Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:13]2[N:12]=[CH:11][N:10](CCCCC(=O)C)[C:9]=2[C:8](=[O:21])[NH:7][C:6]1=[O:22])CCC.[OH-].[Na+].CI>CO.O>[NH:7]1[C:8](=[O:21])[C:9]2[NH:10][CH:11]=[N:12][C:13]=2[NH:5][C:6]1=[O:22]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2CCCCC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: CO
Solvent: O
Product: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Temperature: 48 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
60 g of 3-n-butyl-7-(5'-oxohexyl)-xanthine are added to a solution of 8 g of sodium hydroxide in 160 ml of a methanol/water mixture (1:1). 28 g of methyl iodide are dropwise added to the clear solution having a temperature of 40° C. and the mixture is stirred at 48° C. for 24 hours. After concentration under reduced pressure the residue is diluted with 300 ml of diethylether and the unreacted 3-(n-butyl)-7-(5'-oxohexyl)-xanthine is removed by shaking with 1 N sodium hydroxide. After neutralisation, drying, concentration under reduced pressure and distillation at 140° C. temperature of the mixture and 0.02 mmHg 48.5 g of 1-methyl-3-(n-butyl)-7-(5'-oxohexyl)-xanthine are obtained from the ether phase as a viscous oil (nD20 =1.5320; yield 77.2%, referred to reacted starting xanthine). Analysis: C16H24N4O3 =320.396
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[C:16]([C:18]([OH:20])=O)[N:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O.CN(C=O)C>[O:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][NH:21][C:18]([C:16]2[N:17]=[C:13]([C:10]3[CH:11]=[N:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)[S:14][CH:15]=2)=[O:20])[CH2:25][CH2:26]1
Reactant: O=C(O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NCCN1CCOCC1)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Reaction time: 18 h

Procedure:
To a solution consisting of 2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylic acid (Example 63, 172 mg, 0.61 mmol) in thionyl chloride (10 mL) was added one drop of dry DMF. The solution was heated at reflux for four hours and was subsequently allowed to reach room temperature and stirred for 18 hours. The thionyl chloride was evaporated away under reduced pressure and to the residue was added toluene (2×30 mL), which was evaporated and the residue subjected to high vacuum to remove residual thionyl chloride. The residue was dissolved in dichloromethane (10 mL) and 4-(2-aminoethyl)morpholine (51 mg, 0.051 mL, 0.40 mmol) was added followed by diisopropylethylamine (0.10 mL). The solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between water and diethyl ether. The organics were dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash chromatography (100% dichloromethane to 9:1 v/v dichloromethane-methanol gradient) through a 40-g Silicycle® flash silica cartridge. The title compound was obtained as an off-white solid (63 mg, 61% yield); Rf 0.70 with 9:1 v/v dichloromethane-methanol; 1H-NMR (300 MHz; CDCl3) δ 9.30 (s, 2H), 8.51 (m, 2H), 8.20 (s, 1H), 7.88 (br t, 1H), 7.53 (m, 3H), 3.77 (t, 4H); 3.61 (dt, 2H), 2.64 (t, 2H), 2.54 (t, 4H); MS (ESI+) m/z 396 (M+1); H-PGDS FPBA IC50: 2.5 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH2:25][CH3:26])=[O:6].[S:30](Cl)(Cl)=[O:31]>C(Cl)(Cl)(Cl)Cl>[S:30](=[N:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]=1[CH2:25][CH3:26])=[O:6])=[O:31]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N=S=O)c1
Temperature: 50 °C

Procedure:
