Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH3:11])[C:3]=1[C:12]1[S:13][CH:14]=[C:15]([CH3:17])[N:16]=1.[CH:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C:20]1[C:26]([O:28][C:29](=[O:30])[C:19]2=1)=[O:27]>CC#N.CN(C1C=CN=CC=1)C>[CH3:10][O:9][C:7]([C:5]1[S:6][C:2]([NH:1][C:29]([C:19]2[CH:18]3[CH2:25][CH2:24][CH:21]([C:20]=2[C:26]([OH:28])=[O:27])[CH2:22][CH2:23]3)=[O:30])=[C:3]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:4]=1[CH3:11])=[O:8]
Reactant: O=C1OC(=O)C2=C1C1CCC2CC1
Reactant: COC(=O)c1sc(N)c(-c2nc(C)cs2)c1C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COC(=O)c1sc(NC(=O)C2=C(C(=O)O)C3CCC2CC3)c(-c2nc(C)cs2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of methyl 5-amino-3-methyl-4-(4-methylthiazol-2-yl)thiophene-2-carboxylate (61 mg, 227 μmol, Int1.2) in CH3CN (7 mL) were added DMAP (55.5 mg, 455 μmol) and bicyclo[2.2.2]oct-2-ene-2,3-dicarboxylic anhydride (40.5 mg, 227 μmol, CAS RN 151813-29-5). After stirring at RT for 3 h, the reaction mixture was stirred at 65° C. overnight. The reaction mixture was extracted with EtOAc and 1M aqueous HCl, the organic layer was dried over Na2SO4, filtered and evaporated. The compound was purified by silica gel chromatography using a mixture of CH2Cl2:MeOH (20:1 v/v) as eluant. Brown solid. MS (ESI): m/z=447.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7](=O)[CH2:8][CH2:9][CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:7]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCC=O
Reactant: Nc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCCCNc1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-aminothiazole (1 g, 10 mmol) and butyraldehyde (1.44 g, 20 mmol) were mixed in dichloroethane (45 ml) and then treated with sodium triacetoxyborohydride (6 g, 28 mmol) and acetic acid (3.6 g 60 mmol). The reaction mixture was stirred at r.t. under a nitrogen atmosphere overnight. The reaction mixture then was quenched by 1N NaOH and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, brine and dried over MgSO4. The solvent was evaporated to give 2-butylaminothiazole as a brown residue (1.02 g).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH3:10][CH:11]([Si:13](Cl)([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:12].N1C=CN=C1>CCOC(C)=O>[CH:11]([Si:13]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:3][C:2]1[CH:4]=[CH:5][CH:6]=[CH:7][C:1]=1[O:8][CH3:9])([CH3:12])[CH3:10]
Reactant: COc1ccccc1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: COc1ccccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 180 °C
Yield: 69 %

Procedure:
Guaiacol (2-methoxy-phenol, 34.6 mmol) is mixed with TIPSCl (51.9 mmol) and imidazole (103.8 mmol) in a tube. The mixture is heated in the microwave oven at 180° C. for 3 minutes. The oily mixture is diluted with EtOAc (100 mL) and washed with NaHSO4 (1 M) (2×50 mL) and brine (50 mL). After drying over anhydrous Na2SO4, the filtrate is concentrated. The resultant crude mixture is purified by silica flash chromatography (2% EtOAc/hexane) to yield triisopropyl-(2-methoxy-phenoxy)-silane as a colorless oil. Yield: 69%. 1H NMR (400 MHz, CDCl3) δ 6.8-6.89 (m, 4H), 3.8 (s, 3H), 1.22-1.28 (m, 3H), 1.1 (s, 9H), 1.08 (s, 9H). LC/MS (ES+): (M+1), 281.2. Rf=0.8 (5% EtOAc/hexane). (Note: Alternatively, conventional heating might be adopted in which case NMP is the solvent of choice).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C@@H:12]2[CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[CH3:24])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CNCCN1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
1,1-Dimethylethyl (3S)-4-[(4-chlorophenyl)sulfonyl]-3-methyl-1-piperazinecarboxylate (may be prepared as described in Description 3) (crude weight 24.14 g, theoretical 49.9 mmol) was suspended in 4M HCl in 1,4-dioxane (80 mL, excess) and stirred vigorously for 3 hours. The sample was evaporated, suspended in diethyl ether (100 mL) and filtered through a sinter. The collected solid was dried under vacuum at 40° C. for 18 hours to yield the title compound as a yellow solid (15.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(N(C(C)C)CC)(C)C>>[CH2:27]([O:26][C:24](=[O:25])[NH:22][CH2:21][CH2:20][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNC(=O)OCc2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethylamine (150 mg in 1.5 mL methylene chloride) at -78° C. was added benzyl chloroformate (0.08 mL) and diisopropylethyl amine (0.093 mL) and the mixture warmed to 0° C. After 40 minutes, the reaction was quenched by the addition of saturated ammonium chloride, extracted with ethyl acetate and the organic portion dried over sodium sulfate. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 2:1) gave the title compound (220 mg).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 48 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmium tetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g, 5.5 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 0.46 g (48%) of desired product. MS (m/z): 526 (M+).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>CN(C1C=CN=CC=1)C.C(#N)C>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH:17][S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([CH3:21])([CH3:22])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(C)(C)c1nc2cc(N)ccc2n1CC1CCCCC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCC(C)(C)c1nc2cc(NS(=O)(=O)N(C)C)ccc2n1CC1CCCCC1
Yield: 76.8 %

