Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[F:21][C:22]1[CH:27]=[C:26](F)[C:25]([F:29])=[CH:24][C:23]=1[S:30]([N:33]([CH3:39])[C:34]1[S:38][N:37]=[CH:36][N:35]=1)(=[O:32])=[O:31]>CN(C)C=O.O>[NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[O:18][C:26]3[C:25]([F:29])=[CH:24][C:23]([S:30]([N:33]([CH3:39])[C:34]4[S:38][N:37]=[CH:36][N:35]=4)(=[O:31])=[O:32])=[C:22]([F:21])[CH:27]=3)=[CH:10][C:4]=2[N:3]=1
Reactant: CN(c1ncns1)S(=O)(=O)c1cc(F)c(F)cc1F
Reactant: Nc1nc2cc(-c3cc(Cl)ccc3O)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ncns1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccc3[nH]c(N)nc3c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 2-(2-amino-1H-benzo[d]imidazol-5-yl)-4-chlorophenol (0.40 g, 1.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added sodium hydride (60% w/w dispersion in mineral oil, 0.07 g, 1.8 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 h. 2,4,5-Trifluoro-N-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.52 g, 1.7 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The mixture was partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed with water (10 mL) and brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in ethyl acetate, followed by trituration in hexanes. The solid thus obtained was suspended in water (5 mL) and lyophilized to afford 4-(2-(2-amino-1H-benzo[d]imidazol-5-yl)-4-chlorophenoxy)-2,5-difluoro-N-methyl-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid in 63% yield (0.344 g): 1H NMR (300 MHz, CDCl3) δ10.78 (br s, 1H), 8.42 (d, J=1.9 Hz, 1H), 7.94-7.86 (m, 1H), 7.52-7.48 (m, 1H), 7.45-7.37 (m, 1H), 7.29 (dd, J=8.7, 1.6 Hz, 1H), 7.13 (s, 1H), 7.10-6.99 (m, 2H), 6.91 (d, J=8.1 Hz, 1H), 6.25 (s, 2H), 3.31 (s, 3H); 19F NMR (282 MHz, DMSO-d6) δ −108.7 (d, J=15.0 Hz, 1F), −135.1 (d, J=15.1 Hz, 1F); MS (ES+) m/z 548.7 (M+1), 550.7 (M+1).
Reaction SMILES: C(O[CH2:7][CH:8](O)[CH2:9][O:10][C:11](=O)C=NOC)(=O)C(C)=C.[C:18](OCCC(OC(=O)C=NOC)O)(=[O:22])[C:19](C)=[CH2:20]>C(Cl)(Cl)Cl>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:18]([OH:22])=[CH:19][CH:20]=1
Reactant: C=C(C)C(=O)OCC(O)COC(=O)C=NOC
Reactant: C=C(C)C(=O)OCCC(O)OC(=O)C=NOC
Solvent: ClC(Cl)Cl
Product: COc1ccc(O)cc1

Procedure:
In this way a milky suspension is obtained which is washed twice with 136 g of dichloromethane, then the chloromethylenic phases are reunited, dried over anhydrous magnesium sulphate and finally concentrated under vacuum. In this way 7.5 g of a yellow oil is isolated which is purified by preparative chromatography on a column (500×25) filled with silica of a size grading of 10 micrometers, eluting with a hexane-ethyl acetate mixture 8/2 by volume, which allows the isolation on the one hand of, 5 g (20.4 mmoles) of 1-methacryloyloxy-3-methoxyiminoacetoxy-2-propanol, and on the other hand of, 2 g (8.15 mmoles) of 3-methacryloyloxy-2-methoxyiminoacetoxy-1-propanol characterised by their NMR1H spectra registered in deuterized chloroform.