Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13](S(C)=O)[N:12]=[C:11]([C:18]([NH2:20])=[O:19])[CH:10]=1.C[CH2:22][N:23](C(C)C)[CH:24](C)C.Cl.CNC>O1CCOCC1>[CH3:22][N:23]([CH3:24])[C:13]1[N:12]=[C:11]([C:18]([NH2:20])=[O:19])[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:14]=1
Reactant: COc1ccccc1-c1cc(C(N)=O)nc(S(C)=O)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(C(N)=O)nc(N(C)C)n1
Temperature: 85 °C

Procedure:
6-(2-Methoxyphenyl)-2-(methylsulfinyl)pyrimidine-4-carboxamide (46 mg, 0.15 mmol), 1,4-dioxane (2 mL), DIPEA (80 μL, 0.45 mmol), and dimethylamine hydrochloride (26 mg, 0.3 mmol) were added to a vial (8 mL). The vial was sealed and heated at 85° C. for two days. After the reaction solution cooled to room temperature, the solvent was removed under vacuum in a Savant SpeedVac. The resulting residue was purified by Prep. HPLC. 1H NMR (300 MHz, CDCl3) δ 7.95 (q, J=7.8, 1.8 Hz, 1H), 7.88 (s, 1H), 7.77 (bs, 1H), 7.40 (m, 1H), 7.04 (t, J=9.0 Hz, 1H), 6.98 (d, J=6.0 Hz, 1H), 5.78 (bs, 1H), 3.92 (s, 3H), 3.26 (s, 6H). HPLC ret. time 2.76 min, 10-100% CH3CN, 5 min gradient; ESI-MS m/z 273.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](I)[CH2:23][CH3:24].O>CN(C)C=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][N:12]([CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCCI
Reactant: COc1cccc(C2=CCCNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCC=C(c2cccc(OC)c2)C1
Reaction time: 16 h

Procedure:
A mixture of a solution of 5 g of the product of Step D of Example 3 in 50 ml of dimethylformamide, 7 g of sodium carbonate and 2.3 ml of n-propyl iodide was stirred for 16 hours under an inert atmosphere and was then poured into 250 ml of iced water. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-1-1 cyclohexane-chloroform-triethylamine mixture. The eluate was distilled to dryness under reduced pressure to obtain 4.84 g of 3-(3-methoxyphenyl)-1-propyl-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].N1(CCCCCOC2C=CC(O)=CC=2)C=CN=C1.BrCCCCC(C)(C)C(OCC)=O>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(OCCCn2ccnc2)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: CCOC(=O)C(C)(C)CCCCBr
Agent: Oc1ccc(OCCCCCn2ccnc2)cc1
Product: CCOC(=O)C(C)(C)CCCCCOc1ccc(OCCCn2ccnc2)cc1

Procedure:
p-[3-(1-Imidazolyl)propoxy]phenol and ethyl 7-bromo-2,2-dimethylheptanoate were used as starting compounds in place of p-[5-(1-imidazolyl)pentyloxy]phenol and ethyl 6-bromo-2,2-dimethylhexanoate, respectively, in EXAMPLE 30. The starting compounds were heated and treated in a manner similar to EXAMPLE 30 to give the desired product, ethyl 7-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2-dimethylheptanoate, as an oily substance. ##STR86##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:16]([NH:26][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h

Procedure:
N-(tert-butoxycarbonyl)-L-proline (Aldrich Chemical Company, Milwaukee, Wis.) (137 mg; 0.64 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. n-Decylamine (120 mg; 0.76 mmol), N,N-diisopropylethylamine (181 mg; 1.40 mmol) and PyBOP (397 mg; 0.76 mmol) are added sequentially. The reaction is stirred for 42 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography using a gradient elution (20%→70% ethyl acetate in hexanes) affording the desired product (12) as an oil. ISMS: MH+ 355.2
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[CH:11]2.[CH3:18][C:19](N(C)C)=[O:20]>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[C:11]2[C:19](=[O:20])[CH3:18]
Reactant: COc1ccc2c(ccn2C)c1
Reactant: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)c(C(C)=O)cn2C
Reaction time: 0.08 h

