Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.C1(P([C:41]2[CH:46]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:25][Si:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][O:21][CH2:20][N:4]1[C:5]2[CH:6]=[N:7][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:11])[C:10]=2[C:2]([C:41]#[C:46][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCC[Si](C)(C)C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 60 °C
Reaction time: 24 h
Yield: 439.2 %

Procedure:
To 50 ml of tetrahydrofuran solution containing 16.6 g (purity: 78.4%, 25.0 mmol) of 3-iodo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 18-(b) were added 880 mg (1.25 mmol) of bis(triphenylphosphine)palladium dichloride, 620 mg (3.25 mmol) of cuprous iodide, 1.31 g (5.00 mmol) of triphenylphosphine and 10.5 ml (75.3 mmol) of triethylamine, and the mixture was degassed under reduced pressure and replaced with argon. Then, 11 ml of trimethylsilylacetylene was added to the mixture, and the mixture was stirred at 60° C. for 24 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 10.8 g of the title compound as a yellowish solid. (Yield: 88%)
Reaction SMILES: [O:1]1CCOCC1.[Cl:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][C:16]1[C:15]([CH3:23])([CH3:22])[C:14]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:13]=3[CH2:12][C:11]2=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][C:16]1[C:15]([CH3:22])([CH3:23])[C:14]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:13]=3[C:12](=[O:1])[C:11]2=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(Cl)cc3c1C2
Reactant: C1COCCO1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)c(Cl)cc3c1C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
Under nitrogen atmosphere, to the 1,4-dioxane (1.7 mL)-water (0.1 mL) solution of 2,3-dichloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (Compound Y2, 61.0 mg, 0.176 mmol), DDQ (120 mg, 0.529 mmol) was added and the mixture was stirred at room temperature for 16 hr and 15 min. The reaction mixture was purified by flash column chromatography {Merck Kieselgel60, solution for elution:hexane/ethyl acetate (2:1)} to obtain the title compound (pale orange solid, 16.7 mg, 26%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([CH:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[NH:16][CH:15]=2)[OH:13])[C:6]=1[F:24].O1CCCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:25])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Br:23])[CH:21]=3)[NH:16][CH:15]=2)=[O:13])[C:6]=1[F:24]
Reactant: COC(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Into a reaction flask, {3-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-carbamic acid methyl ester (5, 1.91 g, 4.63 mmol) is combined with 10 mL of tetrahydrofuran and Dess-Martin periodinane (2.36 g, 5.56 mmol). The reaction is stirred at room temperature for 2 hours, then diluted with 50 mL of 1M aqueous potassium carbonate and 50 mL of 1M aqueous sodium thiosulfate and extracted with 3×30 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (6, 1.91 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[C:5]([F:22])=[CH:4][N:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[CH:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C@H:12]1[O:11][C:10](=[O:21])[NH:9][C@@H:8]1[C:6]1[C:5]([F:22])=[CH:4][N:3]=[C:2]([C:24]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2cc(F)ccc2F)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cc(C#Cc3ccccc3)ncc2F)[C@@H](c2cc(F)ccc2F)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16 %

