Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([CH2:6][O:7][C:8]2[C:9]([CH3:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=[N:2]1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]2)=[N:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[CH3:14][C:9]1[C:8]([O:7][CH2:6][C:5]2[CH:4]=[N:3][N:2]([CH:26]3[CH2:27][CH2:28][N:23]([C:20]4[N:19]=[CH:18][C:17]([C:16]([F:15])([F:30])[F:31])=[CH:22][N:21]=4)[CH2:24][CH2:25]3)[N:1]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: OC1CCN(c2ncc(C(F)(F)F)cn2)CC1
Reactant: Cc1ncccc1OCc1cnn[nH]1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncccc1OCc1cnn(C2CCN(c3ncc(C(F)(F)F)cn3)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 3-((1H-1,2,3-triazol-5-yl)methoxy)-2-methylpyridine (0.20 g, 1.05 mmol), in THF (2 mL) at 0° C., was added 1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ol (0.391 g, 1.58 mmol) (Intermediate 20), polymer bound triphenylphosphine (0.527 g, 1.58 mmol), and di-tert-butylazodicarboxylate (0.363, 1.58 mmol). The reaction was allowed to warm to room temperature overnight and was then filtered through a pad of celite washing with THF. The solution was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with 0-60% ethyl acetate in hexane to afford the desired product. 1H NMR (DMSO-d6): δ 8.71 (2H, s), 8.00 (1H, dd), 7.89 (1H, s), 7.47 (1H, dd), 7.19 (1H, dd), 5.18 (2H, s), 4.90 (1H, m), 4.68 (2H, s), 3.31 (2H, m), 2.31 (3H, s), 2.19 (2H, m), 1.92 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=O)[C:4](=O)[CH2:3]1.[Br:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1>ClCCCl>[Br:14][C:15]1[CH:20]=[CH:19][N:18]2[C:17](=[N:21][C:4]3[CH2:3][C:2]([CH3:1])([CH3:13])[CH2:7][CH2:6][C:5]=3[C:8]2=[O:10])[CH:16]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COC(=O)C1CCC(C)(C)CC1=O
Solvent: ClCCCl
Product: CC1(C)CCc2c(nc3cc(Br)ccn3c2=O)C1
Temperature: 25 °C

Procedure:
A solution of methyl 4,4-dimethyl-2-oxocyclohexanecarboxylate (0.5 g, 2.7 mmol, 1 eq), 4-bromopyridin-2-amine (0.51 g, 2.97 mmol, 1.1 eq) and PPA in 1,2-dichloroethane was stirred at 80° C. for 4 hours. After it was cooled to rt, the reaction mixture was quenched with saturated Na2CO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][O:16][CH3:17])[C:10]=2[O:18][CH3:19])[CH2:4][CH2:3]1.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][N:28]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][O:16][CH3:17])[C:10]=2[O:18][CH3:19])[CH2:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NOCc1ccccc1
Reactant: COCc1nccc(NC2CCC(=O)CC2)c1OC
Product: COCc1nccc(NC2CCC(=NOCc3ccccc3)CC2)c1OC

Procedure:
The synthesis was carried out analogously to Example 57 using 4-(4-oxocyclohexylamino)-3-methoxy-2-methoxymethylpyridine (Example 56) and O-benzylhydroxylamine.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][C:12]([N:15]([CH3:17])[CH3:16])=[CH:13][CH:14]=1)C1C=CC=CC=1>[C].[Pd].C(OCC)(=O)C>[CH3:17][N:15]([C:12]1[N:11]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:9]([OH:8])=[CH:14][CH:13]=1)[CH3:16]
Reactant: COC(=O)c1nc(N(C)C)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N(C)C)ccc1O

Procedure:
2.3 g (8 mmol) of methyl 3-benzyloxy-6-(N,N-dimethylamino)picolinate and 0.3 g of 10% palladium carbon were added to 100 ml of ethyl acetate, and was hydrogenated under normal pressure, after the reaction, the reaction product was filtrated and concentrated to obtain a crystal.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:23]=[N:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=2)[CH2:16][CH:17]2C[CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.[CH:33]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(NC(=O)C)=NC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:29]([NH:28][C:25]1[N:24]=[CH:23][C:22]([N:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:13](=[O:14])[N:12]([CH3:33])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:32])=[CH:8][N:9]=2)=[CH:27][CH:26]=1)(=[O:31])[CH3:30]
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(NC(C)=O)nc2)s1
Agent: CC(=O)Nc1ccc(NCC2CCCC2)cn1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)Nc1ccc(N(C(=O)N(C)c2ncc(SCC(=O)O)s2)C2CCCC2)cn1

