Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])[CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)CC(c2cc(F)cc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cc(F)cc(C2CC(C)(C)c3cc(S(=O)(=O)NC4CCC4)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 50.9 %

Procedure:
A mixture solution of 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150 mg, 0.32 mmol), copper(I) iodide (20 mg, 0.1 mmol), 2-amino-2-methyl-propionic acid (135 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-5-fluoro-phenylamino]-2-methyl-propionic acid (79.8 mg, 51.0%) as a white solid: MS (ESI) M+1=490.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:28])[C@H:24]([CH2:26][OH:27])[NH2:25].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:21][O:22][C:23](=[O:28])[CH:24]([NH:25][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:16]([F:19])([F:18])[F:17])[CH2:26][OH:27]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(CO)NC(=O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.29 g (10.93 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.70 g (10.93 mmol) L-serine methyl ester hydrochloride, 1.67 g (10.93 mmol) of hydroxybenzotriazole, hydrate, as well as 1.11 g (10.93 mmol) of triethylamine and 2.26 g (10.93 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethanol and crystallized upon concentration.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][C:32]([F:43])([F:42])[F:31])=[CH:35][CH:36]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2ccc(OC(F)(F)F)cc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-(trifluoromethoxy)benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.43 (m, 1 H), 7.33-7.28 (m, 2 H), 7.26-7.15 (m, 3 H), 7.06 (t, J=3.3 Hz, 1 H), 6.94 (dd, J=5.3, 8.4 Hz, 1 H), 6.29 (dd, J=3.5, 11.7 Hz, 1 H), 5.65-5.55 (m, 2 H), 5.53-5.43 (m, 1 H), 4.32-4.26 (m, 2 H), 2.95-2.81 (m, 2 H), 2.78-2.73 (m, 3 H), 2.14-2.05 (m, 2 H), 0.97 (s, 9 H); LC/MS (m/z) ES+=569.19 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:33]=[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:23](=[O:24])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][NH:20][CH:19]=2)=[O:17])=[CH:11][C:10]=1[F:32].[BH4-].[Na+]>CCO.C1COCC1>[CH:34]([NH:33][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:23](=[O:24])[C:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)=[CH:21][NH:20][CH:19]=3)=[O:17])=[CH:11][C:10]=2[F:32])[CH:6]=[CH:5][N:4]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(NC(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (Preparation 1G, 127 mg, 0.2 mmol) in EtOH (5 mL) and THF (5 mL) at 0° C., was added NaBH4 (300 mg, 7.93 mmol). The mixture was stirred at 0° C. for 3 h, and then at rt overnight. The reaction was quenched with water, extracted with DCM, and dried over MgSO4. After filtration and concentration in vacuo, 120 mg of the desired material was obtained as a white solid. MS (ESI+) m/z 635 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N+:9]=2[O-:23])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cccc(C)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2cccc(C)[n+]2[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
A solution of 2-(4-methylphenyl)-6-methylpyridine (4.5 g) in 100 ml of chloroform was cooled to 0° C., and m-chloroperbenzoic acid (7.7 g) in 50 ml of chloroform was added over a period of 15 minutes. The mixture was stirred at room temperature for 3 hours, then at 50° C. for 2 hours, followed by stirring overnight at room temperature. Solvent was evaporated to a small volume under reduced pressure, and the residue passed through an alumina column, eluting with 2% methanol in methylene chloride to remove benzoic acid. The eluate was flash-Chromatographed on silica gel, eluting with 5% methanol in methylene chloride, to yield 2.8 g of 2-(4-methylphenyl)-6-methylpyridine-N-oxide, m.p. 95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[Cl:31])(=[O:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[C:22]([Cl:31])[CH:23]=1)(=[O:28])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1Cl

