Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>CCOC(C)=O>[CH3:33][O:32][C:28]1[CH:27]=[C:25]([NH:26][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)[CH:24]=[C:23]([O:22][CH3:21])[C:29]=1[O:30][CH3:31]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1cncc(Oc2ccccc2-c2ccccc2)n1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccccc3-c3ccccc3)n2)cc(OC)c1OC
Yield: 60 %

Procedure:
Using Method EE with 2-chloro-6-[(2-phenyl)-phenyl-oxy]-pyrazine (110 mg, 0.39 mmol) and 3,4,5-trimethoxyaniline (84 mg, 0.46 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (101 mg). Yield: 60%. 1H NMR (250 MHz, DMSO-d6) δ 3.41 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.79 (s, 2H, Harom2′+6′), 7.22-7.49 (m, 9H, Harom), 7.66 (s, 1H, HPz 5) 7.88 (s, 1H, HPz 3), 9.51 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:20][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OC1CCCC1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and cyclopentanol. The crude material was purified by flash chromatography to yield the title compound as a yellow solid. MS (m/e): 282.9 ([M−H]−, 100%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].Br[CH2:10][C:11]([OH:13])=[O:12]>C1COCC1>[CH3:3][C:4]([CH3:8])([CH3:7])[CH2:5][O:6][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)CO
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)COCC(=O)O
Reaction time: 0.08 h

Procedure:
NaH (40% oil dispersion, 432 mg) was added to a solution of 2,2-dimethylpropan-1-ol (0.319 ml) in THF (15 ml) at 0° C. After stirring for 5 min, 2-bromoacetic acid (500 mg) was added. The mixture was refluxed under Ar atmosphere for 2 h. The mixture was quenched with water, washed with EtOAc, acidified with 1 M HCl (11 ml) and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (490 mg) as a pale pink oil.
Reaction SMILES: C(O[CH:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1)[CH3:5])C.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1>>[CH2:16]([O:15][CH2:5][CH2:4][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]=[CH2:12])=[CH:13][CH:14]=1)[CH3:17].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1
Reactant: C=Cc1ccc(OC(C)OCC)cc1
Agent: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OCCOCC)cc1