A suspension of 3-amino-N-[2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.100 g, 0.237 mmol) (Example 4.1) in carbon tetrachloride (1 ml) was heated to 50° C. until it became a clear solution. A solution of thionyl chloride in carbon tetrachloride (1.68 M) (0.725 ml, 1.218 mmol) was added and the mixture was heated to 80° C. for one hour. The reaction mixture was evaporated under reduced pressure and the residue was triturated with cyclohexane. The suspension was filtered and the solid dried under high vacuum. The desired compound was obtained as white crystals. M.p. 100-108° C. 1H-NMR as described for Example 2.2. Mass spectrometric analysis: conditions as described for Example 2.1. Calculated exact mass: 468; [M-H]− observed: 467.06.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:11])=[O:10])=[CH:5][CH:4]=1.[CH3:12][C:13]1([CH3:22])[N:18]([O])[C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15][CH2:14]1.C([O:25]C(=O)C)C>[Mo](=O)(=O)=O.O>[CH3:12][C:13]1([CH3:22])[CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[N:18]1[O:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2](=[O:25])[CH3:1])=[CH:4][CH:5]=1)[CH3:11]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Reactant: CCOC(C)=O
Reactant: CCc1ccc(C(C)=O)cc1
Agent: O=[Mo](=O)=O
Solvent: O
Product: CC(=O)c1ccc(C(C)ON2C(C)(C)CCCC2(C)C)cc1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
,A mixture of 4-ethylacetophenone (23 g), 2,2,6,6-tetramethylpiperidine-1-oxyl (10,7 g) and molybdenum(VI)oxide (0,67 g) are purged with Argon for one hour. The mixture is then heated up to 70° C. and the solution prepared under A) is added drop wise under stirring within 5 minutes. Pressure is reduced to 300 mbar and the mixture is heated for 18 hours at 70° C. After the+reaction is completed the mixture is cooled to room temperature and the pressure is allowed to raise to normal pressure. Ethylacetate and water is added. The water phase is separated and extracted three times with ethylacetate. The organic phases are combined, washed with water, dried over Magnesium sulfate and concentrated. Excessive amounts of 2-(4-ethyl-phenoxymethyl)-oxirane are removed at 40° C./0,2 mbar. The raw product is subsequently chromatographically purified on silica with petrolether/ethylacetate=95/5 as eluent. A white+powder is obtained after recrystalization from pentane, corresponding to the compound of formula (104), having a melting point of 61.5-63° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][S:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.S(OC)(O[CH3:29])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH3:29])[S:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NS(=O)(=O)/C=C/c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)/C=C/c1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.13 g (3.25 mmol)) in DMF (7.0 ml), 4-chloro-2-nitro-N-[(trans)-β-styrenesulfonyl]aniline (1.00 g (2,95 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.32 ml (3.38 mmol)) was added. The resulting mixture was stirred at 80° C. for 3 hours, and then poured into water, extracted with diethyl ether. The extract was washed with 1% sodium hydroxide solution, water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Small amount of diethyl ether was added to the residue and crystals separated was filtered and washed to give 0.99 g (95%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-fluorophenoxy)acetic acid methyl ester and 2-(4-bromobenzyl)-3-oxopentanoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH2:7][C:6](=[O:9])[O:5][C:3]1=[O:4].[OH:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCOCC1>[C:3]([C:2]([CH3:10])([CH3:1])[CH2:8][CH2:7][C:6]([O:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1)=[O:9])([OH:5])=[O:4]
Reactant: CC1(C)CCC(=O)OC1=O
Reactant: COc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(COC(=O)CCC(C)(C)C(=O)O)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2,2-dimethylglutaric anhydride (19.34 g), anise alcohol (22.08 g) and triethylamine (19.39 g) in dry dioxane (360 ml) was stirred at 80° C. for 3.5 hours. The reaction mixture was evaporated and the residue was diluted with water and adjusted to pH 9 with potassium carbonate. The aqueous layer was washed with benzene, acidified with dilute hydrochloric acid and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give p-methoxybenzyl 4-carboxy-4-methylvalerate.
