Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[C:7]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:5]=1.O1CCCC1.[OH-].[Li+].Cl>O>[CH:10]1([C:8]2[C:7]([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:19])=[O:2])[CH2:12][CH2:11]1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.1 %

Procedure:
In a 25 mL round-bottomed flask, the above prepared 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl ester (830 mg, 3.02 mmol, Eq: 1.00) was combined with tetrahydrofuran (7 ml) and water (3.5 ml) to give a light yellow bi-phasic system. Lithium hydroxide (86.7 mg, 3.62 mmol, Eq: 1.2) was added and the reaction mixture was stirred vigorously at rt. TLC after ˜20 h showed the reaction to be incomplete with some remaining starting material. More lithium hydroxide (43.3 mg, 1.81 mmol, Eq: 0.6) was added and the reaction mixture was stirred at 40° C. TLC after 1 additional h indicated that the reaction was complete. Work up: 10 ml H2O and 7 ml 1N HCl were added and the reaction mixture was extracted with AcOEt (2×50 ml). The organic layers were washed with H2O/NaCl sol, combined, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with heptane to afford 766 mg of the title compound as white powder; MS (EI) 260.0 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH:30]([CH:33]([CH3:36])[CH2:34]O)([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:31][CH:30]([CH:33]([CH3:36])[CH3:34])[CH3:32])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: CC(C)C(C)CO
Solvent: ClCCl
Product: CC(C)C(C)COC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropanecarboxylate in 30 ml of methylene chloride was added to a mixture of 3 ml of 1-dimethylamino-1-chloro-2-methyl-propen-1-yl [J. Org. Chem., Vol. 35 (1970), p. 3970] in 3 ml of methylene chloride and the mixture was stirred at room temperature for 15 minutes. After cooling the mixture to 5° C., 5 ml of 2-isopropyl-propanol were added thereto and the mixture was stirred at room temperature for 16 hours, was washed with water, with aqueous sodium chloride solution, was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 2.25 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis)2,2-dimethyl-3-[Z-2-(2-isopropyl-propyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+61.5°±2.5° (c=0.5% in benzene).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[C:26]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][C:17]=1[Cl:27].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH:2]([OH:1])[CH2:3][N:23]3[CH2:22][CH2:21][C:20]4[CH:19]=[CH:18][C:17]([Cl:27])=[C:16]([Cl:15])[C:26]=4[CH2:25][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Clc1ccc2c(c1Cl)CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: OC(COc1cccc2[nH]ccc12)CN1CCc2ccc(Cl)c(Cl)c2CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=405 (M+ of free base). α[D]589 =-6.87 (c=0.44, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:10]=2)=[O:8])=[CH:5][CH:4]=1.CSC.B(F)(F)F>ClCCl>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)c2cccc(C(=O)c3ccc(OC)cc3)c2)cc1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(C(=O)c3ccc(O)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.7 %

