Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:26]=4)[C:21]4([CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[Br:39]N1C(=O)CCC1=O>C(#N)C>[Br:39][C:24]1[N:23]=[C:22]2[C:21]3([CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:20][N:19]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[C:7]=3[CH3:18])[C:27]2=[CH:26][C:25]=1[N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Solvent: CC#N
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2nc(Br)c(N3CCOCC3)cc21
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (250 mg, 0.489 mmol) in acetonitrile (6 mL) at 0° C. was added dropwise via syringe over 5 min a solution of N-bromosuccinimide (87 mg, 0.489 mmol) in acetonitrile (4 mL). The reaction was stirred at this temperature for 15 min. After this time the reaction was partitioned between EtOAc (40 mL) and water (15 mL). The separated organic layer was washed with NaHCO3 (15 mL, saturated aqueous solution) and Na2S2O3 (15 mL, saturated aqueous solution) and then it was dried over MgSO4, filtered and evaporated in vacuo to give 5′-bromo-1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dt, J=4.8, 1.4 Hz), 7.83-7.99 (3H, m), 7.70 (1H, dd, J=9.2, 5.9 Hz), 7.42 (1H, ddd, J=6.8, 4.7, 2.2 Hz), 7.28-7.34 (1H, m), 5.97 (1H, s), 4.10-4.20 (2H, m), 3.94-4.06 (2H, m), 3.74-3.84 (4H, m), 3.49-3.64 (2H, m), 2.78-2.94 (4H, m), 2.28-2.46 (5H, m), 1.72-1.88 (2H, m). Mass Spectrum (ESI) m/e=590.0 [(M+1) (79Br)] and 592.0 [(M+1) (81Br)]
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]([CH2:26][O:27][C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([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:20]C1C=CON=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:26][O:27][C:28]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1ccon1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
4.400 g of 1-O-hexadecyl-2-O-(3-isoxazolyl)-3-O-triphenylmethyl-sn-glycerol described in Preparation 4 was dissolved in a mixture of 10 ml of tetrahydrofuran and 90 ml of ethanol and the solution was placed in a Paar apparatus and then shaken in the presence of 4.40 g of 10% w/w palladium-on-carbon in an atmosphere of hydrogen at 4 times atmospheric pressure for 49 hours. After removing the catalyst by filtration, 0.635 g of potassium carbonate was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble material, the solvent was distilled off and the residue was subjected to column chromatography through 100 g of silica gel. 3.327 g of 1-O-hexadecyl-3-O-triphenylmethyl-sn-glycerol was obtained from the fractions eluted with mixtures of hexane and diethyl ether ranging from 19:1 to 9:1 by volume, as white crystals melting at 49°-50° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[CH2:6][CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:23])=[CH:14]\[CH:15]=[CH:16]\[C:17](\[CH3:22])=[CH:18]\[C:19]([OH:21])=[O:20].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:23])=[CH:14]\[CH:15]=[CH:16]\[C:17](\[CH3:22])=[CH:18]\[C:19]([OH:21])=[O:20]
Reactant: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1=O
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
To a solution of 4-hydroxy-9-cis-retinoic acid (16 mg, 0.05 mmole) in CH2Cl2 (1.5 ml) was added Dess-Martin reagent [see Dess and Martin in J. Org. Chem. 48:4155 (1983)] (42 mg, 0.1 mmole) in one portion at 25° C. After stirring for 5 minutes, the mixture was diluted with 10 ml of ether and to this was added saturated aqueous NaHCO3 (5 ml) containing Na2 SO3 (55 mg). The mixture was stirred for 20 minutes to dissolve the solid and the layers separated. The ether layer was washed with H2O (2×5 ml), brine (5 ml) and dried (MgSO4). The solvent was recovered under reduced pressure and residue was subjected to flash column chromatography (silica, 60% ether in Hexane) to give 4-keto-9-cis-retinoic acid (14 mg. 90%), characterized as follows: TLC rf=0.6 (silica, 80% ether in hexane);1HNMR (400 mHz, CDCl3) δ7.05 (dd, J=16, 12 Hz, 1H, olefinic), 6.82 (d, J=16 Hz, 1 H, olefinic), 6.32 (d, J=16 Hz, 1H, olefinic), 6.30 (d, J=16 Hz, 1H, olefinic), 6.20 (d, J=12 Hz, 1H, olefinic), 5.80 (s, 1H, olefinic), 2.5 (t, J=7 Hz, 2H, CH2—CO), 2.31 (s, 3H, CH3), 2.01 (s, 3H, CH3), 1.9 (s, 3H, CH3), 1.89 (m, 2H, CH2), 1.20 (s, 6H, 2×CH3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>ClCCl.CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([N:48]2[CH2:47][CH2:46][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49]2)=[O:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C(=O)O)c1cc(I)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(C)(C)c2cc(I)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