Procedure:
In a 1 mL scint vial, a suspension of optically-enriched (4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one (20 mg, 0.054 mmol), and ethynylbenzene (0.014 mL, 0.129 mmol) in triethyl amine (1.5 mL) was purged with nitrogen for 30 min. Triphenylphosphine (3.7 mg, 0.014 mmol) was added and the suspension stirred for 5 min. To this was added copper (I) iodide (0.408 mg, 2.144 μmol), and bis(triphenylphosphine)palladium(II) chloride (1.8 mg, 2.6 μmol). The vial was purged with nitrogen for an additional 5 min, capped, and immersed in a 90° C. bath for 5 h. The reaction was cooled to room temperature and concentrated. The resulting residue was dissolved in dichloromethane and poured into water. The mixture was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, and concentrated. The material was purified first by reversed phase HPLC (TFA/MeOH/sunfire column) to give an optically enriched mixture of regioisomers. The material was further purified by chiral prep HPLC (Chiralpak AD, A=heptane/0.1% DEA, B=ethanol, 40%→60% over 35 min) to give the title compound (3.4 mg). 1H NMR (CDCl3) δ: 8.52 (d, J=0.9 Hz, 1H), 7.75 (d, J=5.8 Hz, 1H), 7.63 (dd, J=7.3, 2.1 Hz, 2H), 7.38-7.44 (m, 3H), 7.23-7.27 (m, 1H), 7.11-7.17 (m, 2H), 5.79 (br. s., 1H), 5.64 (d, J=5.5 Hz, 1H), 5.08 (d, J=5.5 Hz, 1H). 1H NMR (CDCl3) δ: 8.51 (d, J=0.9 Hz, 1H), 7.73 (d, J=5.5 Hz, 1H), 7.63 (dd, J=7.6, 1.8 Hz, 2H), 7.39-7.46 (m, 3H), 7.23-7.27 (m, 1H), 7.10-7.16 (m, 2H), 5.95 (br. s., 1H), 5.61 (d, J=5.5 Hz, 1H), 5.13 (d, J=5.8 Hz, 1H). Mass spec.: 395.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.Cl.Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1.C([O-])([O-])=O.[Cs+].[Cs+].CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:42][CH:39]2[CH2:40][CH2:41][N:36]([C:31]3[N:30]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:37][CH2:38]2)=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: NC1CCN(c2ncccn2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Oc1cc(NC2CCN(c3ncccn3)CC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), 1-(pyrimidin-2-yl)piperidin-4-amine dihydrochloride (122.5 mg, 0.49 mmol, 1.49 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), KOt-Bu (73 mg, 0.65 mmol, 2.00 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-[bis(4-chlorophenyl)methyl]-4-[[1-(pyrimidin-2-yl)piperidin-4-yl]amino]quinolin-2-ol as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[C:11]([S:12][CH3:13])=[CH:10][C:9]([CH3:14])=[CH:8][C:7]=1Br)=[O:4].C([Li])CCC.[C:23](=[O:25])=[O:24]>C(OCC)C.CCCCCC>[CH3:14][C:9]1[CH:10]=[C:11]([S:12][CH3:13])[C:6]([NH:5][C:3](=[O:4])[C:2]([F:17])([F:16])[F:1])=[C:7]([CH:8]=1)[C:23]([OH:25])=[O:24]
Reactant: CSc1cc(C)cc(Br)c1NC(=O)C(F)(F)F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1cc(C)cc(C(=O)O)c1NC(=O)C(F)(F)F
Reaction time: 2 h
Yield: 74.4 %

Procedure:
Under an atmosphere of argon, 46.6 g (142 mmol) of N-(trifluoroacetyl)-2-bromo-4-methyl-6-(methylthio)aniline in 750 ml of dry diethyl ether were cooled to a temperature of −65° C. At this temperature, 119 ml of a 2.5M solution (297.5 mmol) of n-butyllithium in hexane were added dropwise. The mixture was subsequently stirred at this temperature for 2 h. The contents were then carefully poured onto a mixture of 62.5 g (1.42 mol) of carbon dioxide (as dry ice ground in a mortar) and 150 ml of dry ether. The mixture was thawed to RT and extracted three times with water. The combined aqueous phases were acidified to pH<2 with dilute hydrochloric acid and cooled to a temperature of 0° C.-5° C. The mixture was filtered, giving 31.0 g of 5-methyl-3-(methylthio)-2-(trifluoroacetylamino)benzoic acid as residue.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O)[OH:2].[OH-:9].[Na+]>O>[CH:1]1[CH:3]=[C:5]([C:7]2[CH:6]=[CH:5][CH:3]=[C:1]([OH:2])[CH:8]=2)[C:6]([OH:9])=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: Oc1ccccc1O
Agent: [Na+]
Solvent: O
Product: Oc1cccc(-c2ccccc2O)c1

