Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]#[N:6].CO.Cl.[N:10](OCCCC)=[O:11].[C:17](=O)([O-])[OH:18].[Na+]>CO.C(O)CCC>[CH3:1][O:2][CH:3]([O:18][CH3:17])[C:4](=[N:10][OH:11])[C:5]#[N:6]
Reactant: CCCCON=O
Reactant: COC=CC#N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: CO
Product: COC(OC)C(C#N)=NO
Yield: 50 %

Procedure:
To a flask having an inner volume of 100 ml and equipped with a stirring device and a dropping funnel were charged 3.0 g (36 mmol) of 3-methoxyacrylonitrile, 9.0 g (63 mmol) of a 25.7% by weight hydrogen chloride methanol solution and 15 ml of methanol. Under stirring, 4.7 g (43 mmol) of n-butyl nitrite was gradually added dropwise to the mixture to generate nitrosyl halide and n-butyl alcohol in the system (the method of the above-mentioned (1)), and the mixture was reacted at room temperature for 26 hours. After completion of the reaction, a saturated sodium hydrogen carbonate was added to the mixture to neutralize the mixture, and methanol was removed from the reaction mixture by distillation under reduced pressure. The aqueous layer was extracted with ethyl acetate, the organic layer was taken out, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the concentrate was recrystallized from toluene to obtain 2.6 g of 3,3-dimethoxy-2-hydroxyiminopropionitrile (Isolation yield: 50%) as white solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[N:25]=[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[N:25]=[C:13]2[C:14]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1
Reactant: CCOC(=O)/C=C/c1cccn2nc(C)nc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cccn2nc(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (0.830 g, 20.8 mmol) in dimethyl sulfoxide (10 mL) was added a solution of trimethylsulfoxonium iodide (4.57 g, 20.8 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-8-yl)acrylate (4.00 g, 17.3 mmol) in dimethyl sulfoxide (30 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (1.84 g, yield 43%).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[O:35]1[C:39](C(Cl)=O)=[CH:38][CH:37]=[N:36]1.C(N(CC)CC)C.[C:50](OCC)(=[O:52])C>ClCCl>[O:35]1[CH:39]=[CH:38][C:37]([C:50]([N:22]2[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]3[CH:14]4[CH2:13][CH2:12][CH:11]3[CH2:10][CH:9]([N:8]3[C:7]5[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=5[N:5]=[C:4]3[CH3:3])[CH2:15]4)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)=[O:52])=[N:36]1
Reactant: CCOC(C)=O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccon2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a pre-cooled (0° C.) solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in dichloromethane (3 mL) was added isoxazole-5-carbonyl chloride (7.2 mg, 0.055 mmol) and triethylamine (15 μL, 0.11 mmol). The resulting mixture was stirred overnight at ambient temperature and was then diluted with ethyl acetate (20 mL). After being washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate and evaporated. The crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 1-(8-{2-[1-(isoxazol-3-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as amorphous solid (18.4 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J=1.8 Hz), 7.67 (dd, J=2.6, 7.0 Hz, 1H), 7.43-7.38 (m, 2H), 7.34-7.24 (m, 4H), 7.21-7.13 (m, 2H), 6.74 (d, J=1.8 Hz), 4.64 (br, 1H), 4.23-4.18 (m, 1H), 3.93-3.89 (m, 1H), 3.45-3.27 (m, 4H), 2.58 (s, 3H), 2.44-2.31 (m, 4H), 1.96-1.86 (m, 10H), 1.67-1.60 (m, 2H). HRMS m/z (M+H)+ calcd: 524.3026, obsd: 524.3024.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.[CH3:19][NH:20][CH3:21].CO>CN(C=O)C.C(Cl)Cl>[CH3:19][N:20]([CH2:14][CH:16]([OH:18])[CH2:17][N:8]([C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:9])[CH3:21]
Reactant: CNC
Reactant: BrCC1CO1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CC(O)CN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
4-Nitro-N-methylaniline (1.00 g, 6.6 mmol) was dissolved in DMF (50 ml) and cooled to 0° C. in an ice bath. Sodium hydride (290 mg, 7.2 mmol, 60% dispersion in mineral oil) was added portion wise over 30 mins to give an orange/brown solution. To this was added epibromohydrin (0.62 ml, 7.2 mmol) dropwise and the mixture left to stir at ambient temperature for 12 hours. The mixture was evaporated to give a yellow oily residue, to which was added dimethylamine 2.0 M in MeOH (66 ml, 0.13 mol) and left to stir at ambient temperature for 12 hours. The mixture was evaporated to give a yellow solid, then taken up in DCM (100 ml), washed with H2O (20 ml), brine (20 ml), dried over MgSO4 and evaporated to dryness to give the title product as an orange solid (1.44 g, 86%). NMR (300 MHz): 2.2 (s, 6H), 2.3 (t, 2H), 3.1 (s, 3H), 3.3–3.6 (m, 2H), 3.8 (br s, 1H), 4.8 (d, 1H) 6.8 (d, 2H), 8.0 (d, 2H); m/z: (ES+) 254.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14].[CH3:18][C:19]([CH3:21])=O>>[CH2:11]([N:15]1[C:16](=[O:17])[N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[NH:1][C:19]1([CH3:21])[CH3:18])[CH2:12][CH2:13][CH3:14]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CC(C)=O
Reactant: CCCCN=C=O
Product: CCCCN1C(=O)n2c(nc3ccccc32)NC1(C)C

