Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH:17]=[O:18])[CH:12]=[CH:13][C:14]=1[CH3:15].C(Cl)(Cl)Cl.CCCCCC>C(O)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccc(C(=O)C=O)cc1C
Reactant: CNN=CC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 12.8 %

Procedure:
2-Oxopropanal methylhydrazone (8.18 mmol, 819 mg) synthesized in Reference Synthetic Example 1 and (3,4-dimethylphenyl)(oxo)acetaldehyde (7.57 mmol, 1.227 g) synthesized in Reference Synthetic Example 5 were dissolved in acetic acid (30 mL) and stirred at 100° C. for about 5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and subjected to silica gel column chromatography (n-hexane/AcOEt=2/1, and 4/1) to give the crude product. The crude product was stirred with CHCl3/n-hexane for a while, and then recovered by filtration. The filtered solid was combined with a solid obtained by silica gel thin layer chromatography purification (n-hexane/AcOEt=4/1) of the filtrate to give the desired product as an orange solid (237.5 mg, yield 13%).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: Sc1ccccc1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Fc1nc(Sc2ccccc2)c2[nH]cnc2n1
Temperature: 0 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To a solution of 2-fluoro-6-chloropurine (10.0 g, 57.9 mmol) in methanol (200 mL) is added diisopropylethylamine (25.2 mL, 144.7 mmol). The mixture is cooled to 0° C. and followed by slow addition of thiophenol (11.9 mL, 115.8 mmol) via an addition funnel over one hour. The reaction is stirred at 0° C. for 12 hours. The solvent is then removed under reduced pressure and the solid is collected by filtration and washed twice with hexanes. The collected solid is further purified by re-crystallization from methanol to afford desired product (11.8 g, 83% yield). 1H NMR (400 MHz, (CD3)2SO) δ 7.54 (m, 3H), 7.66(m, 2H), 8.49(s, 1H); MS C11H7FN4S [MH+] 246.04, found: 247.05.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:27]5[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(CO)cc1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (4-methoxy-phenyl)-methanol (98 mg) and tributylphosphine (320 μl) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg). The mixture was stirred under sonication at 50° C. for 1 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM (100 ml), and the DCM layer was washed with water (50 ml) and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as an off-white solid.
Reaction SMILES: C(O[C:4]1([O:10]CC)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)C.C(Cl)(Cl)Cl.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(N(CC)CC)C>[C:18]([N:6]1[CH2:7][CH2:8][CH2:9][C:4](=[O:10])[CH2:5]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC1(OCC)CCCNC1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 8.7 g. of 3,3-diethoxypiperidine in 100 ml. of dry chloroform is treated at 0° C. with 5 g. of triethylamine followed by 5.4 g. of ethyl chloroformate. After stirring at 25° C. for two hours, the solvent is removed in vacuo. The residue is extracted with ether and the extract concentrated in vacuo. This residue is treated with dilute hydrochloric acid for two hours. The solution is then saturated with sodium chloride and extracted with chloroform. The chloroform extract is washed with 5% aqueous sodium bicarbonate solution, dried and concentrated in vacuo to give 1-carbethoxy-3-piperidone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:14]([OH:17])CO)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:8]([C:6]1[C:5]([O:11][CH2:12][CH3:13])=[C:4]([C:3]([CH3:18])=[C:2]([Cl:1])[CH:7]=1)[CH:14]=[O:17])(=[O:10])[CH3:9]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1C(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1C=O
Reaction time: 0.5 h
Yield: 104.8 %

Procedure:
To a solution of 1-[5-chloro-3-(1,2-dihydroxyethyl)-2-ethoxy-4-methylphenyl]ethanone (0.64 g, 2.3 mmol) in tetrahydrofuran (18 mL) and water (11 mL) was added acetic acid (35 μL, 0.61 mmol) and sodium periodate (1.50 g, 7.04 mmol) at 0° C. After stirring for 30 min, the reaction mixture was diluted with water, and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product (0.58 g, 100%). LCMS calculated for C12H14ClO3 (M+H)+: m/z=241.1; Found: 241.1.
Reaction SMILES: [CH3:1][NH:2][CH3:3].N1CCOCC1.Cl[C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([CH2:18][OH:19])[CH:12]=1.ClC1C(CO)=NC=CC=1Cl>C(O)C>[CH3:1][N:2]([CH3:3])[C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([CH2:18][OH:19])[CH:12]=1
Reactant: OCc1cc(Cl)c(Br)cn1
Reactant: CNC
Agent: OCc1nccc(Cl)c1Cl
Solvent: CCO
Solvent: C1COCCN1
Product: CN(C)c1cc(CO)ncc1Br

