Azzindani/Open_Reaction_Data huggingface dataset:
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]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:32][O:33][C:34]1[N:45]=[CH:44][CH:43]=[CH:42][C:35]=1[C:36](N(OC)C)=[O:37]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:36]([C:35]3[C:34]([O:33][CH3:32])=[N:45][CH:44]=[CH:43][CH:42]=3)=[O:37])=[N:3][CH:4]=[C:5]([Cl: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: COc1ncccc1C(=O)N(C)OC
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccnc1OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (612 mg, 1.24 mmol) in THF (5 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 1.55 mL, 3.1 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2,N-dimethoxy-N-methyl-nicotinamide (487 mg, 2.48 mmol) in THF (2 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). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. The obtained residue was purified via column chromatography (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (200 mg) in 29.2% yield. ESMS m/z (relative intensity): 550 (M+H)+ (100), 571.9 (M+Na)+ (80).
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(CCC2C=CC(O)=CC=2)C=1.Cl.ClCCN(C(C)C)C(C)C.[CH:41]([N:44]([CH:76]([CH3:78])[CH3:77])[CH2:45][CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([O:62]C)[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74]C)[CH:70]=3)[CH2:65]2)=[CH:50][CH:49]=1)([CH3:43])[CH3:42]>>[CH:76]([N:44]([CH:41]([CH3:43])[CH3:42])[CH2:45][CH2:46][O:47][C:48]1[CH:49]=[CH:50][C:51]([CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([OH:62])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[CH:70]=[C:69]([OH:74])[CH:68]=[CH:67][C:66]=3[CH2:65]2)=[CH:52][CH:53]=1)([CH3:78])[CH3:77]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(OCCN(C(C)C)C(C)C)cc1)C2
Agent: CC(C)N(CCCl)C(C)C
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(O)cc1)C2
Agent: Cl
Product: CC(C)N(CCOc1ccc(CCc2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1)C(C)C
Yield: 35.8 %

Procedure:
Synthesized from 4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenol and (2-chloroethyl)diisopropylamine hydrochloride according to an analogous synthetic method to Preparation Example 40, diisopropyl {2-{4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenoxy}ethyl}amine (183 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (62 mg).
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12]([OH:14])=O)[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>C(Cl)Cl>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:14])[NH:32][C:31]1[CH:33]=[CH:34][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: CC(C)OC(=O)C(C(=O)O)=C1SCS1
Reactant: Nc1ccc(Cl)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)Nc1ccc(Cl)cc1)=C1SCS1
Reaction time: 1 h

Procedure:
A solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-carboxyacetate (10 g) in methylene chloride (100 ml) was cooled to -10° C. and thereto phosphorous pentachloride (8.9 g) was added portionwise and then stirred for 1 hr. To the reaction mixture pyridine (13.8 ml) and 4-chloroaniline (5.45 g) were added and stirred for 2 hrs. The mixture was washed with dil-HCl, 10% aqueous sodium hydroxide solution and water and then evaporated. The residue was purified with ethyl acetate to afford the titled compound as a white solid. (8.9 g, 61%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][CH2:35][C:36]1[CH:37]=[C:38]([S:42][C:43]2[CH:44]=[N:45][CH:46]=[C:47]([CH:50]=2)[C:48]#[N:49])[CH:39]=[CH:40][CH:41]=1.[OH:51][C:52]1[C:57]([CH3:58])=[C:56](O)[CH:55]=[CH:54][C:53]=1[C:60](=[O:62])[CH3:61]>C1COCC1>[C:60]([C:53]1[CH:54]=[CH:55][C:56]([O:34][CH2:35][C:36]2[CH:37]=[C:38]([S:42][C:43]3[CH:44]=[N:45][CH:46]=[C:47]([CH:50]=3)[C:48]#[N:49])[CH:39]=[CH:40][CH:41]=2)=[C:57]([CH3:58])[C:52]=1[OH:51])(=[O:62])[CH3:61]
Reactant: CC(=O)c1ccc(O)c(C)c1O
Reactant: N#Cc1cncc(Sc2cccc(CO)c2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccc(Sc3cncc(C#N)c3)c2)c(C)c1O
Yield: 50.5 %

