Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:18])[N:3]=1.[CH:19]1([C:22]2[N:26]=[C:25]([CH2:27][N+:28]#[C-:29])[O:24][N:23]=2)[CH2:21][CH2:20]1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH:19]1([C:22]2[N:26]=[C:25]([C:27]3[N:28]=[CH:29][N:3]4[C:4]5[C:9](=[C:8]([CH3:18])[CH:7]=[CH:6][CH:5]=5)[C:10]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)=[N:11][C:2]=34)[O:24][N:23]=2)[CH2:21][CH2:20]1
Reactant: [C-]#[N+]Cc1nc(C2CC2)no1
Reactant: Cc1cccc2nc(Cl)nc(N3CCOCC3)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1c(N1CCOCC1)nc1c(-c3nc(C4CC4)no3)ncn12
Temperature: 0 °C

Procedure:
A mixture of 2-chloro-5-methyl-4-morpholino-quinazoline (1.68 g, 6.4 mmol) and 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole (1.9 g) in 15 ml of dry dimethylformamide was cooled to 0° C. Solid potassium tert-butoxide (1.4 g, 12.5 mmol) was added gradually during 5 min. to the stirred mixture, the temperature being kept below 10° C. The mixture was stirred at ambient temperature for two hors, and then cooled to 0° C. The precipitated crystals were collected by filtration, rinsed on the filter with ethyl acetate and water, and dried to give the title compound as light yellow crystals, m.p. 262°-266° C. Yield 1.29 g.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1[C:25]2[C:20](=CC=CC=2)[CH:19]=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27]>>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:27][C:26]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:25][CH:16]=2)=[O:28])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(C=Cc1ccc(Oc2ccccc2)cc1)c1ccccc1

Procedure:
Synthesised according to example 1.59.1 using 4-phenoxybenzaldehyde (3.0 g, 15.1 mmol) and 1-(naphthalen-2-yl)ethanone (2.58 g, 15.1 mmol); pale yellow solid; yield: 4.70 g (89%);
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:23].[C:24](OC)(OC)(OC)[CH2:25][CH2:26][CH2:27][CH3:28].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:25]([C:24]1[N:6]([CH2:5][CH2:4][CH2:3][S:2][CH3:1])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:23]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CSCCCNc1c(N)cnc2cc(-c3ccccc3)ccc12
Reactant: CCCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCSC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
N4-(3-Methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine (2.75 g, 8.49 mmol), trimethyl orthovalerate (1.7 g, 10 mmol), and pyridine hydrochloride (0.3 g) were dissolved in toluene (28 mL) and heated to reflux for 1.5 h, collecting the volatiles in a Dean-Stark trap. Upon cooling to room temperature, the solvent was removed under vacuum. The resulting solid was slurried in hexanes (100 mL) for 1 h and then collected by filtration to afford 3.0 g of 2-butyl-1-(3-methylsulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:25])[C:14]([N:16]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][S:18][C:17]1=[O:24])=[O:15])[CH:7]=[CH:6]2.O1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(Br)(Br)(Br)[Br:32]>>[Br:32][CH2:27][CH2:28][CH2:29][CH2:30][O:22][C:21]([C@@H:20]1[CH2:19][S:18][C:17](=[O:24])[N:16]1[C:14](=[O:15])[CH:13]([CH3:25])[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)=[O:23]
Reactant: C1CCOC1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2cc(C(C)C(=O)N3C(=O)SC[C@H]3C(=O)O)ccc2c1
Product: COc1ccc2cc(C(C)C(=O)N3C(=O)SC[C@H]3C(=O)OCCCCBr)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 3-(6-methoxy-α-methyl-2-naphthalenacetyl)-(R)-2-oxothiazolidin-4-carboxylic acid (6.79 g, 18.9 mmoles) in tetrahydrofuran (100 ml) triphenylphosphine (9.91 g, 37.8 mmoles) and carbon tetrabromide (12.53 g, 37.8 mmoles) are added. The reaction mixture is left under stirring for 16 hours at room temperature, then the solvent is removed by evaporation at reduced pressure. The obtained crude product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 1.83 g of the ester are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20](O)[CH:21]=[CH:22][C:23]=1[F:24].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][O:16][C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([CH3:17])[CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(O)ccc1F
Reactant: OCC1CCCCN(Cc2ccccc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: Cc1cc(OCC2CCCCN(Cc3ccccc3)C2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-4 (500 mg, 2.280 mmol), 3-methyl-4-fluorophenol (288 mg, 2.280 mmol), and tiphenylphosphine-resin bound (1.060 g @ 2.15 mmol/g) in DCM (20 ml) was treated with DIAD (0.443 ml, 2.280 mmol). The mixture was stirred overnight at RT, filtered, and the filtrate was concentrated. The crude material was purified by gradient elution on silica gel (0 to 50% EtOAc in Hex) to yield 1-5 as a pale yellow oil. Data for 1-5: LRMS m/z (M+H): 328.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[N:11]1[CH:16]=CC=[CH:13][CH:12]=1.C(OCC)(=[O:19])C>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:19][CH2:13][CH2:12][NH:11][CH3:16])=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(C)=O
Reactant: c1ccncc1
Product: CNCCOC(=O)c1cccc(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added 3-chlorobenzoyl chloride (1.92 g) and pyridine (0.97 mL). After stirring at room temperature for 1 hr., the mixture was stirred at 60° C. for 6 hrs. Ethyl acetate (80 mL) was added to the reaction mixture, and the mixture was washed with water (20 mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 22 hrs., diethyl ether (15 mL) was added, and the precipitated solid was collected by filtration.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:18])=[CH:7][CH:8]=2)[O:3]1.[H-].[Na+].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:11][CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(c2ccccc2)c2ccc(O)cc2O1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1ccccc1