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[O:4][CH2:3]1.[CH2:16]1[CH2:39][O:38][C:18]2([CH2:35][CH2:34][C@:33]34[O:36][C@:20]3([CH2:21][CH2:22][C@@H:23]3[C:32]4=[CH:31][CH2:30][C@@:28]4([CH3:29])[C@@H:24]3[CH2:25][CH2:26][C@H:27]4[OH:37])[CH2:19]2)[O:17]1.[NH4+].[Cl-]>O1CCCC1.Cl[Cu]>[CH2:39]1[CH2:16][O:17][C:18]2([CH2:35][CH2:34][C:33]3[C@@:20]([OH:36])([CH2:21][CH2:22][C@@H:23]4[C:32]=3[C@@H:31]([C:11]3[CH:12]=[CH:13][C:8]([CH:5]5[O:6][CH2:7][C:2]([CH3:15])([CH3:1])[CH2:3][O:4]5)=[CH:9][CH:10]=3)[CH2:30][C@@:28]3([CH3:29])[C@@H:24]4[CH2:25][CH2:26][C@H:27]3[OH:37])[CH2:19]2)[O:38]1
Reactant: CC1(C)COC(c2ccc(Br)cc2)OC1
Reactant: C[C@]12CC=C3[C@@H](CC[C@@]45CC6(CC[C@@]34O5)OCCO6)[C@H]1CC[C@H]2O
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc([C@H]3C[C@]4(C)[C@H](O)CC[C@@H]4[C@@H]4CC[C@@]5(O)CC6(CCC5=C43)OCCO6)cc2)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
300 mg of CuCl were added to the Grignard reagent prepared from 4.5 g of 4-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl bromide and 0.8 g of Mg in 15 ml of dry tetra-hydrofuran, followed by 2.2 g of (5α,10α,14β,17α)-3,3-ethylenedioxy-5,10-epoxyoestr-9(11)-en-17-ol, prepared in Example 3, in 10 ml of dry tetrahydrofuran. After stirring for 1 hour at room temperature, the mixture was poured into 200 ml of saturated NH4Cl solution. After extraction with ethyl acetate and washing, drying and concentrating the organic phase, the residue was chromatographed on silica gel using hexane/ethyl acetate 1/1 as eluent. After crystallization from diisopropyl ether, 1.7 g of (5α,11β,14β,17α)-3,3-ethylenedioxy-11[4-(5,5-dimethyl-1,3-dioxan-2-yl) phenyl]oestr-9-ene-5,17-diol were obtained; melting point: 176°-177° C. A solution of 1.5 g of this compound in 30 ml of 80% acetic acid was heated for 45 min. at 75° C. After cooling and neutralizing by concentrated NH4OH, the product was extracted with ethyl acetate. The organic phase was washed, dried and concentrated. The residue was chromatographed on silica gel using hexane/ethyl acetate 1/1 as eluent. After crystallization from diisopropyl ether, 0.6 g of (11β,14β,17α)-11-(4-formylphenyl)-17-hydroxyoestra-4,9-dien-3-one was obtained; melting point: 153°-155° C.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH3:37])=[O:21])[CH2:15]2)[CH:11]=[CH:10][C:9]=1[CH3:38])[CH3:6])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:39][C:5]([O:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH3:37])=[O:21])[CH2:15]2)[CH:11]=[CH:10][C:9]=1[CH3:38])([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1OC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A mixture of 2-methyl-2-(2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-propionic acid ethyl ester (179 mg, 0.31 mmol), potassium carbonate (86 mg, 0.62 mmol), methanol (10 mL) and water (2 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 151 mg (89%) of 2-methyl-2-(2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-propionic acid as a white solid.
