Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[F:26][C:27]([F:38])([F:37])[CH2:28]OS(C(F)(F)F)(=O)=O.[CH3:39]N(C)C=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][C:27]([F:38])([F:37])[F:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:39]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)C3)ccc2[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)ccc2n1CC(F)(F)F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a mixture of 5-(1-isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester (intermediate, 4 g, 1.0 eq.) in dimethylformamide (40 mL) was added sodium hydride (dispersion in oil, 60% in mass, 533 mg, 1.1 eq.) in several portions. The solution was stirred 30 min at 70° C. Then 2,2,2-trifluoroethyltrifluoromethanesulfonate (3.37 g, 1.2 eq.) was added and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was partitioned between an aqueous solution of sodium hydrogenocarbonate and ethyl acetate. The organic layer was washed with water and brine, evaporated in vacuo and then purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 3.9 g (78%) of the desired product as off-white solid. MS (m/e): 413.5 (MH+, 100%)
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[C:12]([C:14]([O:16]C)=O)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][C:19]#[N:20]>>[CH:1]1([O:7][C:8]2[N:13]=[C:12]([C:14](=[O:16])[CH2:18][C:19]#[N:20])[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC#N
Reactant: COC(=O)c1cccc(OC2CCCCC2)n1
Product: N#CCC(=O)c1cccc(OC2CCCCC2)n1

Procedure:
CH3CN addition to methyl 6-(cyclohexyloxy)picolinate following the method described in Example 6 gave 3-(6-(cyclohexyloxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.2 g, quant.).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:19]([C:20]4[CH:21]=[CH:22][C:23]5[N:24]([C:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=6)=[CH:27][N:28]=5)[CH:25]=4)=[CH:18][N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[OH-].[Na+]>C(O)C>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[N:24]2[CH:25]=[C:20]([C:19]3[C:15]([C:12]4[CH:11]=[CH:10][C:9]([C:6]5[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=5)=[CH:14][CH:13]=4)=[N:16][NH:17][CH:18]=3)[CH:21]=[CH:22][C:23]2=[N:28][CH:27]=1
Reactant: COc1ccc(-c2ccc(-c3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3-c3ccc4ncc(-c5ccccn5)n4c3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1ccc(-c2ccc(-c3n[nH]cc3-c3ccc4ncc(-c5ccccn5)n4c3)cc2)c[nH]1
Yield: 50.4 %

Procedure:
A mixture of 114 mg 6-{3-[4-(6-methoxypyridin-3-yl)phenyl]-1-trityl-1H-pyrazol-4-yl}-3-(pyridin-2-yl)imidazo[1,2-a]pyridine (compound in Example 365), 4 mL of 5 N hydrochloric acid and 4 mL ethanol was heated overnight under reflux. The reaction solution was basified with 5 N sodium hydroxide under ice-coolingd water, and the precipitated crystals were collected by filtration. The crystals were dried over hot air at 70° C., then dissolved in a mixture of methanol and dichloromethane and filtered. The filtrate was evaporated, then ethyl acetate was added to the residue which was then triturated, and the crystals were collected by filtration and dried under reduced pressure with a vacuum pump, to give 36 mg of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:21]1([C:27]2[CH:31]=[C:30]([C:32](O)=[O:33])[NH:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[C:21]1([C:27]2[NH:28][N:29]=[C:30]([C:32]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]4)=[CH:4][CH:3]=3)=[O:33])[CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc(-c4ccccc4)[nH]n3)cc2)C1
Temperature: 60 °C
Reaction time: 16.5 h
Yield: 74.5 %

Procedure:
In a 25 mL round-bottomed flask, (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 359 μmol, Eq: 1.00), 3-phenyl-1H-pyrazole-5-carboxylic acid (87.9 mg, 467 μmol, Eq: 1.3) (CAS-1134-49-2), N-Methylmorpholine (109 mg, 118 μl, 1.08 mmol, Eq: 3) and HBTU (204 mg, 539 μmol, Eq: 1.5) were combined with DMF (3.75 ml). The reaction mixture was stirred at 60° C. for 16.5 hours. The mixture was poured into water (10 ml) and extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography. (6 g silica gel (63-200A), eluent: heptane/EtOAc 2:1) to give the title compound as a white solid (120 mg, 74.5%). MS (ISP): 449.5 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:7]2[C@H:8]3[C@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=[CH:4][CH:3]=1)[N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:11][CH2:10][CH2:9]3.C[Si]([N:27]=[C:28]=[O:29])(C)C>O1CCCC1.CCCCC>[NH2:27][C:28]([C:2]1[C:7]2[C@H:8]3[C@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=[CH:4][CH:3]=1)[N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:11][CH2:10][CH2:9]3)=[O:29]
Reactant: Cc1ccccc1N1CCC[C@H]2c3c(Br)cccc3CC[C@@H]21
Reactant: C[Si](C)(C)N=C=O
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCC[C@H]2c3c(cccc3C(N)=O)CC[C@@H]21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of the (-)-trans-1,2,3,4,4a,5,6,10b-octahydro-10-bromo-4-(methylphenyl)benzo[f]quinoline (B-8, 6.60 g, 18.5 mmol) in dry tetrahydrofuran (50 mls) under nitrogen was cooled to -78° C., and t-bulyllithium (1.7M in pentane, 22.3 mls, 38.1 mmol) was added in about 10 seconds. The mixture was stirred at -78° C. for 5 minutes, and trimethylsilylisocyanate (46.5 mmol) was added via a syringe in one shot. The cold bath was removed, and the mixture was stiffed at ambient temperature for 1.5 hours. Water (30 mls) was added, and the mixture was stiffed for 10 minutes. Hydrochloiric acid (10%, 10 mls) was added, and file mixture was stiffed for 30 minutes. The mixture was bascified with 15% NaOH and extracted 3 times with methylene chloride. The extracts were dried (MgSO4), and the solvent was removed under vacuum to leave a white solid containing solvent (10.76 g). A sample (0.52 g) was crystallized from acetonitrile (20 mls) to yield the title compound (-) B-9 as white crystals (0.21 g, m.p. 189°-190° C., [α]D =-183.7° (25° C., THF, C=0.705)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].[I:19]Cl>C(O)(=O)C>[I:19][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: ClI
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccsc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A vial was charged with 199 mg (1.0 mmol) 3-(tert-butoxycarbonylamino)thiophene, 164 mg (2.0 mmol) NaOAc, 4.0 mL HOAc, and a stir bar. The mixture was stirred at room temperature, giving a homogeneous solution “A”. A second vial was charged with 162 mg (1.0 mmol) iodine monochloride and 2.0 mL glacial acetic acid. The second mixture was swirled at room temperature. This second homogeneous solution “B” was added to solution “A” dropwise over three minutes. A white solid began to precipitate immediately. After the addition, the mixture was allowed to stand overnight, at which time the white solid had separated from the brown supernatant. With stirring, 200 uL sat. Na2S2O3/H2O was added, decolorizing the mixture from brown to yellow. 10 mL water was added, and then the mixture was evaporated, affording a semi-solid light brown residue. The residue was partitioned between EtOAc and H2O, and the separated EtOAc phase was washed (sat. NaHCO3, then sat. NaCl). The EtOAc phase was filtered, and concentrated to give 262 mg (81%) of the title compound as light brown crystals. 1H NMR (CDCl3, 300 MHz) δ 7.49 (bs, 1H), 7.45 (d, J=5.4 Hz, 1H), 6.50 (bs, 1H), 1.54 (s, 9H). Method [5]: rt=1.40 min; m/z=269.9 (MH+ minus isobutylene).
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[CH:16][C:15]([C:3]2[O:4][C:5]3[C:10]([C:11](=[S:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:14]1
Reactant: S=c1c(Br)coc2ccccc12
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: S=c1cc(-c2cc[nH]n2)oc2ccccc12
Temperature: 0 °C
Yield: 79 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, pyrazole (136 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography and recrystallized from benzene/hexane to give the titled compound (90.5 mg; yield=84.6%) as white needle crystals. Melting point: 189° C. 1H-NMR(CDCl3, δ ppm): 7.16 (s, H3), 8.50 (d, H5), 7.52-7.60 (m, H6), 7.66 (t, H7), 7.52 (m, H8), 7.82 (d, H3'), 6.60 (dd, H4'), 8.08 (d, H5').
