Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][C:14]([CH3:16])=[CH:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC(C)=CCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCn1ccc([N+](=O)[O-])n1
Yield: 78.5 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 270 mg, 2.39 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL) and a 60% dispersion of sodium hydride in mineral oil (116 mg, 2.90 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, the 1-bromo-3-methyl-but-2-ene (390 mg, 2.60 mmol) was added. The reaction continued to stir under nitrogen for 2 h. The solution was diluted with ethyl acetate (75 mL), washed with water (2×25 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes) afforded 1-(3-methyl-but-2-enyl)-3-nitro-1H-pyrazole (340 mg, 79%) as a yellow oil: H1-NMR (400 MHz, CDCl3) δ 1.79 (3H, s), 1.83 (3H, s), 4.80 (2H, d, J=7.2 Hz), 5.45 (1H, t, J=7.2 Hz), 6.88 (1H, s), 7.43 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[C:4]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[NH:13][N:12]=1
Reactant: CC(=O)O
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(F)c(Nc2cc(OC(C)C)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
(S)-3-(Aminomethyl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)-N6-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine (Example 18; 0.20 g, 0.49 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.49 mmol) were placed in a THF-DCM solution (1:1, 6 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.010 g, 49%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.34 (m, 2H), 7.14 (d, J=10.9 Hz, 1H), 7.02-6.98 (m, 2H), 5.25 (s, 1H), 4.96-4.95 (m, 1H), 4.55-4.52 (m, 1H), 4.30 (d, J=14.8 Hz, 1H), 4.21 (d, J=14.8 Hz, 1H), 2.01 (s, 3H), 1.51 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 444. Found: [M+H]+ 445.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=4[CH3:23])[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2)c1C

Procedure:
89 mg (67%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(2,3-dimethylphenyl)piperazine (49 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1(/[CH:17]=[C:18](\[C:27]2[CH:28]=[N:29][C:30]([S:33][CH3:34])=[CH:31][CH:32]=2)/[C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.CCOC(C)=O>[CH:12]1(/[CH:17]=[C:18](\[C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:34])=[O:9])=[CH:31][CH:32]=2)/[C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Reaction time: 4.5 h

Procedure:
A solution of mCPBA (85% pure, 64 mg, 318 μmol) in CH2Cl2 (1 mL) was added over 5 min to a stirred solution of (E)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 5, 110 mg, 318 μmol) in CH2Cl2 (5 mL) at 0° C. After 4.5 h at 0° C., the reaction mixture was diluted with EtOAc (40 mL). The resulting solution was washed with H2O-saturated aqueous NaHCO3 (1:1, 2×20 mL) and brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc then THF) provided the title compound: RTA=3.32 min; m/z (ES+)=362.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][C:16]=2[O:32][CH3:33])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:34]([NH:36][C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([NH:45][C:46](=[O:53])[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:39][C:38]=3[O:54][CH3:55])=[O:35])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:62](Cl)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CN(C)C=O>[CH2:62]([O:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][C:16]=2[O:32][CH3:33])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:34]([NH:36][C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([NH:45][C:46](=[O:53])[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:39][C:38]=3[O:54][CH3:55])=[O:35])[CH:8]=2)[CH:3]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: COc1cc(NC(=O)c2ccc3cc(O)c(C(=O)Nc4cc(OC)c(NC(=O)c5ccccc5)cc4OC)cc3c2)c(OC)cc1NC(=O)c1ccccc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)c2ccc3cc(OCc4ccccc4)c(C(=O)Nc4cc(OC)c(NC(=O)c5ccccc5)cc4OC)cc3c2)c(OC)cc1NC(=O)c1ccccc1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
2-Hydroxy-3,6-bis(2,5-dimethoxy-4-benzoylaminophenylaminocarbonyl)naphthalene (2.5 g) obtained in Example 10 was mixed with N,N-dimethylformamide (30 g) and the mixture was dissolved by heating to 100° C. under a nitrogen atmosphere. To the solution, potassium carbonate (0.5 g) was gradually added and benzyl chloride (0.46 g) was added dropwise and the mixed solution was reacted for 5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, filtered and then washed with water and methanol to obtain 2.65 g of 2-benzyloxy-3,6-bis(2,5-dimethoxy-4-benzoylaminophenylaminocarbonyl)naphthalene as a greenish yellow crystal (DSC analysis value: 282.8° C.)
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH3:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=S.Cl.C(O)(=[O:35])C>C(OCC)(=O)C.C(OCC)C>[ClH:1].[CH3:2][CH:3]([CH3:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=[O:35]
Reactant: CC(=O)O
Reactant: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2