Procedure:
To a solution of poly(p-hydroxystyrene) (4.0 g) obtained in above (2) and ethyl vinyl ether (1.2 g) in a mixed solvent (35 ml) of 1,4-dioxane and pyridine, a catalytic amount of p-toluenesulfonic acid was added and reacted with stirring at room temperature for 24 hours. The reaction mixture was poured into H2O (1 l) and a white solid was precipitated. The polymer was filtered, washed with h2O and dried under reduced pressure to afford 5.0 g of poly[p-(1-ethoxyethoxy)-styrene/p-hydroxystyrene] as white powder having Mw 10000 (GPC with polystyrene calibration). The polymer was found to have p-(1-ethoxyethoxy)styrene unit and p-hydroxystyrene unit in a molar ratio of ca. 4:6 based on 1HNMR.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[C:4]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)[N:3]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.[W]>[Br:28][CH2:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([CH3:20])[CH:16]=1)[O:12][C:4]1[C:5]([CH:9]([CH3:10])[CH3:11])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Cc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A mixture of 2,4-dichloro-6-(3,5-dimethyl-phenoxy)-5-isopropyl-pyrimidine (9.72 g, 31 mmol), NBS (5.56 g, 31 mmol), and benzoyl peroxide (0.756 g, 3.1 mmol) in carbon tetrachloride (60 ml) was refluxed for 3 hr. under a light of 500 W tungsten lamp. After cooling to room temperature, the reaction mixture was filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:19)) to afford 8 g (62%) of a white solid. m.p. 98-101° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.38 (3H, s), 3.59 (1H, m), 4.47 (2H, s), 6.86 (1H, s), 6.97 (1H, s), 7.13 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=C)=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C1C[O:34]CC1.O>O=[Os](=O)(=O)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=[O:34])=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: C=Cc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCc1cccc(CC)c1-c1cc2c(C=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-3-vinyl-1H-pyrrolo[2,3-c]pyridine (400 mg, 1.0 mmol) in a THF/water mixture (3:1, 10 mL), NaIO4 (0.65 g, 3.0 mmol) and OsO4 (4% in water, 3 drops) are added and the mixture is stirred for 18 hours at room temperature. The solvent is removed under reduced pressure, and the residue is extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 6:1) to afford 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde as a colorless oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][C@H:13]1[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]1.O.CCCCCC.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][C@H:13]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC[C@H]1C[C@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](CO)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
p-Toluenesulfonyl chloride (3.47 g, 18.2 mmol) was added to a solution of the above preparation of (trans)-3-hydroxycyclobutanemethanol, benzoate ester (2.5 g) in dry pyridine (35 ml) under nitrogen, and the mixture was stirred at 60° for 18 hours. Water (20 ml) was added, and heating was continued for 4 hours longer. The reaction was cooled to room temperature and concentrated in vacuo to a solid, which was dissolved in ethyl acetate and water. The ethyl acetate layer was washed with water, saturated aqueous NaHCO3, and water, dried (Na2SO4), and concentrated to a solid (3.8 g). This solid was combined with 1.5 g of solid from a similar preparation. Chromatography of these solids over 200 g of LP-1 silica gel, using hexane-ethyl acetate (6:1), gave (trans)-3-[[(4-methylphenyl)sulfonyl]oxy]cyclobutanemethanol, benzoate ester containing varying amounts of its cis-isomer as shown below:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]=[CH2:15])[C:10]([Cl:19])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a soln of 2-(3,4-dichlorophenyl)pent-4-enoic acid (2.34 g, 9.53 mmol) in methylene chloride (25.0 mL) was added oxalyl chloride (1.61 mL, 19.0 mmol) followed by N,N-dimethylformamide (73.8 uL, 0.953 mmol) After 1 hr of stirring at rt, the solution was concentrated to provide 2-(3,4-dichlorophenyl)pent-4-enoyl chloride as a yellow oil (2.70 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 7.49-7.42 (d, J=8.3 Hz, 1H), 7.40-7.36 (d, J=2.2 Hz, 1H), 7.17-7.10 (dd, J=8.3, 2.2 Hz, 1H), 5.73-5.57 (ddt, J=17.1, 10.2, 6.9 Hz, 1H), 5.15-5.06 (m, 2H), 4.06-3.97 (t, J=7.6 Hz, 1H), 2.97-2.83 (m, 1H), 2.61-2.49 (m, 1H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CCCCCC.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: C=CCOc1ccc(CO)cc1
Yield: 78.4 %

Procedure:
The compound of formula 2 (Z=trifluoromethylsulphonyloxy), methyl 3-(3-allyl-4-trifluoromethylsulphonyloxyphenyl)methyloxyacetate, was prepared as follows. Allyl bromide (4.4 g) was added to a stirred suspension of 4-hydroxybenzyl alcohol (4.34 g) and potassium carbonate (5.00 g) in butanone (40 ml). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled and then filtered. The filtrate was evaporated to give an oil which was purifed by flash column chromatography on silica gel using a 4:1 (v/v) mixture of hexane and ethyl acetate as eluent to give 4-allyloxybenzyl alcohol (4.50 g) as a pale yellow oil; NMR(CDCl3): 1.81(1H,t), 4.48-4.65(4H,m), 5.22-5.48(2H,m), 6.05(1H,m), 6.90(2H,m) and 7.25(2H,m), m/z 164(H).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[F:27][CH:28]([F:38])[O:29]C1C=CC=CC=1CBr.OOS([O-])=O.[K+]>CCO.O>[F:27][CH:28]([F:38])[O:29][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:17][S:14]([CH2:13][CH:9]([CH2:8][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:24])[C:10]([OH:12])=[O:11])(=[O:15])=[O:16]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: FC(F)Oc1ccccc1CBr
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1OC(F)F
Temperature: 25 °C