Procedure:
The title compound was prepared via {2-[3-(6-acetylamino-pyridin-3-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-[5-(cyclopentylmethyl-amino)-pyridin-2-yl]-acetamide and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1>C(Cl)CCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:8][CH2:3][CH2:4][CH3:5])[C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Solvent: CCCCCl
Product: CCCCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)c(C#N)c1=O
Yield: 72.6 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and n-butyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 72.6%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=O)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.S(O)(O)(=O)=O.[NH2:60][C:61]1[NH:62][CH:63]=[CH:64][N:65]=1>C1COCC1.CN(C1C=CN=CC=1)C.CC#N.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19](=[O:21])[NH:60][C:61]2[NH:62][CH:63]=[CH:64][N:65]=2)=[CH:22][CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCC(=O)Nc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.5 %

Procedure:
[4-(4-tert-Butoxycarbonylaminobutyl)phenoxy]acetic acid 33 (1.19 g, 3.68 mmol) was dissolved in anhydrous THF (10 mL), CH2Cl2 (10 mL) and CH3CN (5 mL). To the solution were sequentially added HOAt (200 mg, 1.47 mmol), DMAP (135 mg, 1.10 mmol), and diisopropylethylamine (3.2 mL, 18.40 mmol), followed by the addition of EDC·HCl (1.03 g, 5.35 mmol). The reaction mixture was stirred at room temperature for 15 min. Amino imidazole sulfate (583 mg, 4.41 mmol) was then added and stirring was continued for 48 h. Solvents were removed by rotary evaporation. The residue was taken tip in CH2Cl2 (250 mL), washed with water and brine, and concentrated under reduced pressure. Flash silica gel column chromatography eluting with methanol/dichloromethane (1:30, 1:20, v/v) gave the desired amide as a white solid (0.95 g, 66% yield). 1H NMR (300 MHz, CD3OD) δ 1.40 (s, 9H), 1.42-1.70 (m, 4H), 2.48-2.60 (m, 2H), 3.00-3.20 (m, 2H), 4.65 (s, 2H), 6.79-6.89 (m, 4H), 7.10 (d, 2H). m/z (ESI): 389 [C20H28N4O4+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:12](=[CH:13][CH:14]=1)[C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][NH:6]2.[CH2:15]([N:17](CC)CC)[CH3:16].ClCC#N>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:12]([C:8]([CH2:9][CH2:10][NH:11][CH2:16][C:15]#[N:17])=[CH:7][NH:6]2)=[CH:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Agent: N#CCCl
Solvent: C1CCOC1
Product: COc1ccc2c(CCNCC#N)c[nH]c2c1
Reaction time: 1 h

