Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.CC1(C)COB([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)OC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:3]1[C:2]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)=[CH:6][S:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1scc(Br)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1scc(-c2ccnn2C)c1OC
Reaction time: 12 h
Yield: 852.2 %

Procedure:
Methyl 4-bromo-3-(methyloxy)-2-thiophenecarboxylate (250 mg, 0.10 mmol) [prepared according to Corral, C.; El-Ashmawy, M. B.; Lissavetzky, J.; Basilio, A.; Giraldez, A.; Eur. J. Med. Chem. Chim. Ther. 22; 1987; 251-254.], 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (250 mg, 1.20 mmol), Pd(PPh3)4 (58 mg, 49.8 μmol) and K2CO3 (550 mg, 3.98 mmol) in dioxane (5 mL) and H2O (1 mL) were combined in a sealed tube. After 12 h at 80° C., the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH in DCM) affording the title compound (215 mg, 86%) as a brown residue: LCMS (ES) m/z=253 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO.C([O-])(=O)C.[Na+].[F:17][C:18]([F:25])([F:24])[C:19]([F:23])([F:22])[C:20]#[N:21]>O>[C:3]([C:2](=[C:20]([NH2:21])[C:19]([F:23])([F:22])[C:18]([F:25])([F:24])[F:17])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: N#CC(F)(F)C(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)C(F)(F)F
Yield: 29.1 %

Procedure:
To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:22][CH2:23][N:24]([CH2:37][CH:38]4[CH2:40][CH2:39]4)[CH2:25][CH2:26]3)[C@H:17]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:16]2)=[O:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccc(F)cc2)C1
Reactant: BrCC1CC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(CC3CC3)CC2)[C@H](c2ccc(F)cc2)C1

Procedure:
The title compound, MS: m/e=558.3 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-piperazin-1-yl-piperidin-1-yl]-methanone and bromomethyl cyclopropane.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](=[O:9])[NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>CCOC(C)=O>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:2][C:1]([C:4]1[S:8][C:7](=[O:9])[NH:6][C:5]=1[CH3:10])=[O:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1sc(=O)[nH]c1C
Solvent: CCOC(C)=O
Product: Cc1[nH]c(=O)sc1C(=O)C=CN(C)C
Temperature: 80 °C

Procedure:
5-Acetyl-4-methyl-3H-thiazol-2-one (0.5 g, 3.18 mmol) and tert-butoxy-bis(dimethylamino)methane (Bredereck's reagent; 2.226 mL, 0.477 mmol) were combined and heated at 80° C. for 4 h. Removal of the excess solvent under reduced pressure gave a dark residue. Treatment of this residue with EtOAc afforded the title compound as a solid product, which was collected by filtration (0.074 g, 11%). Anal. RP-HPLC: tR 10.5 min (0-60% MeCN over 20 min). 1H-NMR (DMSO-d6): δ2.33 (3H, s, CH3), 2.70 (3H, s, NCH3), 3.09 (3H, s, NCH3), 5.07 (1H, d, CH, J=12.0), 7.55 (1H, d, J=12.0, CH), 11.23 (1H, s, NH). MS (ESI+) m/z 213.44 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:26]=[CH:25][C:11]([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:33]([CH3:36])([CH3:35])[CH3:34].CCCCCC>O1CCCC1>[C:13]1([N:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:11]2[CH:10]=[CH:9][C:8]([CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:26][CH:25]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C(c1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
4-benzyl-N,N-diphenylaniline (5.0 g, 14.9 mmol) was dissolved in tetrahydrofuran (80 mL) under a nitrogen atmosphere. n-Butyllithium (10.3 mL, 16.4 mmol) was slowly added to the reaction solution at −78° C., and then the reaction mixture solution was stirred at room temperature for 1 hour. Also, the reaction mixture solution with chlorotrimethylsilane (1.8 g, 16.4 mmol) added thereto was stirred at room temperature for 1 hour. The reaction mixture solution was passed through a silica gel column by using hexane as an eluant. After the solvent is removed, the residue material was dried in vacuum to thereby a white solid (5.1 g, yield: 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:15])=O>>[Br:15][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ccnc2cc(Cl)ccc12
Product: Clc1ccc2c(Br)ccnc2c1
Temperature: 140 °C

Procedure:
83.9 g of 7-chloro-4-hydroxyquinoline were added portionwise at 60° to 150 g of phosphorus oxybromide and the mixture was thereafter heated to 140° C. for 6 hours. After cooling, the mixture was treated with 3 l of ice-water and extracted with 2×1.5 l of dichloromethane. After evaporation of the solvent and crystallization from 1.3 l of hexane, 34 g of product were obtained as colourless crystals, m.p.: 102°-103° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:9][NH2:10])[NH2:8].[O:11]1[C:15](=O)[CH2:14][CH2:13][C:12]1=[O:17]>CC(N(C)C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:15]([CH2:14][CH2:13][C:12]([OH:17])=[O:11])[NH:10][N:9]=1
Reactant: NN=C(N)c1ccccn1
Reactant: O=C1CCC(=O)O1
Solvent: CC(=O)N(C)C
Product: O=C(O)CCc1nc(-c2ccccn2)n[nH]1