Procedure:
Mercuric acetate (0.668 g) is added with stirring to a suspension of N-(3-methylbutyl)-10-[(2RS)-1-(1-pyrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (1 g) in acetic acid (20 cc), and the mixture is left to react for 5 hours 30 minutes at a temperature in the region of 20° C. The reaction mixture is diluted with ethyl acetate (150 cc) and distilled water (50 cc) and then treated with caustic soda (d=1.33) to pH 13. The organic phase is separated and the aqueous phase is extracted again with ethyl acetate (2×50 cc). The combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution (100 cc) and then with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.53 g) is purified by chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting successively with a mixture (97.5:2.5 by volume) (100 cc) of methylene chloride and methanol and then with a mixture (95:5 by volume) (200 cc) of methylene chloride and methanol and collecting 15-cc fractions. Fractions 12 to 34 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oil obtained is dissolved in ethyl acetate (10 cc) and a 3N solution (0.5 cc) of hydrochloric acid in ethyl ether is added. The solid formed is drained, washed with ethyl ether (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.37 g) is thereby obtained in the form of a pale yellow solid, m.p. about 100° C. (melts forming a paste), the NMR spectrum of which is identical to that of the product described below in Example 26.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH2:35])=[CH:4][N:3]=1.O=[C:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][NH:35][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:4][N:3]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: COc1cc(-c2csc3c(/C=C/CN)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)N1CCC(NC/C=C/c2cnc(N)c3c(-c4ccc(NC(=O)c5cc6ccccc6n5C)c(OC)c4)csc23)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of N-(4-{4-amino-7-[(1E)-3-aminoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.050 g, 0.104 mmol) and ethyl 4-oxo-1-piperidinecarboxylate (0.017 g, 0.087 mmol) in dichloroethane (1.5 mL) was added sodiumtriacetoxy borohydride (0.036 g, 0.173 mmol). The resulting solution was allowed to stir at room temperature for 12 hours. Upon completion, the reaction solution was treated with an aqueous solution of 10% sodium hydroxide (3 mL) and dichloromethane (3 mL). The two layers were stirred for 15 minutes, followed by filtration through an Empore™ cartridge, and removal of the solvent. The resulting crude product was purified by trituration of the residue in ethanol and collection of the title compound (0.030 g, 45%) as a white powder. LCMS (Conditions a) Rt 3.57 minutes, 639.4 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1 H), 8.01 (dd, J=8.2 Hz, J=7.8 Hz, 1 H), 7.95 (s, 1 H), 7.71 (d, J=8.2 Hz, 1 H), 7.62 (s, 1 H), 7.59 (d, J=8.2 Hz, 1 H), 7.35 (s, 1 H), 7.32 (d, J=8.5 Hz, 1 H), 7.21(d, J=1.9 Hz, 1 H), 7.15 (t, J=7.8 Hz, 1 H), 7.08 (dd, J=8.2 Hz, 1.9 Hz, 1 H), 6.67 (d, J=16.0 Hz, 1 H), 6.29 (td, J=16.4 Hz, J=5.9 Hz, 1 H), 5.61 (s (br), 1 H), 4.04 (s, 3 H), 4.02 (q, J=7.02 Hz, 2 H), 3.91 (s, 3 H), 3.88 (m, 2 H), 3.42 (d, J=5.5 Hz, 2 H), 2.87 (m, 2 H), 2.67 (m, 1 H), 1.83 (m, 2 H), 1.19 (m, 2 H), 1.18 (t, J=7.02 Hz, 3 H).
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O.[CH3:25][C:26]1([CH3:39])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH2:35][C:36](=[O:38])[CH3:37])[O:27]1>C(OCC)(=O)C>[CH3:39][C:26]1([CH3:25])[O:31][C:30](=[O:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH2:35][CH:36]([OH:38])[CH3:37])[O:27]1
Reactant: CC(=O)CCCC1=CC(=O)OC(C)(C)O1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)CCCC1=CC(=O)OC(C)(C)O1
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water, and the solution was then stirred at 32° C. for 30 minutes. Afterward, 300 mg of 2,2-dimethyl-6-(4-oxopentyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the resultant residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the resultant residue wa then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 148 mg (yield 50%) of (-)-2,2-dimethyl-6-(4-hydroxypentyl)-1,3-dioxin-4-one [a compound having the formula (1) in which n is 3, X is a hydrogen atom, Y is the hydrogen atom, and a substituent is present at the 6-position].
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[CH:13]1([C:19]#[CH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:19]2[NH:8][C:7]3[C:2]([CH:20]=2)=[CH:3][C:4]([CH3:12])=[CH:5][C:6]=3[N+:9]([O-:11])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C#CC1CCCCC1
Reactant: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Product: Cc1cc([N+](=O)[O-])c2[nH]c(C3CCCCC3)cc2c1
Yield: 62.4 %