Procedure:
4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (1.27 g, 4.64 mmol) was dissolved in 50 mL dry EtOH and set to stir at room temperature. NaOH pellets (556 mg, 13.92 mmol) were added in one portion, and the reaction mixture was allowed to stir for 10 min. 2-(Difluoromethoxy)-benzyl bromide (1.00 g, 4.219 mmol) was then added, and the reaction mixture was allowed to stir at ambient temperature for 20 h. Upon completion (LCMS), the reaction mixture was diluted with water and the pH was lowered to ˜2. The reaction mixture was then washed 3× with EtOAc. The organic phase was concentrated in vacuo and then diluted with 100 mL aqueous MeOH. Oxone (1.58 g, 2.43 mmol) was added in one portion and the reaction was stirred at room temperature for 4 h. Conversion of sulfide to sulfone was monitored via LCMS. Upon completion, reaction was quenched by the addition of sodium thiosulfate. Salts were filtered, and the reaction mixture was washed 3× with ethyl acetate and dried over sodium sulfate. The organics were evaporated by vacuum under reduced pressure. Product was purified via HPLC. Yield: 195 mg, 19.0%. m/z (LCMS) M+ 422.1. Rf=2.42. δH 12.6 (1H, br s), 7.6–7.2 (4H, m), 7.19 (1H, s) 4.5 (2H, s), 3.5 (4H, m), 3.5 (1H, m), 3.4 (4H, m), 3.2 (2H, d), 2.75 (2H, d).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[CH3:28][NH:29][C:30](=[O:35])[CH2:31][CH2:32][C:33]#[CH:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:34]#[C:33][CH2:32][CH2:31][C:30]([NH:29][CH3:28])=[O:35])[N:3]=[C:4]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:5]4=[N:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:19]1
Reactant: CC(C)CNc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Reactant: C#CCCC(=O)NC
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)CCC#Cc1cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc2c(NCC(C)C)n1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
To a solution of 128 mg (0.3 mmol) 4-{6-bromo-8-[(2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide in 1 mL THF were added 133 mg (1.2 mmol) N-methylpent-4-ynamide, 42 mg (0.06 mmol dichloropalladium-triphenylphosphane (1:2) and 363 mg (1.5 mmol) tetrabutylammoniumfluoride and the mixture was heated at 80° C. for 180 min in a microwave tube. The mixture was evaporated, redissolved in 2 mL DMSO, filtered and purified by HPLC to yield 60 mg (44%) of the title compound. UPLC-MS: RT=1.01 min; m/z (ES+) 459.6 [MH+]; required MW=458.6.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]([CH2:14][C:15]([O:17][CH2:18]C)=[O:16])#[N:13]>CO>[CH3:18][O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[CH:10][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)CC#N
Solvent: CO
Product: COC(=O)C(C#N)=Cc1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
7-azaindole-3-carboxaldehyde (3.36 g, 22.99 mmol) was taken in 60 ml of methanol and cooled to 0° C. Pipepridine (2.5 ml, 25.28 mmol) was added followed by ethyl cyanoacetate (2.23 ml, 25.27 mmol). The reaction was stirred at RT for 5 hrs then concentrated quenched with water and filtered to give a yellow solid product (4.07 g).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([CH:16]([CH3:18])[CH3:17])[C:5]=1[C:6](Cl)=[O:7])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH:16]([C:9]1[CH:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[CH2:6][OH:7])([CH3:18])[CH3:17]
Reactant: CC(C)c1cc(C(C)C)c(C(=O)Cl)c(C(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)c1cc(C(C)C)c(CO)c(C(C)C)c1
Temperature: 25 °C