Procedure:
To a well-stirred solution of 1,3-bis-(4-methoxybenzoyl)benzene 14 (700 mg, 2.02 mmol) in dichloromethane (25 mL) was added boron trifluoride dimethyl sulfide complex (BF3.SMe2, 10 mL). The reaction was stirred for 16 h at room temperature, and then quenched with water, and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified using flash chromatography (silica gel, hexanes:ethyl acetate, 50:50) to afford the pure 1-(4-hydroxybenzoyl)-3-(4-methoxybenzoyl)benzene 16 (0.2 g, 0.60 mmol) as a white solid in a 30% yield; 1H NMR (500 MHz, Acetone-d6): δ 9.19 (s, OH), 7.89 (dt, J=2 Hz, 0.5 Hz, 1H, ArH), 7.85 (dd, J=7.5 Hz, 1.5 Hz, 2H, ArH), 7.72 (ddd, J=10.0 Hz, 5.0 Hz, 3.0 Hz, 2H, ArH), 7.66 (ddd, J=9.5 Hz, 5.0 Hz, 3.0 Hz, 2H, ArH), 7.59 (td, J=7.5 Hz, 0.5 Hz, 1H, ArH), 6.96 (ddd, J=9.5 Hz, 4.5 Hz, 2.5 Hz, 2H, ArH), 6.86 (ddd, J=9.5 Hz, 5.0 Hz, 3.0 Hz, 2H, ArH), 3.78 (s, 3H, OCH3); 13C NMR (125 MHz, Acetone-d6): δ 193.70, 193.56, 163.61, 161.941, 138.58, 138.35, 132.62, 132.41, 132.30, 130.16, 129.67, 128.75, 128.56, 115.25, 113.78, 55.12.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][NH:28][CH3:29])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([NH:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]([CH3:29])[C:45](=[O:46])[CH2:44][O:43][CH3:42])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN(C)C(=O)COC)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 188, 230 mg, 0.490 mmol) in DCM (4 ml) at 0° C. was added NEt3 (0.100 ml, 0.721 mmol) and 2-methoxyacetyl chloride (50 μl, 0.548 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (2-5%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a colorless resin. (UPLC-MS 3) tR 0.91 min, ESI-MS 542.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:15]=2)=O)=[O:9])=[CH:6][C:5]([Br:30])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[NH2:1][C:2]1[C:7]([C:8]2[O:9][C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:6][C:5]([Br:30])=[CH:4][N:3]=1
Reactant: CN(Cc1ccc(C(=O)NNC(=O)c2cc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(Cc1ccc(-c2nnc(-c3cc(Br)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
tert-Butyl N-[[4-[[(2-amino-5-bromo-pyridine-3-carbonyl)amino]carbamoyl]phenyl]methyl]-N-methyl-carbamate (992.3 mg, 2.074 mmol) was dissolved in dry MeCN (15 mL) and cooled in an ice bath under a nitrogen atmosphere. DIPEA (804.2 mg, 1.084 mL, 6.222 mmol) was added via syringe followed by dibromo(triphenyl)phosphorane (1.185 g, 2.696 mmol) portionwise and the reaction allowed to warm to ambient temperature over 15 hours. A further portion of MeCN (15 mL) and dibromo(triphenyl)phosphorane (437.7 mg, 1.037 mmol) were added and the reaction mixture stirred at ambient temperature for a 10 minutes. The precipitate was isolated by filtration and the filtrate concentrated in vacuo. The filtrate was re-dissolved in MeCN (15 mL) and cooled to 0° C. DIPEA (804.2 mg, 1.084 mL, 6.222 mmol) was added followed by dibromo(triphenyl)phosphorane (437.7 mg, 1.037 mmol) and the reaction mixture stirred at 0° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the resultant residue purified by column chromatography (ISCO Companion™, 40 g column, 0-50% EtOAc/Petroleum ether) and the product containing fractions concentrated in vacuo. The residue was combined with the previously obtained precipitate to give the sub-title product as a white solid (682 mg, 63% Yield corrected for residual OPPh3). 1H NMR (400.0 MHz, DMSO) δ 1.39-1.46 (d, 9H), 4.48 (d, J=10.5 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 8.22 (d, J=8.2 Hz, 2H), 8.32 (d, J=2.4 Hz, 1H) and 8.49 (d, J=2.4 Hz, 1H) ppm; MS (ES+) 462.1.
Reaction SMILES: C([Li])(CC)C.C1C[C@H]2N(C[C@H:11]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22]N4C[C@@H:13]2[CH2:12]3)CC1.[CH:23]([N:26]([CH:38]([CH3:40])[CH3:39])[C:27](=[O:37])[O:28]CC1(O)CCCCC1)([CH3:25])[CH3:24].CI.Cl.C[CH2:45][O:46]CC>C1CCCCC1.CCC(C)C>[CH3:25][C:23]1([CH3:24])[N:26]([C:27]([O:28][C@@H:21]([CH3:22])[CH2:20][CH2:19][CH2:18][CH2:11][CH2:12][CH3:13])=[O:37])[C:38]([CH3:39])([CH3:40])[CH2:45][O:46]1
Reactant: CCOCC
Reactant: CC(C)N(C(=O)OCC1(O)CCCCC1)C(C)C
Reactant: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCC(C)C
Solvent: C1CCCCC1
Solvent: CI
Product: CCCCCC[C@H](C)OC(=O)N1C(C)(C)COC1(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
2.8 mmol of a 1.4M sec-butyllithium solution in cyclohexane/isopentane were added to a solution, cooled to -78° C., of 680 mg (2.8 mmol) of (-)-sparteine in 8 ml of anhydrous ether. After stirring at -78° C. for 10 min, a solution of 543 mg (2.0 mmol) of the carbamate from Example 1 of the formula II in 2 ml of ether was added dropwise and the reaction mixture was stirred at -78° C. for 4 hours. After addition of 426 mg (3.0 mmol) of methyl iodide in 2 ml of ether, the reaction was subsequently stirred for 16 hours to complete the reaction, the mixture slowly warming to room temperature. To work up the reaction mixture, it was warmed to room temperature and poured into 10 ml of ether and 10 ml of 2N HCl. The organic phase was separated off, the aqueous phase was extracted three times with 20 ml of ether each time and the combined organic phases were deacidified and dried over solid sodium hydrogen sulphate and sodium sulphate in the amount ratio 1:2. After filtration and removal of the solvent in vacuo, the crude product was purified by chromatography on silica gel (ether/n-pentane 1:10). 491 mg (87%) of the title compound were obtained as a colorless oil of 95% ee. RF =0.74 (silica gel, ether/pentane 1:1), [α]D19 =+15.40 (c=1.20, acetone).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>CC(C)=O.O>[CH3:16][C:17]([CH3:22])=[CH:18][C:19]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: CC(C)=CC(=O)Cl
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(NC(=O)C=C(C)C)cc1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
A mixture of p-anisidine (10 g, 81 mmol, Aldrich) and potassium carbonate (13.5 g, 97.5 mmol, Aldrich) in acetone (125 mL) was cooled to 0° C. and treated with dimethyl acryloyl chloride (10.2 mL, 89.3 mmol). The mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 100% ethyl acetate/dichloromethane) to give 3-methyl-N[4-(methyloxy)phenyl]-2-butenamide (12.4 g, 67%) as a light violet solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (s, 3 H), 2.13 (s, 3 H), 3.71 (s, 3 H), 5.82 (s, 1 H), 6.85 (d, J=9.0 Hz, 2 H), 7.52 (d, J=9.0 Hz, 2 H), 9.67 (s, 1 H); ESIMS (M+H)+=206.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])C1C=CC(F)=CC=1.[CH3:16]C1C=C(C)C=CC=1C=O.F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:27]1[CH:34]=[CH:33][C:30]([CH3:31])=[CH:29][C:28]=1[CH3:16]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(C=O)c(C)c1
Product: COC(=O)C(=O)C(Cl)c1ccc(C)cc1C