Procedure:
Phosphoryl chloride (1.05 ml) was added dropwise to ice-cooled dimethylacetamide (10 ml) and the solution was stirred, in ice, for 5 min. A solution of 5-methoxy-1-methyl-1H-indole (1.4 g) in dimethylacetamide (5 ml) was added dropwise, and the resulting solution was stirred at 85° for 2 h, then cooled, and partitioned between sodium carbonate (2N; 100 ml) and ethyl acetate (2×100 ml). The combined organic extracts were washed with water (2×100 ml), dried and evaporated in vacuo. The residue was purified by FCC eluting with ethyl acetate to give a solid which was crystallised from a mixture of ethyl acetate and hexane to give the title compound (0.6 g), m.p. 167°-168°.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[C:10](O)([C:21]3[C:22]([OH:30])=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)[C:9]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:33]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[CH:15]=[C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]4=[CH:12][C:11]=3[CH:10]([C:21]3[C:22]([OH:30])=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)[C:9]2=[O:32])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCC2)OCCO3
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cc3c(cc2O)OCC3)c2cc3c(cc2N1C(c1ccccc1)c1ccccc1)OCCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 6-(diphenylmethyl)-8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (0.78 g, 1.5 mmol), triethylsilane (1.2 mL) and trifluoroacetic acid (1.2 mL) in dichloromethane (10 mL) was stirred at 0° C. for 1 h and then at ambient temperature for 1 h. The mixture was concentrated in vacuo to afford crude 6-(diphenylmethyl)-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (100%): MS (ES+) m/z 492.1 (M+1).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O>>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]1[O:10][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Nc1ccccc1O
Product: Nc1ccccc1-c1nc2ccccc2o1
Temperature: 0 °C
Yield: 48 %

Procedure:
The reaction of 13.71 g (0.10 mole) of anthranilic acid with 10.91 g (0.10 mole) of ortho-aminophenol was carried out in 100 ml of polyphosphoric acid at 200° C. After 10 hours from the start of the reaction, the reaction mixture was poured into ice water and the precipitate was filtered and dried. The solid thus obtained was purified by column chromatography and concentrated to give 10.28 g (0.048 mole, 49%) of ortho-aminophenylbenzoxazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.O[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:4]([F:9])[CH:3]=1
Reactant: OCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(Br)ccc1OCCN1CCOCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 67.3 %

Procedure:
A mixture of 4-bromo-2-fluorophenol (0.612 g, 3.2 mmol; described: in Finger et al. J. Amer. Chem. Soc. 1959, 81, 94), 4-(2-hydroxyethyl)morpholine (0.47 ml, 3.84 mmol) and triphenylphosphine (1.0 g, 3.84 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and cooled to 0° C. Diethyl azodicarboxylate (0.6 mL, 3.84 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 3.5 h. The solvent was evaporated and the residue partioned between water and methylene chloride. The organic phase was washed twice with a saturated sodium hydrogen carbonate solution, dried (MgSO4) and the solvent was evaporated. The product was purified by column chromatography on silica using a gradient of toluene/acetonitrile, (4:1 to 0:1), as the eluent to give 0.655 g (67% yield) of the title compound as a clear oil: 1H NMR (CDCl3) δ 7.21 (d, J=11 Hz, 1H), 7.16 (m, 1H), 6.83 (t, J=9 Hz, 1H), 4.14 (t, J=6 Hz, 3H), 3.71 (t, J=5 Hz, 4H), 2.80 (t, J=6 Hz, 2H), (t, J=5 Hz, 4H); 13C NMR (CDCl3, 100) δ 154.2, 151.7, 146.5, 146.4, 127.4, 127.4, 120.1, 119.9, 116.8, 116.8, 112.7, 112.7, 68.1, 67.1, 57.6, 54.3; MS (ESP) m/z 304, 306 (M++1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[CH3:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>CN(C)C=O>[CH3:30][C:31]1[CH:32]=[N:33][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:25])([F:26])[F:27])[CH:3]=2)[CH:35]=1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Reactant: Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(C(F)(F)F)c2)c1
Yield: 50.4 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.8 g), 60% sodium hydride in oil (0.15 g), 4-methylpyrazole (0.20 g) and dimethylformamide (25 ml), the product (0.47 g) was obtained as a colorless amorphous solid, MS, m/z: 437.3 (M+H)+, 873.2 (2M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:4]=1[C:5](O)=[O:6])[CH3:2].S(Cl)([Cl:16])=O>>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:4]=1[C:5]([Cl:16])=[O:6])[CH3:2]
Reactant: CCc1cccc(CC)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCc1cccc(CC)c1C(=O)Cl