Procedure:
In this two step synthesis, the first step is the reaction of bis-2-chloroethyl ether with catechol and sodium hydroxide in water. An excess of catechol and a controlled amount of base are used to produce the diphenol (j) without employing a blocking group. The diphenol (j) precipitates from the reaction solution and is washed with water to remove contaminating catechol. The diphenol (j) is then recrystallized from methanol. Based upon the limiting reagent bis-2-chloroethyl ether (i) 40% yields (200 gs) of diphenol (j) have been obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:28]2[CH2:33][O:32][CH2:31][CH2:30][N:29]2C(OC(C)(C)C)=O)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[ClH:41]>O1CCOCC1>[ClH:1].[ClH:41].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C@@H:28]2[CH2:33][O:32][CH2:31][CH2:30][NH:29]2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]4[C@H:25]([CH3:26])[CH2:24][C@H:23]([OH:27])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4COCCN4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4COCCN4)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
(R)-tert-Butyl 3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)morpholine-4-carboxylate (0.0389 g, 0.0680 mmol) was dissolved in dioxane (1 mL) and treated with 4M hydrogen chloride in dioxane (0.425 mL, 1.70 mmol). The solution was stirred at ambient temperature overnight. The reaction was concentrated in vacuo, resuspended in dioxane and concentrated in vacuo. The residue was concentrated from MeOH (3 times) and then dissolved in MeOH. The solution was then added dropwise to Et2O to afford (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-morpholin-3-yl)ethanone dihydrochloride (20 mg, 54%). m/z 472.1/474.0; 1H NMR (400 MHz, CD3OD) d ppm 8.57 (s, 1H), 7.48 (d, 2H), 7.40 (d, 2H), 5.13-5.07 (m, 1H), 4.50 (d, 1H), 4.15-4.05 (m, 1H), 4.01-3.55 (m, 13H), 3.53-3.39 (m, 1H), 2.83-2.73 (m, 1H), 1.65-1.56 (m, 1H), 1.23 (d, 3H)
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:11][S:12][C:13]3[S:14][C:15]([CH3:18])=[N:16][N:17]=3)[CH2:9][S:10][C@H:5]12)=[O:2].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(O)(=O)C>[CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:20])=[C:8]([CH2:11][S:12][C:13]3[S:14][C:15]([CH3:18])=[N:16][N:17]=3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC=O)[C@H]3SC2)s1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC=O)[C@H]3SC2)s1
Reaction time: 16 h

Procedure:
A solution of 7β-formamido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylic acid (8.5 g) in tetrahydrofuran (300 ml.) was treated with an excess of a solution of diphenyldiazomethane in petroleum (300 ml.) and the mixture was kept at 20° for 16 hours. A few drops of acetic acid were added and solvents were removed under reduced pressure. The resulting yellow syrup was dissolved in ethyl acetate and washed with sodium bicarbonate solution. A solid (7.5 g) precipitated and was dried in vacuo. A sample (5.77 g) of the wet solid was dissolved in methylene chloride, and the solution was dried and concentrated under reduced pressure. The residue was crystallised from methanol to give the title ester (5.08 g), m.p. 108° (decomp.), λmax. (EtOH) 268 nm (ε12,400), τ (CDCl3 +a little DMSO-d6) values include 1.50 (d, J 9 Hz; NH), 1.72 (s; HCO), 6.30 (singlet; C-2 CH2) and 7.31 (singlet; CH3).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][Si](C(C)(C)C)(C)C)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc2ccc(-c3nnc4ccccn34)nc12
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(tert-butyldimethylsilyloxy)quinoline (18.92 g, 50.25 mmol) in anhydrous THF (400 mL) at 0° C. was added tetrabutylammonium fluoride (75.4 mL, 1.0 M/THF, 75.4 mmol). After stirring for 1 hour at this temperature the mixture was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with CH2Cl2, filtered and dried in vacuo to provide 11.91 g (90%) of desired product as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A 100 mL round bottom flask was sequentially charged with 5-bromoindole (1.96 g, 10 mmol), p-toluenesulfonyl chloride (2.30 g, 12 mmol), tetrabutylammonium hydrogen sulfate (240 mg, 0.70 mmol) and toluene (40 mL). An aqueous solution of potassium hydroxide (13 mL, 50%) was added dropwise and the mixture was stirred at room temperature overnight. At this point the organic layer was separated, diluted with ethyl ether (40 mL), washed with two portions of dilute potassium hydroxide solution (2×20 mL, 2M) and dried over MgSO4. The solvent was removed at reduced pressure and the product was purified by flash chromatography on silica gel (hexane/ethyl acetate 1:1) to provide the desired product as a light yellow solid (3.50 g, 99% yield). M p 135° C. (lit. 139-140° C., See Fresneda, M. P.; Molina, P.; Bleda, A. J. Tetrahedron 2001, 57, 2355). 1H NMR (400 MHz, CDCl3, J values are reported in Hz, lit. See Fresneda, M. P.; Molina, P.; Bleda, A. J. Tetrahedron 2001, 57, 2355): δ 7.88 (d, J=8.8, 1H), 7.76 (d, J=8.6, 2H), 7.68 (d, J=1.8, 1H), 7.59 (d, J=3.5, 1H), 7.42 (dd, J=8.8, J=2.0, 1H), 7.25 (d, J=8.6, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 145.7, 135.3, 133.9, 132.9, 130.4, 128.0, 127.9, 127.2, 124.5, 117.2, 115.4, 108.7, 22.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])[C@H:9]([C:11](OC)=[O:12])[CH3:10])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]([CH3:10])[CH2:11][OH:12])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1
Reactant: COC(=O)[C@H](C)N(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2Cc2c(F)cccc2F)C(C)CO)cc1OC
Yield: 20.6 %