Procedure:
DMAP (80.1 mg, 0.65 mmol) was added to a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-amine (69.5 mg, 0.18 mmol) (for preparation, see the following steps B, C, D, E and F) in acetonitrile (10 mL) at 0° C., followed by addition of dimethylsulfamoyl chloride (22 uL, 28.7 mg, 0.20 mmol). The resulting mixture was heated at reflux for 20 h and then quenched with MeOH (2 mL). After evaporation of the solvent, the residue was dissolved in EtOAc (100 mL) and washed with NaCl aqueous solution (10 mL) and dried over Na2SO4. After filtration and evaporation, the residue was purified by MPLC (hexanes/EtOAc 1:1 as eluent on silica gel) to give the title compound as a white solid (56.2 mg, 76%), which was converted to a white solid as a TFA salt. 1H NMR (400 MHz, CD3OD): δ 0.84 (t, J=7.52 Hz, 3H), 1.24 (m, 5H), 1.64 (m, 2H), 1.66 (s, 6 μl), 1.71 (m, 1H), 1.78 (m, 2H), 2.01 (q, J=7.55 Hz, 2H), 2.11 (m, 1H), 2.82 (s, 6H), 4.44 (d, J=7.81 Hz, 2H), 7.37 (dd, J=8.98, 2.15 Hz, 1H), 7.69 (d, J=2.15 Hz, 1H), 7.84 (d, J=8.98 Hz, 1H); MS (ESI) (M+H)+: 407.3; Anal. Calcd for C21H34N4O2S+1.0 TFA+0.2 H2O: C, 52.70; H, 6.81; N, 10.69. Found: C, 52.70; H, 6.66; N, 10.45.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([NH:28][CH:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1)[CH3:27].C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:28]([CH2:26][CH3:27])[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl)C1CCNCC1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, tert-butyl 4-ethylaminopiperidin-1-ylcarboxylate, PFTU, and diisopropylethylamine in DMSO at ambient temperature and subsequent reaction with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 3.87 minutes; C24H27Cl2N5O2 (488.42); mass spectrum: (M−H)−=487/489/491 (chlorine isotope).
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[OH:9][CH2:10][C:11]([C@H:13]([C@@H:15]([C@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])=[O:12]>O>[CH2:19]([OH:20])[C@H:17]([OH:18])[C@@H:15]([OH:16])[C@H:13]([OH:14])[C:11]([C:10]([OH:2])=[O:9])=[O:12]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 38 h