Procedure:
Add triphenylphosphine (5.24 g, 20.0 mmol) and diisopropylazodicarboxylate (4.04 g, 20.0 mmol) to a solution of 5-(3-(hydroxymethyl)phenylthio)nicotinonitrile (4.84 g, 20.0 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (3.32 g, 20.0 mmol) in THF (100 mL). Stir the reaction for 24 h. Quench the reaction with water and extract with EtOAc. Dry, filter and concentrate. Purify the residue by flash chromatography on silica gel eluting with a mixture of EtOAc and hexanes (15:85 to 20:80) to give an off-white solid. Recrystallize the solid from a mixture of EtOAc and hexanes to afford the title compound (3.94 g, 50%): 1H NMR (CDCl3) δ 2.14 (s, 3H), 2.57 (s, 3H), 5.18 (s, 2H), 6.44 (d, J=9.0 Hz, 1H), 7.46-7.49 (m, 3H), 7.52 (s, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.62-7.63 (m, 1H), 8.63-8.64 (m, 2H), 12.78 (s, 1H).
Reaction SMILES: [Li+].[BH4-].CO.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([N:28]4[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[CH3:34])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)([CH2:17][CH3:18])[C:13](OC)=[O:14])=[CH:8][CH:7]=1>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([N:28]4[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[CH3:34])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20]2)([CH2:17][CH3:18])[CH2:13][OH:14])=[CH:8][CH:7]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CO)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of LiBH4 (22 mg) in THF (3 mL) was added MeOH (32 mg, 5.43 mmol) and a solution of methyl 2-(4-chlorophenyl)-2-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indol-1-yl)butanoate (105 mg) in THF (3 mL). The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatography on silica gel (25-35% ethyl acetate in hexanes) to afford the title compound as a pale yellow solid. LC/MS m/z=393.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[NH2:11].CC(=O)O[CH2:15][CH3:16].[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[N:11]=[C:3]([CH2:2][CH3:10])[N:11]([CH2:18][CH2:19][C:20]1[CH:16]=[CH:15][CH:23]=[CH:22][CH:21]=1)[C:5]2=[O:7]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CCOC(C)=O
Reactant: CCCCCC
Product: CCc1nc2c(Cl)cccc2c(=O)n1CCc1ccccc1

Procedure:
The title compound was prepared using the procedure described above of the step 1 of example 1 from 3-chloroanthranilic acid (5 g, 29.14 mmol) to give white needle crystal (4.3 g, 47.2%), Rf=0.53 (EA/Hexane=1:2); 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J=7.2 Hz, 3H), 2.79 (q, J=7.2 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 4.20 (t, J=7.6 Hz, 2H), 7.20-7.31 (m, 5H), 7.41 (dd, J=8.0, 7.6 Hz, 1H), 7.89 (d, J=17.6 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 10.5, 27.1, 33.5, 44.7, 121.4, 125.2, 126.4, 126.5, 128.5, 128.7, 130.3, 134.1, 138.1, 143.1, 158.7, 160.5; Anal. (C18H17ClN2O) C, H, N. Calcd: 69.12, 5.48, 8.96. Found: 69.11, 5.38, 8.94.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[S:21][CH:22]=[C:23]([CH2:25][C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=3)[N:24]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[C:37](OCC)(=O)[CH3:38]>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[S:21][CH:22]=[C:23]([CH2:25][C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:37][CH3:38])=[C:30]([O:35][CH2:1][CH3:2])[CH:29]=3)[N:24]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: CCI
Reactant: COc1ccc(-c2nc(CC(=O)Cc3ccc(O)c(O)c3)cs2)cc1OC
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(=O)Cc2csc(-c3ccc(OC)c(OC)c3)n2)cc1OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
Ethyl iodide (0.48 ml, 6.0 mmol) and potassium carbonate (0.62 g, 4.5 mmol) were added at room temperature to a solution (7 ml) of 3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-dihydroxyphenyl)propanone (0.58 g, 1.5 mmol) in DMF, followed by stirring at 60° C. for 1 hour. After cooling to room temperature, ethyl acetate was added to the reaction mixture, the resulting mixture was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). The solvent was distilled off under reduced pressure, and the residue was recrystallized from an ethyl acetate/n-hexane mixed solvent, to thereby obtain 290 mg (yield: 44%) of 3-[2-(3,4-dimethoxyphenyl)thiazole-4-yl]-1-(3,4-diethoxyphenyl)propanone as a white powder.
Reaction SMILES: S(NN)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=O)=O.[CH3:13][CH2:14]O.C([N-][CH:20]([CH3:22])[CH3:21])(C)C.[Li+]>Cl.CN(C)CCN(C)C>[CH2:8]1[C:7]2[C:6](=[CH:5][CH:4]=[CH:10][CH:9]=2)[CH:8]=[C:7]1[CH2:9][C:10]1[CH2:4][C:5]2[C:13]([CH:14]=1)=[CH:21][CH:20]=[CH:22][CH:6]=2
Reactant: CCO
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li+]
Product: C1=C(CC2=Cc3ccccc3C2)Cc2ccccc21
Temperature: 0 °C
Yield: 14 %

