Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](O[C@:9]([C@@H:21]([CH:23]([O:25][Si](C(C)(C)C)(C)C)O)[OH:22])([OH:20])[C:10]([F:19])([F:18])[C:11]([O:13]S(C)(=O)=O)=O)(C(C)(C)C)(C)C.[F:33][C:34]1[C:35]([O:45][Si](C)(C)C)=[N:36][C:37]([O:40][Si](C)(C)C)=[N:38][CH:39]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(Cl)Cl>CO>[F:33][C:34]1[C:35](=[O:45])[NH:36][C:37](=[O:40])[N:38]([C:11]([C:10]([F:18])([F:19])[C@@H:9]([C@@H:21]([CH2:23][OH:25])[OH:22])[OH:20])=[O:13])[CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)OS(C)(=O)=O
Reactant: C[Si](C)(C)Oc1ncc(F)c(O[Si](C)(C)C)n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(n1cc(F)c(=O)[nH]c1=O)C(F)(F)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.1 g. of 3,5-bis(t-butyldimethylsilyloxy)-1-methanesulfonyloxy-2-desoxy-2,2difluororibose, 0.83 g. of 5-fluoro-2,4-bis(trimethylsilyloxy)pyrimidine, and 0.655 g. of trifluoromethanesulfonyloxytrimethylsilane in 20 ml. of methylene chloride was refluxed for approximately 17 hours under nitrogen. The reaction mixture was cooled to room temperature and 3 ml. of methanol was added thereto. The resulting solution was stirred for approximately 30 minutes at room temperature and the precipitated solid was collected by filtration. The filtrate was evaporated to dryness under vacuum at 50° and the residue was dissolved in 15 ml. of methylene chloride saturated with anhydrous hydrogen bromide. The resulting suspension was stirred for approximately 30 minutes and the volatiles were removed in vacuo at 45° . The residue was dissolved in 15 ml. of water and the aqueous solution was extracted one time with 10 ml. of ethyl acetate. The aqueous layer was neutralized with sodium carbonate to a pH of approximately 7 and the solution was evaporated to dryness in vacuo at 50°. The residue was dissolved in about 6 ml. of water and the resulting solution was chromatographed in 2 ml. portions on a Whatman ODS-3 50 cm reverse-phase column using water as the eluent to provide 30 mg. of 1-(5-fluoro-2,4-dioxo-1H,3H-pyrimidin-1-yl)-2-desoxy-2,2-difluorori (CD3OD, 90 MHz) δ 3.63-4.6 (m, 4H), 4.79 (s, 3H), 6.04 (t, J=7 Hz, 1H), 8.07 (d, J=6 Hz, 1H); mass spec. m/e=282 =p.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C=O.Cl.[CH3:19]N(C=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][C:11](=[CH2:19])[C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CN(C)C=O
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Product: C=C1CCc2c(c3ccccc3n2C)C1=O

Procedure:
Accordingly, 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one was synthesized from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one using a formaldehyde reagent (paraformaldehyde) and a mineral acid (HCl) in an aprotic solvent (DMF). Note that this reaction was rapid and high yielding, even though it was performed without using glacial acetic acid as a solvent, and without using a secondary amine as a catalyst.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C[O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:40]/[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33]([OH:42])=[O:32])=[N:3]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.7 %