Procedure:
A solution of commercially available 2,4,6-triiso-propylbenzoyl chloride (35 g, 131.2 mmol) in 400 mL ether was added slowly to a suspension of lithium aluminum hydride (LAH) (4.89 g, 131.2 mmol) in ether (300 mL) at -15° C. The mixture was slowly warmed to room temperature over 18 hours. Saturated Na2SO4 solution was added slowly and the ether layer was separated, dried over MgSO4, and evaporated to dryness. The compound was used in the next step without further purification; NMR (CDCl3):δ1.2-1.4 (m, 18H), 2.8-3.0 (m, 1H), 3.3-3.5 (m, 2H), 4.8 (s, 2H), 7.1 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[O:4].[H-].[Na+].[CH2:17]([O:19][C:20](=[O:23])[CH2:21]I)[CH3:18]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:14])(=[O:13])[N:11]([CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23])[CH3:12])=[O:4]
Reactant: CNS(=O)(=O)c1ccsc1C(=O)OC
Reactant: CCOC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccsc1C(=O)OC

Procedure:
43.5 G. (0.184 mol) of the obtained 3-methylsulfamoyl-thiophene-2-carboxylic acid methyl ester are dissolved in 400 ml. of absolute dimethylformamide are added dropwise at 0° C. during 1 hour to a stirred suspension of 4.5 g. (0.187 mol) of sodium hydride in 50 ml. of absolute dimethylformamide. Then, 40 g. (0.187 mol) of iodoacetic acid ethyl ester dissolved in 50 ml. of absolute dimethylformamide are added dropwise during 2 hours while cooling at 0°-5° C. and the mixture allowed to react for a further 1 hour [until a moistened pH paper shows a pH of 7-8]. The mixture is evaporated in vacuo and the residue taken up with 300 ml. of 0.5-N hydrochloric acid and 300 ml. of methylene chloride. The organic phase is separated, the aqueous phase is back-extracted twice with a small amount of methylene chloride and the combined organic phases are shaken out twice with 100 ml. each time of a 5% sodium bicarbonate solution [the aqueous phases are back-extracted once each time with a small amount of methylene chloride]. The combined organic phases are dried over sodium sulfate and evaporated. The crystalline residue is digested with a small amount of cold ethanol for purification. There is obtained 3-(N-carbethoxymethyl-N-methylsulfamoyl)-thiophene-2-carboxylic acid methyl ester of melting point 83°-85° C.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH2:5][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)CC(C)=O
Reactant: ClCCCCc1ccccc1
Product: O=C(CCCCCc1ccccc1)CC(=O)CCCCCc1ccccc1

Procedure:
Using 2,4-pentanedione (26.7 g, 0.267 mol) and 1-chloro-4-phenylbutane (110 g, 0.65 mol) obtained in Example 13, (2), the reaction was carried out in the same manner as described in Example 17, (1), and the residue was chromatographed on silica gel (Wako Gel C-200) with benzene/n-hexane (from 4:1 to 10:1) as eluent to afford the title compound as a pale yellow oil which was an ca 1:4 mixture of Keto/Enol as seen by the methylene singlet at δ3.52 ppm and the methine singlet at δ5.44 ppm in the 1HNMR spectrum; yield: 2.5 g.
Reaction SMILES: N1C=CC=CC=1.F.[C:8]([O:13][C:14]1[CH2:31][C@@H:30]([O:32][Si](C(C)(C)C)(C)C)[C@H:29](/[CH:40]=[CH:41]/[C@@H:42]([O:50][Si](C(C)(C)C)(C)C)[CH2:43][C@H:44]([CH3:49])[CH2:45][CH2:46][CH2:47][CH3:48])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])(=[O:12])[CH2:9][CH2:10][CH3:11]>>[C:8]([O:13][C:14]1[CH2:31][C@@H:30]([OH:32])[C@H:29](/[CH:40]=[CH:41]/[C@@H:42]([OH:50])[CH2:43][C@H:44]([CH3:49])[CH2:45][CH2:46][CH2:47][CH3:48])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:23])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC(=O)CCCCCSC1=C(OC(=O)CCC)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](C[C@H](C)CCCC)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCCOC(=O)CCCCCSC1=C(OC(=O)CCC)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)C[C@H](C)CCCC
Yield: 71.7 %

