Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].CN(CCN(C)C)C.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CCCCCC>[CH:22]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: BrC1CCCC1
Agent: CN(C)CCN(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FC(F)(F)c1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 10 L jacketed reactor was added dry THF (2.4 L) and magnesium turnings (81.0 g, 3.33 mol, 1.5 eq.) under N2. In a separate flask FeCl3 (36 g, 0.22 mol, 0.1 eq.) was dissolved in THF (150 mL) (caution, exothermic) under N2. This dark brown solution was allowed to cool to ambient temperature and then added over 10 min to the reactor content under N2 at an internal temperature of about 10° C. TMEDA (402 mL) was added to this yellow/green mixture keeping the internal temperature below about 20° C. (slightly exothermic). The resulting rust brown mixture was stirred at ambient temperature for 1 h under N2 then 1 h at 45° C. The reactor contents were allowed to cool below about 20° C. and a mixture of 1-bromo-2-(trifluoromethyl)benzene (500 g, 2.22 mol) and bromocyclopentane (397 g, 2.66 mol, 1.2 eq.) added dropwise under N2 at a rate as to maintain the internal temperature between about 25-30° C. After the addition, the reaction mixture was stirred at about 25° C. under N2 overnight, allowed to cool to an internal temperature of about 0° C. and quenched with 6 N HCl (2 L) at a rate as to maintain the internal temperature below about 15° C. (caution, exothermic). [Note: IPC's after completing the addition and stirring overnight were similar indicating that the reaction may have been completed much sooner.] After the quench, hexane (3 L) was added and the reactor contents were stirred at ambient temperature for 1 h. The phases were separated and the aqueous layer back extracted with hexane (1 L). The combined organic layers were dried (Na2SO4), slurried with silica (750 g) and filtered washing the solids with hexane (1 L). The filtrate was concentrated under reduced pressure (100 torr at 37° C.) to give an amber oil (317 g, 973 Area % by HPLC, 87.7 wt % by HPLC (contained residual hexane by NMR), corrected yield 58′%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[O:15][C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH:13]=C)([OH:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+].C[OH:19]>>[CH2:1]1[O:15][C:4]2([CH2:9][CH2:8][C:7]([CH2:11][CH2:12][CH2:13][OH:19])([OH:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: CO
Reactant: C=CCCC1(O)CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Product: OCCCC1(O)CCC2(CC1)OCCO2

Procedure:
A mixture of 4-(3-butenyl)-4-hydroxy-cyclohexanone ethylene ketal (1.8 g) in methanol (40 mL) was ozonized at -70° C. until a persistent blue color was obtained. The ozonide was decomposed with excess sodium borohydride at -60° C. The reaction was concentrated in vacuo and the residue was partitioned between brine and ethyl acetate. The aqueous layer was extracted several more times with ethyl acetate and the combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash chromatography with ethyl acetate as the eluent to afford 4-(3-hydroxypropyl)-4-hydroxy-cyclohexanone ethylene ketal as an oil.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 18 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2,2-di methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.51–7.41 (s, 1H), 7.34–7.10 (m, 13H), 6.99–6.80 (m, 2H), 4.81 (s, 1H), 3.40–3.26 (m, 2H), 2.96–2.78 (m, 2H), 2.50–2.25 (m, 3H), 1.98–1.82 (m, 2H), 1.79–1.68 (m, 2H), 1.68–1.45 (m, 4H), 1.23 (s, 9H); ESMS m/e: 512.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:21]C(OC(C)(C)C)=O)[C:14]([O:16]C(C)(C)C)=[O:15])[N:6]=1)=[O:4].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH2:21])[C:14]([OH:16])=[O:15])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccn(CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccn(CCC[C@H](N)C(=O)O)n1
Temperature: 25 °C

Procedure:
To a solution of t-butyl (S)-5-(3-methoxycarbonyl-1H-pyrazol-1-yl)-2-(t-butoxycarbonylamino)-pentanoate (0.84 g, 0.21 mmol) in CH2Cl2 (20 mL) at 0° C. is bubbled HCl gas for 30 minutes. Afterward, the solution is warmed to room temperature over 30 minutes. Evaporation of solvent yields (S)-5-(-3-methoxycarbonyl-1H-pyrazol-1-yl)-2-aminopentanoic acid.HCl as a gray-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH2:17][CH3:18]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCCI
Reactant: Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.2 %