Reaction SMILES: [CH3:1][Li].[CH2:3]([N:7]1[C:11]2[CH2:12][O:13][CH2:14][C:15](=[O:16])[C:10]=2[S:9]/[C:8]/1=[N:17]\[C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[CH2:4][CH2:5][CH3:6]>O1CCCC1>[CH2:3]([N:7]1[C:11]2[CH2:12][O:13][CH2:14][C:15]([OH:16])([CH3:1])[C:10]=2[S:9]/[C:8]/1=[N:17]\[C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[CH2:4][CH2:5][CH3:6]
Reactant: [Li]C
Reactant: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)C(=O)COC2
Solvent: C1CCOC1
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)C(C)(O)COC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of methyllithium (0.8 mL, 1.3 mmol, 1.6M in tetrahydrofuran, Aldrich) in tetrahydrofuran (10 mL) was added slowly a solution of Example 10 (0.25 g, 0.63 mmol) in tetrahydrofuran (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes and was allowed to reach room temperature. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-5% methanol in methylene chloride) to afford 92 mg (35%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3H), 1.24-1.37 (m, 2H), 1.39 (s, 3H), 1.56-1.76 (m, 2H), 3.64-3.70 (m, J=3.4 Hz, 2H), 3.79 (s, 3H), 3.92-4.13 (m, 2H), 4.55-4.80 (m, 2H), 5.57 (s, 1H), 7.12 (d, J=9.2 Hz, 1H), 7.46 (dd, J=9.0, 2.9 Hz, 1H), 7.73 (s, 1H)); MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([OH:18])[C:14]([CH3:16])([CH3:15])[CH2:13][C:6]2([O:10][CH:9]([CH3:11])[CH:8]([CH3:12])[O:7]2)[CH:5]=[C:4]1[CH3:17])#[CH:2].ClCCl.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])(=O)=O>O>[C:1]([C:3]1([O:18][Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])[C:14]([CH3:16])([CH3:15])[CH2:13][C:6]2([O:7][CH:8]([CH3:12])[CH:9]([CH3:11])[O:10]2)[CH:5]=[C:4]1[CH3:17])#[CH:2]
Reactant: C#CC1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: C#CC1(O[Si](CC)(CC)CC)C(C)=CC2(CC1(C)C)OC(C)C(C)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Under argon, 8-ethynyl-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-ol (500 mg, 1.99 mmol) was dissolved in a round-bottom flask in abs. dichloromethane (15 ml) and cooled to 0° C., and lutidine (0.58 ml, 4.99 mmol) and triethylsilyl trifluoromethanesulfonate (0.68 ml, 2.99 mmol) were added dropwise. The resulting reaction mixture was stirred at 0° C. for 1 h and at room temperature for a further hour, and water was added after the reaction had ended. The aqueous phase was repeatedly extracted thoroughly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), [(8-ethynyl-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)oxy](triethyl)silane (400 mg, 55% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 5.30 (s, 1H), 4.20 (m, 1H), 3.58 (m, 1H), 2.48 (s, 1H), 2.02 (d, 1H), 1.86 (s, 3H), 1.79 (d, 1H), 1.22 (m, 3H), 1.14-0.93 (m, 9H), 0.75 (m, 6H), 0.53 (t, 9H). A multi-necked round-bottom flask which had been dried thoroughly by heating was flushed with argon and evacuated repeatedly, and zirconocene chloride hydride (311 mg, 1.21 mmol) and degassed abs. tetrahydrofuran (3 ml) were then added under a constant stream of argon. The reaction solution was cooled to 0° C., and a solution of [(8-ethynyl-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)oxy](triethyl)silane in abs. tetrahydrofuran (2 ml) was added dropwise. The resulting reaction solution was stirred at room temperature for 1 h and its analysis by NMR spectroscopy showed complete conversion into the desired biscyclopentadienyldimethyl[(E)-2-{2,3,7,9,9-pentamethyl-8-[(triethylsilyl)oxy]-1,4-dioxaspiro[4.5]dec-6-en-8-yl}vinyl]zirconium. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.75 (m, 4H), 7.36 (m, 6H), 7.27 (d, 1H), 5.39 (d, 1H), 5.31 (s, 1H), 3.69 (m, 1H), 3.62 (m, 1H), 2.10-2.06 (m, 2H), 1.61 (s, 3H), 1.32-1.22 (m, 12H), 0.89 (m, 6H), 0.83 (t, 9H). The synthesis intermediate II.25 obtained in this manner was used in the subsequent reaction in question without further purification.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)=[O:28])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: Cc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-toluidine (104 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the objective product as a solid material.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[C:12]2[C:7](=[C:8]([CH2:13][CH:14]=[CH2:15])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=1.[Cl:18]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P(O)(O)([O-])=O.[K+]>ClCCCl.ClC(Cl)C>[Cl:18][CH:5]1[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH:14]=[CH2:15])[C:4]1=[O:3]
