Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15]CNCC2)[CH:7]=CC=1)([O-])=O.Cl.[CH2:17]([OH:19])[CH3:18]>>[C:17]([C:5]1[CH:4]=[N:1][N:10]([C:15]2[N:10]=[CH:6][CH:5]=[CH:4][N:1]=2)[C:6]=1[CH3:7])(=[O:19])[CH3:18]
Reactant: CCO
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: Cl
Product: CC(=O)c1cnn(-c2ncccn2)c1C

Procedure:
487 mg of 4-acetyl-1-(2-pyrimidinyl)-5-methylpyrazole, 524 mg of the compound obtained in the above (1) and 3.6 ml of a 1N hydrochloric acid/ethanol solution were dissolved in 40 ml of ethanol and heated under reflux for 54 hours. During this period, 4.3 g of paraformaldehyde was added thereto in portions. After cooling, the insoluble matters were collected by filtration. Thus 630 mg of the title compound was obtained in the form of a yellow solid product.
Reaction SMILES: Br[C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].O1CCOCC1>[C:17]([NH:16][S:13]([C:11]1[S:12][C:8]([C:5]2[N:4]=[C:3]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:2]([CH:30]=[CH2:31])=[CH:7][N:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Product: C=Cc1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
The mixture of 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-tert-butylthiophene-2-sulfonamide (1 g, 2.0 mmol, 1.0 eq), tributyl(vinyl)stannane (956 mg, 3.01 mmol, 1.5 eq), Pd (PPh3)2Cl2 (200 mg, 0.28 mmol, 0.14 eq) and Bu4NBr (642 mg, 2.0 mmol, 1.0 eq) in 1,4-dioxane (30 mL) was stirred at 100° C. for 2 h under N2, cooled to room temperature and partitioned between EtOAc and water. The organic layer was concentrated and purified by silica gel chromatography to afford N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-vinylpyrimidin-2-yl)thiophene-2-sulfonamide (755 mg, 80%). LC-MS (m/z)=444 [M+H]+
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Cl:18][C:19]1[C:24]([Cl:25])=[C:23]([Cl:26])[CH:22]=[CH:21][C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[C:24]([Cl:25])=[C:23]([Cl:26])[CH:22]=[CH:21][C:20]=1[S:27]([NH:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][C:6]3[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=3)[C:10]=2[N:11]=1)(=[O:29])=[O:28]
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3Cl)nc1-2

Procedure:
The title compound was prepared from 7-methoxy-4,5-dihydronaphtho(1,2-D)(1,3)thiazol-2-amine hydrobromide (85 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 ng) as described in the synthetic METHOD B to give a white solid (13.1 mg) with purity >90%: MS (pos) m/z 475.3, 477.3
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: c1cscn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12f and thiazole
Reaction SMILES: O.C([O-])=O.[NH4+].C([N:13]1[C@H:19]([CH2:20][OH:21])[CH2:18][C:15]2([CH2:17][CH2:16]2)[CH2:14]1)C1C=CC=CC=1>CO.[Pd]>[CH2:16]1[C:15]2([CH2:18][C@@H:19]([CH2:20][OH:21])[NH:13][CH2:14]2)[CH2:17]1
Reactant: OC[C@@H]1CC2(CC2)CN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: OC[C@@H]1CC2(CC2)CN1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
10% Pd/C (85 g, 4.6 wt % to the tricyclic starting material EP-019647) in a 1 L beaker was wetted with water (500 ml, 5.9 vols to Pd/C) and transferred to a N2 purged reactor. Under N2, charged MeOH (4 L) followed by ammonium formate (1.5 kg, 23.787 mol, 2.98 equiv.). The internal temperature was below 10° C. at the point. The mixture was charged more MeOH (4 L) and then heated to about 15° C. and charged a solution of above (S)-(5-benzyl-5-azaspiro[2.4]heptan-6-yl)methanol (1.78 kg) in MeOH (4 L). The resulting mixture was slowly heated to about 50° C. over the period of about 60 to 80 min. It was kept at this temperature for an additional 60 min at which point the reaction was complete as evidenced by NMR/MS/TLC. Upon cooling down, it was filtered through a pad of celite and the cake washed with DCM (8 L). The filtrate was rotavapped and chased with DCM (8 L) to afford the title compound as a yellowish thick oil. Without purification, it was used directly for the next step. ESI MS m/z (M+H)+ 128.13.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:32])[N:27]3[CH2:30][OH:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.N1C=CC=CC=1.[C:39](Cl)(=[O:43])[CH2:40][CH2:41][CH3:42]>ClCCl>[C:39]([O:31][CH2:30][N:27]1[C:28]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)[CH:29]=2)[CH2:24][CH2:25][C:26]1=[O:32])(=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CCCC(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Yield: 94.7 %

