Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7](O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CN(C=O)C.S(Cl)([Cl:18])=O.O>C1(C)C=CC=CC=1>[Cl:18][CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: CCCC1CCC(O)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1CCC(Cl)CC1

Procedure:
100.0 g (0.70 mol) of 4-propylcyclohexanol are initially introduced in 1200 ml of toluene together with 2.7 ml of DMF, and the mixture is heated to reflux. 255 ml (3.52 mol) of thionyl chloride are carefully metered in, and the batch is heated for a further 4 h. After cooling, the mixture is added to water, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane), giving 1-chloro-4-propylcyclohexane as a colourless liquid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1)[CH3:2].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>>[CH2:12]([O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCc1cc(C)cc(O)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCOc1cc(C)cc(CC)c1

Procedure:
Quantities: 3-ethyl-5-methylphenol (5.0 g, 0.036 mol), 1-bromodecane (11.05 g, 0.05 mol), K2CO3 (30.0 g, 0.2 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:30]1[C:31]([C:35]#[N:36])=[N:32][NH:33][CH:34]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:15]=[CH:16][C:17]([C:30]4[C:31]([C:35]#[N:36])=[N:32][NH:33][CH:34]=4)=[CH:18][CH:19]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(C3(c4ccc(Cl)cc4)CCNCC3)cc2)OC1(C)C
Reactant: N#Cc1n[nH]cc1Br
Product: N#Cc1n[nH]cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1

Procedure:
Following the procedure of Example 1 but using 4-(4-Chloro-phenyl)-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidine instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-1H-pyrazole-3-carbonitrile instead of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride gave the title compound. LC/MS: (PS-A2) Rt 2.22 [M+H]+ 363. 1H NMR (Me-d3-OD) δ 2.52-2.70 (4H, m), 3.10-3.20 (4H, m), 7.25 (4H, s), 7.37 (2H, d), 7.58 (2H, d), 8.02 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[OH:34])[C:5]([NH:7][NH:8][S:9]([NH:12][C:13]([N:15]1[CH2:18][C@H:17]([NH:19]C(=O)OCC2C=CC=CC=2)[C:16]1=[O:30])=[O:14])(=[O:11])=[O:10])=[O:6].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].C1(SC)C=CC=CC=1>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:19][C@H:17]1[CH2:18][N:15]([C:13]([NH:12][S:9]([NH:8][NH:7][C:5](=[O:6])[C:4]2[CH:31]=[CH:32][C:33]([OH:34])=[C:2]([OH:1])[CH:3]=2)(=[O:10])=[O:11])=[O:14])[C:16]1=[O:30]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2ccc(O)c(O)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-[1-[[[[2-(3,4-Dihydroxybenzoyl)hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (0.8 g) was added to a mixture of 3 ml of trifluoroacetic acid and 0.75 ml of thioanisole and the mixture was stirred overnight at room temperature. The trifluoroacetic acid was removed in vacuo and the residue triturated with ether to yield 0.5 g of (S)-3-amino-N-[[2-(3,4-dihydroxybenzoyl)hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate salt.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C)[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[Cl-:18].C[Al+]C.[C:22]([Si:26]([CH2:39][O:40][C:41](=[O:49])[CH2:42][C@@H:43]([CH3:48])[CH2:44][C:45](Cl)=[O:46])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([Si:26]([CH2:39][O:40][C:41](=[O:49])[CH2:42][C@@H:43]([CH3:48])[CH2:44][C:45]([N:7]1[C:8]2[C:4](=[CH:3][CH:2]=[C:10]([Cl:18])[CH:9]=2)[CH:5]=[C:6]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:46])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: CCCCCCc1cc2cc(Cl)ccc2n1C
Reactant: [Cl-]
Reactant: C[C@@H](CC(=O)Cl)CC(=O)OC[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al+]C
Solvent: ClCCl
Product: CCCCCCc1cc2ccc(Cl)cc2n1C(=O)C[C@H](C)CC(=O)OC[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h