Procedure:
2-Pyridinecarbohydrazonamide (0.136 g) and dihydro-2,5-furandione (0.100 g) in 1 ml of dimethylacetamide was heated for 10 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W under nitrogen to leave 3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanoic acid in 1 ml of dimethylacetamide.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:36]2[CH2:41][C@H:40]([CH3:42])[O:39][C@H:38]([CH3:43])[CH2:37]2)=[C:22]([Cl:35])[C:23]([F:34])=[C:24]([CH:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[OH:27])[CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:36]2[CH2:37][C@H:38]([CH3:43])[O:39][C@H:40]([CH3:42])[CH2:41]2)=[C:22]([Cl:35])[C:23]([F:34])=[C:24]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:25]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccn3)c(F)c2Cl)C[C@H](C)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3ccccn3)c(F)c2Cl)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of {5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-chloro-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-fluorophenyl}(pyridin-2-yl)methanol (Intermediate 62, 100 mg, 0.165 mmol) in anhydrous DCM (5 mL) was added NMO (37 mg, 0.323 mmol) and TPAP (0.1 eq) at 0° C. and the mixture was allowed to stir for 1 hour at room temperature. The reaction mixture was filtered and the solvents were removed under vacuum and the residue was purified over silica gel chromatography column using ethyl acetate-pet. ether gradient to give product as a solid. Yield: 90 mg, (90%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=O.[CH:20]([NH:23][NH:24][C:25]([C:27]1[CH:31]=[CH:30][O:29][CH:28]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[CH:31]=[CH:30][O:29][CH:28]=1)=[O:26])=[O:19]
Reactant: CC(C)NNC(=O)c1ccoc1
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccoc2)C(C)C)c1C
Yield: 41.4 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (227 mg, 0.89 mmoles) and furan-3-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.89 mmoles) in DMF (8 mL) was treated with triethylamine (0.37 mL, 2.67 mmoles), HOBT (144 mg, 1.07 mmoles) and EDCI (205 mg, 1.07 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (149 mg, 41%). LC-MS m/e 405.52 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH:10]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:25][O:26][NH2:27].N1C=CC=CC=1.Cl>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:27][O:26][CH3:25])[CH:10]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CON
Reactant: CC(C(=O)c1ncc(Cl)cc1Cl)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(c1ncc(Cl)cc1Cl)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To 1.00 g of N-[2-(3,5-dichloropyridin-2-yl)-1-methyl-2-oxoethyl]phthalimide in 10 ml of ethanol, 2.39 g of methoxyamine hydrochloride and 3.40 g of pyridine were added and refluxed with heating for 18 hours with stirring. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 30 ml of 1N aqueous hydrochloric acid and extracted with ethyl acetate (40 ml×2). The resulting organic layers were combined, washed with 30 ml of 1N aqueous hydrochloric acid and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 0.81 g of the desired product as a colorless resinous substance.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)[CH:3]=1.[CH3:35][O-:36].[Na+]>CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:4]3[CH:3]=[C:2]([O:36][CH3:35])[N:7]=[CH:6][N:5]=3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCNc4cc(Cl)ncn4)CC3)nc3ccccc32)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ncn1

Procedure:
A mixture of 6 parts of N-[1-[2-[(6-chloro-4-pyrimidinyl)-amino]ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 2.5 parts of a sodium methoxide solution 30% and 40 parts of methanol was stirred and refluxed overnight. The reaction mixture was evaporated and water was added to the residue. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.4 parts of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(6-methoxy-4-pyrimidinyl)amino]-ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 145.8° C. (compound 98).
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[OH:14])=[O:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:7]2[O:14][CH:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:3](=[O:4])[NH:5][C:6]=2[CH:11]=1
Reactant: COc1ccc(O)c(NC(=O)C(Br)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)NC(=O)C(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound obtained in Step A (5 g; 14.87 mmol) is dissolved in 15 ml of dimethylformamide (1 ml/1 mmol), and then potassium carbonate (1.5 eq.; 22.31 mmol; 3.08 g) is added. The solution is stirred at ambient temperature for 2.5 hours, and then 60 ml of water are added and a precipitate is formed. After one night in a refrigerator, the solid is filtered through fritted glass, rinsed with water, and dried under a dynamic vacuum under P2O5 to yield the title product, which is used in the subsequent reaction without being further purified.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[N:30][CH:31]=5)[C:26]4=[O:35])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[N:30][CH:31]=5)[C:26]4=[O:35])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ccc5cnccc5c4=O)c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: Cc1cc2nc(-c3ccnc(-n4ccc5cnccc5c4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 170 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-oxo-2,6-naphthyridin-2(1H)-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (15.5 mg, 0.024 mmol) in pyridine (0.8 mL) was added LiI (100 mg, excess). The reaction mixture was heating in a microwave at 170° C. for 90 min. The mixture was concentrated in vacuo and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H28ClN4O4S: 611.2; found: 611.2. 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.81 (d, J=6.0 Hz, 1H), 8.75-8.71 (m, 2H), 8.60 (s, 1H), 8.27 (d, J=7.6 Hz, 1H), 7.99 (d, J=3.6 Hz, 1H), 7.94 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.53-7.48 (m, 3H), 6.94 (d, J=8.0 Hz, 1H), 5.32 (s, 1H), 2.59 (s, 3H), 1.00 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9]([O:11]C(=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=O)([O-:3])=[O:2].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]>CN(C)C=O>[NH2:13][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][C:8]=1[C:9]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[Cl:16])=[O:11]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Reactant: NCc1ccccc1Cl
Solvent: CN(C)C=O
Product: Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.1 %