Procedure:
To a stirred suspension of Compound 2A (3 g, 6.27 mmol) in dichloromethane (30 mL) was added pyridine (2.54 mL, 31.35 mmol) followed by butyryl chloride (0.98 mL, 9.41 mmol) over 1-2 mins. The resultant solution was stirred at room temperature for 1 h 30 mins. The reaction was quenched with methanol (2 mL) and the mixture diluted with 1:1 NaHCO3 (aq)/brine (50 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (10 mL) and the combined organics dried over MgSO4. After filtration, the volatiles were removed and the residue azeotroped with toluene (3×10 mL). The crude material was purified by silica chromatography eluting 8% Methanol/(1:1 ethyl acetate/dichloromethane) to provide the desired product, Compound 2B (3.26 g, 5.94 mmol, 95% yield).
Reaction SMILES: [N:1]1([C:7]([O:9]C(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=O)[CH:22](C)[CH3:23]>ClCCl>[C:7]([N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1)(=[O:9])[CH:22]([CH3:23])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCNCC1
Reaction time: 0.5 h

Procedure:
Tert-butyl piperazinecarboxylate (2.93 g) and triethylamine (4.39 ml) were dissolved in dichloromethane (60 ml) and then, while being cooled with ice, isobutyryl chloride (1.84 ml) was added thereto. After being stirred for 30 minutes, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated under a vacuum. To 1.79 g of part of the resulting residue, trifluoroacetic acid (9 ml) was added and the mixture was stirred for 30 minutes at room temperature. Then, the reaction mixture was concentrated under a vacuum. The residue was dissolved in methanol (20 ml) and then 2N hydrochroric acid methanol solution (10 ml) was added thereto. After being stirred for 10 minutes, the reaction mixture was concentrated under a vacuum. The residue, with 10% aqueous sodium hydroxide solution added thereto, was extracted with chloroform. The extract was washed with water and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum to yield 0.85 g of the aimed compound.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[N:10]([C:14]3[CH:19]=[C:18]([S:20]([C:23]([CH3:31])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:24])(=[O:22])=[O:21])[C:17]([O:32][CH3:33])=[CH:16][C:15]=3[Cl:34])[C:11](=[O:13])[NH:12][C:7]2=[C:6]([CH3:35])[CH:5]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:44]([O:46][C:47]([O:49][CH:50](Cl)[CH3:51])=[O:48])[CH3:45]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][C:15]1[CH:16]=[C:17]([O:32][CH3:33])[C:18]([S:20]([C:23]([CH3:24])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:31])(=[O:22])=[O:21])=[CH:19][C:14]=1[N:10]1[C:8]2=[N:9][C:4]([C:1]([O:3][CH:44]([O:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH3:45])=[O:2])=[CH:5][C:6]([CH3:35])=[C:7]2[NH:12][C:11]1=[O:13]
Reactant: CCOC(=O)OC(C)Cl
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(C)cc(C(=O)O)nc32)cc1S(=O)(=O)C(C)(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)OC(C)OC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(S(=O)(=O)C(C)(C)c4ccccc4)c(OC)cc3Cl)c2n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 5-carboxy-3-[2-chloro-4-methoxy-5-(1-methyl-1-phenyl-ethylsulfonyl)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (49 mg), potassium carbonate (17 mg) and potassium iodide (8 mg) in N,N-dimethylformamide (1 mL) was added 1-ethoxycarbonyloxyethyl chloride (0.015 mL), and the mixture was stirred at 60° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/2) to give the title compound (29 mg).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][C:24]2[C:28](=[O:29])[CH2:27][CH:26]([OH:30])[CH:25]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32][C:33]([CH3:41])([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:34][SH:35].C(NC(C)C)(C)C>>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH:21]=[CH:22][CH2:23][C@@H:24]2[C@@H:25]([S:35][CH2:34][C:33]([OH:32])([CH3:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C@H:26]([OH:30])[CH2:27][C:28]2=[O:29])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC(C)(O)CS
Reactant: O=C(CCCC=CCC1=CC(O)CC1=O)Oc1ccc(NC(=O)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: CCCCCC(C)(O)CS[C@H]1[C@H](O)CC(=O)[C@@H]1CC=CCCCC(=O)Oc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
Analogously to Example 5, by reaction of 7-(3-hydroxy-5-oxo-1-cyclopenten-1-yl)-hept-5-enoic acid p-benzoylaminophenyl ester with 2-hydroxy-2-methyl-heptanethiol in the presence of diisopropylamine, 11α,15-dihydroxy-15-methyl-9-oxo-13-thia-5-prostenoic acid p-benzoylaminophenyl ester is obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:34]=[C:33]3[C:29]([CH2:30][C:31](=[O:35])[NH:32]3)=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:30]1[C:29]2[C:33](=[CH:34][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)=[CH:27][CH:28]=2)[NH:32][C:31]1=[O:35])([CH3:3])[CH3:2]
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc(C(C)C)c(OC)c(C(C)C)c2)c1