Procedure:
To the solution of 5-chloro-2-hexyl-1-methyl-1H-indole in methylene chloride was added dimethyl aluminum chloride at 0 0 C and was stirred for 60 minutes. Then to this mixture, 4-chlorocarbonyl-3-(R)-methyl-butyric acid (tert-butyl-diphenyl-silanyl)-methyl ester was added and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:5][Mg]Cl.[Mg].CC1C=C(C=C(C)C=1)CCl.[CH2:23]([C:25]([CH3:27])=[O:26])[CH3:24]>C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:5][C:25]([OH:26])([CH2:23][CH3:24])[CH3:27]
Reactant: Cc1cc(C)cc(C[Mg]Cl)c1
Reactant: CCC(C)=O
Agent: Cc1cc(C)cc(CCl)c1
Agent: [Mg]
Solvent: CCOCC
Product: CCC(C)(O)Cc1cc(C)cc(C)c1
Reaction time: 2 h

Procedure:
3,5-dimethylbenzylmagnesium chloride was manufactured from 2.6 g of magnesium powder and 15.5 g of 3,5-dimethylbenzyl chloride dissolved in 200 ml of diethyl ether and reacted with 7.5 g of methyl ethyl ketone in a temperature range of from 20° C. to 25° C. After 2 hours, the whole was poured onto ice and acidified, and the organic phase was separated off and extracted by shaking with water and sodium bicarbonate solution. After drying the organic phase with solid potassium carbonate, fractional distillation was carried out. 13 g of end product were obtained in a temperature range of from 63° C. to 65° C. at 0.12 mbar.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34]N)[CH:29]=1>>[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=1
Reactant: COC(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: COC(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 3-hydrazino-benzoic acid methyl ester according to example 43 gave the desired product. MS: M=451.0 (M+H)+
Reaction SMILES: I(O)(=O)(=O)=O.[C:6]([O:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[O:28]C1CCCCCCCC)(=[O:8])[CH3:7]>O.O1CCOCC1>[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[O:28])(=[O:8])[CH3:7]
Reactant: CCCCCCCCC1OC1CCCCCCC=COC(C)=O
Agent: [O-][I+3]([O-])([O-])O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCCCCCCCCC=O
Temperature: 25 °C

Procedure:
To a solution of 31 g (0.11 moles) of crystallic periodic acid (HIO4, 2H2O) in 50 ml of water a solution of 25 g (0.076 moles) of 9.10-epoxy-octadecen-1-ol acetate in 220 ml of dioxane is added in 10 minutes. The reaction mixture is stirred at room temperature for a night, then poured onto water. The aqueous suspension is extracted twice with a total amount of 500 ml of petroleum ether, washed with water, dried with magnesium sulfate, the solvent is distilled off, and the residue is distilled in vacuo, under argon. The nonanal forming as a side-product is the first to distille over (b.p.: 80°-85° C., 9.75 g, 90%). The 9-acetoxy-nonanal distils over at 160°-162° C.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[O:4].Cl.[NH:7]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:8]([C:16](O)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>O.CN(C=O)C>[NH:7]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:8]([C:16]([NH:1][NH:2][C:3]([NH2:5])=[O:4])=[O:17])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NNC(N)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
In 5 ml of water is dissolved 2.50 g (22 mM) of NH2NHCONH2.HCl, the solution is neutralized with 3.14 ml of TEA, and 40 ml of DMF is added. To this solution are added 3.0 g of Z-Phe-OH, 2.0 g of HONB and 2.3 g of DCC. The mixture is stirred for 24 hours, the precipitated DCU filtered off, the solvent distilled off and the residue dissolved in 200 ml of ethyl acetate. The solution is washed with aqueous sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is then distilled off, the residue is treated with ether, and crystals are collected by filtration. Yield 2.7 g; m.p. 119°-121° C., [α]D21.5 -14.4° (c=1.01, DMF), Rf1 0.29.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl[CH2:16][C:17]1[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1>>[S:20]1[CH:21]=[C:17]([CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]1=2
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: ClCc1csc2ccccc12
Product: O=C(O)c1cc2ccccc2n1Cc1csc2ccccc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-chloromethyl-benzo[b]thiophene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 306.4 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.ClCC(OC(=O)CCl)=O.[CH2:19]([N:21](CC)CC)[CH3:20].O>C1C=CC=CC=1>[NH2:21][CH2:19][CH2:20][NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CCN(CC)CC
Agent: O=C(CCl)OC(=O)CCl
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C)nc(NCCN)c1
Reaction time: 3 h