Procedure:
A mixture of 2,2-dimethyl-7-hydroxy-4-phenylchroman (3.72g), sodium hydride (0.53g, 60% dispersion in oil) and 2-dimethylaminoethyl chloride (1.58g) in toluene (59 ml) was stirred and boiled under reflux for 6 hours. Water was added to the cooled mixture and the organic layer was separated and extracted with 5N hydrochloric acid (3 × 30 ml). The combined acid extract was basified, extracted with ether and the ether extract dried (magnesium sulphate). Removal of the solvent gave 2,2-dimethyl-7-dimethylaminoethoxy-4-phenylchroman which was isolated as its hydrochloride salt, m.p. 165°-167° C.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[ClH:9].[CH3:10][NH:11][CH3:12].[CH2:13]=O.Cl>C(O)C.CC(C)=O>[ClH:9].[CH3:10][N:11]([CH3:13])[CH2:12][CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1cccs1
Reactant: C=O
Reactant: CNC
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CN(C)CCC(=O)c1cccs1
Yield: 155.1 %

Procedure:
A mixture of 2-acetylthiophene (63.1 g, 0.5 mol), dimethyl-amine hydrochloride (53.0 g, 0.65 mol), paraformaldehyde (19.8 g, 0.22 mol), and 12N hydrochloric acid (1 ml) in ethanol (80 ml) was refluxed for one and one-half hours. The solution was diluted with ethanol (100 ml) and acetone (500 ml). The solution was chilled overnight and the resulting solid was collected by filtration to yield 75.0 g (73%) of 3-dimethylamino-1-(2-thienyl)-1-propanone hydrochloride as a colorless crystalline solid. mp=182° C.-184° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4](C(=O)C2C=CC=CC=2)[CH2:3]1.[O:23]([CH2:30]CN1CCC(O)(C2C=CC=CC=2)C(C(=O)C2C=CC=CC=2)C1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[O:23]([CH2:30][CH2:1][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1ccccc1)C1CN(CCOc2ccccc2)CCC1(O)c1ccccc1
Reactant: CN1CCC(O)(c2ccccc2)C(C(=O)c2ccccc2)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: c1ccc(OCCN2CCC(c3ccccc3)(c3ccccc3)CC2)cc1