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-(3-ethoxyphenyl)-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-(3-ethoxyphenyl)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH:1]1([N:5]2[C:9]([C:10](=O)/[CH:11]=[CH:12]/N(C)C)=[CH:8][N:7]=[C:6]2[CH3:17])[CH2:4][CH2:3][CH2:2]1.[N:18]1([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[O:21]1[CH2:22][CH2:23][N:18]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]3[N:33]=[C:10]([C:9]4[N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[C:6]([CH3:17])=[N:7][CH:8]=4)[CH:11]=[CH:12][N:32]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:20]1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C1CCC1
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)n1C1CCC1

Procedure:
The title compound was prepared from (2E)-1-(1-cyclobutyl-2-methyl-1H-imidazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (Method 37 of WO 03/076435; 233 mg) and N-(4-morpholin-4-ylphenyl)guanidine (Method 4, 405 mg) by the procedure of Example 111 to yield a white solid (228 mg, 61%). NMR: 1.59-1.72 (m, 2H), 2.32-2.44 (m, 4H), 2.75 (s, 3H), 3.21-3.28 (m, 4H), 3.84-3.92 (m, 4H), 5.40 (quintet, 1H), 7.09 (d, 1H), 7.24-7.32 (m, 2H), 7.66 (d, 2H), 8.11 (s, 1H), 8.57 (d, 1H), 9.77 (brs, 1H); m/z 391.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]([C:20](=[CH:26]OCC)[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]>C(O)C>[NH2:19][C:18]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[N:10]=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a stirred suspension of 4-fluorophenylhydrazine hydrochloride (9.76 g, 60 mmol) in ethanol (250 ml) was added triethylamine (9.2 ml, 62 mmol) and to the resulting amber solution was added ethyl 2-cyano-3-ethoxyacrylate (10.15 g, 60 mmol). The solution was heated at reflux temperature for 3.5 hours. The solution was allowed to cool to room temperature and after standing overnight the resultant solid was filtered off, washed with small amount of ethanol and then ether before being dried under vacuum to give the title compound (12.1 g) as an off white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].C(=O)([O-])O.[Na+].[CH3:14][C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]=1[C:26](Cl)=[O:27]>O.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:26]([C:16]1[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][O:19][C:15]=1[CH3:14])=[O:27]
Reactant: NCc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1onc(-c2ccccc2)c1C(=O)NCc1ccccn1
Yield: 92.5 %