Procedure:
The title compound was prepared from 2-aminobenzimidazole, acetone, and n-butyl isocyanate, conducting the initial condensation and subsequent base hydrolysis of the intermediate 10-N-butylcarbamoyl precursor as described in Example 1. The solid product had mp 142°-149° C. (dec.). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:11](N)[CH:10]=1)([O-:8])=[O:7].S([O-])([O-])=[O:26].[Na+].[Na+]>O>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:11]([OH:26])[CH:10]=1)([O-:8])=[O:7]
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Reactant: O=S([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2O)cc1
Reaction time: 2 h
Yield: 150.4 %

Procedure:
In a beaker, a mixture of 15.0 mL water and 11.0 mL concentrated sulfuric acid was added to 13.0 g 4,4'-dinitro-2-aminobiphenyl, and agitation was carried out for 2 h while heating, whereupon 26.5 g crushed ice were added. An aqueous solution of 3.51 g sodium sulfite was then added dropwise while on an ice bath, and mixing was carried out for 10 min, whereupon the mixture was allowed to stand for a few minutes. A solution produced by adding 33.4 mL concentrated sulfuric acid to 25 mL water was then boiled, and into this was slowly dropped the reaction mixture indicated above. After continuing boiling for 5 min, the solution was poured into a beaker on an ice bath. The product was then suction-filtered, and the filtrate cake was purified using column chromatography to obtain 10.9 g 4,4'-dinitro-2-hydroxybiphenyl (yield 83.9%) in the form of a yellow-brown powder. The boiling point of the product was 220°-222° C.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:32].[Cl:32][C:31]1[C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:35])=[O:5])[S:12][CH:13]=2)=[N:27][CH:28]=[C:29]([C:33]#[N:34])[CH:30]=1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C#N)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(C#N)cc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 157.1 %

Procedure:
2-[(4-{2-[(3-Chloro-5-cyanopyridin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (0.37 g) obtained in Example 282-1 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, dissolved in ether, and 4N hydrochloric acid/ethyl acetate was added. The precipitated crystals were collected by filtration to give the title compound (280 mg) as white crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1>CN(C)C=O.C(OCC)C>[Br:1][C:18]1[CH:17]=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:22]=[CH:21][C:19]=1[NH2:20]
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1ccc(Cc2ccncc2)cc1Br
Reaction time: 1 h