Procedure:
Substituting 33% w/w dimethylamine in ethanol (15 ml) for morpholine and 4-chloro-5-bromo-2-hydroxymethylpyridine (5 g) for 3,4-dichloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3D gave after chromatography (silica, chloroform:methanol, 98:2) 4-dimethylamino-5-bromo-2-hydroxymethylpyridine, 3.62 g, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([CH3:16])=[N:14][CH:13]=[N:12]1)[NH2:8]
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CO
Product: Cc1ncnn1-c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
10% Palladium on carbon (1.5 g, 14.1 mmol) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (3.7 g, 17 mmol) dissolved in methanol (200 mL). The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The crude reaction mixture was filtered through a short plug of diatomaceous earth (Celite®). The reaction vessel and Celite® were rinsed with fresh methanol. The combined filtrates were concentrated in vacuo. The residue was dried under high vacuum to afford 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (3.14 g, 91% yield) as a blackish/grey solid. LC-MS (M+H)+ 193.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.91 (s, 1H) 7.14 (t, J=8.55 Hz, 1H) 6.43-6.53 (m, 2H) 4.04 (br. s., 2H) 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH2:24]Cl.CS(F)(=O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1
Reactant: ClCCl
Agent: CS(=O)(=O)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1ccc(N(C)CCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 1.0 g. of ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate, 20 ml. of dry dichloromethane and 2.5 ml. of methane sulfonyl fluoride is stirred for 18 hours, then refluxed for 3 hours. The solution is poured into 30 ml. of water and adjusted to pH 10 with 10N sodium hydroxide. The dichloromethane layer is separated and saved. The aqueous layer is extracted with two 20 ml. portions of dichloromethane. The organic layers are combined, washed with 10 ml. of water, dried over anhydrous magnesium sulfate, and evaporated to yield 1.80 g. of the desired product as a light yellow oil.
Reaction SMILES: CC(C)CC=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:10][CH2:9]1.[O:32]=[O+][O-]>ClCCl>[O:32]=[C:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:10][CH2:9]1
Reactant: CC(C)CC=C(CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: O=C(CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2 g of trans-2-[4-(5-methyl-2-phenyl-hex-2-enyloxy)-cyclohexyl]-isoindole-1,3-dione in 100 mL of dichloromethane cooled to −78° C. was dispersed a stream of ozone from an ozone generator until a blue color persisted. The excess ozone was purged with nitrogen until the blue color dissipated, and 5 mL of methyl sulfide was added. After warming to room temperature over 30 min, the solution was concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-30% ethyl acetate in hexane gave 1.8 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 8.0 (d, 2H), 7.8 (m, 2H), 7.6 (t, 1H), 7.5 (t, 2H), 4.8 (s, 2H), 4.18 (m, 1H), 3.5 (m, 1H), 2.35 and 2.25 (overlapping dd and d, 4H), 1.8 (d, 2H), 1.5 (dd, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH3:11])[N:5]=[C:4]([SH:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.Br[CH2:26][CH2:27][CH2:28]Br>O>[OH:10][CH2:9][CH2:8][C:7]1[C:2](=[O:1])[N:3]2[C:4]([S:12][CH2:26][CH2:27][CH2:28]2)=[N:5][C:6]=1[CH3:11]
Reactant: BrCCCBr
Reactant: Cc1nc(S)nc(O)c1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc2n(c(=O)c1CCO)CCCS2
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 30 parts of 4-hydroxy-2mercapto-6-methyl-5-pyrimidineethanol, 25 parts of potassium carbonate, 270 parts of N,N-dimethylacetamide and 75 parts of water was stirred at room temperature and 36 parts of 1,3-dibromopropane were added at once: temperature rises to 50° C. The whole was stirred overnight at room temperature. The reaction mixture was evaporated and water was added to the residue. The solid product was washed with water and dried in vacuo at 100° C., yielding 21 parts (58%) of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one; mp. 155° C. (intermediate 166).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9](N)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C(#N)C.N(OCCCC)=O.[BrH:26]>[Cu]Br>[Br:26][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:11][C:10]=1[CH3:12]
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1N
Reactant: Br
Agent: [Cu]Br
Agent: CCCCON=O
Solvent: CC#N
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: 25 °C

