, described in Example XIV, in 10 cm3 of glacial acetic acid and 0.65 g of powdered zinc is heated at reflux with stirring for 1 hour. There is then slowly added 0.9 cm3 of concentrated HCl. Reflux is again maintained for one hour after the end of the addition of the HCl and there is again added 0.9 cm3HCl. The mixture is then brought for one hour again to the boiling temperature of acetic acid and then left to stand overnight. The next day the reaction mixture is poured into 20 cm3 of 6N HCl and extracted three times with 30 cm3 of ethyl ether. The combined ether phases are washed with water, decanted and dried on sodium sulfate. After evaporation of the solvent 0.5 g of yellow powder is obtained which is then dissolved in methylene chloride. The solution is deposited on a silica gel chromatography column. After concentration of the fractions containing the pure expected product and drying, 0.32 g of ethyl 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methylene]-2-methylsulfone in the form of white crystals whose melting point is 174° C. is obtained.
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>O1CCOCC1>[C:1]1([S:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:14][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: O=S(=O)(c1ccccc1)C1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)C1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 55 %

Procedure:
To a microwave vial were charged 4-(phenylsulfonyl)piperidine (300 mg, 1.33 mmol), 2-chloro-3-(trifluoromethyl)pyridine, (484 mg, 2.66 mmol), diisopropylethylamine (0.695 mL, 3.99 mmol) and 1,4-Dioxane (0.2 mL). The reaction mixture thus prepared was irradiated at 200° C. for 1 hour. The reaction was complete as determined by TLC. The residue was added with saturated NH4Cl (aq.) and extracted with ethylacetate, washed with 10% HCl (aq.), water then brine. Organic layer was dried over MgSO4. Solvent evaporation afforded 2-[4-(phenylsulfonyl)piperidin-1-yl]-3-(trifluoromethyl)pyridine in 55% yield (270 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:18]#[N:19])[C:7]=1[C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[F:17].O.O.[Sn](Cl)Cl>O1CCCC1.C(O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]([C:7]2[C:6]([C:18]#[N:19])=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[CH:13]=1
Reactant: N#Cc1cccc(F)c1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cccc(F)c1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6,2′-Difluoro-5′-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) in tetrahydrofuran (20 mL) and ethanol (20 mL) was treated with tin(II) chloride dihydrate (9.86 g, 43.8 mmol) and the mixture left to stir at ambient temperature for 18 h. The solvent was evaporated and the residue stirred with 2 N sodium hydroxide solution (40 mL) for 2 h. The resulting suspension was diluted with water (100 mL) and extracted with dichloromethane (3×200 mL). The combined organics were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give 5′-amino-6,2′-difluorobiphenyl-2-carbonitrile as a brown oil (2.87 9,100%): δH (360 MHz, CDCl3) 3.74 (2H, s), 6.68 (1H, m), 6.73-6.77 (1H, m), 7.02 (1H, dd, J 9 and 9), 7.37-7.49 (2H, m), 7.56-7.65 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][CH2:6]2.Cl.[N:16]1[O:17][N:18]=[C:19]2[CH:24]=[C:23]([CH2:25][O:26][NH2:27])[CH:22]=[CH:21][C:20]=12.N1C=CC=CC=1.[N+](C1C=CC(CO/N=C2\CCCC3C\2=CC(OC)=C(OC)C=3)=CC=1)([O-])=O>C(O)C.C(OCC)(=O)C.CCCCCC>[N:16]1[O:17][N:18]=[C:19]2[CH:24]=[C:23]([CH2:25][O:26]/[N:27]=[C:8]3\[CH2:7][CH2:6][C:5]4[C:9]\3=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:22]=[CH:21][C:20]=12
Reactant: NOCc1ccc2nonc2c1
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: COc1cc2c(cc1OC)/C(=N/OCc1ccc([N+](=O)[O-])cc1)CCC2
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc2c(cc1OC)/C(=N/OCc1ccc3nonc3c1)CC2
Yield: 85.3 %

Procedure:
5,6-Dimethoxy-1-indanone (38 mg, 0.19 mmol) was subjected to reaction with O-(benzo[c][1,2,5]oxadiazol-5-ylmethyl)hydroxylamine hydrochloride (39 mg, 0.19 mmol) in ethanol (2 mL) and pyridine (0.2 mL, 2.58 mmol) under the same conditions as described for (E)-6,7-dimethoxy-3,4-dihydronaphthalen-1(2H)-one O-4-nitrobenzyl oxime. Subjection of the material obtained on work up to flash chromatography (3:7 v/v ethyl acetate/hexane elution) afforded the title compound as off-white crystals (55 mg, 82%), m.p. 163-166° C., Rf 0.4.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C@@H:3]([NH:7][S:8]([C:11]1[CH:21]=[CH:20][C:14]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O.CN(C=O)C>ClCCl>[CH3:1][CH:2]([CH3:22])[C@@H:3]([NH:7][S:8]([C:11]1[CH:21]=[CH:20][C:14]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])[C:4]([Cl:26])=[O:5]
Reactant: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)Cl)C(C)C)cc2s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic acid (54 mg, 0.15 mmol) prepared in Example 14 was dissolved in dichloromethane (2 mL) and cooled down to 0° C., and added oxalylchloride (0.04 mL, 3 equi.) and DMF of catalytic amount. The reaction solution was subjected at room temperature for 3 hours. Then, the reaction solution was distilled and dried under reduced pressure to remove the solvent. And then, (2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl) amino]butanoic chloride thus obtained was dissolved in THF (1 mL). Hydroxylamine hydrochloride (0.11 g, 10 equi.) and NaHCO3 (0.15 g, 12 equi.) were dissolved in THF/H2O (1 mL/1 ml) and cooled down to 0° C. The above acid chloride THF solution was slowly added to hydroxylamine solution while maintaining the temperature of 0° C. The solvent was removed from the reaction solution after 1 hour. Then, the product was extracted with ethylacetate (5 mL) and washed with H2O and 0.1N HCl, dried over MgSO4, distilled under reduced pressure and dried under vacuum, to prepare the titled compound, (2R)-N-hydroxy-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butyric amide(50 mg, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9].[ClH:35].C(O)C.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:35].[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Yield: 68 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 68% of theory, C25H24N6O3S (488.57) Rf value: 0.14 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) EKA mass spectrum: (M+H)+ =489
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Mg].[CH:14](=[O:18])[CH:15]([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH:14]([C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[OH:18]
Reactant: CC(C)C=O
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Mg]
Product: CC(C)C(O)c1ccc(OC(F)(F)F)cc1

Procedure:
The target compound is obtained analogously to method described for Example 1a). First of all a Grignard is prepared from 23.7 g (96 mmol) 1-bromo-4-(trifluoromethoxy)-benzene and 2.35 g (97 mmol) magnesium, which is then reacted with 7.3 g (100 mmol) isobutyraldehyde. After working up and purification by column chromatography 14.8 g of a brown oil are obtained which is further reacted directly.