Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=C)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=[O:16])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2nnc(C(C)C)n2n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nnc2ccc(C=O)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
The 3-isopropyl-6-vinyl-[1,2,4]triazolo[4,3-b]pyridazine (3.28 g, 17.4 mmol, Preparation #1) in 1,4-dioxane (75 mL) and water (15 mL) was treated with osmium tetroxide (3.5 mL, 0.28 mmol, 2.5 wt % in 2-methyl 1-propanol) and then sodium periodate (7.45 g, 34.9 mmol) was added. The mixture was stirred at ambient temperature for about 1 h and then diluted with 1,4-dioxane (50 mL) and filtered through Celite®. The filter cake was washed with 1,4-dioxane then EtOAc. The filtrate was concentrated under reduced pressure and then the residue was purified by flash chromatography on silica gel with DCM/MeOH (9:1) as an eluent to give the title compound (2.30 g, 69.4%) as a beige solid: 1H NMR (CDCl3) δ 1.61 (d, 6H), 3.76 (m, 1H), 7.65 (d, 1H), 8.21 (m, 1H), 10.06 (d, 1H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:17]([NH:19][C:20]3[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)=[O:41])=[O:25])=[CH:22][C:21]=3[O:52][CH3:53])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:54][O:55][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C.Cl>[OH-].[Na+].CO>[OH:55][CH2:54][C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[C:12]([C:17]([NH:19][C:20]1[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=3[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])=[O:25])=[CH:22][C:21]=1[O:52][CH3:53])=[O:18])[CH:13]=[CH:14][CH:15]=2
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2c1cc(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n2C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CO)cc12
Yield: 89.2 %

Procedure:
The solution of 4-[(1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (615 mg) in 1N sodium hydroxide aqueous solution (3.1 ml) and methanol (10 ml) was stirred at ambient temperature overnight. The resulting solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate (20 ml). The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; 8-10% methanol in chloroform) to give 4-[(2-hydroxymethylindol-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (362 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1([C:7]2[C:8](=[O:32])[NH:9][C:10](/[C:13](/[C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23](F)[CH:22]=3)=[CH:14]/[C@H:15]3[CH2:19][CH2:18][C:17](=[O:20])[NH:16]3)=[CH:11][CH:12]=2)[CH2:6][CH2:5]1.O>CO>[CH:4]1([C:7]2[C:8](=[O:32])[NH:9][C:10](/[C:13](/[C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([O:2][CH3:1])[CH:22]=3)=[CH:14]/[C@H:15]3[CH2:19][CH2:18][C:17](=[O:20])[NH:16]3)=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(=O)[nH]2)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(=O)[nH]2)ccc1S(C)(=O)=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A 28% solution of sodium methoxide in methanol (14 μL) was added to a solution of 3-cyclopropyl-6-{(E)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one obtained in Example 4-386 (10 mg) in methanol (0.5 mL), after which the mixture was stirred at 70° C. for 30 minutes. The reaction solution was left to cool to room temperature. 3-Cyclopropyl-6-{(E)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (50 mg), methanol (3 mL) and a 28% solution of sodium methoxide in methanol (80 μL) were then added, after which the mixture was stirred at 70° C. for two hours. The reaction solution was left to cool to room temperature and a 28% solution of sodium methoxide in methanol (1 mL) was then added, after which the mixture was stirred at 70° C. for one hour. The reaction solution was left to cool to room temperature, and water was then added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (methanol:ethyl acetate=1:10) to give the title compound as a pale yellow solid (40 mg, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:25]=[CH:26][C:27]([N:30]6[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]6)=[N:28][CH:29]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[CH:29]=[N:28][C:27]([N:30]6[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]6)=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)nc5)nn34)ccnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N6CCNCC6)nc5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 50 mL recovery flask was charged with tert-butyl 4-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (0.250 g, 0.44 mmol), TFA (0.75 ml, 9.6 mmol), and DCM (1.50 ml, 23 mmol), then stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, then quenched with sat. aq. NaHCO3. The mixture was diluted with DCM (60 mL), resulting in an emulsion. The emulsion was filtered to give a brown solid. The solid was triturated with a combination of DCM/MeOH/MeCN and filtered to give 7-methoxy-4-((6-(6-(piperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)quinoline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5](O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[CH:32]1[CH:37]=[CH:36][C:35]([CH2:38][SH:39])=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([S:39][CH2:38][C:35]1[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: SCc1ccccc1
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Product: CCCCCCCN(CCc1ccc(CC(SCc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 50 and substituting benzylthiol as the nucleophile to give an approximate 1:1 mixture of ethyl and methyl ester as a clear film (58 mg, 95%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:15]([CH3:58])[C:16](=[O:57])[C:17]([CH3:56])=[C:18]2[C:23]=1[C:22](=[O:24])[N:21](CC1C=CC(OC)=CC=1)[C:20](=[O:34])[N:19]2[C:35]1[CH:36]=[C:37]([CH:53]=[CH:54][CH:55]=1)[C:38]([N:40]1[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]1)=[O:39].CO>C1(OC)C=CC=CC=1>[F:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[N:15]([CH3:58])[C:16](=[O:57])[C:17]([CH3:56])=[C:18]2[C:23]=1[C:22](=[O:24])[NH:21][C:20](=[O:34])[N:19]2[C:35]1[CH:55]=[CH:54][CH:53]=[C:37]([C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])[CH:36]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)c2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: COc1ccccc1
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)[nH]c(=O)n(-c3cccc(C(=O)N4CCNCC4)c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 15.2 %