Procedure:
3-Chloro-4-methylphenol (2.00 g) was dissolved in N,N-dimethylformamide (10.0 ml), and potassium carbonate (2.91 g) and 1-propyl iodide (2.62 g) were added. The mixture was stirred at room temperature for 20 hr, and the reaction mixture was concentrated under reduced pressure. Water was added, and the mixture was extracted with AcOEt. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with hexane:ethyl acetate=5:1. The objective fraction was concentrated under reduced pressure to give 2-chloro-4-(1-propoxy)toluene (2.18 g) as a colorless oil.
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[O:10]>C(O)=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([OH:1])=[O:10]
Reactant: O=Cc1ccccn1
Reactant: OO
Solvent: O=CO
Product: O=C(O)c1ccccn1

Procedure:
To mention specific examples of the reaction conditions, one to two equivalent amount of hydrogen peroxide is added to the pyridine-2-carbaldehyde derivative (8) in a formic acid solvent, and the mixture can be treated at room temperature for about 1 hour to 2 days, thus to produce the pyridine-2-carboxylic acid derivative (9).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:11]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[H][H]>CO.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C@@H:12]2[CH2:13][CH2:14][C@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:11]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc([N+](=O)[O-])cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
A 500 mL parr shaker flask was charged with 10% Pd/c (4.75 g) and to this was added 100 mL of methanol to cover the catalyst. A solution of the nitro intermediate from Step I (8.5 g, 18.5 mmol) in methanol (80 mL) was then added to the suspension, followed by 15.4 mL of 1.0 M hydrogen chloride in methanol solution. The reaction vessel was set under 50 PSI hydrogen gas and the mixture aggitated overnight. An aliquot was taken and analyzed through the LC-MS which showed complete reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:26]2[O:27][C:28]([C:31](O)=[O:32])=[CH:29][O:30][C:25]=2[CH:24]=1>>[OH:22][C:23]1[C:35]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][C:26]2[O:27][C:28]([C:31]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:32])=[CH:29][O:30][C:25]=2[CH:24]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)(C)c1cc2c(cc1O)OC=C(C(=O)O)O2
Product: CC(C)(C)c1cc2c(cc1O)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Yield: 83 %

Procedure:
That compound is obtained in a yield of 83% starting from 1-[bis-(4-fluorophenyl)methyl]piperazine and 6-hydroxy-7-tert-butyl-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:28][OH:29]>>[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:28][O:29][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OCC1CCc2ccccc2O1
Reactant: Clc1nc2ccccc2nc1N1CCNCC1
Product: c1ccc2c(c1)CCC(COc1nc3ccccc3nc1N1CCNCC1)O2
Yield: 23 %

Procedure:
The title product was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (described in Example 162. Step 1) and 3,4-dihydro-2H-chromen-2-ylmethanol.* The product was obtained as a yellow amorphous substance: yield 23%; mp 202-204° C.; HRMS m/z calcd for C13H16N4O2(M)+376.1899, found 376.1899. Anal. (C22H24N4O2.HCl) H; C: calcd, 61.32; found. 60.7; N: calcd, 13.00; found 13.5.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]1([OH:14])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:25]>C1COCC1>[CH2:15]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][C:11]1([O:14][CH3:25])[CH2:12][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CI
Reactant: OC1(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
Treat a 0° C. solution of 1-(2-(dibenzylamino)ethyl)cyclopropanol (3 g, 10.6 mmol) in THF (50 mL), under N2, portion wise with NaH (60%, 0.85 g, 21.3 mmol), stir at 0° C. for 0.5 h, add iodomethane (1.82 g, 12.8 mmol) drop wise, warm to RT and stir for 3 h. Cool the mixture to 0° C., quench with satd. NH4Cl and partially concentrate. Extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to afford the title compound (1.2 g, 38%). 1H NMR (400 MHz, CDCl3): δ 7.39-7.21 (m, 10H), 3.60 (s, 4H), 3.12 (s, 3H), 2.65 (t, J=8 Hz, 2H), 1.75 (t, J=8 Hz, 2H), 0.68-0.65 (m, 2H), 0.34-0.31 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[Si:8]([O:25][CH:26]([CH3:30])[C:27](=[S:29])[NH2:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[Si:8]([O:25][CH:26]([C:27]1[S:29][CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:28]=1)[CH3:30])([C:21]([CH3:22])([CH3:23])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(N)=S
Reactant: O=C(O)C(=O)CBr
Solvent: C1CCOC1
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nc(C(=O)O)cs1
Temperature: 25 °C