Procedure:
6-Iodo-4-methyl-2-nitroaniline (500 mg, 1.8 mmol) and cyclohexylacetylene (0.23 ml, 1.8 mmol) were reacted according to the same procedure as Preparation 19 to give the title compound (290 mg, Yield 62%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)=[N:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:10]1[N:9]=[N:8][C:7]([C:5]2[S:6][C:2]([Br:1])=[N:3][N:4]=2)=[N:11]1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: Brc1nnc(-c2nnn[nH]2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc(-c2nnc(Br)s2)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazole (1 g, 4.3 mmol) in DMF (20 mL) was added Cs2CO3 (2.1 g, 6.45 mmol) and ethyl bromoacetate (0.95 mL, 8.6 mmol). The resulting solution was stirred at 90° C. for 1 hour. The mixture was partitioned between EtOAc (100 mL) and water (200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. Chromatography over silica afforded the title compound as a white solid, contaminated with the 1-alkylated isomer ethyl[5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazol-1-yl]acetate. 1HNMR (CDCl3, 300 MHz): δ 5.70 (s, 2H), 4.26 (q, J=7 Hz, 2H), 1.28 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[O:14])=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (21 mg, 0.068 mmol) in dichloromethane (1 mL) was added 4-phenylpiperidine (17 mg, 0.068 mmol, 1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O2: 346.1681, found 346.1685.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][C:6](=[CH:9][O:10]C)[CH2:5][CH2:4]2)[O:2]1.O>C(O)(=O)C>[CH:9]([CH:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]1)=[O:10]
Reactant: COC=C1CCC2(CC1)OCCO2
Solvent: CC(=O)O
Solvent: O
Product: O=CC1CCC(=O)CC1
Yield: 92.7 %

Procedure:
A mixture of 10.55 g of 1,1-ethylenedioxy-4-(methoxymethylene)cyclohexane, 130 ml of water and 200 ml of glacial acetic acid was heated to reflux for 1 hour. The solvent was subsequently distilled off on a rotary evaporator and the distillate was extracted twice with methylene chloride. The distillation residue (a yellow oil) was diluted with 200 ml of water, neutralized with sodium carbonate solution and extracted three times with methylene chloride. The organic phases were washed with saturated sodium carbonate solution and the aqueous phases were back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and evaporated. Distillation of the residual, yellow oil gave, at 70° C./0.15 Torr, 6.7 g (93%) of 4-formylcyclohexanone.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([CH2:13][C:14]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12].O.COC(CC1C(Cl)=C(N)C=CC=1C(OC)=O)=O>C(#N)C>[CH3:9][O:10][C:11]([CH2:13][C:14]1[CH:23]=[C:22]([NH2:24])[C:21]([Cl:1])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)Cc1cc(N)ccc1C(=O)OC
Reactant: O=C1CCC(=O)N1Cl
Agent: COC(=O)Cc1c(C(=O)OC)ccc(N)c1Cl
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C