Procedure:
2-amino-4,6-dimethylpyridine(1.69 g), chloroacetic anhydride(3.54 g), and triethylamine(3.83 ml) were stirred in benzene(30 ml) for 1 hour while being cooled with ice. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. To the solution of the residue in dimethylformamide(23 ml) was added potassium phthalimide(2.82 g) and then the mixture was refluxed with stirring for 3 hours. After a large amount of water was added thereto, the depositing crystals were collected by filtration. The solution of the crystals in ethanol(50 ml), with hydrazine monohydrate(1.34 ml) added thereto, was refluxed with stirring for 3 hours and then concentrated under a vacuum. The residue, with water added thereto, was acidified with sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then was concentrated under a vacuum. The solution of the residue in tetrahydrofuran(45ml) was dropped into the suspension of lithium aluminium hydride(0.64 g) in tetrahydrofuran(45 ml) while being cooled with ice and the mixture was stirred at room temperature for 1 hour. A small amount of water was added thereto and then the resulting deposit was filtrated out. The filtrate was concentrated under a vacuum, thereby yielding 1.90 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:16](=[O:17])[NH:15][C:14]([CH3:18])=[N:13]2)=[C:4]([F:19])[CH:3]=1.Br[CH2:21][CH2:22][CH2:23][F:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:16](=[O:17])[N:15]([CH2:21][CH2:22][CH2:23][F:24])[C:14]([CH3:18])=[N:13]2)=[C:4]([F:19])[CH:3]=1
Reactant: FCCCBr
Reactant: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc(OC(C)C)c(Cl)cc2F)c(=O)n1CCCF
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A stirred solution of 1.8 g (0.006 mole) of 1-[4-chloro-2-fluoro-5-(1-methylethoxy)phenyl]-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 1.8 g (0.013 mole) of 1-bromo-3-fluoropropane and 0.30 g (0.010 mole) of potassium carbonate in dimethylformamide was heated at 55°-65° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into ice-water. The mixture was extracted with diethyl ether and the extract dried with magnesium sulfate. The extract was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel using 9:1 methylene chloride:heptane as eluant. The appropriate fractions were combined and concentrated under reduced pressure to give 1.0 g of 1-[4-chloro-2-fluoro-5-(1-methylethoxy)phenyl]-4-(3-fluoropropyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as an oil.
Reaction SMILES: [N:1]1([C:9](OC(C)(C)C)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[NH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22](N)=O)[CH2:17]1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[CH3:22][CH:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:9]([NH2:1])=[O:10])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: NC(=O)C1CCCNC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCN(C(N)=O)C1
Product: O=C(O)[C@H]1CCCN1
Yield: 65 %