Reaction SMILES: [K+].[OH:2][CH2:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6]([O-:8])=[O:7].[C:11]1([CH2:17]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[C:11]1([CH2:17][O:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4][CH2:3][OH:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(CCO)C(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
A mixture of 4-hydroxy-2,2-dimethylbutyric acid monopotassium salt (10.6 g,62.35 mmol) and phenylmethyl bromide (11.63 g, 68 mmol) in 100 ml of DMF was stirred at room temperature for 24 hours and then the mixture was poured into ice/water. The mixture was extracted with ether (3×) and the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica, 12-66% of ethyl acetate/hexane) to afford 10.02 g (72%) of 4-hydroxy-2,2-dimethylbutyric acid phenylmethyl ester.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)C.[CH2:10]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][CH:23]2[C:28]([N:30]([C:37]1[CH:38]=[N:39][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=1)[CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][CH:23]2[C:28]([N:30]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH3:1])[CH:36]=1)[C:37]1[CH:38]=[N:39][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=1)=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOCCOCCO
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: COCCOCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment of diethylene glycol monoethyl ether (1.5 mL) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) in the same manner as in Example 394, 5-benzyloxy-N-({1-[2-(2-methoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.89 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[CH2:20](Br)[CH:21]=[CH2:22]>>[CH2:22]([N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:18]([Cl:19])=[CH:17][C:5]=2[N:6]=[C:7]1[C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Product: C=CCn1c(-c2ccc(C=O)cc2)nc2cc(Cl)c(Cl)cc21

Procedure:
1-Allyl-5,6-dichloro2-(4-formylphenyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and allylbromide by following General Procedure 3.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[NH:18])OC)[N:7]=1)[C:3]([NH2:5])=[NH:4].C(N(CC)CC)C.[C:26]([NH:29][NH2:30])(=O)[CH3:27].[C:31]([O-:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([O-:36])=[O:35]>CO>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH3:27][C:26]1[N:18]=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:8]2[N:7]=[C:6]([NH:2][C:3]([NH2:5])=[NH:4])[CH:10]=[N:9]2)[NH:30][N:29]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: CC(=O)NN
Reactant: COC(=N)CCCCn1ncc(NC(=N)N)n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(CCCCn2ncc(NC(=N)N)n2)n1
Product: O=C(O)/C=C/C(=O)O
Yield: 19 %

Procedure:
Crude methyl 5-(4-guanidino-1,2,3-triazol-2-yl)valerimidate hydrochloride (0.42 g.) in MeOH (8 ml.) was treated with triethylamine (0.35 g.) followed after 0.5 hours by acethydrazide (0.13 g.). After a further 0.5 hours the solution was heated under reflux for 6 hours then evaporated to dryness. The residue was purified by medium pressure chromatography using chloroform/MeOH/aqueous ammonia (s.g. 0.880) 8:2:0.1 v/v/v as eluant to give a gum which was converted to the fumarate in MeOH. The solid was filtered and washed with warm MeOH to give 3-methyl-5-[4-(4-guanidino-1,2,3-triazol-2-yl)butyl]-1,2,4-triazole fumarate (yield 19%) having the following n.m.r. in d6DMSO:- 1.4-2.1 (m, 4H); 2.15 (s, 3H); 2.61 (t, 2H); 4.4 (t, 2H); 6.68 (s, 1H); 7.08 (s, 1H); 7.26 (br s, 4H).
