Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:3]=1.[H-].[Na+].[CH2:13]([N:23]=[C:24]=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>CN(C)C=O>[CH2:13]([NH:23][C:24]([NH:10][S:7]([C:4]1[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=1)(=[O:9])=[O:8])=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH:10][S:7]([C:4]1[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=1)(=[O:9])=[O:8])=[O:22]
Reactant: Cc1cc(S(N)(=O)=O)cs1
Reactant: O=C=NCCCCCCCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)NC(=O)NCCCCCCCNC(=O)NS(=O)(=O)c2csc(C)c2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of 0.35 g 5-methyl-thiophene-3-sulfonic acid amide (example 46a) in 10 ml dimethylformamide was added 0.080 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 30 min. To the resulting solution was added dropwise 0.180 g heptamethylene diisocyanate (CAS18020-78-5) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was washed with ethyl acetate and purified by chromatography on 100 ml MCl gel with a gradient (water 0-50% acetonitrile) The product fractions were collected and the product was precipitated by adjusting the pH to 2.00 by addition of 1N hydrochloric acid. The solid was collected by filtration and washed with water and dried to constant weight to yield 0.24 g of the title compound as white powder. MS (ISN) M−H+=536.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(F)cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
4-chloro-3-fluorophenol (2.38 g, 16.2 mmol) was dissolved in DCE (32 mL) and tetrabutylammonium bromide (0.524 g, 1.62 mmol) was added. HNO3 70% (2.1 mL, 32 mmol) was diluted with H2O (18.9 mL) to make a 7% HNO3 solution. This solution was added to the reaction mixture which was then stirred at rt for 4 h at which time the reaction was judged complete by TLC. The reaction was poured into H2O and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step A (2.29 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (br. s., 1H), 8.18 (d, J=8.1 Hz, 1H), 7.10 (d, J=10.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[N-:16]=[N+:17]=[N-:18].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CCO.O.[Cu]I>[N:16]([C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc2[nH]c3ccc(Br)cc3c2c1
Temperature: 95 °C

Procedure:
3,6-Dibromocarbazole (0.500 g, 1.538 mmol), NaN3 (0.120 g, 1.846 mmol), CuI (0.029 g, 0.154 mmol), L-proline (0.053 g, 0.461 mmol) and NaOH (0.019 g, 0.461 mmol) were dissolved in 7:3 EtOH/H2O (3.0 mL) and heated to 95° C. under a N2 atmosphere for 24 h. The completed reaction was partitioned between EtOAc/H2O (3×) and the combined organics were washed with satd. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by chromatography (SiO2, 0-15% EtOAc/toluene), followed by HPLC (Phenomenex SiO2 Luna 10μ, 250×21.2 mm column, 50% EtOAc/Hexane, 21 mL/min, retention time=48 min) to afford the desired product.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CC#N>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:6]([N:8]([CH2:14][C:15]([F:17])([F:18])[F:16])[CH2:9][C:10]([F:11])([F:12])[F:13])=[O:7])([O-:23])=[O:22]
Reactant: NCc1ccncc1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CC#N
Product: O=C(c1ccc(NCc2ccncc2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
4-Fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (120 mg, 0.345 mmol) and 4-(aminomethyl)pyridine (0.070 mL, 0.380 mmoL) were stirred in 3 mL of CH3CN. The solvent was concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO3, brine and dried over anhydrous Na2SO4. The product was purified by flash chromatography on silica gel using EtOAc as eluent affording the title compound as yellow oil. Yield: 145 mg (79%); 1H NMR (CDCl3) 4.19 (q, J=8.59 Hz, 4H), 4.71 (d, J=6.25 Hz, 2H), 6.69 (d, J=8.79 Hz, 1H), 7.45 (m, 3H), 8.32 (s, 1H), 8.65 (d, J=6.25 Hz, 2H), 8.73 (m, 1H); MS (ESI) 437.24 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[CH2:16](I)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(OCC)C>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COc1cccc(OC)c1
Reactant: CCCCCCCI
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCc1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
1,3-dimethoxybenzene (0.25 mol, 34 ml) was dissolved in THF (1 liter, dried) and the resultant solution was cooled in an ice bath. n-Butyl lithium (200 ml, 0.32 moles) was added over a period of one hour. The resultant solution was stirred for 2 hours in an ice bath. Solution was then cooled to -78° C. and n-heptyl iodide (226 ml, 0.22 moles) was quickly added. The solution was then allowed to warm to room temperature and stirred overnight then refluxed for 2 hours. The solution was cooled and a mixture of diethyl ether and water was added. The ether layer was collected, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed by HPLC (eluted with hexane) to yield 34.0 g of the title product.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.C(N(CC)C(C)C)(C)C.[C:40]([O:44][C:45](=[O:52])[NH:46][CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)([CH3:43])([CH3:42])[CH3:41].FC(F)(F)C(O)=O>CN1CCCC1=O.O>[C:40]([O:44][C:45](=[O:52])[NH:46][CH:47]1[CH2:51][CH2:50][N:49]([C:16]2[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=[C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])[N:6]=3)[N:15]=2)[CH2:48]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)C1
Temperature: 150 °C
Yield: 57.4 %