Procedure:
A solution of 18.34 g (0.103 mol) of N-bromosuccinimide in 60 ml of dimethylformamide is added dropwise, shielded from light, to a solution of 20 g (0.1084 mol) of 4-(4-pyridylmethyl)aniline in 180 ml of dimethylformamide. After 1 hour, the solvent is evaporated off under reduced pressure and the solid is taken up in 200 ml of dichloromethane. The solution is subsequently washed with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. After customary treatment of the organic phase, an oil is obtained which is taken up in 500 ml of diethyl ether, and the whole is left in a refrigerator for 2 days. After filtration, the expected product is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][NH:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([OH:13])=[O:12].[C:15](=O)([O-])[O-:16].[K+].[K+].C(Cl)(Cl)=O.C(OCC)(=O)C>O>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][N:5]1[C:15](=[O:16])[O:12][C:11](=[O:13])[C:7]2[N:6]1[CH:10]=[CH:9][CH:8]=2
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCNn1cccc1C(=O)O
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCn1c(=O)oc(=O)c2cccn21
Temperature: 0 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To a solution of 1-(3-methyl-butylamino)-1H-pyrrole-2-carboxylic acid (Example 1d, 0.25 g, 1.27 mmol) in water (2 mL) was added potassium carbonate (0.175 g, 1.27 mmol). The reaction mixture was cooled to 0° C. and phosgene (20% solution in toluene) (0.95 mL, 1.91 mmol) was slowly added dropwise. The resulting yellow solution was stirred for 16 h. Ethyl acetate (4 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexane, 20-50%) to afford the desired product, 4-(3-methyl-butyl)-6-oxa-3a,4-diaza-indene-5,7-dione (0.16 g, 0.72 mmol, 57% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (6H, d, J=6.8 Hz), 1.56 (2H, m), 1.65 (1H, m), 4.16 (2H, t, J=7.2 Hz), 6.50 (1H, m), 7.08 (1H, m), 7.70 (1H, m).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([F:12])=[C:4]([F:13])[C:3]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20].[Li]CCCC.[CH:26](N1CCOCC1)=[O:27].Cl>C1COCC1>[F:13][C:4]1[C:5]([F:12])=[C:6]2[O:10][C:9]([CH3:11])=[CH:8][C:7]2=[C:2]([CH:26]=[O:27])[C:3]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: O=CN1CCOCC1
Reactant: COCCOCOc1c(F)c(F)c2oc(C)cc2c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCOc1c(F)c(F)c2oc(C)cc2c1C=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
27.2 g (77.5 mmol) of 4-bromo-6,7-difluoro-5-(2-methoxyethoxymethoxy)-2-methylbenzofuran are initially introduced at −75° C. in 500 ml of THF, and 52.0 ml (85.2 mmol) of n-BuLi (15% soln. in hexane) are added. After 2 h at this temperature, 15.5 ml (155 mmol) of N-formylmorpholine are metered in, and the batch is stirred at this temperature for 2 h. The reaction soln. is slowly warmed to −10° C. and hydrolysed using dil. HCl. The batch is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=2:1→n-heptane:MTBE=1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-:17])=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cccc2ccc[n+]([O-])c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.5 %

Procedure:
To a solution of 8-methylquinoline (1.00 g, 6.98 mmol) in DCM (21 ml) was added 3-chlorobenzoperoxoic acid (2.35 g, 10.5 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was diluted with EtOAc and washed with 20% sodium sulfite, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on the silica gel eluting with a gradient of 1-10% MeOH/DCM to yield the desired compound (0.440 g, 2.76 mmol, 39.6% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:35]2[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=2)=[CH:19]/[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:14][CH:13]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[C:35]2[CH:36]=[CH:37][C:38]([C:10]#[C:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[CH:39][CH:40]=2)=[CH:19]/[CH2:20][O:21][C:22]2[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:24]([CH3:34])[CH:23]=2)=[CH:16][CH:17]=1
Reactant: C#CCN1CCC(O)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCC(O)CC3)cc2)cc1C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
4-Hydroxy-1-propargylpiperidine (280 mg, 2.01 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (450 mg, 0.82 mmol; prepared as described in example 7) in a mixture of tetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooled to 0° C.; tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and copper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/methanol 10:0-4:6) yielding methyl (E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[C:56]([O:60][C:61](=[O:79])[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][NH2:78])([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C.C1COCC1>[C:56]([O:60][C:61](=[O:79])[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][NH:78][C:16](=[O:18])[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCN
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)CCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
3-[(2-Benzyloxycarbonylethyl) tert-butoxycarbonylamino]propionic acid (0.17 g, 0.48 mmol) was dissolved in DMF (2 mL) and HOBt (0.065 g, 0.48 mmol) and EDAC (0.093 g, 0.48 mmol) were added. The mixture was stirred for 30 min., and DIEA (0.083 mL, 0.48 mmol) was added and 17-aminoheptadecanoic acid tert-butyl ester (0.15 g, 0.44 mmol) dissolved in THF (3 mL)+DMF (0.5 mL) was added. The reaction was stirred for 2 days. The reaction was concentrated and the residue was dissolved in AcOEt (50 mL) and washed with 0.2 N HCl (2×15 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. The product was purified by flash chromatography (Silica) eluting with AcOEt/Heptane (1:1, 7:3, 8:2) then DCM, DCM:methanol (8:2) and 5% AcOH in DCM. The appropriate fractiones were pooled and concentrated under vacuum. The residue was dissolved in DCM. Silica was added and the product was concentrated onto the silica under vacuum. The silica was used in another flash chromatography, eluting with AcOEt/heptane (3:7 and 1:1). The appropriate fractiones were pooled and concentrated under vacuum to yield 135 mg.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[O:7]2.[C:16]([CH:18]=[C:19]([O-])[CH3:20])#[N:17].[Na+].[NH2:23][C:24]([CH3:33])=[CH:25][C:26](=[O:32])[CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1.C(O)(=O)C>CC(O)C>[CH:28]1([CH2:27][C:26]([C:25]2[CH:12]([C:9]3[CH:10]=[CH:11][C:2]([F:1])=[C:3]4[C:8]=3[O:7][C:6]([CH3:14])=[CH:5][C:4]4=[O:15])[C:18]([C:16]#[N:17])=[C:19]([CH3:20])[NH:23][C:24]=2[CH3:33])=[O:32])[CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(=O)c2c(F)ccc(C=O)c2o1
Reactant: CC(N)=CC(=O)CC1CCC1
Reactant: CC([O-])=CC#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccc(F)c3c(=O)cc(C)oc23)C(C(=O)CC2CCC2)=C(C)N1