Procedure:
Gluconobacter oxydans L-8 (FERM-P No. 8355) was cultivated in a 30 l jar fermentor in the same manner as described in Example 5. After 38 hours of cultivation, 1.5 l of the culture was harvested to obtain the cells. 10 g of the cells were suspended into 60 ml of 10 mM potassium phosphate buffer (pH, 7.0) and homogenized by a Dyno mill homogenizer (Willy, A. Bachofen Co.) with glass beads at 2000 rpm for 4 minutes at 4° C. The homogenate was centrifuged at 5000 rpm for 10 minutes to remove the intact cells. 2 ml of the supernatant thus obtained was mixed with 1 ml of 0.5M potassium phosphate buffer (pH, 7.0) and 6 ml of water containing 100 mg of L-sorbose and incubated at 30° C. for 4 hours. As a result, 25 mg of 2-keto-L-gulonic acid was formed.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH2:12].CO>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:1](=[O:3])[CH3:2])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1Br
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
Acetic anhydride (3.11 ml, 3.37 g, 33 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 3-bromo-4methoxyaniline (6.06 g, 30 mmol) in dichloromethane (60 ml). The mixture was stirred at room temperature for 90 minutes, methanol (10 ml) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) and water (50 ml) were added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous hydrochloric acid (1M, 100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate (20 ml)/hexane (50 ml) and the solid was collected and dried in vacuo to give the title compound as a tan solid (6.41 g, 88%), 1H NMR (360 MHz, CDCl3) δ 7.68 (1H, d, J=2.5 Hz), 7.45 (1H, dd, J=8.8, 2.5 Hz), 7.36 (1H, br s), 6.84 (1H, d, J=8.8 Hz), 3.87 (3H, s), and 2.16 (3H, s).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][CH:6]1[OH:15])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.C(O)(C)C>[C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(O)C(C(C)(C)C)C1
Agent: O=[Cr](=O)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(C)(C)C1CCC(=O)C(C(C)(C)C)C1
Temperature: 5 °C
Yield: 100.2 %

Procedure:
200 g (0.944 mole) of the 2,4-di-tert-butylcyclohexanol as prepared in Synthetic Example 2 and 2 l of acetone were introduced into a 3 l reactor. Then 320 g of a Jones reagent was added dropwise thereto under ice-cooling at 5° C. over 1.5 hour. After completion of the reaction, isopropyl alcohol was added to the reaction mixture until the brown color of the excessive reagent disappeared. Then the reaction mixture was allowed to stand. After separating the acetone reaction solution, the acetone solution was neutralized with sodium carbonate. Then the solution was filtered and the acetone was distilled off under reduced pressure to give 199 g of crude 2,4 di-tert butylcyclohexanone. This product had a cis/trans ratio of 92/8. It was subjected to precision distillation in a Helipack packing column of a number of theoretical plates of 5 to give 160 g of 2,4 di-tert-butyl cyclohexanone (b.p.: 93.5 to 94° C./3 mm Hg). The cis/trans ratio of this product was 94/6.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2B(O)O)[CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[N:32]=[CH:33][CH:34]=[CH:35]2)(=[O:14])=[O:13])(=[O:22])=[O:23]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1cccc2cccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc4cccnc34)c2c1
Yield: 1.8 %

Procedure:
2-Methylsulfonyl-N-(3-quinolin-8-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 2 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 1.17 g of 8-quinolineboronic acid, 80 ml of dimethylformamide, 7.5 ml of a saturated aqueous sodium hydrogencarbonate solution and 98 mg of tetrakis(triphenylphosphine)palladium[0]. 30 mg of 2-methylsulfonyl-N-(3-quinolin-8-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 219° C. (analysis C23H18N4O4S2% calculated C, 57.73; H, 3.79; N, 11.71; O, 13.37; S, 13.4. % found C, 57.10; H, 4.11; N, 11.19; S, 11.94).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.[Na].Br[CH:47]([CH2:49][CH2:50][CH3:51])[CH3:48].O>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH:47]([CH2:49][CH2:50][CH3:51])[CH3:48])=[CH:36][CH:35]=2)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: CCCC(C)Br
Reactant: CCc1cc(NC(CC)c2ccc(O)cc2)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(C)Oc1ccc(C(CC)Nc2cc(CC)nc(Cl)n2)cc1
Reaction time: 8 h
Yield: 32.7 %