Procedure:
28.5 g of 6-methoxytryptamine were refluxed in 300 ml of tetrahydrofuran in the presence of 42 ml of triethylamine and 11.4 ml of chloroacetonitrile were added over 2 hours. The heating was continued for 1 hour and after allowing the temperature to return to the ambient, the precipitate was eliminated by filtration. The filtrate was concentrated to dryness under reduced pressure and the residue was taken up in ethyl acetate, washed with water, dried and the solvent was eliminated under reduced pressure to obtain 17.9 g of the expected product melting at approx. 80° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].F[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:15][C:16]([O:20]C)(OC)[CH3:17])[C:7]=1[F:22]>CO>[C:16]([CH2:15][C:8]1[C:7]([F:22])=[C:6]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13])(=[O:20])[CH3:17]
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(F)c1F)OC
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(CC(C)=O)c1F
Temperature: 5 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
A solution of sodium methoxide (freshly prepared from sodium (1.71 g) and methanol (35 ml)) was added to a solution of 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene (16.2 g, 62 mmol), (prepared as described above), in methanol (200 ml) cooled at 5° C. The mixture was left to warm to ambient temperature and was stirred for 3 days. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and 2N hydrochloric acid (1 ml). The organic layer was concentrated to a total volume of 100 ml and THF (100 ml) and 6N hydrochloric acid (25 ml) were added. The mixture was stirred for 1 hour at ambient temperature. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (3/7) to give 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (12.7 g, 90%).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=O)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([C:49]1[CH:50]=[C:51]([CH:56]=[C:57]([CH2:60]C)[C:58]=1[OH:59])[C:52]([NH:54]O)=[NH:53])[CH3:48]>C(Cl)Cl>[CH2:47]([C:49]1[CH:50]=[C:51]([C:52]2[N:54]=[C:9]([C:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=3)[O:11][N:53]=2)[CH:56]=[C:57]([CH3:60])[C:58]=1[OH:59])[CH3:48]
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Reactant: CCc1cc(C(=N)NO)cc(CC)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of 2-isobutyl-6-methyl-isonicotinic acid hydrochloride (2.18 g, 9.53 mmol) and DIPEA (3.69 g, 28.6 mmol) in DCM (10 mL), TBTU (3.67 g, 11.44 mmol) is added. The mixture is stirred for 5 min before 3,5-diethyl-4,N-dihydroxy-benzamidine (1.85 g, 9.53 mmol) is added. The mixture is stirred at rt for 1 h. The mixture is diluted with DCM, washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude 2-isobutyl-6-methyl-isonicotinic acid (3-ethyl-4,N-dihydroxy-5-methyl-benzamidine) ester (LC-MS: tR=0.79 min, [M+1]+=370.06) is dissolved in dioxane (50 mL) and heated to 100° C. for 4 h. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (1.97 g) as a colourless oil; LC-MS: tR=0.93 min; [M+1]+=352.16; 1H NMR (CDCl3): δ 7.85 (s, 2 H), 7.75 (s, 1 H), 7.70 (s, 1 H), 5.05 (s br, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.69 (s, 3H), 2.37 8 s, 3H), 2.19 (hept, J=7.5 Hz, 1H), 1.34 (t, J=7.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(C2=CCCCC2)n1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1cccc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-cyclohexenyl-pyridine-2-carboxylic acid (0.8 g, 3.94 mmol) in ethanol (50 mL) was added 10% palladium on carbon (20%, 0.16 g) under an atmosphere of nitrogen. The suspension was degassed under vacuum and exchanged with hydrogen several times. The mixture was stirred under hydrogen balloon at ambient temperature overnight. The reaction mixture was filtered through a pad of celite, the pad was washed with ethanol and the combined filtrates were concentrated to dryness. The crude title compound (0.62 g, green oil) was used for the next reaction step without further purification; MS (EI): m/e 206.2 [M+H]+
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:17]([CH3:16])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1nc(Cl)nc(Cl)n1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
Cyanuric chloride (7.30 g, 39.6 mmol) was dissolved in toluene (100 ml), cooled to -15° C., added with anhydrous sodium carbonate (4.19 g, 39.6 mmol), stirred for 10 minutes and gradually added dropwise with N-methylaniline (4.24 g, 39.2 mmol) dissolved in toluene (50 ml). This reaction mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using n-hexane and ethyl acetate (4: 1) as eluant, to obtain 6.13 g (yield: 60.6%) of 2,4-dichloro-6-(N-methyl-N-phenylamino)-1,3,5-triazine as colorless crystals having melting point of 131.5° C.-132.5° C.
Reaction SMILES: O1CCCC1.[C:6]([C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)(=[O:8])[CH3:7].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].B.CSC.O>COC(C)(C)C>[OH:8][C@@H:6]([C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH3:7].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: CC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: B
Agent: c1cc[cH-]c1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CSC
Product: C[C@@H](O)[c-]1cccc1
Reaction time: 0.5 h

Procedure:
Subsequently, 1.0 l of tetrahydrofuran and 750 g (3.29 mol) of acetylferrocene (dried overnight at 40° C. in vacuo) were added to the catalyst solution thus obtained and dissolved by further addition of 1.0 l of tetrahydrofuran. The amount of catalyst was thus 6.8 mol%. At 20°-25° C., a further 145 ml of borane-dimethyl sulphide adduct (1.75 mol altogether) was added dropwise and uniformly over a period of 3 hours. After stirring for a further 30 minutes, the reaction mixture was hydrolysed while cooling by addition of 2.0 l of water, with care being taken to ensure that the temperature did not rise above 30° C. Subsequently, 2.0 l of tert-butyl methyl ether were added, the phases were separated and the aqueous phase was extracted once more with 1.0 l of tert-butyl methyl ether. The combined organic phases were dried over magnesium sulphate and the solvent was distilled off.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[O:4][C:5]([CH3:14])([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:14][C:5]1([CH3:13])[O:4][C:3](=[O:15])[C:2]([NH:1][CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)CC(C)C
Reactant: CC1(C)OC(=O)C(N)=C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(C)C)NC1=C(c2ccccc2)C(C)(C)OC1=O
Temperature: 130 °C