Procedure:
(1H-Indazol-3-ylmethyl)triphenylphosphonium bromide (2.5 g, 5.30 mmol) was dissolved in methanol (40 mL) and the solution was added with 2-formylbenzoic acid methyl ester (954 mg, 5.80 mmol) and potassium carbonate (2.20 g, 15.8 mmol), followed by stirring at room temperature for 2.5 hours. The reaction mixture was added with water and the precipitated solid was collected by filtration. The solid was added with 2 mol/L aqueous sodium hydroxide solution (75 mL) and heated under reflux in THF (50 mL). The mixture was extracted with ethyl acetate and the aqueous layer was neutralized by 6 mol/L hydrochloric acid. The precipitated solid was collected by filtration and the obtained solid was dried to obtain (E)-2-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 36%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(COc2ccc(Cc3cc(-c4cccnc4)on3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynylpyridine (50 mg, 0.485 mmol) and (4-benzyloxy-phenyl)-acetohydroximoyl chloride (214 mg, 0.776 mmol) described in Manufacturing Example 1-1-3 was added triethylamine (270 μL, 1.94 mmol), which was stirred for 2.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (80 mg, 48%).
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]([O:8][C@@H:9]([C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[Cl:24])[C:10]([OH:12])=[O:11])([CH3:7])([CH3:6])[CH3:5].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[C:4]([O:8][C@@H:9]([C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[Cl:24])[C:10]([O:12][CH2:1][CH3:2])=[O:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCI
Reactant: Cc1cc2ccccc2c(Cl)c1[C@H](OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Ethyl iodide (0.35 mL, 1.5 eq.) was added to a mixture of (S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetic acid (900 mg, 2.93 mmol, 1 eq.) and Cs2CO3 (1.91 g, 2 eq.) in DMF (920 mL) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. Ethyl acetate was added and organic layer separated and washed with brine (2×). The organic layer was dried (MgSO4) and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give a colorless oil (0.911 g, 93%). 1H-NMR: 300 MHz, (CDCl3) δ: 8.23 (d, 1H), 7.62 (d, 1H), 7.63 (s, 1H), 7.46 (m, 3H), 6.10 (s, 1H), 4.06 (dd, 2H), 2.42 (s, 3H), 1.18 (s, 9H), 1.08 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:21]4[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:25])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C.O>[CH3:23][N:19]1[C:20](=[O:22])[C:21]2[N:13]([CH2:12][C:11]3[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]4[CH:28]=[CH:29][C:2]([O:1][CH2:38][CH2:39][N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[CH:14]=[N:15][C:16]=2[N:17]([CH3:25])[C:18]1=[O:24]
Reactant: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(O)cc3)cc2)n(C)c1=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(OCCN4CCOCC4)cc3)cc2)n(C)c1=O
Yield: 42.4 %

Procedure:
A solution of 7-[4-(4-hydroxybenzoyl)benzyl)-1,3-dimethylxanthine (170 mg), potassium carbonate (200 mg) and 1-chloro-2-morpholinoethane hydrochloride (87 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate: acetone =1:1:1) to provide the title compound (93 mg).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=1.O[Li].O>C1COCC1.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:17])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(-c2ccccn2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Yield: 106.4 %

Procedure:
To a solution of the compound of 3-(2-pyridyl)-phenyl acetic acid methyl ester (3.8 g, 16.7 mmol) in THF (50 mL) was added a solution of LiOH.H2O (780.2 mg, 18.6 mmol) in H2O (10 mL). The reaction was stirred at room temperature until TLC analysis indicated the complete consumption of starting material (2 h). The reaction mixture was concentrated to remove THF, then neutralized to pH=7 by the addition of IN HCl, diluted with brine (50 mL), and washed with CHCl3 (100 mL) The aqueous layer was readjusted back to pH=7 by the addition on IN NaOH and washed with fresh CHCl3 (100 mL). After repeating this procedure once more, the organic layers were combined, dried, filtered (MgSO4) and concentrated to give 3.79 g of the title compound: MS (ES+) 214.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1)=[O:9]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC[C@H]1C(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
To a solution of (S)-1-methylpyrrolidine-2-carboxylic acid (258 mg, 2 mmol) in DMF (4 mL) was added 3-nitroaniline (276 mg, 2 mmol) and HATU (760 mg). After stirring for 20 h, it was added with EtOAc, washed with Sat. NaHCO3, brine, dried and concentrated to give (S)-1-methyl-N-(3-nitrophenyl)pyrrolidine-2-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][C:12](=[O:32])/[C:13](=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]2)=[C:21]([F:31])[CH:20]=1)/[CH2:14][CH2:15][CH2:16]Cl)[CH3:10].[H-].[Na+].O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:11]1[CH2:16][CH2:15][CH2:14]/[C:13](=[CH:18]\[C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([F:31])[CH:20]=2)/[C:12]1=[O:32])[CH3:10]
Reactant: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)NC(C)c3ccc(F)cc3F)cc2F)cn1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(/C=C3\CCCN(C(C)c4ccc(F)cc4F)C3=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
DIEA (0.12 mL), WSC (88 mg), and HOBT (62 mg) were added to a solution of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid trifluoroacetate (100 mg) and 1-(2,4-difluorophenyl)ethylamine (54 mg) in DMF (5 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 98 mg of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [1-(2,4-difluorophenyl)ethyl]amide. (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [1-(2,4-difluorophenyl)ethyl]amide (98 mg) was dissolved in DMF (3 mL). 60% sodium hydride (10 mg) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Saturated sodium bicarbonate water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extraction layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 69 mg of the title compound as a racemate. The compound (20 mg) was separated by CHIRALCEL OJ-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol-hexane system) to obtain the title optically active compound with a retention time of 18 minutes (Example 82) (7 mg) and the title optically active compound with a retention time of 24 minutes (Example 83) (4 mg). The property values of the title compound are as follows.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)/[C:3]/1=[CH:12]/[C:13]([NH2:15])=[O:14].[CH3:16][OH:17]>[N+]([O-])([O-])=O.[Ag+]>[F:11][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH:2]([O:17][CH3:16])/[C:3]/2=[CH:12]\[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1
Reactant: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Reactant: CO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: COC1Cc2ccc(F)cc2/C1=C/C(N)=O
Yield: 32 %

