Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([CH2:11][C:12]#[N:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>O1CCCC1>[CH3:24][C:23]1[C:18]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][C:12]#[N:13])=[N:19][CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CCOC(=O)C(CC#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)(C(=O)OCC)c1ncc([N+](=O)[O-])cc1C

Procedure:
2-(Cyanomethyl)malonic acid diethyl ester (G. Casini et al, Ann. Chim. (Rome), 51, 366-74 (1961) (81 g) was reacted with sodium hydride (8.9 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (G. E. Hawkins & A. Roe, J. Org. Chem., 14, 328 (1949)) (58.5 g) was added and the internal temperature was raised to 95°-105° C. (some tetrahydrofuran was distilled off) over 11 hours. The reaction mixture was partitioned between chloroform and water (pH of aqueous phase was lowered to 3), the chloroform extracts were dried and concentrated in vacuo to give an oil (132 g). The oil was distilled under vacuum, the distillate collected at 60°-98° C. (vapour temp.) 0.2 mm Hg was discarded. The residues from the distillation (65 g) were dissolved in chloroform and filtered through a silica column and then concentrated, treated with charcoal and recrystallised from chloroform/petroleum ether (40°-60° C.) to give the title compound (30 g) m.p. 78°-80° C.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:2][CH2:3][CH2:4][NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([F:6])=[CH:8][CH:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCCBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCBr)c1ccc(F)cc1
Temperature: 5 °C

Procedure:
To a suspension containing 0.23 mol of-bromoethylamine hydrobromide in 200 ml of chloroform, stirred at 5° C., is added dropwise a solution containing 0.21 mol of 4-fluorobenzoyl chloride in 50 ml of chloroform, followed by a solution containing 0.46 mol of triethylamine in 100 ml of chloroform. The mixture is then stirred at room temperature for 1 hour and then at reflux for 4 hours. After cooling and evaporation of the solvent, the residue is taken up in 200 ml of ether. After filtration of the salts and concentration of the solvent, the expected product is obtained by purification of the residue by chromatography on a column of silica, using a dichloromethane/acetone (98/2) mixture as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=1[NH2:14]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:14][C:13]3[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(-c3ccc(Cl)cc3)[nH]c2c1
Yield: 87 %

Procedure:
Prepared from 4-chlorobenzoic acid (17.83 g, 0.114 mol) and 2-amino-5-nitroaniline (18 g, 0.114 mol), in a manner similar to that of Example 9b. Yield: 87%; Rf (6/4 toluene/ethyl acetate): 0.61; m.p.: 302.5-305° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[C:9]=2/[CH:23]=[CH:24]/[CH:25]([OH:34])[CH2:26][C:27](=[O:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:21])[CH3:22])[C:9]=2/[CH:23]=[CH:24]/[C@@H:25]([OH:34])[CH2:26][C@@H:27]([OH:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A solution of (E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoic acid, methyl ester (357 mg, 0.77 mmol) in THF (12 ml) was treated with triethylborane (1.0M in THF, 1.62 ml, 1.62 mmol). Twenty five milliliters of air was bubbled through the solution and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to -78° C. and treated with NaBH4 (29.4 mg, 0.78 mmol) followed by dropwise addition of dry methanol (1.90 ml). After stirring at -78° C. for 1.5 hours, the mixture was quenched with 30% H2 O2 (3.5 ml) in H2O (11 ml). The mixture was kept at -78° C. for 15 minutes, then warmed to room temperature and stirred for 30 minutes. The solution was poured into 50% saturated NaHCO3 and extracted with Et2O (3×). The Et2O extracts were combined, washed with H2O, saturated NaHCO3 and brine, then dried (Na2SO4). Filtration and removal of the solvent gave a yellow oil which was chromatographed (Flash, Merck SiO2, 40% EtOAc in hexane) to afford (3R, 5S, 6E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]3,5-dihydroxy-6-heptenoic acid, methyl ester (320 mg, 89%) as a colorless oily foam.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[N:15]([O-])=O.[Na+]>Cl.O>[ClH:1].[ClH:1].[N:3]1([C:8]2[CH:14]=[CH:13][C:11]([NH:12][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(-n2ccnc2)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 567.9 %