Procedure:
When proceeding as described in Example 2 but replacing the corresponding 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1 -(2-phenoxyethyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in the presence of anhydrous aluminum chloride, 13 g. of 1-(2-phenoxyethyl)-4,4-diphenylpiperidine are obtained. Its boiling point is 145° C./0.01 mm. Hg. The compound yields a fumaric acid salt melting at 199.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]([O:26][CH3:27])=[O:25])=[N:14]1.S(OCC)(O[CH2:32][CH3:33])(=O)=O.[H-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH2:32][CH3:33])=[C:16]([S:19][C:20]([F:21])([F:22])[F:23])[C:15]([C:24]([O:26][CH3:27])=[O:25])=[N:14]1
Reactant: COC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Reactant: CCOS(=O)(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1c(SC(F)(F)F)c(C(=O)OC)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
The intermediate was prepared according to process SCHEME I of EXAMPLE 1c by reacting 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methoxycarbonyl-4-trifluoromethylsulfenyl-5-hydroxypyrazole with diethyl sulfate and sodium hydride in dioxane. The following spectral data were obtained: MS, m/e=482(M+); NMR (CDCl3) δ1.43 (t, J=7.0 Hz, C2H5), 3.73 (s, OCH3), 4.4 (q, J=7.0, OCH2), and 7.76 (s, 2H aromatic).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:12]1)[C:8](=[O:43])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:39]([Si:36]([CH3:38])([CH3:37])[O:35][CH:11]1[CH2:10][CH:9]2[N:13]([C:14](=[O:34])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH:23]3[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]2=[O:43])[CH2:24]3)[CH2:12]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(O[Si](C)(C)C(C)(C)C)CN3C2=O)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Compound 126 (450 mg, 0.734 mmol) was dissolved in THF/MeOH/H2O (2:1:1). LiOH, 1M (7.4 ml, 7.4 mmol) was added and the reaction mixture was allowed to stir at RT over night. Acidification (5% citric acid) followed by extraction with chloroform gave the title compound (321 mg, 75%). M+H=586.
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH3:19])[CH:4](O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.CCN(C(C)C)C(C)C.[Si:52]([O:59][CH2:60][C@@H:61]1[C@@H:65]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:64][NH:63][CH2:62]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]>C(Cl)Cl>[Si:52]([O:59][CH2:60][C@@H:61]1[C@@H:65]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:64][N:63]([CH:4]([CH:3]([CH2:18][CH3:19])[CH2:1][CH3:2])[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:6])[CH2:62]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(F)c1
Reactant: CCC(CC)C(O)C(=O)OCc1ccc(OC)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCC(CC)C(C(=O)OCc1ccc(OC)cc1)N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)C1
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A solution of 0.82 g (2.93 mmol) of 3-Ethyl-2-hydroxyvaleric acid, 4-methoxybenzyl ester (step B) in 5 mL of dry CH2Cl2 was cooled in a −78° C. bath and 0.6 mL (3.57 mmol) of trifluoromethanesulfonic anhydride was added. After 5 min, 0.46 mL (4 mmol) of 2,6-lutidine was added and stirred for 15 min. To this solution, 1.3 mL (7.47 mmol) of DIEA was added and after 10 min a solution of 0.907 g (2.93 mmol) of 3-(R)-t-butyldimethylsilyloxymethyl-4-(S)-(3-fluorophenyl)pyrrolidine in 5 mL of CH2Cl2 was added. The cold bath was removed and the reaction was stirred overnight. The reaction was quenched with saturated NaHCO3 and extracted with Et2O. The combined Et2O layer was washed with brine, dried and concentrated. The residue was purified on a flash column using 10% EtOAc-hexane to isolate 1.1 g of the desired product as a mixture of two diastereomers. 1H NMR (CDCl3) 0.06 and 0.16 (6H), 0.87 (m, 15H), 1.2-3.6 (m, 13H), 3.82 (2s, 3H), 5.11 (s, 2H), 6.8-7.4 (m, 8H),
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[H-].[Na+].[H][H].S(OCC)(O[CH2:31][CH3:32])(=O)=O>O1CCCC1.CO>[Cl:1][C:2]1[C:3]([NH:10][C@H:11]2[CH2:12][CH2:13][C@@H:14]([CH:17]([O:22][CH2:31][CH3:32])[C:18]([F:19])([F:20])[F:21])[CH2:15][CH2:16]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCOS(=O)(=O)OCC
Reactant: [H][H]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(O)C(F)(F)F)CC2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC([C@H]1CC[C@@H](Nc2ncnc(CC)c2Cl)CC1)C(F)(F)F
Temperature: 25 °C