Reactant: C=CCc1cccc2c1CC=C2O[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: C=CCc1cccc2c1CC(Cl)C2=O
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
8 g of 3-trimethylsilyloxy-7-(2-propenyl)-indene in 25 ml of 1,2-dichloroethane is cooled to 0° C.; 31 g of N-chlorosuccinimide in 80 ml of dichloroethane is introduced over 25 minutes, with agitation for 30 minutes at 0° C.; 0.6 g of N-chlorosuccinimide in 15 ml of dichloroethane and a few mg of paratoluene sulphonic acid are added. After 30 minutes of agitation at 0° C., the reaction mixture is poured over an iced aqueous solution saturated with monopotassium phosphate, with agitation for 16 hours at 20° C. After decanting and extracting with methylene chloride, the extracts are dried, and concentrated to dryness under reduced pressure. The residue is chromatographed on silica, eluting with a hexane-isopropyl ether mixture (7-3). The fractions recovered are concentrated and chromatographed again on silica, eluting with a hexane-isopropyl ether mixture (3-1) and 2.75 g of expected product is isolated.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>O>[CH:15](=[N:9][C:8]1[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=1[S:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)CCCSc1ccccc1N
Solvent: O
Solvent: Cc1ccccc1C
Product: CN(C)CCCSc1ccccc1N=Cc1ccccc1

Procedure:
A mixture of 51g of 2-(3-dimethylaminopropylthio)aniline, 26g of freshly distilled benzaldehyde and 200 ml of xylene is refluxed under an atmosphere of nitrogen. The water formed in the reaction is collected in a Dean-Stark tube; the theoretical quantity is collected after 4 hours of refluxing. The xylene and any unchanged benzaldehyde are removed on the steam bath at 30 mm of Hg, finally at 2 mm of Hg. Fractionation of the residue yields 56g of the title compound, boiling point 182°-189° C. at 0.4 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH:32][CH:33]3[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]3)=[O:31])[C:10]=2[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([NH:32][CH:33]3[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]3)=[O:31])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)NC1CC(C)(C)NC(C)(C)C1)C(=O)NC3=O
Agent: BrB(Br)Br
Product: CC1(C)CC(NC(=O)CCn2c3ccc(O)cc3c3c4c(c(-c5ccccc5Cl)cc32)C(=O)NC4=O)CC(C)(C)N1
Reaction time: 48 h
Yield: 47 %

Procedure:
Demethylation of (124) prepared as described in example 237 with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (125) as a yellow powder (47%), mp 293–299° C. (dec). 1H NMR δ [(CD3)2SO] 11.08 (br s, 1H), 9.38 (br s, 1H), 8.72 (br, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.83 (d, J=7.1 Hz, 1H), 7.75 (s, 1H), 7.60–7.44 (m, 5H), 7.14 (dd, J=8.8, 2.4 Hz, 1H), 4.70 (t, J=5.8 Hz, 2H), 3.90 (m, 1H), 2.54 (t, J=5.8 Hz, 2H), 1.45–1.31 (m, 2H), 1.30 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.22 (s, 3H), 1.09–9.93 (m, 2H). Found: C, 58.67; H, 5.37; N, 8.41. C32H33ClN4O4.1.25CH2Cl2 requires C, 58.79; H, 5.27; N, 8.25.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:23][CH:24]([CH:37]([CH3:39])[CH3:38])[CH:25]([O:30]C(=O)C(C)(C)C)[C:26]([F:29])([F:28])[F:27])=[O:22])[C:16]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)=C[CH:14]=2)=[O:11])[CH:5]=[C:4]([CH3:45])[N:3]=1.O.[OH-].[Li+].[Cl-].[NH4+:50]>O1CCCC1.CO.O>[CH3:45][C:4]1[CH:5]=[C:6]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:23][CH:24]([CH:37]([CH3:39])[CH3:38])[CH:25]([OH:30])[C:26]([F:28])([F:27])[F:29])=[O:22])[C:16]([C:40]3[S:41][CH:42]=[CH:43][CH:44]=3)=[N:50][CH:14]=2)=[O:11])[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(COC(=O)Nc2ccc(-c3cccs3)n(CC(=O)NC(C(C)C)C(OC(=O)C(C)(C)C)C(F)(F)F)c2=O)cc(C)n1
Agent: [Cl-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(COC(=O)Nc2cnc(-c3cccs3)n(CC(=O)NC(C(C)C)C(O)C(F)(F)F)c2=O)cc(C)n1