Procedure:
A solution of 100 mg (0.49 mmol) of 5-fluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 50.96 mg (0.49 mmol) of sodium 1-cyanoprop-1-en-2-olate, 92.90 mg (0.49 mmol) of 4-amino-1-cyclobutylpent-3-en-2-one and 0.04 ml (0.67 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The resulting residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). 40.4 mg (20.5% of theory) of the title compound are obtained as yellow crystals.
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33](=O)[CH2:34]Br)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]2[N:10]=[C:11]([C:12]3[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=3[CH3:17])[S:22][CH:34]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Agent: Cc1ccc(C([O-])=S)s1
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)c(OC)c3)cs2)c(C)s1
Yield: 89.2 %

Procedure:
Methyl 4-4-(3,4-dimetioxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 1-(3,4-dimethoxyphenyl)-2-bromoethan-1-one (0.467 mmol; 120 mg) in a manner similar to Example 22, step (a) to afford 148 mg (85% yield) of methyl 4-[4-(3,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [K].[OH:2][N:3]1[CH:7]=CN=[N:4]1.Cl[C:9]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:10]#[N:11].[CH3:26][N:27](C)C=O>>[C:10]([C:9]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[O:2][N:3]1[CH:7]=[N:27][CH:26]=[N:4]1)#[N:11]
Reactant: On1ccnn1
Reactant: CN(C)C=O
Reactant: N#CC(Cl)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K]
Product: N#CC(On1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.5 g (12 mmol) of the potassium salt of N-hydroxytriazole in 20 ml of absolute dimethylformamide were initially taken under nitrogen. A solution of 3.16 g (12 mmol) of 2-chloro-2,2-di-(4-fluorophenyl)-acetonitrile in dimethylformamide was added dropwise to this solution, a slightly exothermic reaction taking place. The mixture was stirred for a further 3 hours at room temperature. The reaction solution was evaporated down, the residue was added to water and the mixture was extracted with ethyl acetate. The product was obtained from ethyl acetate in the form of a pale yellow oil, which crystallized out on stirring with diisopropyl ether.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[OH:8])[CH2:2][CH2:3][CH3:4].[C:11]([CH2:13][C:14](O)=[O:15])#[N:12].CN(C=O)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:5][C:6]([CH:7]([O:8][C:14](=[O:15])[CH2:13][C:11]#[N:12])[CH3:9])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: N#CCC(=O)O
Reactant: CCCCOC(=O)C(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOC(=O)C(C)OC(=O)CC#N

Procedure:
A mixture of 292.32 g of butyllactate, 204.14 g of cyanoacetic acid, and 14.66 g of 4-dimethylaminopyridine (DMAP) in 2000 ml of CH2Cl2 was stirred in a 3 L three-neck round bottom flask equipped with a mechanical stirrer. About 50 ml of N-N′-dimethylformide (DMF) was added to make a clear solution. The above clear solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (495.19 g in 500 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.