Procedure:
150 mg (0.21 mmol, purity approx. 71%) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was dissolved, in a reaction vessel suitable for a microwave, in 1-methyl-2-pyrrolidone (3.1 ml), and 0.22 ml (1.24 mmol) of N,N-diisopropyl ethylamine and 154 mg (0.83 mmol) of tert.-butyl-pyrrolidin-3-ylcarbamate were added. Then the reaction vessel was sealed with a septum and was heated for 6 h at 150° C. in the microwave. After cooling, water was added to the reaction mixture, and trifluoroacetic acid extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated by evaporation. The residue was purified by preparative HPLC (acetonitrile:water (+0.1% trifluoroacetic acid) gradient). 69 mg of the title compound was obtained (59% of theor.).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[O:9][C:10](=[O:25])[C:11]([NH:14]C(OCC1C=CC=CC=1)=O)([CH3:13])[CH3:12]>CO.[Pd]>[CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][C:4]([CH3:7])([CH3:8])[CH:3]1[O:9][C:10](=[O:25])[C:11]([NH2:14])([CH3:13])[CH3:12]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)OC1C(C)(C)CCC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)C(=O)OC1C(C)(C)CCC1(C)C

Procedure:
N-Cbz-2-aminoisobutyric acid 2,2,5,5-tetramethylcyclopentyl ester is dissolved in CH3OH and hydrogenated over 10% Pd/C in a Paar hydrogenation apparatus. When the reaction is complete the mixture is filtered through Celite and concentrated to yield 2-aminoisobutyric acid 2,2,5,5-tetramethylcyclopentyl ester (600 mg).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.Cl>CCO>[CH:17]1([NH:16][C:9]2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=[C:11]([S:14][CH3:15])[N:10]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cnc(SC)nc1NC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(NC2CCCC2)n1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
NaOH (1 M aq, 31 mL) was added to a suspension of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (11.7 g, 41.6 mmol) in EtOH (14 mL) and the resulting mixture was heated at reflux for 1.5 h. The reaction mixture was cooled to RT and HCl (1 M aq) was added until pH 4 was reached. The white solid, which crashed out of solution, was collected by filtration, washed with water and heptane and then dried under reduced pressure to afford 10.241 g (97% yield) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid.
Reaction SMILES: C(OC1C(C(O)=O)=NC=CC=1OC)C1C=CC=CC=1.C([O:27][C:28]1[C:29]([C:36]([OH:38])=O)=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)C1C=CC=CC=1.COC1C=CC(O[C:46]2[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=2)=CC=1.C1(N)CCCCC1>>[OH:27][C:28]1[C:29]([C:36]([NH:50][CH:49]2[CH2:51][CH2:52][CH2:46][CH2:47][CH2:48]2)=[O:38])=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Reactant: COc1ccc(OCc2ccccc2)c(C(=O)O)n1
Agent: COc1ccnc(C(=O)O)c1OCc1ccccc1
Solvent: NC1CCCCC1
Product: COc1ccc(O)c(C(=O)NC2CCCCC2)n1

Procedure:
The procedure of Example 29 was repeated, except that 3-benzyloxy-4-methoxypicolinic acid was changed to 3-benzyloxy-6-methoxypicolinic acid and 4-(4′-methoxyphenoxy)aniline was changed to cyclohexylamine. Thus, the title compound was prepared.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])(OC(C)(C)C)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1-c1ccncc1NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNc1cnccc1-c1ccccc1C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
N-Boc-4-o-tolyl-pyridin-3-ylamine (45 mg, 0.158 mmol) in THF (0.5 mL) under argon was treated with LAH in THF (1.0M, 0.20 mL, 0.2 mmol). The reaction mixture was then heated to reflux for 6 hours. After cooling, Na2SO4×10H2O was carefully added and the reaction mixture was stirred for 1 h after which a colorless solid formed. The solid was removed by filtration and all volatiles were evaporated to yield the desired compound as a solid (29 mg, 93%).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:17]=1[NH2:18]>>[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:17]=1[NH:18][C:12](=[O:13])[CH2:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1cc(C)c(N)cc1C
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1cc(C)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)cc1C
Yield: 14.3 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.2 g) and 2,4,5-trimethylaniline (0.13 g) to give the title compound as a white solid (0.042 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl)(=[O:11])[CH3:10].[OH-].[Na+]>C(O)C>[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCCCCCl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)OCCCCSc1ccc(Cl)cc1