Procedure:
15.0 g (54 nunol) of CH2(1-indanone)2, prepared as described above, and 24.3 g (2.4 equiv.) of tosyl hydrazine were placed in a 250 ml round-bottom flask and 100 ml EtOH added. Then 10 drops of 37% HCl were added and the reaction mixture brought to reflux under nitrogen. On coming to reflux, everything dissolved and a clear brown solution resulted. After refluxing for 10 minutes, a white jelly-like material began to precipitate. This was washed with MeOH and then dried under vacuum. This gave 21 g (63%) of the bis(hydrazone). 10.8 g (17.6 mmol) of the bis(hydrazone), suspended in 250 ml N,N,N′,N′-tetramethyl-ethylene diamine (TMEDA) in a large Schlenk tube, was slowly added to 15.2 g (141 mmol, 8 equivalents) of lithium diisopropylamide, dissolved in 50 ml TMEDA and cooled to 0° C. The solution changed from yellow to purple and then to dark purple. It was allowed to warm to room temperature and then decanted onto ice to give a yellow solution. On washing with 100 ml aqueous NaHCO3 the solution became purple. This was extracted copiously (3×250 ml) with Et2O, the Et2O extracts combined and dried over MgSO4. These were evaporated to a brown oil which was extracted with pentane. Working up of the pentane extracts afforded 0.59 g (14%) of bis(2-indenyl)methane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[CH3:16][O:17][C:18](=[O:21])[CH:19]=[CH2:20].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.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>[CH3:16][O:17][C:18]([CH:19]=[CH:20][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1)=[O:21]
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1CCC2
Reactant: C=CC(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Temperature: 120 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A suspension of 7-bromo-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (528 mg, 2.0 mmol), acrylic acid-methyl ester (0.36 ml, 4.0 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) and triethylamine (0.56 ml, 4.0 mmol) in DMF (25 ml) is stirred for 3 hours at 120° C. The batch is diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Purification of the residue on silica gel with dichloromethane-ethanol yields 550 mg (99%) of product.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:11][C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH2:29][CH:30]=[O:31].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:30]([OH:31])[CH2:29][C:23]3[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=CCc1c(Cl)cccc1Cl
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)Cc2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A solution of butyl lithium in hexane (5.1 mL; 2.5M) is treated with a solution of 3-cyclopentyloxy-4-methoxyphenyl bromide (3.45 g) in dry tetrahydrofuran (30 mL) at -70° C. and the solution is then stirred at -70° C. for 1 hour. It is then treated dropwise with 2,6-dichlorophenylacetaldehyde (2.4 g), while keeping the temperature below -60° C. When the addition is complete the temperature is allowed to rise to room temperature and the solution is stirred for a further 2 hours. The reaction mixture is treated with aqueous ammonium chloride solution (50 mL) and the solution is extracted with diethyl ether (2×200 mL). The combined extracts are dried and concentrated, to give a yellow oil, which is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:8 v/v), to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethanol (1.6 g),in the form of a white solid, m.p. 87°-89° C.
Reaction SMILES: [H-].[Na+].O[N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:22]1[C:27]([CH3:28])=[N:26][CH:25]=[CH:24][N:23]=1.[OH2:29]>CN(C)C=O>[CH2:7]([O:6][C:5]([NH:4][C:15]1[CH:20]=[CH:19][C:18]([C:25]2[N:26]=[C:27]([CH3:28])[C:22](=[O:29])[NH:23][CH:24]=2)=[CH:17][CH:16]=1)=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1nccnc1Cl
Reactant: O
Reactant: O=C(OCc1ccccc1)N(O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(NC(=O)OCc3ccccc3)cc2)c[nH]c1=O