Procedure:
0.61 g of 5-chloro-6-ethyl-4-[cis-4-(1-hydroxy-2,2,2-trifluoroethyl)cyclohexylamino]pyrimidine were added to a suspension of 0.08 g of sodium hydride (80% dispersion in oil) in 10 ml of tetrahydrofuran, and the mixture was stirred at 50° C. until the evolution of hydrogen had ended. 0.28 g of diethyl sulfate were added, and the mixture was heated under reflux for 4 hours. The mixture was cooled to room temperature and a small amount of methanol was added dropwise to destroy excess sodium hydride, the mixture was concentrated and the residue was taken up in dilute ammonia solution and dichloromethane. The organic phase was dried and concentrated. Purification was carried out by silica gel chromatography (petroleum ether/ethyl acetate 1:1). to give the title product as a colourless oil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:12]=2[CH:11]=1
Reactant: Cc1ccc(O)c(I)c1
Reactant: C#Cc1ccccc1
Product: Cc1ccc2oc(-c3ccccc3)cc2c1

Procedure:
The general procedure was used to convert phenylacetylene and 4-methyl-2-iodophenol to the title product. Purification by flash chromatography (hexanes as the eluent) gave the analytically pure product as a white solid (353 mg, 85% yield). 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=7.16, 2H), 7.41-7.30 (m, 5H), 7.06 (d, J=7.35, 1H), 6.88 (s, 1H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 155.92, 153.29, 132.2, 130.57, 129.27, 128.70, 128.35, 125.49, 124.79, 120.70, 110.61, 101.06, 21.30. Anal. Calcd. for C15H12O: C, 86.51; H, 5.81. Found C, 86.28; H, 5.90. m.p.: 131° C. (lit., 6131-133° C.).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=O)=[CH:25]2.N1CCCCC1>C(O)C>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH:31]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:25]2
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A mixture of 6-phenyl-2-oxindole (45 mg, 0.21 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 68 mg (76%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH3:6][C:7](=[CH2:10])[CH2:8][OH:9].CC(N=NC(C#N)(C)C)(C#N)C>C(O)(=O)C>[CH2:1]([P:3]([CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])(=[O:5])[OH:4])[CH3:2]
Reactant: C=C(C)CO
Reactant: CCP(O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Product: CCP(=O)(O)CC(C)CO
Yield: 92.1 %

Procedure:
94 g (1 mol) of ethylphosphonous acid (produced as in Example 1) and 114 g (1 mol) of 2-methyl-2-propen-1-ol are initially charged in 200 ml of glacial acetic acid in a four-neck round-bottom flask equipped with stirrer, reflux condenser, thermometer and nitrogen inlet and heated. At about 100° C., 98.4 g of a 5% solution of AIBN in glacial acetic acid are added dropwise over 1 h. Thereafter, the solvent was distilled off in vacuo to leave 153 g of ethyl(2-methyl-3-hydroxypropyl)phosphinic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C.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.CN(C)C(=O)C>[O:25]=[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[CH:3]=1)[C@@H:10]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(Br)c1
Reactant: OB(O)c1ccncc1
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: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccncc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 15.7 %