Procedure:
N-Chlorosuccinimide (1.0 g, 7.3 mmol) was added to a solution of methyl 2-methoxycarbonylmethyl-4-aminobenzoate (1.5 g, 6.6 mmol) in acetonitrile (10 mL). The mixture was stirred while heating under reflux for 1 hour. After the reaction solution was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Then, the resulting solid was washed with ethyl acetate to give a 0.9:1 mixture of the title compound and methyl 2-methoxycarbonylmethyl-4-amino-3-chlorobenzoate (1.5 g, 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]#[CH:49])=[CH:44][CH:43]=1.C(N(CC)CC)C>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:10]1[O:11][CH2:12][CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:49]#[C:48][C:45]3[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2ccc(C3CCOC(c4c(F)cccc4F)=N3)cc2)cc1

Procedure:
In 2 mL of dichloromethane, the product of Step C (0.07 g) was combined with tetrakis(triphenylphosphine)palladium(0) (0.010 g), copper(I) iodide (0.006 g), triphenylphosphine (0.006 g), (4-fluorophenyl)acetylene (prepared by the method of A.D. Allen and C. D. Cook, Can. J. Chem. (1963), 41, 1084; 0.15 g), and triethylamine (2 mL) and the mixture heated at reflux until thin layer chromatographic analysis showed consumption of starting material. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the title product, a compound of this invention, as a solid melting at 95°-110° C. (material prepared on larger scale, identical by 1H NMR spectroscopy, was recrystallized from ethyl acetate/hexane to give a solid melting at 102°-104° C.). 1H NMR (CDCl3) δ2.0 (m, 1H), 2.4 (m, 1H), 4.3 (m, 1H), 4.5 (m, 1H), 4.8 (m, 1H), 6.9-7.1 (m,4H), 7.3-7.4 (m,3H), 7.5-7.6 (m,4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[O:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>CN(C=O)C>[N:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH2:11][O:10][C:9](=[O:19])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: O=C1OCC(c2ccncc2)=C1c1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 80 °C
Yield: 17.5 %

Procedure:
To a stirred solution of 3-(4-hydroxyphenyl)-4-(pyridin-4-yl)furan-2(5H)-one (700 mg, 2.76 mmol) in DMF (10 mL) was added K2CO3 (763.6 mg, 5.5 mmol) followed by 2-(chloromethyl)quinoline (711 mg, 3.32 mmol). The reaction mixture was then heated at 80° C. for 2 h, quenched with cold water, and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl) furan-2(5H)-one (190 mg, 19%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.61 (d, J=7.7 Hz, 2H), 8.42 (d, J=7.1 Hz, 1H), 8.04-7.96 (m, 2H), 7.81-7.76 (m, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.44-7.36 (m, 4H), 7.11 (d, J=7.2 Hz, 2H), 5.40 (s, 2H), 5.34 (s, 2H). MS: M+H: m/z=395.1 and HPLC: 95%, (Condition-H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2CCN(S(C)(=O)=O)CC2)c2ccccc2n1

Procedure:
2-Methyl-4-piperazin-1-yl-quinoline (227.3 mg, 1 mmol) was dissolved in anhydrous dichloromethane (7 ml), triethylamine was added (209 μl, 1.5 mmol), followed by methanesulfonyl chloride (85 μl, 1.1 mmol) which was added dropwise with ice-cooling. The mixture was diluted with dichloromethane and washed with 5% sodium bicarbonate solution. The wash solution was extracted with dichloromethane, the organic phases were combined and washed with 5% sodium bicarbonate solution, water and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure 265 mg of a white foam were obtained (0.87 mmol, 87%) which was used directly in the next step.