Procedure:
To a cooled (-15° C.) and stirred suspension of 4-(imidazol-1-yl)aniline dihydrochloride (20 g, 86.16 mmol) in concentrated hydrochloric acid (100 ml) was added dropwise, over 1 hour, a solution of sodium nitrite (6.25 g, 9.05 mmol) in water (40 ml). After a further 10 minutes of stirring at -12° C., the mixture was quickly filtered to remove a solid, and the filtrate was added portionwise to a cooled (-20° C.) and stirred solution of tin (II) chloride dihydrate (100 g) in concentrated hydrochloric acid (50 ml) at such a rate as to maintain the internal temperature below -10° C. (15 minutes). The mixture was allowed to warm to 5° C. over 30 minutes, and the solid was collected and washed with diethyl ether (4×100 ml). The above solid was suspended in water (200 ml) and basified with 4N sodium hydroxide solution and extracted with ethyl acetate (5×500 ml). The combined organic solutions were dried (Na2SO4) and filtered. The filtrate was vigorously stirred while hydrogen chloride was being bubbled through the solution until a deep red mixture was obtained. Stirring was continued for a further 20 minutes to give a cream solid which was collected by filtration and dried over phosphorus pentoxide-potassium hydroxide under high vacuum to leave 12.7 g (60%) of the title compound: δH (360 MHz, DMSO-d6) 7.20 (2H, d, J=9.0 Hz), 7.73 (2H, d, J=9.0 Hz), 7.91 (1H, t, J=1.5 Hz), 8.23 (1H, t, J=1.7 Hz), 9.71 (1H, t, J=1.3 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.O[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CO.C(Cl)Cl>[CH3:26][N:23]1[CH2:22][CH2:21][N:20]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:5]3[CH:6]=[N:7][C:8]4[NH:9][CH2:10][CH2:11][CH:2]([O:1][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[C:3]=4[CH:4]=3)=[CH:17][CH:16]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Reactant: Oc1cccnc1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(Oc3cccnc3)CCN4)cc2)CC1
Yield: 20 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (20 mg) was reacted with 3-hydroxypyridine (16.2 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (20% yield). LCMS: m/z=430.17 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.12 (m, 1H), 2.30-2.34 (m, 1H), 2.33 (s, 3H), 2.34-2.56 (m, 4H), 3.40-3.70 (m, 4H), 3.70-3.90 (m, 2H), 5.24 (bs, 1H), 5.44 (t, J=3.5 Hz, 1H), 7.26-7.29 (m, 1H), 7.31-7.37 (m, 1H), 7.41-7.50 (m, 4H), 7.58 (d, J=2.0 Hz, 1H), 8.28-8.33 (m, 2H), 8.43 (d, J=2.5 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]([CH2:6][OH:7])=[CH:4][N:3]=[CH:2]1.[C:8](N1C=CN=C1)([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:9]>C(Cl)Cl>[N:10]1([C:8]([O:7][CH2:6][C:5]2[O:1][CH:2]=[N:3][CH:4]=2)=[O:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: OCc1cnco1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCc1cnco1)n1ccnc1
Reaction time: 2 h