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH2:17][CH:18]([OH:25])[CH2:19][NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)C>[C:21]([NH:20][CH2:19][CH:18]([OH:25])[CH2:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[N:7][C:2]([NH:27][NH2:28])=[CH:3][CH:4]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: NN
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(OCC(O)CNC(C)(C)C)c1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(NN)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
A stirred mixture of 6-chloro-3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]pyridazine and hydrazine hydrate in ethanol was heated under reflux for 3 hours. Evaporation of the reaction mixture under reduced pressure gave the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:4][C:2]([CH3:1])([O:5][C:6]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])=[CH:15][CH:16]=1)=[O:18])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCOc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 314 mg(1.246 mmole) of t-BOC amine from Example 216 in 10 mL of methylene chloride was added pyridine (147 mg, 1.869 mmol, 1.5 eq) followed by benzenesulfonyl chloride (242 mg, 1.370 mmol, 1.1 eq) at room temperature. The reaction mixture was stirred at room temperature overnight and then partitioned between water and chloroform. The organic layer was separated and washed with 1N hydrochloric acid, water and brine and then dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by flash colunto chromatography (eluant 2:1 hexanes/ethyl acetate) to give 248 mg (51%) of the product: 1H NMR (200 MHz, CDCl3) δ8.01 (d, 1H, J=8Hz), 7.67 (d, 2H, J=8Hz), 6.92 (d, 2H, J=9Hz), 6.72 (s, 1H, N-H), 6.70 (d, 2H, J=9Hz), 4.90 (bs, 1H, N-H), 3.89 (t, 2H, J=5.0Hz), 3.40 (q, 2H, J=5.0Hz), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and benzenesulfonyl chloride (105 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 ml, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). Then, the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (40 g) column, eluting with 5-25% ethyl acetate in hexanes, to afford [4-(4-benzenesulfonylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (108 mg, 76%) as a white foam. HRMS calcd. for C26H21ClNO4S [(M−H)−] 478.0885, obsd. 478.0884.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[Br:5][C:6]1[C:11]([CH3:12])=[C:10]([Cl:13])[N:9]=[N:8][C:7]=1[NH2:14]>CCO>[ClH:1].[Br:5][C:6]1[C:7]2[N:8]([CH:2]=[CH:3][N:14]=2)[N:9]=[C:10]([Cl:13])[C:11]=1[CH3:12]
Reactant: O=CCCl
Reactant: Cc1c(Cl)nnc(N)c1Br
Solvent: CCO
Product: Cc1c(Cl)nn2ccnc2c1Br
Product: Cl
Temperature: 110 °C
Yield: 88.4 %

Procedure:
Chloroacetaldehyde (1.6 ml, 10 mmol, 50% in H2O) was added to a solution of crude 4-bromo-6-chloro-5-methylpyridazin-3-amine (0.5 g, 2 mmol) from 1b in EtOH (5 mL). The mixture was heated in a sealed vial at 110° C. for 2 h. Solvent was removed in vacuo and the resulting solid was suspended in acetone/Et2O (1/1, 5 mL), filtered, and then washed with Et2O to give 8-bromo-6-chloro-7-methylimidazo[1,2-b]pyridazine HCl salt (0.5 g, >90% pure).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[O:14][C:10]=3[CH:9]=2)=[C:4]([N+:21]([O-])=O)[CH:3]=1.CC(O)=O.CO>C(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[O:14][C:10]=3[CH:9]=2)=[CH:19][CH:20]=1
Reactant: CSc1nc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2o1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CSc1nc2ccc(CNc3ccc(Br)cc3N)cc2o1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a stirred solution of 4-bromo-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline (704 mg, 1.79 mmol), HOAc (2.1 mL) and methanol (2.1 mL) in DCM (18 mL) at 0° C. was added zinc dust (1.16 g, 17.9 mmol) portionwise. After stirring for 2 h, the mixture was filtered. The filtrate was washed with aq NaHCO3 and brine. The organic layer was dried over NaSO4, filtered and concentrated under reduced pressure to give 4-bromo-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (469 mg, 71.9%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.72-7.60 (m, 2H), 7.53 (d, J=5.4 Hz, 1H), 6.68 (s, 1H), 6.49 (d, J=1.8 Hz, 1H), 6.23 (d, J=8.1 Hz, 1H), 5.36 (t, 1H), 4.90 (s, 2H), 4.38 (d, J=6.0 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 365 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:32][N:33]([CH:35]=[N:36][C:37]1[CH:38]=[C:39]([CH:46]=[CH:47][N:48]=1)[C:40](N(OC)C)=[O:41])[CH3:34]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:40]([C:39]3[CH:46]=[CH:47][N:48]=[C:37]([N:36]=[CH:35][N:33]([CH3:34])[CH3:32])[CH:38]=3)=[O:41])=[N:3][CH:4]=[C:5]([CH3:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccnc(N=CN(C)C)c1