Procedure:
2,6-Diethylcyanobenzene was prepared by converting 2,6-diethylaniline to a diazonium salt and then reacting the diazonium salt with copper cyanide. Hydrolysis of 2,6-diethylcyanobenzene was effected by reaction with sodium hydroxide in ethylene glycol to provide 2,6-diethylaminocarbonyl benzene. The latter compound was reacted with phosphoric acid to provide 2,6-diethylbenzoic acid. Reaction of the benzoic acid with thionyl chloride afforded 2,6-diethylbenzoylchloride as an oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:28]([O:33][CH3:34])(=[O:32])[C:29]([CH3:31])=O>CO.[Pd]>[C:1]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH:29]([C:28]([O:33][CH3:34])=[O:32])[CH3:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Dissolve 7.6 g Nα -Boc-Nε -Cbz-L-lysine and 2.04 g methyl pyruvate in 75 ml methanol. Add 2 g 10% palladium on charcoal and hydrogenate at an initial pressure of 40 psig for 3 hours at room temperature. Filter the solution and concentrate the filtrate at aspirator pressure to obtain Nα -Boc-Nε -(1-methoxycarbonylethyl)-L-lysine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])[CH:15]=4)=[N:11][C:10]=3[CH:31]=2)[CH2:3][CH2:2]1.Cl.[C:33](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:25])[CH3:33])[CH3:22])[CH:15]=4)=[N:11][C:10]=3[CH:31]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl [(1S)-2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]isoxazol-3-yl}oxy)-1-methylethyl]carbamate (510 mg) in ethyl acetate (11 mL) was added 4M hydrogen chloride/ethyl acetate (12 mL), and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in pyridine (1.5 ml). Acetic anhydride (1.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol), and recrystallized (hexane/ethyl acetate) to give the title compound (182 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)#[N:2].S([O-])([O-])(=O)=O.[Mg+2].[C:24]1([CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:31][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)#[N:2]
Reactant: N#Cc1cccc(Cc2ccccc2C=O)c1
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: N#Cc1cccc(Cc2ccccc2C=NC(c2ccccc2)c2ccccc2)c1
Temperature: 4 °C