2-(4-iodo-2-pyridyl)-2-methyl-propanoic acid (100 mg, 0.3435 mmol) was added to dichloromethane (5 mL) followed by the addition of [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate (110.3 mg, 0.3435 mmol), diisopropyl ethyl amine (88.79 mg, 119.7 μL, 0.6870 mmol) and tert-butyl piperazine-1-carboxylate (83.18 mg, 0.4466 mmol). Some N,N-dimethylformamide (1 ml) was added to help dissolution. The mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with dichloromethane, washed with water (×2). The extracted organic layer was dried over MgSO4, filtered and concentrated in vacuo to a solid. The residue was purified by column chromatography (ISCO Companion, 80 g column) loaded with dichloromethane and eluted with 100% diethyl ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as an off-white solid (90 mg, 57.03% Yield). LC/MS m/z 460.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:27])=[C:20]([C:22](OCC)=[O:23])[CH3:21])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:22](=[O:23])[C:20]([CH3:21])=[C:19]([CH3:27])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methylpropenyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 155°-157° C.,
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:29]>C(O)C>[NH2:29]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:6]
Reactant: N
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To a solution of 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate (3.21 g) in ethanol (5 ml), 20% ethanolic ammonia (15 ml) was added, and the mixture was allowed to stand in a refrigerator overnight. The solvent and ammonia were distilled off to give crude 2-(4-benzhydryl-1-piperazinyl)ethyl 3-aminocrotonate as an oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:15]([NH:16][C:17](=[O:24])[CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:14](=[O:25])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12].[OH-].[Na+:27]>O>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:15]([NH:16][C:17](=[O:24])[CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:14](=[O:25])[N:9]2[C:10]=1[C:11]([O-:13])=[O:12].[Na+:27]
Reactant: CON=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1

Procedure:
A solution of 3-methoxyiminomethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (1 g) in water (100 ml) is neutralized with aqueous 2N-sodium hydroxide to pH 6.5. The solution is lyophylized to give a solid mass of sodium 3-methoxyiminomethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylate (1.1 g) which is readily soluble in water.
Reaction SMILES: CO[Na].[CH3:4][O:5][CH:6]([CH:8]1[CH:10]([CH3:11])[O:9]1)[CH3:7].[CH3:12][OH:13].OS(O)(=O)=O>CO>[CH3:12][O:13][CH:10]([CH:8]([OH:9])[CH:6]([O:5][CH3:4])[CH3:7])[CH3:11]
Reactant: COC(C)C1OC1C
Reactant: CO
Agent: CO[Na]
Agent: O=S(=O)(O)O
Product: COC(C)C(O)C(C)OC

Procedure:
3-Pentanone was brominated to get 2,4-dibromo-3-pentanone (1.2.4.11) using conventional methods. The dibromoketone was reduced with BH3*THF to the corresponding alcohol (1.2.4.15). This compound was reacted with MeONa in methanol to yield 2-(1-bromoethyl)-3-methyl oxirane (1.2.4.13) which after reaction with MeOH/H2SO4 gave 2-bromo-3-hydroxy-4-methoxy pentane (1.2.4.38). This intermediate was reacted again with MeONa in methanol and the resulting 2-(1-methoxyethyl)-3-methyl oxirane (1.2.4.22) was reacted again with MeOH/H2SO4 to yield 2,4-dimethoxy-3-hydroxy pentane (1.2.4.39). After oxidation with CrO3/Py in methylenechloride the resulting ketone was reacted with trimethylsulfoxonium iodide to give the title compound (1.2.4.37).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[CH3:38][O:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][N:44]=[CH:43]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:45]3[C:46]4[C:42](=[CH:41][C:40]([O:39][CH3:38])=[CH:48][CH:47]=4)[CH:43]=[N:44]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 110 °C