Procedure:
A flask containing 3-bromopyruvic acid (317 mg, 1.901 mmol) was put under nitrogen atmosphere. 2-(tert-butyldiphenylsilyloxy)propanethioamide (653 mg, 1.901 mmol) was dissolved in dry THF (8 ml) and added through a septum. The following mixture was refluxed for two hours and then allowed to cool to RT. The solvent was evaporated and extracted with DCM/water and the combined organic phases were evaporated. 1H-NMR (400 MHz; DMSO-d6): δ 1.07 (s, 9H), 1.35 (d, 3H), 5.14 (q, 1H), 7.39-7.54 (m, 2H), 7.57-7.61 (m, 2H), 7.26-7.69 (m, 2H), 8.38 (s, 1H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[C:7]([CH3:20])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[CH:10]=1.CC[N+](CC)(CC)CC.CN(C=O)C>C(OCC)(=O)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>[CH3:20][C:7]1[C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:10][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[N:8]=1
Reactant: C=CC#N
Reactant: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1/C=C/C#N
Yield: 191.3 %

Procedure:
A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.036 g, 0.00013 mol), and tetraethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019 mol) was microwaved at 120° C. for 2 h. The solution was then diluted with ethyl acetate and washed with water (×2) and brine successively. The organic phase was dried and concentrated in vacuo to give 62 mg of the product as an orange solid. The orange solid was purified by prep-LCMS to give 12 mg of an off-white solid as a trifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL) to provide the purified product as a pale green solid. (dried at 60° C. for 4 h, 9 mg , 28% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([OH:26])[C:14]([CH2:23][CH:24]=[CH2:25])=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:26][CH3:27])[C:14]([CH2:23][CH:24]=[CH2:25])=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCc1cc(OCC)c2c(c1O)S(=O)(=O)N(Cc1ccccc1)C2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 2-benzyl-4-ethoxy-6-allyl-7-hydroxysaccharin (2.45 g), potassium carbonate (2.76 g) and methyl iodide (1.84 g) in acetone was heated at 50° C. with stirring for two hours, then poured with stirring into ice-water (500 mL). The resulting gooey precipitate crystallized overnight affording 2-benzyl-4-ethoxy-6-allyl-7-methoxysaccharin, 2.35 g, 92% yield, mp 92°-94° C.
Reaction SMILES: [C:1]([CH:5]1[O:9][C:8]([CH2:15][C:16]([OH:18])=[O:17])([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:7](=[O:19])[O:6]1)([CH3:4])([CH3:3])C.[CH2:20](O)[C:21]1C=CC=C[CH:22]=1.[H-].[Na+]>C1COCC1>[CH2:5]([O:6][C:7](=[O:19])[C:8]([OH:9])([CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])[CH2:15][C:16]([OH:18])=[O:17])[C:1]1[CH:3]=[CH:22][CH:21]=[CH:20][CH:4]=1
Reactant: CC(C)=CCC1(CC(=O)O)OC(C(C)(C)C)OC1=O
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC(O)(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A solution of dioxolanone 74 (120 mg, 0.444 mmol, 1.00 equiv) in THF (4.5 mL) was cooled to 0° C. and benzyl alcohol (69 μL, 0.67 mmol, 1.5 equiv) was added via syringe followed by a 60% dispersion of NaH in mineral oil (45 mg, 1.1 mmol, 2.5 equiv) which resulted in vigorous evolution of gas. The solution was allowed to stir at 0° C. for 30 min, at which time the reaction was quenched with 4.5 mL NaHCO3, removed from the cold bath and allowed to warm to room temperature. The solution was then poured into H2O (4.5 mL), washed with CH2Cl2 6 mL), acidified to pH<5 with 1N HCl, and then extracted with Et2O (4×6 mL). The combined ethereal phases were dried over MgSO4 and solvent removal by rotary evaporation yielded a white solid which was purified by silica gel column chromatography (70:28:2 hex:EtOAc:HOAc) to yield 75 (114 mg, 88%) as a white solid. Rf=0.39 (60:38:2 EtOAc:Hex:HOAc); 1H NMR (500 MHz, CDCl3) δ 7.35 (m, 5H, ArH), 5.20 (s, 2H, PhCH2), 5.07 (m, 1H, vinyl H), 3.00 (d, 1H, J=16.7 Hz, C(O)CH2), 2.76 (d, 1H, J=16.7 Hz, C(O)CH2), 2.41 (m, 2H, CHCH2), 1.67 (d, 3H, J=0.7 Hz, CH3), 1.54 (d, 3H, J=0.7 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ 176.43, 174.60, 136.79, 135.21, 128.71, 128.64, 128.61, 116.45, 75.41, 67.95, 42.69, 38.14, 26.06, 18.09; IR (neat film) 3483 (br m), 2968 (m), 1736 (s), 1498 (w), 1195 (s) cm−1; HRMS (ESI) m/z calcd for C16H20O5Na (M++Na+) 315.1208, observed 315.1214; [α]D=−18° (c 2.98, CHCl3).