Procedure:
Oxazol-5-ylmethanol (0.15 g, 1.51 mmol) in anhydrous CH2Cl2 (5 mL) under a dry N2 atmosphere was treated with 1,1′-carbonyldiimidazole (0.20 g, 1.23 mmol) at ambient temperature and stirred for 2 hours to provide the title compound in a solution of CH2Cl2 which was used in subsequent Examples without further manipulation.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])[CH:11]=[CH:10][C:8]=2[CH:9]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:8]2[CH:9]=[C:5]([CH2:4][CH2:3][C:1]3[NH:30][N:29]=[N:28][N:2]=3)[O:6][C:7]=2[CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCC#N)oc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCc3nnn[nH]3)oc2c1
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A mixture of 2-(2-cyanoethyl)-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (1.20 g), sodium azide (1.09 g), ammonium chloride (0.90 g) and N,N-dimethylformamide (30 ml) was stirred at 130° to 140° C. for 16 hours. The reaction mixture was poured over water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; the residue was subjected to silica gel column chromatography. From the fraction eluted with methanol-chloroform (5:95, v/v), 5-[2-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]ethyl ]-1H-tetrazole (1.05 g, 78%) was obtained, which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 177° to 178° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18](Cl)=[O:19]>CCOCC>[Cl:14][C:15]([Cl:22])([Cl:21])[CH2:16][O:17][C:18]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:19]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: C1CNCCN1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(OCC(Cl)(Cl)Cl)N1CCNCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 0.5 mol of piperazine and 0.5 mol of triethylamine in ether is added dropwise 0.25 mol of 2,2,2-trichloroethylchloroformate. The reaction mixture is stirred for 1-6 hours at room temperature (ca. 25° C.) and is then worked up with aqueous weak basic solution to give 1-(2,2,2-trichloroethoxycarbonyl)piperazine. This is reacted with p-nitrobenzenesulfonyl chloride in a non-polar solvent, e.g., tetrahydrofuran, to give 1-(p-nitrobenzenesulfonyl)-4-(2,2,2-trichloroethoxycarbonyl)piperazine.
Reaction SMILES: CC(O)=O.[O:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.[NH2:13][C:14]1[CH:15]=[C:16]([C@H:20]([OH:24])[CH2:21][C:22]#[N:23])[CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:24][C@@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][CH2:11][CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)[CH:15]=1)[CH2:21][C:22]#[N:23]
Reactant: N#CC[C@@H](O)c1cccc(N)c1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#CC[C@@H](O)c1cccc(NCC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
CH3COOH (1 mL) was added to a solution of tetrahydro-2H-pyran-4-carbaldehyde (0.7 g, 6.12 mmol) and (R)-3-(3-aminophenyl)-3-hydroxypropanenitrile (1.0 g, 6.12 mmol) in CH2Cl2 (20 mL) at 0° C. followed by the addition of Na(OAc)3BH (3.89 g, 18.34 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with NaHCO3 (50 mL), extracted with EtOAc (200 mL), organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (50% EtOAc: hexanes) gave (R)-3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)propanenitrile as a pale yellow liquid. Yield (1.0 g, 63%); 1H NMR (400 MHz, DMSO-d6) δ 7.02 (t, J=8.0 Hz, 1H), 6.62 (s, 1H), 6.51 (d, J=7.2 Hz, 1H), 6.47 (d, J=7.6 Hz, 1H), 5.77 (d, J=4.4 Hz, 1H), 5.68 (t, J=5.2 Hz, 1H), 4.73 (dd, J=10.8, 4.8 Hz, 1H), 3.85 (dd, J=10.8, 2.8 Hz, 2H), 3.26 (t, J=11.2 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.82 (dd, J=16.8, 4.8 Hz, 1H), 2.73 (dd, J=16.8, 6.8 Hz, 1H), 1.81-1.75 (m, 1H), 1.66 (d, J=12.8 Hz, 2H), 1.23-1.19 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27].O>CN(C)C=O>[F:27][C:26]([F:29])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1
Reactant: Fc1ccccc1C(F)(F)F
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2nn(-c3ccccc3C(F)(F)F)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a stirred suspension of 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were evaporated. The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g of (24%) of product, mp 110°-111° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH2:21])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B.C[N+]([O-:29])(C)C.[Cl-].[Na+]>COCCOCCOC.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:22])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][OH:29])[CH:15]=2)[CH:10]([CH3:23])[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C[N+](C)(C)[O-]
Reactant: C=Cc1cccc(C2(C)CCN(C(=O)CCCCC)CC2C)c1
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCCCCCN1CCC(C)(c2cccc(CCO)c2)C(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a stirred solution of 1-hexanoyl-3,4-dimethyl-4-(3-vinylphenyl)-piperidine (Preparation 8, 50 mg, 0.16 mmol) in bis(2-methoxyethyl)ether (1.5 mL) at 0° C. under nitrogen was added dropwise borane (1.0 M in tetrahydrofuran, 0.35 mL, 0.35 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then for 2 hours at room temperature. Trimethylamine N-oxide (48 mg, 0.64 mmol) was subsequently added and the reaction mixture heated at reflux under a nitrogen atmosphere for 2 hours. To the cooled reaction was then added diethyl ether (10 mL) and saturated aqueous sodium chloride solution (10 mL). The phases were separated and the aqueous layer was further extracted with diethyl ether (10 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1.5 g) eluted with ethyl acetate:hexane (50:50) to give the title compound as an oil (30 mg).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:9](=O)[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[N:18]=[C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([OH:15])=[C:13]([CH3:14])[CH:8]1[CH3:7]
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Reactant: Nc1nccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC1=CC(=Nc2nccs2)C(C)C(C)=C1O
Temperature: 25 °C
Yield: 15 %