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 133 mg of 4-acetylamino-3-chloro-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.24 (s, 3H), 7.36 (d, 1H, J=2.4), 7.40–7.60(m, 8H), 7.66 (d, 1H, J=2.0 Hz), 7.71 (d, 1H, J=8.8 Hz), 8.36 (d, 1H, J=8.8 Hz), 9.63 (s, 1H). MS: m/z 463.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCc2ccc(F)cc2)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:7]=2[C:8]#[N:9])[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:30][C:26]1[CH:25]=[C:24]([C:11]2[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:29]=[CH:28][N:27]=1
Reactant: Clc1cc(Br)ccn1
Reactant: CC1(C)OB(c2ccc(OCC3CC3)c(C#N)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(-c2ccnc(Cl)c2)ccc1OCC1CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
A solution of 2-cyclopropylmethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.0 g, 0.010 mol) in acetonitrile (60 ml) and water (20 ml) is degassed for 10 min. 4-Bromo-2-chloropyridine (1.92 g, 0.010 mol), potassium carbonate (2.76 g, 0.02 mol) and tetrakis(triphenyl phosphine)palladium(0) (0.11 g, 0.0001 mol) are added. The reaction mixture is stirred at 90° C. for 6 h. The mixture is cooled to room temperature, filtered and evaporated in a rotary evaporator. The residue is taken up in ethyl acetate (200 ml), washed with water (2×200 ml) and saturated sodium chloride solution (1×200 ml). The mixture is subsequently dried over sodium sulfate, evaporated in a rotary evaporator and chromatographed for purification, giving 2.1 g of a pale-yellow solid;
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][C:15](=[O:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]1=[O:25])=O>CO.C(Cl)Cl>[C:11]([S:10][C@H:9]1[NH:6][C:7](=[O:25])[C@@H:8]1[O:14][C:15](=[O:24])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)C(=O)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)S[C@H]1NC(=O)[C@@H]1OC(=O)COc1ccccc1

Procedure:
A solution of 129 mg (0.34 mmole) of (3S,4R)-2-(4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl)-2-oxoacetic acid methyl ester (crude product) in 10 ml of 1% aqueous methanol is stirred for 4 hours at room temperature. The reaction mixture is diluted with 50 ml of methylene chloride, washed in succession with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1) and yields the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][O:19][S:18](=[O:21])[O:17][CH2:16]2)=[CH:11][CH:10]=1.C([O:38]CC)C>C(#N)C.O>[O:21]=[S:18]1(=[O:38])[O:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:7]3[N:6]=[CH:5][N:4]=[C:3]([O:22][CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)[C:2]=3[CH3:1])=[CH:10][CH:11]=2)[CH2:16][O:17]1
Reactant: Cc1c(Oc2ccc(C3COS(=O)OC3)cc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Reactant: CCOCC
Solvent: O
Solvent: CC#N
Product: Cc1c(Oc2ccc(C3COS(=O)(=O)OC3)cc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a solution of iso-butyl 4-((5-methyl-6-(4-(2-oxido-1,3,2-dioxathian-5-yl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate (100 mg, 0.000198 mole) in acetonitrile (1.2 mL) were added NaIO4 (59 mg, 0.000277 mole) and RuCl3.3H2O (0.5 mg, 0.0000198 mole) in 0.2 mL water. After stirring the suspension at 30° C. for 30 minutes, 0.8 mL water and 1.2 mL diethyl ether were added. The layers were separated, and the aqueous layer was extracted with diethyl ether. The combined ether layer was dried over sodium sulfate, the solvents were evaporated to yield 50 mg product as white solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:53][CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cc(CCCOC)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.2 M) was added ethyl 4-bromobutanoate (1.6 eq.) and cesium carbonate (1.3 eq.). The reaction was heated to 80° C. for 3 h. After cooling down to rt, the reaction was diluted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 50% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.[C:16]([C:18]1[CH:19]=[C:20]([NH:30][C:31]([C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:37]=2[CH3:38])=[O:32])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)#[N:17]>O>[C:16]([C:18]1[CH:19]=[C:20]([NH:30][C:31]([C:33]2[CH:34]=[N:35][N:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[C:37]=2[CH3:38])=[O:32])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][N:27]([C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:26][CH2:25]1)#[N:17]
Reactant: Cc1c(C(=O)Nc2ccc(N3CCNCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Reactant: Cc1oncc1C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1oncc1C(=O)N1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(F)cc4)c3C)cc2C#N)CC1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
5-Methylisoxazole-4-carbonyl chloride (1.4 g) synthesized according to the method described in J. Chem. Soc. Perkin Trans. I, pp. 1875–1879 (1988) was added to a pyridine solution (20 ml) containing N-[3-cyano-4-(piperazin-1-yl)phenyl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (4 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under pressure. Diisopropyl ether was added to the obtained residue to allow crystallization. The crystals were recrystallized from hydrous dimethylformamide to give the title compound (2.9 g), melting point: 208° C.
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][NH:38][CH2:39][CH:40]([N:44]2[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]2)[C:41](O)=[O:42])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][NH:38][CH2:39][CH:40]([N:44]2[CH2:45][CH2:46][N:47]([S:50]([CH3:53])(=[O:51])=[O:52])[CH2:48][CH2:49]2)[C:41]([NH:2][OH:1])=[O:42])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)NO)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
63 mg (0.5 mmol) of 1-hydroxybenzotriazole and then 88 mg (0.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added to a solution of 200 mg (0.4 mmol) of 3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid in 6 ml of dimethylformamide. The reaction medium is stirred for 10 min at ambient temperature and then 68 mg (0.5 mmol) of O-tert-butyldimethysilylhydroxylamine are added. The reaction medium is then stirred at ambient temperature for 24 h, hydrolyzed by adding 2 ml of a 5% aqueous citric acid solution, and stirred for a further 30 minutes. After extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by chromatography on silica gel, elution being carried out with a 95/5 dichloromethane/methanol mixture. 100 mg (50%) of 3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide are obtained in the form of a white solid with a melting point of 86° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[F:10].CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[C:4]=2[F:9])[CH:21]=[CH:20][N:19]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1F
Yield: 65.9 %