Procedure:
A mixture of 3-amino-5,5-dimethyl-4-phenyl-2(5H)-furanone (175 mg, 0.86 mmol), methyl 2-bromo-4-methylpentanoate (360 mg, 1.73 mmol) and cesium carbonate (310 mg, 0.95 mmol) in DMF (4 mL) was heated to 130° C. for 18 h. The mixture was cooled, diluted with EtOAc and washed with water (2×) and brine, then dried over MgSO4 and concentrated. Purification by flash chromatography (20% EtOAc/hexanes) provided methyl 2-[(5,5-dimethyl-2-oxo-4-phenyl-2,5-dihydro-3-furanyl)amino]-4-methylpentanoate.
Reaction SMILES: C(=[N:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:35])[C:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[C:21]([CH:25]([CH3:27])[CH3:26])[O:22]2)=[CH:17][CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.N>O1CCCC1>[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:35])[C:20]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[C:21]([CH:25]([CH3:26])[CH3:27])[O:22]2)=[CH:17][CH:16]=1
Reactant: CC(C)c1oc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)c1oc2cc(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7-(benzhydrylideneamino)-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (5.72 g, 12 mmol) in tetrahydrofuran (150 ml) is treated with 2M HCl solution (150 ml) and allowed to stir at room temperature for 1 hour. The solution is basified with 17% ammonia solution (150 ml), and the mixture is extracted with ethyl acetate (3×200 ml). The organic extracts are combined, dried (MgSO4), filtered and concentrated to afford a yellow suspension. The suspension is triturated with hexanes to afford the title compound as a pale yellow solid, which is isolated by filtration and dried in vacuo overnight.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C=CC1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CCOC(=O)C=CC1CCNCC1
Yield: 93.2 %

Procedure:
To a solution of 1.6 g of ethyl 3-(1-benzylpiperidin-4-yl)propenoate in 1,2-dichloroethane (30 ml) was added at 0° C. 0.74 ml of 1-chloroethyl chloroformate and the resulting mixture was stirred at the same temperature for 15 minutes and then heated under reflux for 1 hour. After distilling off the solvent under reduced pressure, 50 ml of methanol was added to the residue and the resulting mixture was heated under reflux for 1 hour. Then the mixture was made weakly alkaline with a dilute aqueous solution of sodium hydroxide and the solvent was distilled off under reduced pressure. To a solution of 1.0 g of ethyl 3-(piperidin-4-yl)propenoate thus obtained and 0.64 g of 8-(chloroethyl)-1OH-pyrazino[2,3-b][1,4]benzothiazine in N,N-dimethylformamide (30 ml) was added 1.1 g of anhydrous potassium carbonate and the resulting mixture was stirred by heating to 60° C. for 1 hour. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with methanol/dichloromethane) to thereby give 0.6 g of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=1[CH:21]=O>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=1[CH:21]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: O=C1c2ccccc2CCc2ccccc21
Product: COc1ccc(OC)c(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 36 %

Procedure:
Following procedures essentially as described in Preparation 5 and Example 28, above, and using dibenzosuberone (2.00 g, 10.29 mmol) and 2,5-dimethoxybenzaldehyde (1.71 g, 10.29 mmol) affords 1.27 g (36%) of the title compound as a yellow solid. 1H-NMR (CDCl3) δ 2.74-3.67 (br m, 4H), 3.34 (s, 3H), 3.83 (s, 3H), 6.27 (d, 1H), 6.65 (dd, 1H), 6.77 (d, 1H), 6.98-7.28 (m, 8H), 7.56 (dd, 1H); HPLC shows 99% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[CH:16]=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC2CO)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCCC2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a mixture of 8.64 g of 1-[(4-methylphenyl)sulfonyl] 2-pyrrolidinemethanol and 14.2 ml of triethylamine in 100 ml of dry methyl sulfoxide is added slowly a solution of 16.16 g of sulfur trioxide pyridine complex in 100 ml of dry methyl sulfoxide. The solution is stirred at room temperature for one hour, then poured onto 1 l of ice water. The mixture is extracted with ethyl acetate. The combined organic extracts are washed with 1N citric acid (twice), water (twice), a saturated sodium bicarbonate solution then a saturated brine solution. After drying over magnesium sulfate, the solvent is removed under reduced pressure and the residue crystallized from chloroform/hexane. The solid is dried in vacuo at 40° giving 5.75 g of a solid, mp 136°-136.5° dec, [α]D23 -121.0° (c 2, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[NH2:6]
Reactant: NC(=O)c1ccccc1N
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccccc1C(N)=O
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
A mixture of 2-aminobenzamide (100 g), ethyl bromoacetate (97.74 ml) and potassium carbonate (253.78 g) in N,N-dimethylformamide (400 ml) was stirred at 60° C. for 4.5 hours. After cooling, the reaction mixture was poured into ice-water (2 l) and the resulting crystals were collected by filtration. Thus obtained product was purified by recrystallization from ethanol to give ethyl N-(2-carbamoylphenyl)aminoacetate (123.93 g).