Procedure:
Aluminium chloride (1.57 g, 11.76 mmol) was added in small portions to a solution of crude tert-butyl 4-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoyl)piperazine-1-carboxylate (1 g, 1.176 mmol) in Anisole (5 ml). The resulting reaction mixture was stirred at room temperature for 17 h, methanol (10 ml) was added dropwise and the resulting mixture was concentrated in vacuo. Aq. ammonia was added to the resulting residue and the reaction mixture was extracted several times with DCM. The combined organic phase was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo and the residue was purified by column chromatography over neutral alumina to afford the titled compound (23) (0.113 g).
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])[CH:3]=1.[BH4-].[Na+]>CCO>[I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([CH3:17])([CH3:16])[CH2:12][OH:13])[CH:3]=1
Reactant: COC(=O)C(C)(C)n1cc(I)c2cnccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CO)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
To a solution of methyl 2-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)-2-methylpropanoate (Preparation 67, 10.8 g, 31.38 mmol) in EtOH (100 mL) was added sodium borohydride (2.37 g, 62.8 mmol) and the reaction stirred at room temperature for 5 hours. The reaction was quenched by the addition of water (100 mL) and the phases separated through a phase separation cartridge. The organic layer was concentrated in vacuo to afford and orange oil that was triturated with ether to afford an orange solid as the title compound (3.86 g, 39%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[CH2:20]Br>CCO>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[CH2:20][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: Fc1cc(CBr)cc(F)c1F
Solvent: CCO
Product: Fc1cc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc(F)c1F

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 3,4,5-trifluorobenzylbromide (0.20 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[CH3:11][C:12](O)([CH:14]=[CH2:15])[CH3:13]>C(O)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:15][CH:14]=[C:12]([CH3:13])[CH3:11])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: C=CC(C)(C)O
Solvent: O=CO
Product: CC(C)=CCc1cc(C)c(O)c(C)c1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
2,3,6-Trimethylphenol (68 g, 0.5 mol) and formic acid (100 mL) were combined and warmed to 50°-55° C. with vigorous agitation. To this mixture was added 2-methyl-3-buten-2-ol (47.3 g, 0.55 mol) dropwise over 0.25 h. The reaction mixture was stirred for an additional 2 h at 50° C., and then quenched into water 8300 mL). The crude product was isolated by extraction with toluene (3×100 mL) followed by washing with water (200 mL), 5% sodium bicarbonate (2×100 mL), and brine (3×100 mL). Evaporation of the solvent and distillation afforded 61 g of the phenol, bp 145°-150° c. (2 mm). NMR (CDCl3) δ1.7 (6H, s), 2.2 (9H, s), 3.2 (2H, bd), 4.4 (1H, s, exchanged with D2O), 5.2 (1H, m), 6.8 (1H, s). IR (film) 3700, 1460, 1200, 1090 cm-1. MS (m/e) 204 (M+), 189, 174, 190, 136.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(N(C(C)C)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][NH2:2])=[O:16])=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.4 %