Procedure:
A mixture of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide (2.60 g, 9.60 mmoles) and silver nitrate (5.10 g, 27.43 mmoles, Aldrich) in methanol (200 mL) was refluxed for 8 hours. Additional silver nitrate (5.10 g, 27.43 mmoles) was added and the mixture was refluxed for 18 hours. The mixture was filtered, and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel, eluting with hexane:ethyl acetate (1:4), gradually increasing the polarity to 100% ethyl acetate. The fractions containing the compound with Rf=0.15 with hexane:ethyl acetate (1:1) as the eluant were combined and evaporated in vacuo and dried in a vacuum at 50° C. for 18 hours to give 0.68 g (32%) of crude (Z)-2-(6-fluoro-2-methoxy-1-indanylidene)acetamide as a tan solid. Recrystallization from ethyl acetate:hexane mixtures gave 0.49 g (23%) of (Z)-2-(6-fluoro-2-methoxy-1-indanylidene)acetamide as an off-white solid, mp 128°-130° C.; 1H-NMR (DMSO-d6): d 7.13-7.48 (m, 5H), 6.54 (s, 1H), 5.34 (d, 1H), 3.25 (s, 3H), 3.05 (dd, 1H, J=5.7 Hz, 17.3 Hz), and 2.87 (d, 1H, J=17.1 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1.Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:30][C:28]([F:29])([F:31])[C:25]1[N:23]2[N:24]=[C:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]4[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=4)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]3)[CH:20]=[CH:21][C:22]2=[N:27][N:26]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CCOC(=O)c1cccc(C2CCNCC2)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Temperature: 125 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
Ethyl 3-(piperidin-4-yl)benzoate (1.195 g, 5.12 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.49 mmol) and DIPEA (1.174 mL, 6.74 mmol) in DMA (10 mL). The resulting solution was stirred at 125° C. for 2 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and purified by flash silica chromatography, eluting with 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to give a beige solid, which was triturated with ether to give ethyl 3-[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]benzoate (0.805 g, 42.7%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>CN(C=O)C>[CH3:14][C:11]1([CH3:13])[C:10](=[O:15])[C:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:7][CH:6]=2)[O:12]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC1(C)OC(c2ccc(O)cc2)=C(c2ccncc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(c2ccc(OCc3ccc4ccccc4n3)cc2)=C(c2ccncc2)C1=O
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a room temperature solution of 5-(4-hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl) furan-3(2H)-one (280 mg, 0.9 mol) in DMF (5 mL), K2CO3 (413 mg, 2.98 mol) was added and the reaction mixture was stirred for 30 min. 2-Chloro methyl quinoline (235 mg, 1.09 mol) was then added to the reaction and stirring was continued for 2 h at 85° C. The reaction mixture was then quenched with cold water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2,2-dimethyl-4-(pyridin-4-yl)-5-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (240 mg, 57%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.58-8.54 (m, 2H), 8.42 (d, J=7.8 Hz, 1H), 8.04-7.98 (m, 2H), 7.80 (t, J=7.6 Hz, 1H), 7.68 (d, J=7.4 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.58 (d, J=7.4 Hz, 2H), 7.30-7.24 (m, 2H), 7.19 (d, J=7.2 Hz, 2H), 5.43 (s, 2H), 1.50 (s, 6H). MS: M+H: m/z=423.0. HPLC: 96%, (Condition-1).
Reaction SMILES: [I-:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N+:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:7]([CH3:20])[C:6]2([CH3:22])[CH3:21].S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[I-:1].[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N+:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:28][CH3:29])=[O:18])=[C:7]([CH3:20])[C:6]2([CH3:22])[CH3:21]
Reactant: CCO
Reactant: CC1=[N+](CCCCCC(=O)O)c2ccc(Br)cc2C1(C)C
Agent: O=S(=O)(O)O
Agent: [I-]
Product: CCOC(=O)CCCCC[N+]1=C(C)C(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Yield: 82 %