Procedure:
Pyridine (3.24 ml) was dissolved in 120 ml of dichloroethane, followed by addition of 1.10 ml of titanium tetrachloride. The mixture was heated under reflux for 15 minutes. Then, 3.00 g of 2,3,5-trimethyl-1,4-benzoquinone and 2.00 g of 2-aminothiazole were added, and the resultant mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad, and the insoluble matter was washed with chloroform. The filtrate was concentrated, and the crude product obtained was purified by silica gel column chromatography (diethyl ether-hexane =1:19 1:4) to give 0.70 g of 4-(2-thiazolylimino)-2,3,6-trimethylphenol as a pale red solid melting at 95°-96° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.FC(F)(F)C(O)=O.[Cl:21][C:22]1[N:32]=[N:31][C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=2[CH:23]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:28]3[CH2:27][CH2:26][C:25]4[N:31]=[N:32][C:22]([Cl:21])=[CH:23][C:24]=4[CH2:30][CH2:29]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Clc1cc2c(nn1)CCNCC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(Cl)nnc2CC1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 3-chloro-6,7,8,9-tetrahydro-5H-1,2,7-triaza-benzocycloheptene trifluoroacetate. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 27 mg (32% of theory). ESI-MS: m/z=407 (M+H)+; Rt(HPLC): 1.10 min. (Method J).
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.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1B(O)O.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:34]1[CH:33]=[CH:32][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)(=[O:13])=[O:14])(=[O:22])=[O:23]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccc4ccccc4c3)c2c1
Yield: 29 %

Procedure:
2-Methylsulfonyl-N-(3-naphthalen-2-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 298 mg of 2-naphthaleneboronic acid, 20 ml of dimethylformamide, 1.88 ml of a saurated aqueous sodium hydrogencarbonate solution and 24.5 mg of tetrakis(triphenylphosphine)palladium[0]. 120 mg of 2-methylsulfonyl-N-(3-naphthalen-2-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 221° C. (analysis C24H19N3O4S2 % calculated C, 60.36; H, 4.01; N, 8.80; O, 13.40; S, 13.43. % found C, 60.09, H, 4.06; N, 8.55; S, 13.51).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1>>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([C:8]5[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[CH:21][CH:22]=2)=[O:31])[N:35]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CS(=O)(=O)c1ccc(-c2ccn3c(-c4ccc(CN)cc4)cnc3c2)cc1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO[Si](C)(C)C(C)(C)C)n1
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCO[Si](C)(C)C(C)(C)C)n1

Procedure:
Prepare the title compound in a manner analogous to Example 1 from 4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzylamine and {5-tert-butyl-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2H-pyrazol-3-yl}-carbamic acid 2,2,2-trichloro-ethyl ester. MS (ES), m/z 701 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)ccc1OC
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Br)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A mixture of methyl 6-bromo-3-methoxypicolinate (4 g, 18.4 mmol) and LiOH—H2O (1.6 g, 36.9 mmol) in dioxane/H2O (5/1, 40 mL) was stirred at RT overnight. After pH was adjusted to 7, the mixture was filtered to provide crude 6-bromo-3-methoxypicolinic acid (3.1 g, yield: 81%). 1H-NMR (CDCl3, 400 MHz) δ 10.71 (m, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.01 (s, 3H). MS (M+H)+: 232/234.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[C:25]([C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:26][O:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[C:25]1[C:24]([CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:28]([CH:29]([CH3:31])[CH3:30])[O:27][N:26]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 65 °C
Yield: 55.9 %

Procedure:
A mixture of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (222 g, 0.8 mol), 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (292 g, 0.96 mol) and cesium carbonate (312 g, 0.96 mol) in DMF (1.5 L) was heated at 65° C. for 28 hours. Additional 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (105 g, 0.34 mol) dissolved in DMF (150 mL) was added. The mixture was cooled to room temperature and poured into water (5 L) with stirring. The resulting taffy was separated from the supernatant and stirred with ethyl acetate (2.5 L) for 3 hours at room temperature. The resulting suspension was filtered and the filter cake was dried to yield methyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate as a solid (245 g, 56%). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=9 Hz, 1H), 8.28 (d, J=1 Hz, 1H), 8.11 (m, 3H), 7.72 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.53 (m, 1H), 6.93 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.93 (s, 3H), 3.47 (m, 1H), 1.33 (d, J=7 Hz, 6H). ES-LCMS m/z 547 (M+H)+.