Procedure:
) A solution of hydrazine (0.023 mol) and N,N-dimethyl-4-pyridinamine (catalytic quantity) in CH2Cl2 (50 ml) was cooled in an ice-water bath. Half of a solution of 4-benzoylbenzoyl chloride (0.023 mol) in CH2Cl2(60 ml) was added dropwise. The other half of this solution, and a solution of N,N-bis(1-methylethyl)ethanamine (0.023 mol) in CH2Cl2 (40 ml) were added simultaneously and dropwise. The resulting reaction mixture was stirred for 5 hours at RT. The crude reaction mixture was filtered and the filtrate was washed with water and extracted. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 1.9 g (34%) of 4-benzoylbenzoic acid hydrazide (interm. 12)
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:11][C:8]1[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(Cl)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cl)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
5-Chloro-2-furancarboxylic acid ethyl ester (8 g) (synthesized in accordance with the method described in Chem. Pharm. Bull., 40, 1966 (1992)) was dissolved in ethanol (50 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with diethyl etherhexane to give 5-chloro-2-furancarboxylic acid (5.3 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:6]([CH3:12])=[N:7]2.[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:23][CH2:12][C:6]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Cc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2nc1CBr
Temperature: 25 °C
Reaction time: 21.5 h

Procedure:
5-Chloro-2-methyl-3-(2-(trifluoromethyl)phenyl)quinoxaline (1.4455 g, 4.479 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.6404 g, 2.240 mmol) were suspended in carbon tetrachloride (44.79 mL, 4.479 mmol). To the mixture was added benzoyl peroxide (0.1447 g, 0.4479 mmol) and the mixture was heated at reflux. After 21.5 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 9% gradient of EtOAc in hexane over 2 min, then 9% isocratic of EtOAc for 13 min, then 9 to 100% gradient of EtOAc in hexane over 23 min, then 100% isocratic of EtOAc for 4 min as eluent to give 2-(bromomethyl)-5-chloro-3-(2-(trifluoromethyl)-phenyl)quinoxaline as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (1H, dd, J=8.4, 1.4 Hz), 8.13 (1H, dd, J=7.8, 1.2 Hz), 7.81-8.03 (5H, m), 4.69 (2H, dd, J=88.4, 10.2 Hz); LC-MS (ESI) m/z 400.9 and 403.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[OH:12])[O:8][C:7](=[O:14])[CH:6]=[C:5]2[CH3:15].[CH2:16](I)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[O:12][CH2:16][CH3:17])[O:8][C:7](=[O:14])[CH:6]=[C:5]2[CH3:15]
Reactant: CCI
Reactant: Cc1cc(=O)oc2c(F)c(O)c(F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1c(F)cc2c(C)cc(=O)oc2c1F
Yield: 44.3 %

Procedure:
A solution of Compound 5 (0.10 g, 0.47 mmol) and ethyl iodide (112 μL, 1.4 mmol) in acetone (10 mL) is stirred at reflux with potassium carbonate (207 mg, 1.5 mmol) for 72 hours, during which additional ethyl iodide (2×200 μL) is added at 24 and 48 hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated to a colorless solid. This solid is purified by preparative TLC (silica gel, 1000 μm plate, eluting with ethyl acetate/hexanes 1:1) to give 50 mg of nonfluorescent Compound 7 as a colorless solid. UV-vis (MeCN): 298 nm, ε=7,770 cm-1M-1 ; 279 nm, ε=11,080 cm-1 M-1. Rf (ethyl acetate/hexanes 3:2) 0.75. 1H NMR (CDCl3) 7.10 (dd, 1H), 6.28 (s, 1H), 4.38 (q, 2H), 2.39 (s, 3H), 1.42 (t, 3H). 19F NMR (CDCl3) 132.2 (t, 1F), 146.9 (d, 1F). Anal. calcd for C12H10O3F2 : C, 60.00; H, 4.20; N, 0.00; Found: C, 59.98; H, 4.27; N, 0.01.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2C=C1.[N:12]([O-])=O.[Na+].Cl.O.[O:18]1[CH2:23][CH2:22]OCC1>>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[C:22]([CH:23]=[O:18])=[N:12]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: C1COCCO1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=Cc1cccc2[nH]nc(C=O)c12