Procedure:
To a 250 mL flask were added 16 (2.0 g, 4.17 mmol), ethanol (60 mL) and conc. sulfuric acid (0.2 mL). The mixture was heated at reflux for 2 h and then was cooled to rt. The ethanol was removed in vacuo and the residue was partitioned between water (40 mL) and DCM (80 mL). The organic layer was washed with 1 M HCl (40 mL), water (40 mL) and then with a solution of sodium iodide. It was dried (MgSO4) and evaporated in vacuo to afford 17 as a brown solid (1.74 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:11]=[CH:10][N:9]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: Clc1ccccc1-c1nc[nH]c1-c1ccccc1Cl
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccccc2Cl)c1-c1ccccc1Cl
Yield: 23.6 %

Procedure:
4,5-Bis(2-chlorophenyl)imidazole (1.2 g) (Chem. Ber., 1959, 92, 338-343) and ethyl 8-bromooctanoate (2.1 g) were reacted in a method similar to Example 9. Column chromatography on silica gel eluted with a dichloro-methane:ethanol gradient gave 4,5-bis(2-chlorophenyl)-1-(7-ethoxycarbonyl-heptyl)imidazole (0.45 g, 23.7%) as an oil. NMR d (CDCl3) . 1.0-1.8(11H, m, 4×CH2, CH3), 2.2(2H, t, CH2C=0), 3.8 (2H, m, N--CH2), 4.1(2H, q, CH20C=O), 7.1-7.45 (8H, m, ArH), 7.69 (1H, s, N=CH)ppm
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15]N(C)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.BrC1C=CC(CC=[O:27])=C(NC2CCN(C)CC2)C=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][O:27][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(n2ccc3ccc(Br)cc32)CC1
Reactant: CN1CCC(Nc2cc(Br)ccc2CC=O)CC1
Product: Brc1ccc2ccn(C3CCOCC3)c2c1

Procedure:
6-Bromo-1-(N-methyl-piperidin4-yl)-indole; from 4-Bromo-2-[(N-methyl-piperidin-4-yl)amino]-phenylacetaldehyde, dimethyl acetal (108 mg, 0.30 mmol). Yield 69.4 mg (79%).
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.Cl>C(O)(=O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:6](=[O:7])[C:4]([Br:5])=[C:2]([Br:3])[CH:1]=[N:18]2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: O=c1c(Br)c(Br)cnn1-c1ccc(F)cc1
Temperature: 115 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
Mucobromic acid (5.0 g, 19.4 mmol) dissolved in acetic acid (110 mL) was treated with 4-fluorophenyl hydrazine.HCl, and the heterogeneous mixture brought to reflux at a bath temperature of 115° C. for 15 hours. During the course of reaction, the mixture became a homogeneous deep red solution, and upon cooling to 23° C., a crystalline precipitate formed. The solution was poured into ice water (1000 mL) and stirred for 20 minutes. The yellow/brown crystals were filtered off, washed with additional cold water, and dried in vacuo to provide 5.8 g (86%) of product. (J. Het. Chem., 1993, 30, 1501; Heterocycles 1985, 23, 2603) 1H NMR (300 MHz, DMSO-d6) δ 7.31–7.41 (m, 2H), 7.57–7.64 (m, 2H), 8.29 (s, 1H). MS (DCI+) m/z 347 (Br79Br79 M+H)+, m/z 349 (Br79Br81 M+H)+, m/z 364 (Br79Br79 M+NH4)+, and m/z 366 (Br79Br81 M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1CCN(c2cccc(Br)c2)C1=O
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(CC2CCN(c3cccc(Br)c3)C2=O)CC1

Procedure:
The title compound was prepared from 1-(3-bromophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 1-(2-methoxyethyl)piperazine, in the same manner as in Preparation Example 1(8).