Reaction SMILES: C1(O)C=CC=CC=1.[OH-].[Na+].[CH3:10][NH:11][CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1.[O:21]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=O)C1C=CC=CC=1>C1COCC1>[CH3:10][N:11]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:21])[CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 15 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of phenol (2.18 g, 23.2 mmol) in THF (25 mL) was added 50% NaOH solution (1.86 g, 23.2 mmol) at ambient temperature. After the exotherm subsided, N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.95 g, 23.2 mmol) was added. The solution was cooled to 15° C., and then a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 25 mL of THF was added slowly. An ice bath was used to maintain the temperature between 15 and 20° C. Following a 5 mL THF rinse, the reaction was allowed to warm to ambient temperature. After three hours, an additional aliquot of 50% NaOH solution (90 mg, 2.3 mmol) was added. After 19 hours, the reaction was quenched by the addition of 100 mL of water and the THF removed under reduced pressure. The remaining aqueous phase was washed with MTBE (3×60 mL), toluene (70 mL) was added, and the pH was adjusted to 3.7 with 4 N HCl. The layers were separated, and the aqueous phase was extracted with two additional aliquots (70 mL) of toluene. The combined toluene extracts were concentrated in vacuo. The resulting oil was crystallized using toluene and heptane to give the title compound (5.1 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([OH:12])[CH2:7]2.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O1C2C(=CC=CC=2)CCC1O.C(OC(=O)C)(=O)C>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][C:8](=[O:12])[CH2:7]2
Reactant: OC1COc2c(Br)cccc2C1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: OC1CCc2ccccc2O1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C1COc2c(Br)cccc2C1
Reaction time: 0.17 h

Procedure:
The 8-bromo-3-chromanol was oxidized in small portions (400 mg, 1.7 mmol) in order to achieve better total yields. Dry pyridine (1.1 ml) was added to CH2Cl2 (60 ml), dried over P2O5 and CrO3 (0.69 g, 6.9 mmol) and molecular sieves were added to that solution. After 15 min the chromanol was added together with acetic anhydride (0.66 ml). The mixture was stirred for 10 min and then passed with suction through a column containing SiO2 (10 g), eluting with CH2Cl2. The collected eluate was evaporated and toluene was added after each evaporation (2-3 times), leaving the pure 8-bromo-3-chromanone (200 mg). GC/MS showed M+ /M+2 at m/e=226.25(89%)/228.25(82%).
Reaction SMILES: ClC([C@H:13]1[C@H:15]([C:16](Cl)=[O:17])[C:14]1([CH3:20])[CH3:19])C(Cl)(Cl)C1C=CC(Cl)=CC=1.[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH:31]=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C-:37]#[N:38].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[C:37]([CH:31]([O:32][C:16]([CH:15]1[CH2:13][C:14]1([CH3:20])[CH3:19])=[O:17])[C:30]1[CH:33]=[CH:34][C:35]([F:36])=[C:28]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:29]=1)#[N:38]
Reactant: [C-]#N
Reactant: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Cl)C(Cl)(Cl)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CC1(C)CC1C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1

Procedure:
6.36 g (0.017 mole) of trans-3-(1,2,2-trichloro-2-(4-chloro-phenyl)-ethyl)-2,2-dimethyl-cyclo-propane-1-carboxylic acid chloride and 3,67 g (0.017 mole) of 3-phenoxy-4-fluoro-benzaldehyde were together added dropwise to a mixture of 1.13 g of sodium cyanide, 1.7 ml of water, 100 ml of n-hexane and 0.6 g of tetrabutylammonium bromide at 20°-25° C., whilst stirring, and the mixture was then stirred at 20°-25° C. for 4 hours. 300 ml of toluene were subsequently added to the reaction mixture, and the mixture was extracted twice by shaking with 300 ml of water each time. The organic phase was separated off and dried over magnesium sulphate, and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.5 g (86% of theory) of trans-3-(1,2,2-trichloro-2-(4-chloro-phenyl)-ethyl)-ethyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid α-cyano-3-phenoxy-4-fluorobenzyl ester were obtained as a viscous oil. ##STR35##