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 2,4-dimethylbenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[CH3:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[CH3:33]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Product: Cc1cc(-c2cc(NC(=O)c3cncnc3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; LC-MS (UV peak area/ESI) 100%, 421.0698 (M−H)−.
Reaction SMILES: [S@:1]1(=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][O:2]1.[O-:11]I(=O)(=O)=O.[Na+].O>C(#N)C.C([O-])(O)=O.[Na+].CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[S:1]1(=[O:11])(=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@@H:4]2[CH2:3][O:2]1
Reactant: O=[S@]1OCC2CCCCN21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=S1(=O)OC[C@H]2CCCCN21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1-oxide (1.09 g, 6.76 mmol) in anhydrous acetonitrile (10 mL) was added sodium (meta)periodate (1.6 g, 7.436 mmol), followed by ruthenium(III) chloride hydrate (14 mg, 0.0676 mmol), and then H2O (10 mL). The mixture was stirred at 0° C. for 10 min and at rt for 20 min, then diluted with saturated NaHCO3 (30 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (80 mL) and dichloromethane (80 mL). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography (silica gel, 2% EtOAc in dichloromethane) to afforded the title product as a clear, colorless oil (0.890 g, 69%).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][N:27]1[C:31](=[O:32])[C:30]2[C:33]([CH:39]([CH3:41])[CH3:40])=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:29]=2[S:28]1(=[O:43])=[O:42].O>CO.CN(C=O)C>[CH:39]([C:33]1[C:30]2[C:31](=[O:32])[N:27]([CH2:26][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:10]=3)[S:28](=[O:43])(=[O:42])[C:29]=2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=1)([CH3:41])[CH3:40]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: O=C1CC(c2ccccc2)=NN1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(-c3ccccc3)nn1-c1ccccc1)C2=O
Temperature: 20 °C
Reaction time: 21 h
Yield: 52.6 %