Procedure:
A mixture of 144.6 g of p-chlorothiophenol, 150.6 g of 4-chlorobutyl acetate, 80 g of 50% aqueous solution of sodium hydroxide and 750 ml of ethyl alcohol was heated under reflux for 5 hours. The alcohol was distilled off and ether was added to the cool mixture. After washing with dilute sodium hydroxide solution and then water, the ether solution was dried, evaporated to dryness and distilled. The product was collected at 110°-116° and 0.01 mm, ND25 1.5480.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][CH3:12].N1C=CC=CC=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([NH:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][CH3:12])(=[O:31])=[O:30]
Reactant: CCOC(=O)c1cc(N)c2[nH]cc(CC)c2c1
Reactant: O=S(=O)(Cl)CCCCCl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(NS(=O)(=O)CCCCCl)c2[nH]cc(CC)c2c1
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of ethyl 7-amino-3-ethyl-1H-indole-5-carboxylate (D222) (150 mg, 0.65 mmol, 1 equiv) in CH2Cl2 (10 ml) at room temperature were added pyridine (115 μl, 1.42 mmol, 2.2 equiv), 4-chloro-1-butanesulfonyl chloride (D20) (259 mg, 1.36 mmol, 2.1 equiv) and DMAP (8 mg, 0.065 mmol, 0.1 equiv) and the resulting mixture was stirred for 1 h then diluted with AcOEt and washed with a 2N aqueous HCl solution and brine, then dried over MgSO4 and concentrated in vacuo to give ethyl 7-{[(4-chlorobutyl)sulfonyl]amino}-3-ethyl-1H-indole-5-carboxylate (D242) (230 mg, 92%) as a purple oil which was used in the next step without further purification. [M+H]+=387.3, RT=3.35 min.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#N)=[CH:7][CH:6]=1.[Br:14][C:15]1[CH:20]=C[C:18]([N+:21]([O-])=[O:22])=[CH:17][CH:16]=1.O>CO.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:22][N:21]=[C:18]3[CH:17]=[CH:16][C:15]([Br:14])=[CH:20][C:12]=23)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: COc1ccc(CC#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2onc3ccc(Br)cc23)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 148 g of potassium hydroxide in 300 ml of anhydrous methanol at 0° C. was added 21.3 g (0.145 mole) of 4-methoxy phenylacetonitrile. The mixture was stirred at 0° C. for 10 min. and then a solution of 25.4 g (0.126 mol) of p-bromo nitrobenzene in 300 ml of tetrahydrofuran and methanol (1:2) was slowly added over a period of 1 h. The deep purple mixture was continuously stirred and maintained at 0°-5° C. during addition. The temperature was then raised to 55° C. using a hot water bath and reaction mixture was stirred for another 3 h. On cooling, the reaction mixture was poured into 1500 ml of water, and the brown precipitate was separated by suction filtration. The product was washed twice with water followed by cold methanol. The yellow solid so obtained was recrystallized twice from methanol to give needle like light yellow crystals. Yield 19.5 g (51%). mp 137.1° C. Anal. calcd. for C14H10NO2Br: c, 55.29; H, 3.31; N, 4.61. Found: C, 54.99; H, 3.14; N, 4.62.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH3:14])=[C:8]2[C:4]=1[CH2:5][C:6]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]2=[O:15].Br.O>C(O)(=O)C>[CH3:22][C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]2[C:8](=[C:9]([CH3:14])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[OH:2])[C:7]1=[O:15]
Reactant: COc1cc(C)c2c(c1OC)CC(C)(c1ccccc1)C2=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c2c(c1O)CC(C)(c1ccccc1)C2=O