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[NH:6][CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:28]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=3[Cl:20])(=[O:30])=[O:29])=[CH:15][CH:14]=2)[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1[nH]cc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 70 mg (0.271 mmol) of 2-acetylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide and 70 mg (0.285 mmol) of 2,3-dichlorobenzene-sulphonyl chloride in 1.5 cm3 of pyridine is stirred at room temperature for 24 hours and then the reaction medium is evaporated to dryness under reduced pressure. The crude product is purified by flash chromatography [eluent; dichloromethane/methanol (97/3 by volume)]. After concentrating under reduced pressure the fractions containing the expected product, 22 mg of 2-acetylamino-4-[4-(2,3-dichlorobenzenesulphonylamino)phenyl]-1H-pyrrole-3-carboxamide are obtained in the form of a beige solid melting at 265° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:18]O>[Pd]>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]=[CH:18]1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCCO
Reactant: CO
Agent: [Pd]
Product: COC(=O)c1cccc2ncn(CCO)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Suspension of methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate (3.06 g, 12.7 mmol) in methanol (130 mL) was hydrogenated at atmospheric pressure over 10% palladium on activated charcoal for 10 min. The mixture was filtered through a pad of Celite and the solvent was removed in vacuum. The residue was dissolved in formic acid (60 mL) and heated at 100° C. for 45 min and then kept at ambient temperature overnight. Excess of the formic acid was removed under reduced pressure. The residue was dissolved in methanol (100 mL) and treated with concentrated ammonia in methanol (20 mL) for 50 min followed by evaporation of the volatiles. Purification by column chromatography on silica using dichloromethane in methanol 95:5 afforded methyl 1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate, 2.31 g (83%). %). MS (ESI) m/z 221 [M+H]. 1H NMR (400 MHz, CD3OD) δ ppm 3.78 (t, J=5.05 Hz, 2H), 3.96 (s, 3H), 4.70 (t, J=5.05 Hz, 2H), 7.33 (t, J=7.83 Hz, 1H), 7.84-7.91 (m, 2H), 8.20 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](Cl)([Cl:16])=[O:15].CN(C)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:16][C:14]([O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[O:15]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,6-Diisopropylphenol (8.9 g; 0.05 mole) was dissolved in 35 mL benzene and cooled to -3° C. after which liquid phosgene (7.0 mL condensed at -70° C.) was added dropwise maintaining a temperature range of 0° to 3° C. N,N-dimethylaniline (6.0 g; 12.2 m mole) was added dropwise and stirred at 0° C. for 15 minutes. The yellow green suspension was quenched with 5 mL water and the layers were separated. The organic portion was washed with HCl (1N, 5 mL), saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated to dryness to give a green liquid which was distilled affording 2,6-diisopropylphenyl chloroformate as a yellow liquid. ##STR13##
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH:18]=1)[CH:16]=O>>[S:9]1[C:8]([CH2:16][C:15]2[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[Cl:19])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1ccc2sccc2c1
Product: Clc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
Thianaphthene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([CH3:19])([CH3:17])[CH3:18])=[CH:13][CH:14]=3)[C:9]([S:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:41])=[C:8]2[CH2:27][C:28]([OH:30])=[O:29])=[CH:31][CH:32]=1
Reactant: CC(C)(C)c1ccc2c(c1)c(Sc1ccccc1)c(CC(=O)O)n2Cc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)c(S(=O)c1ccccc1)c(CC(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (-10°) solution of 1-(p-chlorobenzyl) -5-(t-butyl)-3-phenylthioindole-2-acetic acid (67 mg) from Example 12 in 1.45 mL dry methylene chloride, under nitrogen, was added 34 mg of m-chloroperbenzoic acid. The reaction mixture was stirred at -10° for 1 h and room temperature for 30 min. The reaction mixture was then diluted with ether and washed with water (2×) and brine and dried over MgSO4. Filtration and concentration gave a solid which was passed through a short column of silica gel. Elution with ethyl acetate gave the title compound, mp 160°-161° (dec.).