Yield: 12.7 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol) in toluene (1 mL) was added copper (I) iodide (3.52 mg, 39.3 μmol), sodium iodide (105 mg, 702 μmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (12.7 mg, 89.5 μmol). The reaction mixture was sealed under nitrogen and the mixture heated at 110° C. for 15 h. 5-Methoxy-1H-indazole (52.0 mg, 351 μmol) and potassium phosphate tribasic (156 mg, 737 μmol) were added and the mixture was degassed, filled with nitrogen, and the mixture heated at in sealed tube at 110° C. for 15 h. The mixture was filtered, the cake washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-Butyl-2-(5-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 13%). 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.52 (d, J=9.0 Hz, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.75 (s, 1H), 7.10-7.22 (m, 2H), 5.71 (s, 2H), 3.93 (s, 3H), 3.53-3.64 (m, 2H), 1.61 (s, 9H), 0.89-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][OH:13])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH3:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH3:11][N:8]1[C:7]([CH2:12][OH:13])=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:22]1[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=[C:21]1[CH3:20])=[N:3][C:4]=2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cn1c(CO)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)n(C)c2n1

Procedure:
(2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methanol (4.0 g) was reacted with 2-Methylbenzimidazole (1.96 g) via General Procedure I for Buchwald coupling. The solids were filtered from the reaction mixture while still warm. Water was added to the filtered reaction mixture (5 times the volume of DMF) to precipitate the product out of the reaction mixture. The precipitated orange solid was filtered and dried under vacuum for quantitative yield of (9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CCC.[CH2:22]([O:24][C:25](=[O:31])[CH2:26][C:27](=[O:30])[CH2:28]Cl)[CH3:23]>C(#N)C>[CH2:22]([O:24][C:25](=[O:31])[CH2:26][C:27](=[O:30])[CH2:28][S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:23]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCC(=O)O
Product: CCOC(=O)CC(=O)CSc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a 0° C. solution of 3-methoxy-benzenethiol (5.75 g, 41.0 mmol) and potassium carbonate (11.45 g, 82.02 mmol) in acetonitrile (150 mL) is added butanoic acid, 4-chloro-3-oxo-butanoic acid ethyl ester 6.12 mL, 45.11 mmol). The mixture is stirred at room temperature for 2 hours and filtered through a pad of diatomaceous earth. The filtrate is concentrated under reduced pressure. The residue is purified via silica gel chromatography eluting with 25-30% EtOAc/Hexanes to provide the title compound (10.9 g, 99%). MS: 267.0 (M−1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[Na].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:13])=[O:14])[CH:6]=[CH:5]2)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2cc(S(=O)(=O)O)ccc2c1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 6-aminonaphthalene-2-sulfonic acid, sodium salt (3 g, 12.2 mmol) in 70 mL of water is added solid NaOH (1.01 g, 25 mmol) at room temperature. The mixture is stirred for 1 hour, and benzyl chloroformate (3.43 mL, 24 mmol) is then added. The resulting mixture is stirred over a period of 16 hours. The crude product is treated as in EXAMPLE 24, Part A to give 4.70 g of crude N-CBz-6-aminonaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (2.3 g, 6.10 mmol) in 15 mL of thionyl chloride is heated at 80° C. for 5 hours. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is diluted with EtOAc and washed successively with water (2×), saturated NaHCO3 solution and saturated NaCl. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to give a solid. The crude product is triturated from 50% EtOAc/hexanes to afford the title compound (0.50 g, 1.33 mmol) as a beige solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH3:3].[CH3:15]C1C=C2C(=CC=1)NC(=O)C2=O.BrCCC>>[CH3:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[C:6]2=[O:13]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CCCBr