Procedure:
To a stirred suspension of 3.58 g of 2-(3-cyanobenzyl)benzaldehyde and 10.4 g of anhydrous magnesium sulfate was added 3.6 ml of diphenylmethanamine, and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give an oil that crystallised on addition of diethyl ether and cooling to 4° C. to give 4.11 g of N-[2-(3-cyanobenzyl)benzylidene]-1,1-diphenylmethanamine, melting at 113-115° C. A stirred solution of 1.0 g of N-[2-(3-cyanobenzyl)benzylidene]-1,1-diphenylmethanamine in 15 ml of tetrahydrofuran was cooled to −78° C. and 6.7 ml of a 1 M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 20 min then 0.9 ml of propargyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction mixture was diluted with 25 ml of saturated aqueous ammonium chloride and extracted into dichloromethane. The combined organic extracts were dried over sodium sulfate the evaporated to give crude N-(diphenylmethylidene)-2-(3-cyanobenzyl)-a-2-propynyl-benzenemethanamine which was not characterised due to instability. The crude product was dissolved in 20 ml of acetone and 5 ml of 1 M hydrochloric acid added. The solution was stirred at room temperature for 3 h then cooled to 4° C. overnight. The acetone was removed by evaporation and the crude product redissolved in 20 ml of dichloromethane. The solution was extracted with two 20 ml portions of 2N hydrochloric acid. The combined acid extracts were washed with 10 ml of dichloromethane and then basified with 4N sodium hydroxide solution. The basic extracts were combined and reextracted with three 20 ml portions of dichloromethane, the combined organic extracts were dried over sodium sulfate and evaporated to give 120 mg of product. The product was dissolved in 1 ml of methanol and 57 mg of fumaric acid was added. The product was crystallised by trituation with ether and cooling to 4° C. to yield 120 mg of 2-(3-cyanobenzyl)-a-2-propynyl-benzenemethanamine (E)-butenedioate, melting at 182-184° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>ClCCl>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([N:1]([C:2]3[C:7]4[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=4[CH:5]=[CH:4][CH:3]=3)[C:27](=[O:26])[C:22]=12)=[O:25]
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: Cc1oc2c(N)cccc2c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc2c(N3C(=O)c4c(Cl)ccc(Cl)c4C3=O)cccc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A mixture of 7-amino-2,3-dimethylbenzo[b]furan (161 mg), triethylamine (202 mg) and 3,6-dichlorophthalic anhydride (261 mg) in dichloromethane (5 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was washed with 1N-hydrochloric acid and brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol and treated with diazomethane. The separated solid was collected and washed with methanol to give 7-(3,6-dichlorophthalimido)-2,3-dimethylbenzo[b]furan (250 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:15])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:12]=[CH:13][C:14]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:15])[CH:3]=[C:2]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc(Br)c1OC
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(C(=O)C=Cc2cc(OC)c(OC)c(-c3cccs3)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
3-(3-Bromo-4,5-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one (0.105 g, 0.2 mmol) from Ex-1A was dissolved in ethylene glycol dimethyl ether (20 mL). Tetrakis(triphenylphosphine)palladium(0) (0.116 g, 0.1 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 5 min. 2-Thiopheneboronic acid (0.128 g) and sodium carbonate solution (2 M, 0.5 mL) were added. The mixture was stirred at reflux under nitrogen overnight. Upon cooling to room temperature it was poured into water (100 mL) and extracted with dichloromethane (100 mL). The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate, 4:1, 2:1) gave 0.079 g (90%) of the desired 3-[3,4-dimethoxy-5-(thien-2-yl)phenyl]-1-(3,4,5-trimethoxyphenyl)-2-propen-1-one product as a slightly yellow residue. 1H-NMR (300 MHz, CDCl3): 7.79 (d, 1H), 7.56 (m, 2H), 7.42 (d, 1H), 7.39 (d, 1H), 7.29 (s, 2H), 7.10-7.16 (m, 2H), 3.89-4.00 (m, 15H). Anal. Calculated for C24H24O6S C: 65.44, H: 5.49, S: 7.28; found C: 65.69, H: 5.59, S: 6.99.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20](F)=[C:21]([CH3:23])[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4C(=O)OC[C@H]4C)c(C)c3)CC2)c(C)c1
Yield: 17.9 %

Procedure:
By reaction and treatment in the same manner as in Example 240 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-5-methylpyridin-3-yl)methanone (720 mg) described in Preparation Example 148 and (R)-4-methyloxazolidin-2-one (443 mg) described in Preparation Example 25, the title compound (161 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]I>[Ag]=O.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:27])[CH2:18][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Temperature: 80 °C
Reaction time: 13 h
Yield: 89.9 %

Procedure:
1-benzyloxycarbonyl-3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (1.40 g, 3.89 mmol), N,N′-dimethylformamide (7 ml), silver oxide (9.0 g, 39 mmol) and methyl iodide (24 ml, 389 mmol) were placed in a shaded and sealed tube, and this mixture was stirred for 13 hours in an oil bath of 80° C. The reaction solution was then filtered through cellite (ethyl acetate washing) and the filtrate was then diluted with ethyl acetate (100 ml). The organic layer was then washed with water (50 ml×3) and saturated saline solution (50 ml) in that order, and dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 1.31 g (89%) of the title compound was obtained in the form of a pale-yellow syrup an n-hexane:ethyl acetate=2:1 eluate. The instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.