Procedure:
To a stirred suspension of sodium hydride (2.1 g, 50% in oil) in dry dimethylformamide (35 ml) with external cooling was added portionwise, benzyl N-hydroxy-N-phenylcarbamate (10.6 g). After 5 minutes a brown solution was obtained to which was added 2-chloro-3-methylpyrazine (5.5 g) and the mixture was allowed to attain room temperature. The solution was poured into water (200 ml) and the aqueous phase decanted from the dark oil. The aqueous solution deposited a yellow solid which was collected and washed with ethanol to give 5-(4-benzyloxycarbonylaminophenyl)-3-methyl-2(1H)-pyrazinone (1.55 g. m.p. 238°-240° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=O)[CH2:5][C:6]([O:8]CC)=[O:7].[N:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].[O-]CC.[Na+].O>C(O)C>[CH2:23]([NH:22][C:20]([C:19]1[CH:25]=[CH:26][C:16]([N:13]2[C:4]([CH2:3][CH:2]([CH3:1])[CH3:12])=[C:5]([C:6]([OH:8])=[O:7])[N:15]=[N:14]2)=[CH:17][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)CC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC(C)C)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
Ethyl 5-methyl-3-oxohexanoate (1.20 g, 6.99 mmol, 1.4 eq.) obtained in Example 93a) and 4-azido-N-ethylbenzamide (1.00 g, 4.99 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (491 mg, 6.49 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 18 hr. Water (20 ml) was added to the reaction mixture, and ethanol was evaporated. The residue was diluted with 2% aqueous sodium carbonate solution (25 ml), and the mixture was washed with ethyl acetate-hexane (2:1, 45 ml). The organic layer was extracted with 1% aqueous sodium carbonate solution (15 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (40 ml and 30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (1.45 g, 4.58 mmol, 91.7%).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[Cl:17][C:18]1[CH:23]=C[C:21](O)=[CH:20][CH:19]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:25]([CH:21]=[CH:20][CH:19]=1)[O:28][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncccc2c2cc(Oc3cccc(Cl)c3)ccc12
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), 4-chlorophenol (72 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 mL), and stirred for 20 minutes at 180° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to provide 74 (59 mg, 98% yield) as a tan solid. LC-MS (M+H=323, obsd.=323). 1H NMR (400 MHz, d6-DMSO): δ 12.02 (s, 1H), 8.77 (dd, 1H), 8.51 (dd, 1H), 8.33 (d, 1H), 8.15 (d, 1H), 7.52 (m, 2H), 7.23 (m, 4H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.[Si:35]([O:42][CH2:43][CH2:44]Br)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:44][CH2:43][O:42][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCO[Si](C)(C)C(C)(C)C)c2cc1OC
Reaction time: 16 h

Procedure:
0.049 g of sodium hydride (at 60%) is added to a solution of 0.5 g of 2-(5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 12.5 ml of anhydrous dimethylformamide, under an inert argon atmosphere at a temperature in the region of 20° C. Agitation is maintained at this temperature for 30 minutes. 0.264 ml of 2-tert-butyldimethylsilyloxyethyl bromide is added. The reaction medium is agitated at the same temperature for 16 hours. 25 ml of water and 20 ml of ethyl acetate are added. After separation by settling out, the organic phase is dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents, argon). The fractions containing the product are concentrated under reduced pressure. 0.47 g of 2-[5,6-dimethoxy-1-(2-tert-butyldimethylsilyloxyethyl)indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[CH3:9][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:9][C:4]1([CH2:7][NH2:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CC1CCOCC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(CN)CCOCC1
Reaction time: 12 h

Procedure:
A mixture of tetrahydropyran-4-carbonitrile (5.00 g) and THF (50 ml) was admixed at 0° C. with lithium hexamethyldisilazide (1 M, 63 ml) and, after 90 minutes, methyl iodide (4.26 ml) was added dropwise with good cooling. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in THF (200 ml), and lithium aluminum hydride (3.79 g) was added. The mixture was boiled at reflux for 6 hours. Water (3.8 ml) and then sodium hydroxide solution (40%; 3.8 ml) were cautiously added dropwise to the cooled suspension. The precipitate was filtered off and the filtrate was concentrated. This afforded the product with the molecular weight of 129.20 (C7H15NO); MS (ESI): 130 (M+H+).