Procedure:
Using as the material and reagent a hydrogen fluoride-pyridine solution (0.2 ml) and butyl (11R,12S,13E,15S,17R)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (138 mg), the same procedure as in Example 2 was performed to obtain butyl (11R,12S,13E,15S,17R)-9-butyryloxy-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (69 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.O>[Br:21][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CBr)c2ccccc12
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a stirred solution of 4-methyl-1-naphthonitrile (5 g, 30 mmol) in CCl4 (50 mL) under argon atmosphere was added NBS (6.06 g, 34.09 mmol), and the reaction mixture was degassed for 30 min. AIBN (0.3 g, 2.1 mmol) was added, and the resultant reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 52%): mp 131-133° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 8.24 (m, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.78 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 4.95 (s, 2H); ESIMS m/z 245.92 ([M+H]+); IR (thin film) 2217 cm−1.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10](OC(OCC)OCC)C>B(F)(F)F.CCOCC>[O:1]1[CH:10]=[N:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:2]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(=N)NO
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)c1ncon1
Yield: 83.7 %

Procedure:
To a suspension of ethyl 2-(hydroxyamino)-2-iminoacetate (3 g, 22.71 mmol) in triethylorthoformate (14 mL, 84.08 mmol) was added boron trifluoride diethyl etherate (0.144 mL, 1.14 mmol). It was heated for 90 minutes. The reaction mixture was concentrated under reduced pressure and the residue dissolved in chloroform. The resulting organic layer was washed with aqueous hydrochloric acid 2N (2×80 mL), aqueous sodium bicarbonate 4% (1×80 mL) and water (2×80 mL), it was dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to yield the title compound (2.70 g, 79%) as a yellow oil.
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15].[C:17]1([CH2:23][CH2:24][CH:25]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH:25]([CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][C:14](=[O:16])[C:8]=2[CH:9]=1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=CCCc1ccccc1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CC(CCc2ccccc2)Oc2ccc(F)cc21

Procedure:
Pyrrolidine (2.4 mL) was added to a solution of 2'-hydroxy-5'-fluoroacetophenone (15.1 g) and 3-phenylpropanal (13.2 mL) in toluene (30 mL), and the mixture heated under reflux in a Dean-Stark apparatus for 3 hours, cooled, diluted with ethyl acetate and washed with aqueous 1N HCl, aqueous 1N NaOH, H2O, brine, dried (Na2SO4), filtered and evaporated, and the residue purified by column chromatography (6:1 hexane/diethyl ether, SiO2) to yield 2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one (18 gm, Rf=0.3 4:1 hexane/diethyl ether).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:25]([O-])=O)[C:16]1=[O:28])[C:11]([O:13][CH3:14])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO>[Pd]>[NH2:25][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH:23]=[CH:24][N:15]([C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:11]([O:13][CH3:14])=[O:12])[C:16]2=[O:28]
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(N)cccc2c1=O
Reaction time: 2 h

Procedure:
A round bottom flask was charged with (R)-methyl 3-(tert-butyldimethylsilyloxy)-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanoate (5.5 g, 0.014 mol), methanol (100 mL, 2 mol) and palladium, 10% weight on charcoal (0.3 g, 0.003 mol) was added and the reaction stirred under hydrogen atmosphere (1 atm) for 2 h. The reaction was filtered over celite, the solvent was removed under reduced pressure and the residue purified by flash chromatography (40 g silica gel, 0-10% MeOH/DCM) to yield the product as a yellow sticky mass. MS m/z=377.5 (M+H).