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(=O)c1ccnc(N=CN(C)C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (367 mg, 0.775 mmol) in THF (2 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 0.94 mL, 1.866 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-(dimethylamino-methyleneamino)-N-methoxy-N-methyl-isonicotinamide (349 mg, 1.47 mmol) in THF (1 mL) at 0° C. The mixture was stirred at room temperature for 6 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (230 mg) in 52% yield. ESMS m/z (relative intensity): 570.1 (M+H)+ (100).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10](O)[C:11]2[CH:16]=[CH:15]C=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[CH2:20]([Cl:22])Cl>>[Cl:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]([C:11]2[CH:16]=[CH:15][C:20]([Cl:22])=[CH:13][CH:12]=2)[Cl:3])=[CH:8][CH:7]=1
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1ccc(Cl)cc1
Product: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reaction time: 18 h
Yield: 88.4 %

Procedure:
Thionyl chloride (10 mL, 137 mmol) was added dropwise to 4-chlorobenzhydrol (12.66 g, 50 mmol) in CH2Cl2 (200 mL) under nitrogen over 15 min. After 18 h and solvent removal in vacuo, the crude product was dissolved in methylene chloride (250 mL) and washed with saturated NaHCO3 (3×50 mL), dried over Na2 -SO4, and concentrated in vacuo to a thin, amber oil (12.53 g). Upon standing at room temperature for 1 h, crystallization occured to give pure product (12.5 g, 88.4%) as a white solid, mp 61°-64° C. DCI/MS (M+1) 235. 400 MHz 1H NMR (CDCl3)δ: 7.35 (m, 8H), 6.05 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:4]([OH:6])=O.C(N(CC)CC)C.[Cl:23][C:24]1[CH:35]=[C:28]2[C:29](OC(=O)[NH:33][C:27]2=[CH:26][CH:25]=1)=[O:30]>O.C(#N)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[NH:33][C:4](=[O:6])[CH:3]([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[NH:2][C:29](=[O:30])[C:28]=2[CH:35]=1
Reactant: NC(CCc1ccccc1Cl)C(=O)O
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1NC(CCc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-(2-chlorophenyl)butanoic acid hydrochloride (1.49 g, 1 eq) was dissolved in water/acetonitrile 1:1 (24 mL:24 mL), and triethylamine (1.67 mL, 2 eq) was then added. 5-Chloroisatoic anhydride (1.18 g, 1 eq) was added in about 10 portions giving time between each addition for the previous portion to dissolve. After all of the anhydride was added the reaction was stirred at room temperature overnight. Any solids present after reaction were filtered off. The filtrate was concentrated in vacuo, azeotroped with acetonitrile, re-dissolved in AcOH (60 mL) and heated to 130° C. for 6 h. The crude mixture was then concentrated, and the residue was rinsed with NaHCO3(aq), stirring the slurry for 30 minutes before collecting the solid by filtration. The crude solid was washed with acetonitrile. 1H-NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.74 (d, 1H), 7.68 (s, 1H), 7.59 (d, 1H), 7.40-7.03 (m, 5H), 3.66 (q, 1H), 2.75 (m, 2H), 2.03 (m, 1H), 1.83 (m, 1H). MS (ES+) m/z 371.0 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])=[O:5].N1C=CC=CC=1.[F:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1>[F:28][CH2:29][C:30]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:31]
Reactant: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2N)c(C)c1
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
4.0 g of N-(2-amino-5-nitrobenzoyl)-2,4-dimethylaniline and 2.36 g of pyridine are dissolved in 50 ml of tetrahydrofuran, and 2.18 g of fluoracetyl chloride are added dropwise thereto under ice-cooling. The mixture is then stirred at room temperature for 5 hours. The mixture is concentrated under reduced pressure to remove tetrahydrofuran, and 100 ml of water are added to the residue. Crystalline precipitates are collected by filtration and recrystallized from a mixture of dimethylformamide and ethanol (1:2). 4.3 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2,4-dimethylaniline are obtained as colorless needles.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC(C)([O-])C.[K+].C(O)(C)(C)C.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[C:26]([O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Reaction time: 0.03 h
Yield: 36.5 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (5.00 g, 40.9 mmol) in DMF (40 mL) was added 1M potassium tert-butoxide in tert-butanol (40.9 mL, 40.9 mmol). The reaction was stirred for 2 minutes and tert-butyl bromoacetate (6.61 mL, 40.9 mmol) was added. The reaction was stirred for 1 hour and was quenched with 200 mL water. The product was extracted into EtOAc and the organic solution was washed with water, dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash chromatography on silica gel (9:1 hexanes:EtOAc) afforded the title compound of Step A as a clear oil (3.53 g). 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 7.48 (m, 2H), 7.32 (s, 1H), 7.21 (m, 1H), 4.56 (s, 2H), 1.45 (s, 9H).