Procedure:
To a 25 ml of flask was added ethyl 2-((S)-1-(3-bromophenylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 107.1.B (165 mg, 0.41 mmole), pyridine-4-yl boronic acid (53 mg, 0.43 mmole), tetrakis(triphenylphosphine)palladium (94 mg, 0.081 mmole), potassium carbonate (112 mg, 0.81 mmole), 0.2 ml of water and 2 ml of N,N-dimethylacetamide. The reaction mixture was stirred at 80° C. for 5 hours. Then, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed on silica gel to give 107.1.C (26 mg, 16% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.53 (s, 1H), 8.67 (d, J=5.8 Hz, 2H), 8.01 (s, 1H), 7.70-7.27 (m, 10H), 4.17-4.10 (m, 2H), 3.50 (dd, J=9.0, 4.3 Hz, 1H), 3.36 (s, 2H,), 3.35 (dd, J=14.1, 4.3 Hz, 1H), 2.92 (dd, J=14.1, 9.0 Hz, 1H), 1.99 (brs, 1H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]2[O:7][C:8]([CH3:23])([CH3:22])[C@@H:9](OS(C)(=O)=O)[C@H:10]([NH:11][C:12](=[N:14][C:15]#[N:16])[CH3:13])[C:5]=2[CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>C(#N)C>[C:1]([C:3]1[CH:25]=[CH:24][C:6]2[O:7][C:8]([CH3:23])([CH3:22])[CH:9]=[C:10]([N:11]([C:12](=[N:14][C:15]#[N:16])[CH3:13])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1OS(C)(=O)=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(C1=CC(C)(C)Oc2ccc(C#N)cc21)C(C)=NC#N

Procedure:
6.0 g of 6-cyano-2,2-dimethyl-4-[(N-cyano-acetimidoyl)amino]-2H-benzo[b]pyran obtained in Example 34 was suspended in 200 ml of acetonitrile, and 6.12 g of potassium carbonate, 0.75 g of potassium iodide and 7.53 g of ethyl bromoacetate were added thereto. The mixture was stirred under reflux for 2 hours. Then, the reaction mixture was cooled and then filtered to remove insoluble potassium carbonate and potassium bromide The filtrate was distilled to remove acetonitrile under reduced pressure. The residue was dissolved in 250 ml of ethyl acetate, washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual solid was recrystallized from ethyl acetate/n-hexane to obtain 4.8 g of the above identified compound in the form of crystals.
Reaction SMILES: [C:1]([NH:7][NH2:8])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[O:9]=[C:10]=[N:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14]>O1CCOCC1>[C:1]([NH:7][NH:8][C:10]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:9])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)NN
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Solvent: C1COCCO1
Product: C=CCCC(=O)NNC(=O)N[C@H](C(=O)OC)C(C)C
Reaction time: 3 h

Procedure:
To a 1.6 M solution of pent-4-enohydrazide (from Step 2) in dioxane, 1 eq. of methyl N-(oxomethylene)-L-valinate, (prepared as described in J. Het. Chem. 1990, 739) was added. After sting at RT for 3 h, volatiles were removed in vacuo, to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (d, J 2.1, 1H), 7.86 (d, J 2.2, 1H), 6.48 (d, J 8.1, 1H), 5.86-5.76 (m, 1H), 5.04 (dd, J 17.2, 1.5, 1H), 4.96 (d, J 18.2, 10.3, 1H), 4.09 (dd, J 8.7, 5.7, 1H), 3.64 (s, 3H), 2.32-2.24 (m, 2H), 2.22-2.15 (m, 2H), 2.08-1.90 (m, 1H), 0.94 (d, J 3.9, 3H), 0.92 (d, J 3.9, 3H). MS (ES+) C12H21N3O4 requires: 271 found: 272 (M+H+).