Procedure:
4′-Chloro-3-methylbiphen-4-ylamine (16.5 g, 0.077 mol) is added to acetonitrile (140 ml) and stirred at room temperature until dissolution is complete. The reaction mixture is cooled to between −5° C. and 0° C., tent-butyl nitrite (90%, 12.4 ml, 0.093 mol) is added dropwise and the reaction mixture is maintained at between −5 and 0° C. for 30-40 minutes. The mixture is added slowly to the preheated (50° C.) suspension of copper (I) bromide (5.8 g, 0.04 mol) in hydrobromic acid (5.8 ml) and stirred at 50° C. for 10-15 minutes. The reaction mixture is cooled to room temperature, then poured into ice-cold water and extracted with ethyl acetate (3×300 ml). The organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to yield 4-bromo-4′-chloro-3-methylbiphenyl (11.5 g).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[N:6]=1.CS(O[CH2:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][C:4]1[S:3][C:2]([S:1][CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:6][C:5]=12)[CH3:21]
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2c1CCc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate (1.80 g, 5.60 mmol) in N,N-dimethylformamide (15 mL) was added 2,2-diphenylethyl methanesulfonate (1.80 g, 6.20 mmol) followed by addition of potassium carbonate (857 mg, 6.20 mmol), and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 2.70 g of ethyl[[2-(2,2-diphenylethyl)thio-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound (2.00 g, 3.99 mmol) in ethanol (8 mL)-water (2 mL) was added sodium periodate (4.30 g, 19.9 mmol) and the mixture was refluxed for 14 hours. This reaction mixture was diluted with ethyl acetate and water and, after phase separation, the aqueous layer was extracted with ethyl acetate. The pooled organic solution was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. To a solution of the above concentration residue in tetrahydrofuran (16 mL)-methanol (4 mL) was added 1N-aqueous sodium hydroxide solution (2 mL) dropwise, and the mixture was stirred at room temperature for 10 minutes. The solvent was then distilled off under reduced pressure. To the residue was added 1N-hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to provide 0.72 g of the title compound. Yield 41%.
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:3].[C:10](#[N:14])[C:11]([CH3:13])=[CH2:12]>C(O)C>[NH2:14][C:10]1[CH:11]([CH3:13])[CH2:12][N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:3]=1
Reactant: C=C(C)C#N
Reactant: NNc1ccccn1
Agent: [Na]
Solvent: CCO
Product: CC1CN(c2ccccn2)N=C1N

Procedure:
A 1.02 g. amount of sodium metal is dissolved in 250 ml. of absolute ethanol, then 21.8 g. of 2-hydrazinopyridine is added, followed by 13.4 g. of methacrylonitrile. The reaction mixture is refluxed for 16 hours, then the solvent is removed in vacuo. The solid is recrystallized twice from 3A ethanol after treatment with activated charcoal to give 4.30 g. of a tan solid. The above recrystallization filtrates are combined and evaporated in vacuo to a solid. The solid is dissolved in dichloromethane and passed through a hydrous magnesium silicate. The filtrate is concentrated while adding hexane at reflux to crystallize an additional 16.4 g. of the desired product (total 20.79 g.) as tan crystals, m.p. 149°-151° C.
Reaction SMILES: C([Li])CCC.C([Sn]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(CCCC)CCCC)CCC.[CH3:34][Si:35]([CH3:44])([CH3:43])[C:36]1[O:40][CH:39]=[C:38]([CH:41]=[O:42])[CH:37]=1.[C:45](OC(=O)C)(=[O:47])[CH3:46]>CCCCCC.O1CCCC1>[C:45]([O:42][CH:41]([C:38]1[CH:37]=[C:36]([Si:35]([CH3:44])([CH3:43])[CH3:34])[O:40][CH:39]=1)[CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=[O:47])[CH3:46]
Reactant: CC(=O)OC(C)=O
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCC[Sn](CCCC)(CCCC)COCCCc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)OC(COCCCc1ccc2ccccc2c1)c1coc([Si](C)(C)C)c1
Reaction time: 0.08 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 0.69 ml, 1.1 mmol) was added dropwise to a solution of (2-naphthyl)propyl tributylstannylmethyl ether (511.9 mg, 1.05 mmol) in tetrahydrofuran (5 ml) at -78° under argon. After 5 minutes, a solution of 5-trimethylsilyl-3-furaldehyde (176 mg, 1.05 mmol) in tetrahydrofuran (1/2 ml) was added, followed by acetic anhydride (0.1 ml, 1.58 mmol) after 25 minutes. Stirring was continued at -78° for 1 hour and the mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed using 10% ethyl ether/petroleum ether. The title ester was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[Cl:23]N1C(=O)CCC1=O.O>CN(C)C=O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[C:8]([Cl:23])[C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)cc1C(N)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)c(Cl)c1C(N)=O
Yield: 45 %