Product: CCCN1C(=O)C(=O)c2cc(C)ccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using 5-methyl isatin (purchased from Fisher Scientific) and 1-bromo-propane (purchase from Fisher Scientific). 1H NMR δ 7.41 (m, 2H), 6.80 (d, 1H), 3.67 (t, 2H), 2.33 (s, 3H), 1.72 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH:34](=O)/[CH:35]=[CH:36]/[CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH3:42]>>[CH2:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH:34]/[CH:35]=[CH:36]/[CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH3:42]
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC/C=C\CC/C=C/C=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CC/C=C\CC/C=C/C=CCc1ccccc1
Yield: 60.9 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.05 g, 6.82 mmol, 1.0 equiv.), n-BuLi (1.6M in hexanes, 4.3 mL, 6.82 mmol, 1.0 equiv.) and (2E,6Z)-nona-2,6-dienal (1.41 g, 10.2 mmol, 1.5 equiv.), 0.94 g (61%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([S:14][C:15]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:9]1)=O)CCC>C(OCC)(=O)C>[C:25]1([C:24]2[C:15]([S:14][CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCCOC(=O)N1CCCC(Sc2nc3ccccc3cc2-c2ccccc2)C1
Solvent: CCOC(C)=O
Product: c1ccc(-c2cc3ccccc3nc2SC2CCCNC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(1-Butoxycarbonyl-3-piperidylthio)--3-phenylquinoline (4.2 g.) was added to 6 M-hydrogen chloride in ethyl acetate (50 ml.), and the mixture was stirred at ambient temperature for 1 hr. The solvent was evaporated and the residual oil was dissolved in diethyl ether (100 ml.) and extracted with 1 M-hydrochloric acid solution (20×30 ml.). The hydrochloric acid extract was adjusted to pH 10 with saturated sodium carbonate solution and extracted with diethyl ether (2×100 ml.). The diethyl ether extract was washed with brine (75 ml.) and then dried (MgSO4). The solvent was evaporated to give 3-phenyl-2-(3-piperidylthio)quinoline which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:25]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH:28]=[CH:27][N:26]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1cc(-c2ccccc2)ccn1
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Temperature: 25 °C
Yield: 81.7 %

Procedure:
2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (5.96 g, 19.28 mmol), 2-chloro-4-phenylpyridine (4.39 g, 23.13 mmol), tris(dibenzylideneacetone)palladium(0) (0.353 g, 0.386 mmol) and 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.8 g, 1.951 mmol) were charged into a 500 mL 2-neck flask. Potassium phosphate tribasic (12.26 g, 57.8 mmol) was then dissolved in 45 mL of water. This solution was charged into the reaction mixture. The reaction mixture was degassed with nitrogen then was heated to reflux overnight. The reaction mixture was cooled to room temperature. The toluene layer was separated and was dried over magnesium sulfate. These organics were filtered and concentrated under vacuum. The crude product was passed through a silica gel column using 70-99% toluene/heptanes followed by 5-15% ethyl acetate/toluene. Some of the impure product fractions were columned on silica gel using 5-15% ethyl acetate/DCM. All the clean product fractions were combined yielding 2-methyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (5.3 g, 15.76 mmol, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CN1CCNCC1)c1ccc(F)cc1
Yield: 88.8 %

Procedure:
tert-Butyl 4-(2-(4-fluorophenyl)-2-oxoethyl)piperazine-1-carboxylate (8.65 g, 26.8 mmol), 4 M HCl in dioxane (6 mL) and dioxane (20 mL) were stirred at 43° C. for 1 h. The solvent was removed under reduced pressure and the residue was dried in a vacuum oven to yield the title compound (5.29 g). Exact mass calculated for C12H15FN2O: 222.1. Found: 223.4 (M+H+).
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH2:14]([NH2:17])[CH2:15][CH3:16]>O1CCCC1>[CH2:14]([NH:17][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=1)[CH2:15][CH3:16]
Reactant: CCCN
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
At room temperature, 10 g (0.05 mol) of 4-sulfamoylbenzoic acid are dissolved in 100 ml of tetrahydrofuran and admixed with 8.1 g (0.05 mol) of N,N′-carbonyldiimidazole. After 30 minutes at room temperature and a further 30 minutes at reflux temperature, 2.9 g (0.05 mol) of propylamine are added at room temperature. After 2 hours, the reaction mixture is concentrated and stirred with water, the precipitate is filtered off with suction and dried.