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[N:18][C:19](=[O:30])[N:20]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH:21]=4)[S:15][C:8]=23)=[C:4]([F:33])[CH:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:48])[CH2:44][C:45](O)=[O:46].C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.C(Cl)CCl>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:43]([NH:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[O:48])[CH:32]=[CH:31][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19](=[O:30])[N:20]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:21]=3)[S:15][C:8]=12
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
To a solution of the amine 416 (0.16 mmol) in DMF (1 mL) was added acid 27 (38 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol) and EDC×HCl (46 mg, 0.24 mmol). The mixture was stirred at room temperature for 16 h. The solvent was evaporated, then the residue was purified by flash chromatography with gradient of methanol (0-5%) in dichloromethane, followed by preparative HPLC purification with gradient of methanol (20-100%) in water to give title compound 412 (14 mg, 13% yield). MS (m/z): 659.1 (M+H). 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.64 (s, 1H), 9.16 (d, J=3.3 Hz, 1H), 8.69 (d, J=3.3 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.98 (s, 1H), 7.88 (dd, J=13, 2.3 Hz, 1H), 7.51 (t, J=9.0 Hz, 1H), 7.43 (dd, J=8.8, 1.6 Hz, 1H), 7.11-7.05 (m, 2H), 6.94-6.90 (m, 1H), 6.67 (d, J=4.7 Hz, 1H), 4.05 (t, J=6.5 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 3.55-3.50 (m, 4H), 2.63 (t, J=5.5 Hz, 2H), 2.46-2.42 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[OH2:19]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([C:3]12[CH2:4][C:5]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:11][CH:9]([CH2:8][C:7]([OH:19])([CH2:6]3)[CH2:12]1)[CH2:10]2)[CH3:2]
Reactant: CCC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC12CC3CC(O)(C1)CC(c1ccccc1)(C3)C2
Temperature: 4 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a solution of 0.03 mol of chromiumtrioxide, in 20 ml glacial acetic acid and 20 ml acetic anhydride, add 0.0095 mol of 1-ethyl-3-phenyl adamantane (II) at 0° C. and stir for 24 hours at 4° C. Pour the reaction mixture into water and extract with three portions of pentane. Wash the organic phase with saturated sodium chloride solution, dry over magnesium sulfate, filter and evaporate to dryness under vacuum. Hydrolize the residue with 20 ml of 2N NaOH and 50 ml of methanol. Remove the methanol under vacuum and dilute the residue with water. Then extract with three portions of ether. Dry the organic phase, filter and evaporate to dryness under vacuum. Recrystallize the residue from cyclohexane. (Yield: 50%).
Reaction SMILES: C([O:4][C@H:5]1[C@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@H:15]([CH3:26])[O:14][C@@H:6]1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+]>CO>[S:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@H:6]1[O:14][C@@H:15]([CH3:26])[C@@H:16]([OH:22])[C@@H:17]([OH:18])[C@@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](Sc2ccccc2)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
Compound of example 8 (224 g) is dissolved in methanol (500 ml) and NaOMe (2 g, 37 mmol) is added. The reaction mixture is stirred at 40° C. for 21/2 h. Methanol (250 ml) is distilled off and CO2 is bubbled through the remaining solution for 5 min reaching pH=7. The reaction mixture is evaporated and isobutyl acetate (450 ml) is added. 50 ml of solvent is evaporated and the resulting mixture is subjected to crystallization by letting it at room temperature for 24 h. The white crystalline solid formed is filtered and washed with tert-butyl methyl ether (200 ml) giving 110 g (73%) of product after drying.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([C:15]1[C:16](=[O:26])[O:17][C:18]([OH:25])=[C:19]([C:22](=O)[CH3:23])[C:20]=1[OH:21])(=[O:14])[CH3:13]>CO>[C:12]([C:15]1[C:16](=[O:26])[O:17][C:18](=[O:25])[C:19](=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH3:23])[C:20]=1[OH:21])(=[O:14])[CH3:13]
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)c([N+](=O)[O-])c2)C(=O)OC1=O

Procedure:
Following the procedure of Example 1, 3 g. (0.0195 mol) of 4-amino-2-nitrophenol is added to a refluxing solution of 4.1 g. (0.0195 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol and the mixture is refluxed for about two hours. Filtration of the reaction mixture yields 5-acetyl-4-hydroxy-3-[1-(3-nitro-4-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 236°-237° C. (dec.).