Procedure:
To a suspension of 5-nitroisatoic anhydride (300 mg) in dimethylformamide (4 mL) was added 2-chlorobenzylamine (245 mg), and the mixture was stirred for 15 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-amino-N-(2-chlorobenzyl)-5-nitrobenzamide as yellow powders (397 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[O:28][CH3:29])=[CH:22][C:21]=2[N+:31]([O-:33])=[O:32])=[CH:18][N:19]=1)[CH2:12][CH:13]=[CH2:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:34][Si:35]([CH2:38][CH2:39][O:40][CH2:41]Cl)([CH3:37])[CH3:36]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:15]1[N:19]([CH2:41][O:40][CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[O:28][CH3:29])=[CH:22][C:21]=2[N+:31]([O-:33])=[O:32])[N:16]=1)[CH2:12][CH:13]=[CH2:14])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: C[Si](C)(C)CCOCCl
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc(NC(=O)OC)cc2[N+](=O)[O-])[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc(NC(=O)OC)cc2[N+](=O)[O-])cn1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flame-dried 25 mL round bottom flask was charged with NaH (0.092 g, 2.295 mmol) and then THF (4.17 mL) was added to give a gray suspension. The suspension was cooled to 0° C. and then a clear, yellow solution of 135B (0.9 g, 2.086 mmol) in THF (4.17 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to rt and stirring was continued at rt for additional 0.5 h. The yellow suspension was again cooled to 0° C. and then SEM-Cl (0.370 mL, 2.086 mmol) was added dropwise. The resulting cloudy reaction mixture was stirred at 0° C. After 1 h, the reaction was stopped and quenched with saturated NH4Cl followed by dilution with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated. The yellow oil weighing 1.6 g was purified by silica gel chromatography. The desired product from the reaction was obtained as yellow foam (0.424 g, 36%). MS (ESI) m/z: 562.0 (M+H)+. 1D NOE confirmed the regioisomeric position of SEM on the imidazole ring.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[N:19][OH:20])[C:11]1=[O:21].[OH-:22].[Na+]>CO.O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12](=[N:19][OH:20])[C:11]([OH:21])=[O:22]
Reactant: [OH-]
Reactant: Cc1ccc(Cl)c(N2C(=O)C(=NO)c3ccccc32)c1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=NO)C(=O)O)c1Cl

Procedure:
A solution of 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione-3-oxime (2.25 9) in 6 N NaOH (10 ml) and 4 ml MeOH is heated at 50° C. for two days without a reflux condenser. The resulting residue is taken up in water (50 ml) and filtered. It is neutralized with 1 N HCl with ice bath cooling. The precipitate is collected by filtration. The residue is air dried, dissolved in ether, and filtered. 2-[(2,6-Dichloro-3-methylphenylamino]-α-(hydroxylimino)-benzeneacetic acid (0.28 g, 50%) is precipitated from the ether solution by the addition of hexane, mp 152°-154° C. dec.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl.[C:17]([Cl:25])(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[ClH:25].[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH:15][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Agent: Cl
Product: CN1CCC(Oc2cccc(NC(=O)c3ccncc3)n2)CC1
Yield: 89.1 %

Procedure:
Using a method similar to example 160 using 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60, 150 mg, 0.724 mmol) and isonicotinoyl chloride hydrochloride (192 mg, 1.08 mmol) yields the title compound (225 mg, 89%). Mass spectrum (ion spray): m/z 313.1 (M+1); Analysis calculated for C17H21N4O2Cl.0.2H2O. Theory: C, 57.93; H, 6.12; N, 15.90. Found: C, 57.78; H, 6.28; N, 15.88. mp=254-256° C.
Reaction SMILES: C1(C=C(C2C=CN=CC=2)C(=[O:11])C)C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[C:26]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[C:27](=[O:42])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:11][C:26]2([C:27](=[O:42])[CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:43]2[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)C(=Cc2ccc(F)cc2)c2ccncc2)CC1
Reactant: CC(=O)C(=Cc1ccccc1)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)C2(c3ccncc3)OC2c2ccc(F)cc2)CC1

Procedure:
1,1-Dimethylethyl 4-[2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate was prepared by the same method as described for step 3 of Example A-2 by replacing 4-phenyl-3-(4-pyridyl)-3-butene-2-one with the α,β unsaturated ketone of step 3 of the present Example.