Procedure:
141.7 g (0.478 mole) of the 2,3-dihydro-4,5-dimethoxy-2,7-dimethyl-2-phenyl-1H-inden-1-one obtained according to Example 2(d) are boiled under slight reflux for 45 minutes with a mixture of 275 ml of aqueous 48% strength hydrobromic acid, 475 ml of glacial acetic acid and 72 ml of 33% strength hydrogen bromide in glacial acetic acid and then the reaction mixture is poured into 3000 ml of a mixture of ice and water. The product so obtained is extracted twice with ether and the ethereal phases are washed once with water, once with dilute sodium bicarbonate solution, and twice with water again. The ethereal phases are dried over sodium sulphate, filtered, and concentrated to dryness by evaporation in vacuo in a rotary evaporator. The crude residue of 135 g of brown crystals is dissolved warm in 250 ml of ethyl acetate and filtered. Subsequently, 500 ml of petroleum ether having a boiling range of 40°-60° are added. On leaving to stand, the product crystallises out and can be filtered and dried. In this manner 2,3-dihydro-2,7-dimethyl-4-hydroxy-5-methoxy-2-phenyl-1H-inden-1-one having a melting point of 136°-139° is obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[C:27](O)[CH:26]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].IC.O.CN(C)[CH:54]=[O:55]>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[C:27]([O:55][CH3:54])[CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cc(O)cc3occ(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccccc3)coc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6-hydroxy-3-(2-phenylethyl)benzofuran (25 mg) and potassium carbonate (18 mg) in N,N-dimethylformamide (1 mL) was added iodomethane (0.007 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.008 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (8 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8](/[CH:25]=[CH:26]/[C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:12]([OH:23])[CH2:11][C@H:10]1[CH3:24].[C:34](=O)(O)[O-].[Na+].CI.O>CC(N(C)C)=O>[CH3:34][O:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17]/[CH:16]=[CH:15]\[CH2:14][C@@H:13]1[C@@H:9]([C@@H:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)/[CH:25]=[CH:26]/[C:27]([CH3:32])([CH3:33])[CH2:28][CH2:29][CH2:30][CH3:31])[C@H:10]([CH3:24])[CH2:11][CH:12]1[OH:23]
Reactant: CCCCC(C)(C)/C=C/[C@H](OC1CCCCO1)[C@H]1[C@H](C)CC(O)[C@@H]1C/C=C\CCCC(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CI
Solvent: O
Product: CCCCC(C)(C)/C=C/[C@H](OC1CCCCO1)[C@H]1[C@H](C)CC(O)[C@@H]1C/C=C\CCCC(=O)OC
Temperature: 25 °C
Reaction time: 25 h

Procedure:
The crude optically active (5Z,11alpha,13S,14E)-13-(2-tetrahydropyranyloxy)-11,16,16-trimethyl-9-hydroxyprosta-5,14-dien-1-oic acid (11.7 g) in dimethylacetamide (60 mL) solution was treated with sodium bicarbonate (14.0 g) and methyl iodide (13.0 mL). The mixture was stirred under argon at room temperature while protected from direct light for 25 hours. The mixture was then poured into water (200 mL) and the product was extracted three times using 100 mL hexane each time. The combined extracts were washed with water, aqueous methanol (1:1), and brine. After drying over sodium sulfate and evaporation of solvent, 11.1 g (92%) of crude optically active (5Z,11alpha,13S,14E)-13-(2-tetrahydro-pyranyloxy)-11,16,16-trimethyl-9-hydroxyprosta-5,14-dien-1-oic acid methyl ester was obtained as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2([CH2:25][CH2:26][CH2:27][CH3:28])[O:22][C:21](=[O:23])[CH:20]=[C:19]([OH:24])[CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1>[CH2:25]([C:17]1([CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[O:22][C:21](=[O:23])[CH:20]=[C:19]([OH:24])[CH2:18]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC1(CCc2ccc(OCc3ccccc3)cc2)CC(O)=CC(=O)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared by debenzylation of 1.7 g (4.5 mmol) of 6-[2-(4-benzyloxy-phenyl)-ethyl]-6-butyl-4-hydroxy-5,6-dihydro-pyran-2-one (prepared in the paragraph above) using 0.15 g of 20% Pd on carbon and 75 mL of THF under hydrogen atmosphere as described in General Method 4. 1H NMR (DMSO-d6) δ 0.80 (t, 3 H), 1.2 (m, 4 H), 1.61 (m, 4 H), 1.81 (m, 2 H), 2.38 (d of ABX q, 1 H), 2.49 (d of ABX q, partially obscured by DMSO, 1 H), 4.89 (s, 1 H), 6.6 (d, 2 H), 6.91 (d, 2 H), 9.08 (s, 1 H), 11.25 (s, 1 H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:17])[CH2:8][C:9](=[O:16])[CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:5].[C:18](Cl)(=[O:20])[CH3:19].[Cl-].[NH4+]>ClCCl.N1C=CC=CC=1>[CH2:4]([O:6][C:7](=[O:17])[CH:8]([C:18](=[O:20])[CH3:19])[C:9](=[O:16])[CH2:10][O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:5]
Reactant: CCOC(=O)CC(=O)COC(C)(C)C
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C(C)=O)C(=O)COC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of dry magnesium chloride (0.471 g) in dichloromethane (6 ml) was treated with 4-tert-butoxy-3-oxo-butyric acid ethyl ester [1.00 g, Reference Example 43]. This mixture was cooled to 0° C., then treated with pyridine (0.80 ml), then stirred for 15 minutes at 0° C. and then treated with acetyl chloride (0.352 ml). After stirring for a further 15 minutes at 0° C. and then for 1 hour at ambient temperature the reaction mixture was treated with saturated aqueous ammonium chloride solution and then extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated to yield 2-acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester (1.15 g) as a yellow oil which was used without further purification. LC-MS (METHOD B): RT=3.16 minutes; 243 (M−H)−.