Procedure:
A mixture 2,4-dihydro-2,5-diphenyl-3H-pyrazol-3-one (Formula III: R1 =R2 =Ph; R3 =H) (651 mg; 2.76 mmol) and Cs2CO3 (450 mg; 1.38 mmol) in methanol (12 ml) was stirred at 20° C. for 5 hours. The solvent was concentrated in vacuo, and the residue was dried in vacuo overnight. To a solution of the above residue in 12 ml of DMF was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (800 mg, 2.3 mmol) and the resulting mixture was stirred at room temperature (20° C.) for 21 hours and then poured into water. The above mixture was extracted with ether (3×) and the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue (yellow foam, 854 mg, 74%) was purified by flash column chromatography (silica gel; 18-50% ethyl acetate in hexane) and by recrystallization from ethyl acetate/hexane to afford 609 mg of 4-isopropyl-6-methoxy-2-(1,3-diphenylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =R2 =Ph; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white foam, m.p. 62°-76° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.Br[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].O.[OH-].[Cs+]>CN(C=O)C>[Si:34]([O:33][CH2:32][CH2:31][N:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 3 h
Yield: 56.6 %

Procedure:
To N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol) in DMF (5 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (37 mg, 0.16 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves (2 g). The reaction mixture was stirred for 3 hours and then concentrated. Purification by silica gel chromatography (DCM/MeOH 10:1) gave the desired product (16 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1.ClC1C=C(Cl)C=CC=1C(O)C1C=CC(Cl)=CC=1>>[F:21][C:19]([F:20])([F:22])[C:13]1[CH:12]=[C:11]([F:10])[CH:18]=[CH:17][C:14]=1[CH:15]([OH:16])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: Clc1ccc([Mg]Br)cc1
Agent: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Product: OC(c1ccc(Cl)cc1)c1ccc(F)cc1C(F)(F)F

Procedure:
This material was prepared from 4-chlorophenylmagnesium bromide (28.6 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (26.0 mmol) using the procedure described for compound (2) (6.04 g, 76%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].C([Li])CCC>C1COCC1>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:3]#[CH:2]
Reactant: Clc1ccc(C=C(Br)Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1,1-dibromo-2-(2,4-dichlorophenyl)ethene (14 g, 42.4 mmol) in THF (100 ml) at −78° C. under nitrogen was treated with butyllithium (1.6 M solution in hexane, 28 ml, 44.8 mmol). after being stirred for 1 hour at −78° C, the reaction mixture was warmed to room temperature and stirred for another hour. The reaction was quenched with water and the product was extracted with hexanes. The extract was dried over MgSO4, filtrated and concentrated in vacuo to give the product. (Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:21]2[CH2:23][CH2:22]2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:35])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:21]2[CH2:23][CH2:22]2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:35])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 130.1 %

Procedure:
100 mg (0.29 mmol) of the compound from Example 227 were introduced into 15 ml of dichloromethane at 0° C., 72 mg (0.29 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 135 mg of the title compound as mixture of diastereomers.
Reaction SMILES: N1C=CN=C1.Cl[Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].CN(C=O)C.[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[C:33]([OH:35])[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1>C(OCC)(=O)C.O>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[C:33]([O:35][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH:34]=[C:25]([C:24]([O:23][CH3:22])=[O:36])[CH:26]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
After adding 5.1 g of imidazole and 12.9 ml of chlorotriisopropylsilane to a 100 ml DMF solution containing 10.5 g of 5-hydroxyisophthalic acid dimethyl ester, the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with ice-cooled 1N hydrochloric acid, water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (21.53 g) as a colorless oil.