Procedure:
Under N2 atmosphere, the Boc-DPro-3-piperidinamide was dissolved in ml of CH2Cl2 and 10 ml of trifluoracetic acid added while stirring. The reaction mixture was stirred for 30 min. All volatiles were removed under vacuum and the residue dissolved in 30 ml of CH2Cl2 and washed with 10 ml saturated NaHCO3 aqueous solution. The organic layer was removed and the aqueous layer extracted with CH2Cl2 (3×10 ml). The organic layer was dried over anhydrous sodium sulfate and filtered and the solvent was removed by vacuum. The residue was further purified by column chromatography (SiO2, CHCl3/MeOH, 85:15) to afford 0.65 mmol (65%) of compound (1) which was characterized by TLC and mass spectra, M+=196.3.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[N:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][N:21]=1.C(Cl)CCl.[Br:31][C:32]1[C:33]([CH2:49][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:36]([CH:40]=1)[C:37](O)=[O:38]>CN(C)C=O>[Br:31][C:32]1[C:33]([CH2:49][N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[C:36]([CH:40]=1)[C:37]([NH:26][C:23]1[CH:24]=[CH:25][N:20]=[N:21][CH:22]=1)=[O:38]
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Nc1ccnnc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccnnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
Diisopropylethylamine (0.08 ml, 0.47 mmol), HOBT (43.0 mg, 0.28 mmol), 4-pyridazinamine (33.4 mg, 0.35 mmol) and EDC (90 mg, 0.47 mmol) were added to a solution of 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 7; 95 mg, 0.23 mmol) in N,N-dimethylformamide (5 ml). The mixture was stirred overnight, the solvent removed in vacuo and the solid recrystallised with 1:1 methanol/DMSO to give the title compound as a white solid. 56.1 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH:20]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:21][C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH:20]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CCCCCCCCCCCC(CC(=O)OCc1ccccc1)OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)CCCCCCCCCCCC(CC(=O)O)OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of benzyl 3-(N-tertiarybutoxycarbonyl-L-phenylalanyl)oxy-15-methylhexadecanoate (2.85 g) in methanol (50 ml) was added 10% palladium on active carbon (0.5 g) and water (5 ml). The mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was filtered off and the solvent was removed under reduced pressure to give 3-(N-tertiarybutoxycarbonyl-L-phenylalanyl)oxy-15-methylhexadecanoic acid as an oil (2.31 g).
Reaction SMILES: C(OC([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][O:8]1)C)C.B.[Na]>C(O)C.[Ni](Cl)Cl>[OH:6][CH:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[CH:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:9][O:8]1
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC[C@H](C)[C@@H]12
Agent: Cl[Ni]Cl
Agent: B
Agent: [Na]
Solvent: CCO
Product: COC(=O)C1COC(O)[C@H]2[C@@H]1CC[C@@H]2C
Temperature: 80 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
Methyl (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-7-methyl-1, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[c]pyran-4-carboxylate (1.0 g, 0.0035 mol) obtained in Example 4 was dissolved in 20 ml of ethanol suspending nickel chloride (1.14 g), and 10 ml of an ethanol solution of sodium boron hydride (830 mg, 0.021 mol) was added. Thereafter, the reaction solution was stirred at 80° C. for 3 hours under heat-reflux. The reaction mixture solution was filtered by a celite, and was once concentrated under a reduced pressure. The residual matter was dissolved in 100 ml of ethyl acetate, washed with water (50 ml×3) and dried by the addition of magnesium sulfate. The residual matter was further filtered, and the solvent was distilled off under a reduced pressure. The residual matter was dissolved in 30 ml of tetrahydrofuran without purification and was stirred at room temperature for 2 hours after the addition of 10 ml of 2N hydrochloric acid solution. After the reaction