Reaction time: 2 h

Procedure:
To a solution of 2-[5-(2,6-dimethylpyrid-4-ylmethoxycarbonylamino)-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyridinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-pivaloyloxypropyl)acetamide (1.44 g) in tetrahydrofuran (10 mL) and methanol (10 mL) was added a solution of lithium hydroxide monohydrate (0.92 g) in water (20 mL). The resulting solution was stirred for 2 h, diluted with saturated ammonium chloride (30 mL), and extracted with ethyl acetate. The ethyl acetate solution was dried and evaporated. The resulting material was chromatographed, eluting with ethyl acetate, to provide the alcohol (0.39 g) as a yellow foam; TLC: Rf =0.24, ethyl acetate; MS: m/z=568(M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]([CH:15]=C)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].CC(C)=[O:30].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:1][C:2]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]([CH:15]=[O:30])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2F)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2F)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.40 g) in a mixed solvent of acetone (5.00 mL)-acetonitrile (5.00 mL)-water (5.00 mL) were added osmium oxide (fixed catalyst I) (0.14 g) and sodium periodate (1.17 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.40 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CCOCC>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(CC)CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC(CC)COS(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
2-Ethylhexanol (50.51 g, 0.384 tool) and pyridine (260 mL) are combined in a flask fitted with a condenser, internal thermometer, mechanical stirrer and argon inlet. The solution is cooled to -5° C. and to it is added p-toluenesulfonyl chloride (89.63 g, 0.416 mol) in portions via Gooch tubing so as to maintain the reaction temperature -5°-5° C. After 3 h, (40 mL) is added in portions so as to keep the temperature of the reaction below 5° C. The reaction mixture is warmed to room temperature and then poured into a separatory funnel containing 540 mL of ether. The layers are separated and the organic layer is washed with 5 M H2SO4 (2×140 mL), saturated CuSO4 solution (140 mL), water (2×140 mL) and saturated NaHCO3 solution (140 mL). After drying over MgSO4, the organic layer is filtered, and concentrated to leave a light yellow liquid as 2-ethyhexanyl p-toluenesulfonate. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].O[NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)=[NH:27]>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[O:22][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[N:25]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Reactant: N=C(NO)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCCc2nc(-c3ccc(O)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A stirred solution of 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (100 mg, 0.29 mmol) in DMF (4 ml) was treated with CDl (52 mg, 0.32 mmol). After 1 h, N,4-dihydroxybenzenecarboximidamide was added and the mixture heated at 100° C. for 6 h. On cooling, the reaction mixture was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. Purification by MDAP afforded the title compound as a pale grey solid (72 mg).
Reaction SMILES: C[O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)/[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>CO>[CH3:19][O:18][C:14]1[CH:13]=[C:12](/[C:7](/[CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:20])=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: CCCC/C(=C/C=C/C(=O)OC)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC/C(=C/C=C/C(=O)O)c1cccc(OC)c1
Reaction time: 2 h
Yield: 75.4 %

Procedure:
As described in Example 99, (2E,4Z)-5-(3-methoxyphenyl)-2,4-nonadienoic acid methyl ester (11 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2 hours the reaction was worked up in the usual way to yield 7.87 g of (2E,4Z)-5-(3-methoxyphenyl)-2,4-nonadienoic acid. A portion was crystallized from ether-hexane to give the analytical sample, mp 106.5°-107.5° C.