Procedure:
A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (4.06 g, 20 mmol, commercially available) and thionyl chloride (5 mL) was heated under reflux for 3 h. Evaporation of all volatiles afforded 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (4.4 g, 93%) as yellow oil, which was used without further purification in the next reaction. To a mixture of an aqueous solution of 2-picolylamine (0.182 g, 1.68 mmol) in water (2 mL) and ethyl acetate (4 mL) were added sodium hydrogen carbonate (362 mg, 4.2 mmol) in one portion. Then, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid chloride (0.31 g, 1.4 mmol) in ethyl acetate (2 mL) was added dropwise with vigorous stirring under ice-bath cooling keeping the temperature at 0° C. After addition, the reaction mixture was stirred at room temperature for 18 h. The resulting solution was then diluted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were then washed with brine, dried over sodium sulphate) and concentrated to afford the title compound (0.38 g, 93%) as a white solid. MS: m/e: 294.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(C)cc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1-c1ccccc1

Procedure:
A solution of product from step C, (9.5 g; 42 mmol), N-bromosuccinimide (NBS) (8.22 g; 46.2 mmol), 2,2′-azobis(2′-methylpropionitrile) (25 mg; 0.15 mmol) and benzoylperoxide (25 mg; 0.1 mmol) in CCl4 (100 ml) was heated at reflux for 5 hours. The solid was filtered and the filtrate evaporated to give methyl 4-bromomethyl-2-phenylbenzoate as an oil (9.43 g; 74%) which was used in the next step without further purification.
Reaction SMILES: C(O[CH:5]([O:9][C:10](=[O:12])[CH3:11])[C:6]([CH3:8])=[CH2:7])(=O)C.[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C=CC>>[C:10]([O:9][CH:5]=[C:6]([CH3:7])[CH2:8][C:16]1[CH:17]=[CH:18][C:13]([O:19][CH3:20])=[CH:14][CH:15]=1)(=[O:12])[CH3:11]
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Reactant: COc1ccccc1
Solvent: C=CC
Product: COc1ccc(CC(C)=COC(C)=O)cc1
Temperature: 24.5 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
In an argon gas atmosphere, a four necked flask having a capacity of 200 ml was charged with 19.22 g (100 m moles) of 3,3-diacetoxy-2-methylpropene having a purity degree of 89.6% by mass and 108.14 g (1.0 mole) of anisol. Then, the resultant mixture was mixed with 1.42 g (10 m moles) of boron trifluoride-diethylether complex at an internal temperature of 24° C. for 2 minutes. The mixture was stirred at an internal temperature of 24 to 25° C. for one hour to cause the mixed propene compound and anisol to react with each other. After the reaction was completed, the resultant reaction liquid was washed two times with 20 ml of water and further with 20 ml of saturated aqueous sodium chloride solution. The resultant reaction liquid was subjected to a layer separation treatment, the resultant organic layer was removed by a distillation under reduced pressure (20 mmHg, 55 to 57° C.), the resultant residue was refined by a chromatography on silica gel using an eluting solvent:hexane/ethyl acetate mixture in a mixing volume ratio: 10/1. As a colorless liquid fraction, the target 1-acetoxy-2-methyl-3-(4-methoxyphenyl)propene was obtained in a yield of 93.4% in an amount of 20.58 g.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[C:3]([CH:15]=O)[C:2]=1[CH:17]=O.[CH2:19]([C:23]#[N:24])[CH2:20][C:21]#[N:22].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[C:21]([C:20]1[C:19]([C:23]#[N:24])=[CH:15][C:3]2[C:2](=[CH:1][C:14]3[C:5]([CH:4]=2)=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=3)[CH:17]=1)#[N:22]
Reactant: N#CCCC#N
Reactant: O=Cc1cc2cc3ccccc3cc2cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc2cc3cc4ccccc4cc3cc2cc1C#N
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.5 g of anthracene-2,3-dialdehyde (E. Mallonli et al., Synthesis 1980, page 689), 1.8 g of succinodinitrile, 3 g of K2CO3 and 250 ml of dimethyl sulfoxide is heated with stirring at 60°-70° C. for 30 minutes. It is then cooled to 15° C. and 50 ml of water are added. The precipitate which has been deposited is filtered off and is sublimed at 300° C. Yield 485 mg (12%), λmax : 772 nm.
Reaction SMILES: [OH:1][C:2]([C:28]([F:31])([F:30])[F:29])([CH2:16][C:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2)=[O:4].[Cl:32]N1C(=O)CCC1=O>CO>[Cl:32][C:24]1[CH:25]=[C:20]([C:17]([CH3:18])([CH3:19])[CH2:16][C:2]([OH:1])([C:28]([F:31])([F:29])[F:30])[C:3]([NH:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:11](=[O:12])[O:10][CH2:9]3)=[O:4])[CH:21]=[CH:22][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(c2)COC3=O)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: COc1ccc(C(C)(C)CC(O)(C(=O)Nc2ccc3c(c2)COC3=O)C(F)(F)F)cc1Cl
Temperature: 0 °C