Procedure:
To 1.1 g of methyl N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]alaninate in 15 ml of tetrahydrofuran are added, at room temperature, 158 mg of lithium aluminium hydride. After refluxing for 5 hours, the mixture is cooled to room temperature and hydrolysed with 15% sodium hydroxide solution. The medium is taken up in ethyl acetate and washed with water, the phases are separated by settling and the organic phase is dried over anhydrous sodium sulfate. The organic phase is concentrated and the residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) toluene/ethyl acetate mixture to give 0.215 g of the expected product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=O.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>CC(O)=O>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:11][C:3]3[N:2]([CH3:1])[C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cc4ccccc4n3C)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 1-methyl-1H-indole-2-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 390.3 (M+H)+.
Reaction SMILES: B.[N+:2]([C:5]1[CH:6]=[C:7]([C:14](O)=[O:15])[C:8](=[CH:12][CH:13]=1)[C:9](O)=[O:10])([O-:4])=[O:3]>O1CCCC1>[N+:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][OH:10])=[C:7]([CH2:14][OH:15])[CH:6]=1)([O-:4])=[O:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(CO)c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 92.3 %

Procedure:
To a stirred solution of borane.tetrahydrofuran complex (70 mL of 1.5 M solution in tetrahydrofuran/diethyl ether) cooled to 0° C. under nitrogen was added a solution of 4-nitrophthalic acid (7.01 g; 33.2 mmol) in tetrahydrofuran (50 mL) dropwise over a 20 minute period. At the end of the addition, the mixture was allowed to stir for 3.5 h at 0° C. The mixture was allowed to warm to room temperature and then refluxed for 18 h. The mixture was allowed to cool to room temperature, quenched with methanol and concentrated in vacuo. The residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate solution followed by brine solution. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuo to give 5.61 g (92%) of 4-nitro-1,2-di-hydroxymethyl benzene as a white solid: ES-LRMS calcd for C8H8NO4 (M+−1) 182, found 182.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]2[N:44]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)[C:43]3[CH:53]=[CH:54][CH:55]=[CH:56][C:42]=3[N:41]=2)[CH2:35][CH2:34]1>ClCCl>[F:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][N:44]2[C:43]3[CH:53]=[CH:54][CH:55]=[CH:56][C:42]=3[N:41]=[C:40]2[NH:39][CH:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][NH:30][C:11](=[O:13])[CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:34][CH2:35]2)=[CH:47][CH:48]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1c[nH]c2ccccc12)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a stirred mixture of 3.5 parts of 1H-indol-3-acetic acid, 4.05 parts of N,N-diethylethanamine and 260 parts of dichloromethane were added 5.1 parts of 2-chloro-1-methylpyridinium iodide and stirring was continued for 15 minutes at room temperature. Then there were added 7.2 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and the whole was stirred for 1 hour at room temperature. The reaction mixture was poured onto water and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.5 parts (43%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1H-indol-3-acetamide; mp. 193.6° C. (compound 77).