Procedure:
Using a procedure analogous to Example A2, 4-amino-2,3-difluorophenol (6 g, 41.4 mmol), potassium tert-butoxide (4.9 g, 43.5 mmol) and 2,4-dichoropyridine (6.1 g, 41.4 mmol) were combined to afford 4-(2-chloro-pyridin-4-yloxy)-2,3-difluorophenylamine (7 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=6.0 Hz, 1H), 7.05 (s, 1H), 6.95 (m, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 5.60 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18]OCC)[C:6]=2[CH:22]=1.C(OC(=O)C)(=O)C.[IH:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][I:30])[C:6]=2[CH:22]=1
Reactant: I
Reactant: CCOCCCC1c2ccccc2C=Cc2ccc(Cl)cc21
Solvent: CC(=O)OC(C)=O
Product: Clc1ccc2c(c1)C(CCCI)c1ccccc1C=C2
Temperature: 65 °C

Procedure:
3-Chloro-5-(3-ethoxypropyl)-5H-dibenzo[a,d]cycloheptene (0.03 mole) is dissolved in 45 ml. of acetic anhydride. The solution is heated to 65°C. and nitrogen is passed through while 30 ml. of hydriodic acid (sp. gr., 1.5) is added gradually, keeping the temperature below 90°C. The solution is heated to approximately 80°C. for 30 minutes, then cooled and poured into ice-water. The product is extracted into ether, the extract washed with dilute sodium thiosulfate solution, followed by dilute sodium bicarbonate solution and finally with water. The product is isolated by evaporation of the ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([OH:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[N:10]2)=[CH:5][CH:4]=1.Br[CH2:20][N:21]1[C:25](=[O:26])[C:24]2[C:27]([CH:33]([CH3:35])[CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[S:22]1(=[O:37])=[O:36].[F-].[K+]>CN(C=O)C.O>[CH:33]([C:27]1[C:24]2[C:25](=[O:26])[N:21]([CH2:20][O:14][C:13]3[N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[N:10]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:12]=3)[S:22](=[O:37])(=[O:36])[C:23]=2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)([CH3:35])[CH3:34]
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2O)cc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2OCN2C(=O)c3c(C(C)C)cc(OC)cc3S2(=O)=O)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A mixture of 1-(4-methoxyphenyl)-3-trifluoromethyl-5-hydroxy pyrazole (489 mg; 1.89 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (600 mg, 1.72 mmol), and KF (200 mg; 3.44 mmol) in DMF (8 ml) was stirred at 20° C. for 2 hours and the mixture was diluted with water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 25-50% ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to afford 418 mg (46%) of 4-isopropyl-6-methoxy-2-[1-(4-methoxyphenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-CH3O--Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 111°-113° C.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([CH2:11][CH:12]1[CH2:15][CH2:14][CH2:13]1)[C:6]([O:8]CC)=[O:7])C.[OH-].[K+]>C(O)C.O>[CH:12]1([CH2:11][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:16])=[O:3])[CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C(CC1CCC1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CC1CCC1)C(=O)O
Temperature: 110 °C
Yield: 34.6 %

Procedure:
A solution of 2-cyclobutylmethyl-malonic acid diethyl ester (4.68 g, 20.5 mmol) in ethanol (45.4 mL) was treated with a solution of potassium hydroxide (3.45 g, 61.5 mmol) in water (11.4 mL). The reaction was then heated to 110° C. overnight. After this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with water (50 mL) which was then acidified with a 2N aqueous hydrochloric acid solution and then extracted with a 90/10 methylene chloride/methanol solution (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-cyclobutylmethyl-malonic acid (1.22 g, 34.7%) as a tan solid. This material was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[N:20]1([C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=3)[CH:28]=[CH:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3cccc(-n4cccn4)c3)cc2)c1

Procedure:
3-(3′-Pyrazol-1-yl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using the procedure described above for the synthesis of Example 4 from 3-(4-iodo -phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3-(1H-pyrazol-1-yl)phenylboronic acid (available from ASDI Inc., Newark, Del.). Mass spectrum MH+=371.