Procedure:
A solution of 2-aminocarbonylamino-5-(2-naphthyl)pyrrole-3-carboxamide (Compound No. 1-1, 92 mg, 0.31 mmol) and N-chlorosuccinimide (46 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred at 60° C. for 2 hours. After cooling, water (10 mL) was added thereto, the precipitated solid was filtered off, and washed with water (10 mL) and acetone (10 mL). The obtained solid was dried at 50° C. under reduced pressure to give the target compound (46 mg) as a pale brown solid (Yield 45%).
Reaction SMILES: O.[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O-:34])=[O:33].Cl.C(O)C>O>[OH2:15].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33]
Reactant: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 8 h
Yield: 169.1 %

Procedure:
1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid sodium salt hydrate (0.62 g), from the previous alternative, and aqueous hydrochloric acid (2 molar) were combined in refluxing ethanol (13 mL) and water (1.3 mL). The mixture was cooled, granulating overnight, chilled in ice and the resulting slurry was filtered. The product solids were dried, yielding the title compound, 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid hydrate (0.5 g, 83%, containing 2% water by weight). Anhydrous Mol wt (calc) 438.41, MS: 439.35 (MH+), 437.20 (M−). 1H NMR (DMSO-d6): δ 3.97 (s, 3H), 7.13 (s, 1H), 7.30-7.75 (complex, 10H), 7.92 (s, 1H), 10.21 (s, 1H). HPLC retention time 9.29 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[C:19](OC=O)(=O)C.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1>ClCCl.C1COCC1>[CH3:18][C:9]1[S:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH2:17])[C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:19])=[CH:7][CH:6]=1
Reactant: CC(=O)OC=O
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNc1ccc(-c2c(C)sc3ncnc(N)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
A −20° C. suspension of Example 1E (400 mg, 1.56 mmol) in dichloromethane (10 mL) and THF (10 mL) was treated with formic acetic anhydride (0.135 mL, 1.7 mmol), stirred for 1 hour, and concentrated. The concentrate was suspended in benzene (50 mL), treated with 65% Red-Al in toluene (2.4 mL, 7.8 mmol), stirred at room temperature for 20 minutes than heated to reflux for 6 hours. The reaction was cooled to room temperature and partitioned between Rochelle's salt and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 7% methanol/dichloromethane to provide the desired product (86 mg). MS(ESI(+)) m/e 271 (M+H)+.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: Cc1ccc(CCl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(CN2C(=O)C(CCO)Oc3ccccc32)cc1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G alkylating with 4-methylbenzyl chloride, in 50% overall yield. This material was crystallized from ether to afford a white solid, mp 92°-94° C.; IR (KBr) 3496, 1659, 1503, 1405, 1304, 1283, 1248, 1063, 801 cm-1 ; 1H NMR (CDCl3) δ 2.18-2.36 (m, 5H), 3.91 (q, J=5.7, 2H), 4.83 (dd, J=7.4, 5.7, 1H), .5.12 (s, 2H), 6.90-7.00 (m, 4H), 7.13 (s, 4H); MH+ at m/z=298; Anal. Calc'd for C18H19NO3 : C, 72.71; H, 6.44; N, 4.71. Found: C, 72.71; H, 6.48; N, 4.65.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:5]=1[C:6](OC)=[O:7])(=[O:3])[CH3:2].[CH3:17][NH2:18]>C(O)C>[OH:3][C:1]1([CH3:2])[C:4]2[C:5](=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[C:6](=[O:7])[N:18]1[CH3:17]
Reactant: CN
Reactant: COC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Solvent: CCO
Product: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)O
Yield: 85 %

Procedure:
A mixture of methyl 2-acetyl-6-nitrobenzoate (2 g, 8.96 mmol) and 33% methylamine in ethanol (10 mL) was stirred at reflux for 14 h. The solvents were removed under reduced pressure to afford 1.7 g of the desired product (yield: 85%). 1H NMR (CDCl3, 300 MHz): δ=1.80 (s, 3 H), 3.05 (s, 3 H), 7.78 (m, 2 H), 7.95 (m, 1 H).