Procedure:
The commercially available 1H-indole-4-carbaldehyde is reacted with NaNO2 in the presence of HCl and H2O in dioxane to produce the title pound.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[S:8](=O)[C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]1=2)C=C.FC(F)(F)C(O[C:27](=O)[C:28](F)(F)F)=O.[CH:35](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:35]([C:9]1([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[S:8][C:7]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:6]=2[C:5]1=[O:4])[CH:27]=[CH2:28]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CCO[C@H]1c2ccc(Cl)cc2S(=O)[C@H]1Cn1ccnc1
Reactant: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCC1(Cn2ccnc2)Sc2cc(Cl)ccc2C1=O

Procedure:
Reflux 15.2 g (47.1 mmole) of cis 3-allyloxy-6-chloro-2,3-dihydro-2-(1H-1-imidazolylmethyl)benzo[b]thiophene-1-oxide and 9.97 mL (70.6 mole) of trifluoroacetic anhydride in 150 mL of toluene for 1 hr. Pour the reaction mixture into 1 liter of CHCl3 and extract it with 1 liter of 5% aqueous Na2CO3 followed by 1 liter of H2O. Dry the organic layer over anhydrous MgSO4 and evaporate the solvent in vacuo. Chromatograph the oily residue on 500 g of silica gel eluting with CHCl3 to give 2-allyl-6-chloro-2,3-dihydro-2-(1H-1-imidazolylmethyl) benzo[b]thiophene-3-one, a gum, m/e 304.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:20][C:17]1([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[CH2:19][CH2:18]1
Reactant: CC1(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1(N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
4-(1-Methylcyclopropan-1-yl)piperazine-1-carboxylic acid benzyl ester (509 mg, 1.86 mmol) was dissolved in ethanol (20 mL), and 10% palladium hydroxide/carbon (100 mg) was added thereto. The mixture was stirred for 20 hours at room temperature under a hydrogen stream at normal pressure. The catalyst was separated by filtration, and then the reaction liquor was concentrated under reduced pressure, and dried to obtain the title compound (193 mg, 74%) as an oily matter. This compound was used in the subsequent reaction without performing further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)(O)[CH2:13][CH3:14])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](\[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)/[CH2:13][CH3:14])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)butan-2-ol (0.2 g, 0.542 mmol) was dissolved in dry DCM (10 mL) and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.1 mL, 1.6 mmol) diluted with dry DCM (2 mL) was added dropwise. Stirring was continued for 1 h at 0° C. and then at RT for 2 h. The solution was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.36 (d, 2H), 7.30 (s, 1H), 6.98 (m, 2H), 6.82 (d, 2H), 6.70 (s, 1H), 3.60 (s, 2H), 2.70 (m, 4H), 2.50 (m, 5H), 1.20 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=3)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>ClCCl>[C:29]1([C:16]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:10][CH:11]=3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=3)[N:17]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(N)cc3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(NS(=O)(=O)C(C)C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
Propane-2-sulfonyl chloride (300 mg, 2.10 mmol, 5.00 equiv) was added to a solution of methyl 3-(4-aminophenyl)-2-phenylquinoxaline-6-carboxylate (150 mg, 0.42 mmol, 1.00 equiv) and DIEA (545 mg, 4.22 mmol, 10.00 equiv) in dichloromethane (30 mL) at 0° C., and the resulting solution was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate/petroleum ether (1:10)), affording 170 mg (87%) of methyl 2-phenyl-3-(4-(propan-2-ylsulfonamido)phenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([Li])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OC(N[C@H](C(O)=O)C)=O)C.C1([Mg]Br)C=CC=CC=1>CCOCC.O1CCCC1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: [Li]c1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: CCOC(=O)N[C@@H](C)C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
The techniques which resulted in successful amido acylation of benzene using phenyllithium were next applied to the Grignard reaction. N-ethoxycarbonylalanine was treated with 300 mol percent of phenylmagnesium bromide at -78° C. and allowed to warm to room temperature. The desired ketone was not observed. Several hours of refluxing in ether and tetrahydrofuran yielded biphenyl and starting material which was optically intact.