solution was neutralized by adding 50 ml of saturated sodium bicarbonate solution, it was extracted by ethyl acetate (50 ml×3). After the organic layer was joined, it was dried by the addition of magnesium sulfate, filtered, and then concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=7:3 eluent was distilled off. A colorless oily substance was thus obtained, i.e., methyl (4aS, 7S, 7aR)-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1-hydroxy-7-methylcyclopenta[c]pyran-4-carboxylate (480 mg, yield=63.7%). This methyl (4aS, 7S, 7aR)-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-1-hydroxy-7-methylcyclopenta[c]pyran-4-carboxylate had the following physicochemical properties:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:21])[C:11]([Cl:20])=[C:12]([O:16][CH2:17][C:18]#[N:19])[CH:13]=2)[C:8]1=[O:22])(=[O:3])[CH3:2].N12CCCC1=CCCN2.[CH:32]([C:34]([CH3:36])=[O:35])=[CH2:33].C(OCC)(=O)C>O1CCCC1.N12CCCC1=CCCN2.C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1([CH2:33][CH2:32][C:34](=[O:35])[CH3:36])[CH2:15][C:14]2[C:9](=[C:10]([Cl:21])[C:11]([Cl:20])=[C:12]([O:16][CH2:17][C:18]#[N:19])[CH:13]=2)[C:8]1=[O:22])(=[O:3])[CH3:2]
Reactant: C=CC(C)=O
Reactant: CC(=O)OCCC1Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Agent: C1=C2CCCN2NCC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)CCC1(CCOC(C)=O)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
{[2-(2-Acetoxyethyl)-6,7-dichloro-2,3-dihydro-1-oxo-1H-inden-5-yl]oxy}acetonitrile (3.42 g, 10 mMole) is dissolved in tetrahydrofuran (30 ml), warmed to 40° C. and diazabicyclo[4.3.0]non-5-ene (50 microliters) added. Then methyl vinyl ketone (1.2 g, 17 mMole) is added and the mixture stirred at 50°-52° C. for two hours. More methyl vinyl ketone (600 mg) and diazabicyclo[4.3.0]non-5-ene (2 drops) are added and stirring and heating continued for another 2 hours. The solution is cooled, treated with ethyl acetate (50 ml) and poured into ice water (250 ml) containing acetic acid (1 ml). The organic layer is separated and the aqueous layer extracted first with methylene chloride and then with ether. The combined organic layers were dried over MgSO4 and the solvent removed by evaporation in vacuo to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([C:11]([F:13])([F:14])[F:12])=[CH:6][C:5]=1[NH:15][C:17](=[O:19])[CH3:18]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (42.0 g, 122 mmol) in toluene (400 mL) was treated with acetic anhydride (12.8 mL, 135 mmol) and the mixture was heated to reflux for 16 h under nitrogen. It was then allowed to cool to r.t. and diluted with water. The mixture was rendered neutral by adding small portions of sodium hydrogencarbonate, and the organic layer was separated. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized in hexanes to give 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (43.4 g, 112 mmol, 92%) as a white powder, m.p. 96-98° C., ESI-MS: m/z 388 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:17]2[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=2)[C:20]#[N:21])[C:6]2[N:7]=[C:8]([O:13]C)[N:9]=[C:10]([O:11]C)[C:5]=2[C:4]([CH3:16])([CH3:15])[O:3]1>C(Br)(=O)C>[OH:1][C:2]1([C:17]2[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=2)[C:20]#[N:21])[C:6]2[NH:7][C:8](=[O:13])[NH:9][C:10](=[O:11])[C:5]=2[C:4]([CH3:15])([CH3:16])[O:3]1
Reactant: COc1nc(OC)c2c(n1)C(O)(c1cc(C)cc(C#N)c1)OC2(C)C
Agent: CC(=O)Br
Product: Cc1cc(C#N)cc(C2(O)OC(C)(C)c3c2[nH]c(=O)[nH]c3=O)c1
Yield: 25.1 %

Procedure:
A solution of 3-(7-Hydroxy-2,4-dimethoxy-5,5-dimethyl-5,7-dihydro-furo[3,4-d]pyrimidin-7-yl)-5-methyl-benzonitrile (0.027 g, 0.080 mmol) in acetyl bromide (2.0 mL) was heated at 60° C. for 3 h. Reaction mixture was concentrated and purified by reverse phase HPLC (Phenomenex Synergi® column, 5 to 100% acetonitrile/H2O) to give a desired product (0.0063 g, 25%). 1H NMR (300 MHz, CD3OD): δ 7.76 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 2.38 (s, 1H), 1.60 (s, 3H), 1.59 (s, 3H). Mass spectrum: 314.0 (M+H)+.