Procedure:
To a solution of 1.1 g of dl-5-chloro-6-ethyl-4-(α-ethyl-4-hydroxybenzyl)aminopyrimidine.sodium salt dissolved in 30 ml of N,N-dimethylformamide was added 0.6 g of 2-bromopentane, and the mixture was stirred at 90° to 100° C. for 8 hours. After completion of the reaction, the reaction mixture was poured into water and separated oily product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and ethyl acetate was distilled off under reduced pressure. The oily product obtained was isolated by column chromatography (Wako Gel C-200, trade name, eluted with toluene:ethyl acetate=7:1) to give 0.4 g of the desired product as pale yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C1S(=O)(=O)CCC1>O>[F:22][C:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7][O:8][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=1
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 15.7 %

Procedure:
A mixture of ethyl-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (0.96 g, 3.37 mmol), Selectfluor (1.25 g, 3.53 mmol), and tetramethylene sulfone (7.5 g, 62.5 mmol) was heated to 120° C. for 8 hours. After cooling to room temperature, the reaction mixture was diluted with water, stirred for 5 minutes and the resulting white crystals were collected, washed with water and purified by silica gel chromatography eluting with dichloromethane to obtain the title compound (147 mg, 0.53 mmol).
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=[N:33][CH:32]=1.CN>>[CH3:32][NH:33][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Agent: CN
Product: CNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Yield: 72 %

Procedure:
As described for example 90, 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester was converted, using methylamine (2 M in THF) instead of cyclopropylmethylamine, to the title compound (71 mg, 72%) which was obtained as a white solid. MS: m/e=378.4 [M+H]+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:52][C:53]([F:70])([F:69])[C:54]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][C:55]=1[C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62]>CN(C=O)C.O>[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([N:66]2[CH2:67][CH2:68][N:63]([C:61](=[O:62])[C:55]3[CH:56]=[C:57]([F:60])[CH:58]=[CH:59][C:54]=3[C:53]([F:70])([F:69])[F:52])[CH2:64][CH2:65]2)=[O:31])=[CH:24][CH:25]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
HOBt (25 mg, 0.185 mmol) and DIPEA (22 mg, 0.175 mmol) were added to a stirred solution of N-biphenyl-4-yl-malonamic acid (50 mg, 0.175 mmol) in DMF (3 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (50 mg, 0.26 mmol) followed by (2-trifluoromethyl-5-fluoro-phenyl)-piperazin-1-yl-methanone hydrochloride (60 mg, 0.193 mmol) were added. The reaction mixture was stirred at room temperature overnight. Water was then added and the resulting precipitate was filtered. The solid was purified by column chromatography using silica gel 60-120 mesh and 40% ethyl acetate in hexane as eluant to afford 34 mg (38%) of N-biphenyl-4-yl-3-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 514.17M+1)+, 95.5%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.75 (m, 1H), 7.6 (m, 6H), 7.44 (t, 2H), 7.35 (t, 1H), 7.2 (m, 1H), 7.06 (m, 1H), 4.0 (m, 2H), 3.7 (m, 4H), 3.56 (s, 2H), 3.48 (s, 1H), 3.26 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)=[O:18])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Yield: 50.9 %

Procedure:
Reaction of 4-aminoacetophenone (75 mg, 0.55 mmol) in THF (6 mL) with 4-biphenylcarbonyl chloride (147 mg, 0.68 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (4-acetyl-phenyl)-amide (90 mg, 0.28 mmol, 50% yield) as a white powder after washing by water and ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][N:5]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1
Reactant: Brc1c[nH]nc1-c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Temperature: 90 °C
Reaction time: 60 h
Yield: 62.5 %

Procedure:
A suspension of 4-bromo-3-phenyl-1H-pyrazole (6.13 g, 27.5 mmol), trityl chloride (15.3 g, 55.0 mmol), and K2CO3 (11.4 g, 82.5 mmol) in DMF (100 mL) was stirred for 60 h at 90° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, concentrated under reduced pressure. The residue was recrystallized from hexane/THF to give the title compound (8.00 g, 63% yield) as a white solid: mp 181-183° C.; 1H NMR (300 MHz, CDCl3): δ ppm 7.16-7.22 (6H, m), 7.28-7.41 (13H, m), 7.87-7.91 (2H, m). Anal. Calcd for C28H21BrN2: C, 72.26; H, 4.55; N, 6.02. Found: C, 72.43; H, 4.66; N, 5.91.