Procedure:
22 mg of 5-[2-hydroxy-4-(4-methoxyphenyl)-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide is stirred in 1.5 ml of methanol with 20 mg of N-chlorosuccinimide for 5 hours. The mixture is then dispersed in ice water, sodium bicarbonate solution and ethyl acetate, the ethyl acetate phase is dried, and it is concentrated by evaporation. 20 mg of 5-[4-(3-bromo-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide, which melts after recrystallization from isopropyl ether at 189-191° C., is thus obtained.
Reaction SMILES: [OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[NH:5][C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[OH:1][C:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[N:5]([CH3:24])[C:4](=[O:14])[C:3]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23]
Reactant: CON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one [starting material (SM) prepared according to WO09/049,851] (500 mg, 1.58 mmol) in tetrahydrofuran (20 ml) at 0° C. was added a 1.0 M lithium bis(trimethylsilyl)amide solution in hexanes (3.32 ml, 3.32 mmol) dropwise over 15 minutes. The mixture was stirred one hour at 0° C., treated with methyl iodide (0.099 ml, 225 mg, 1.59 mmol) dropwise over 10 minutes, and further stirred at 0° C. for 30 minutes and at room temperature for one hour. The reaction mixture was quenched over cold saturated aqueous ammonium chloride and extracted with tert-butyl methyl ether (3×), the combined organic phases washed with brine, dried over sodium sulfate and concentrated. The residue (210 mg) was suspended in hexane, stirred at room temperature for 10 minutes, filtered and dried. Yield: 171 mg of a clean mixture of starting material (SM) and 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a beige solid. 1H-NMR and LC-MS analysis of the crude material indicated a ˜1:2.5 ratio of this mixture SM/compound P2.2.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4](OC)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:8]([CH3:12])[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1c(C)ccnc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(Cl)c1CO
Temperature: -20 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A solution of 1.9 g (10.0 mmoles) of methyl 2-chloro-4-methylnicotinate dissolved in 5.0 ml of THF was gradually added, at −65 to −60° C., to a suspension of 0.4 g (10.0 mmoles) of lithium aluminum hydride in 30 ml of tetrahydrofuran. The mixture was stirred for 30 minutes and at −20° C. for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 0.6 g (yield: 38.2%) of (2-chloro-4-methylpyridin-3-yl)methanol.