Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[Cl:23][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.6g (93.5 mmoles) of 2-(3-hydroxymethylphenoxy)methylquinoline is dissolved in 30 ml of methylene chloride and 3 drops of dimethylformamide is added. 60.7 ml of a 2.0M solution of thionyl chloride in methylene chloride is then added dropwise at 0° C. The mixture is allowed to warm to room temperature and stirred for 5 hours. The solution is worked with sodium bicarbonate solution, dried, concentrated in vacuo and the crude product purified by silica gel HPLC to yield 12.1 g 2-(3chloromethylphenoxy)methylquinoline as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>CC(=O)CC>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12])[CH2:6][NH:7][CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17]
Reactant: COc1cc(CN)cc(OC)c1OC
Reactant: O=S1(=O)CCCO1
Solvent: CCC(C)=O
Product: COc1cc(CNCCCS(=O)(=O)O)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 3,4,5-trimethoxybenzylamine (2.2 mL, 12.7 mmol) in 2-butanone (20 mL) was added 1,3-propane sultone (1.66 g, 13.3 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The product was suspended in 90% Acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 sec., the solid was collected by filtration, and dried in vacuo; affording compound AY, 2.61 g (64%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.C([O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O)C>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:23]2([CH3:25])[O:26][C:20](=[O:19])[CH2:21][CH2:22]2)=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(C)=O
Reactant: Brc1ccsc1-c1cccs1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1(c2ccsc2-c2cccs2)CCC(=O)O1
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
3-Bromo-2,2′-bithiophene (1.00 g, 4.08 mmol) in dry diethylether (35 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 2.50 mL, 4.08 mmol) in dry diethylether (35 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled ethyllevulinate (0.58 mL, 4.08 mmol) was added to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 20 mL) and water (80 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by gradient column chromatography (eluent hexane/EtOAc 95:5) to afford the title compound as a yellow oil (0.35 g, 28%). 1H-NMR (CDCl3): δ=7.38 (dd, J=5.1 Hz, J=1.3 Hz, 1H), 7.27 (d, J=5.3 Hz, 1H), 7.15 (d, J=5.3 Hz, 1H), 7.09 (dd, J=3.7 Hz, J=1.3 Hz, 1H), 7.04 (dd, J=5.1 Hz, J=3.7 Hz, 1H), 2.59-2.40 (m, 2H), 2.19-2.12 (m, 2H), 1.69 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[Cl:11][S:12](O)(=[O:14])=[O:13].S(=O)(=O)(O)N>>[N+:1]([C:4]1[CH:9]=[C:8]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)Cl
Agent: NS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
137.1 g (1.0 mol) of o-nitrotoluene are added dropwise to 535.9 g (4.6 mol) of chlorosulfonic acid and 2 g of sulfamic acid such that the temperature does not exceed 40° C. The mixture is then stirred at 40° C. for 1 hour and slowly heated to 105° C. It is then stirred at 105° C. for 6 hours, cooled and added dropwise to ice water at 0 to 5° C. The precipitated crystals are filtered off with suction and washed with ice water. 236.1 g of 2-nitrotoluene-4-sulfonyl chloride (water content 10.8%), corresponding to 210.6 g (89% of theory), having a melting point of 40° C. are obtained.
Reaction SMILES: Br.C([O:5][C:6]1[CH:7]=[C:8]([CH:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[C:10]([O:12]C(=O)C)[CH:11]=1)(=O)C.O.CCOCC>C(O)C.[Pd]>[OH:5][C:6]1[CH:7]=[C:8]([CH:16]([OH:23])[CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:9]=[C:10]([OH:12])[CH:11]=1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(O)CNC(C)(C)C)c1
Agent: [Pd]
Agent: Br
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CC(C)(C)NCC(O)c1cc(O)cc(O)c1

Procedure:
1.1 g of this salt were dissolved in warm absolute ethanol and 0.1 g 10% palladium charcoal were added. The solution was then hydrogenated at 50°C. and 5 atmospheres pressure overnight. The catalyst was filtered off and the volume of the solution reduced by evaporation. The hydrobromide of 1-(3',5'-diacetoxyphenyl)-2-(t-butylamino)-ethanol with 1 mole of water was precipitated by the addition of ether. M.p. 108°-111°C. The protective acetyl groups may be removed by boiling the 1-(3',5'-diacetoxyphenyl)-2-(t-butylamino)-ethanol hydrobromide with 1% hydrobromic acid for three hours. After evaporation and drying the product was recrystallized as described in Example 2c.
Reaction SMILES: CN(C)C=O.[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](OS(C(F)(F)F)(=O)=O)=[C:15]([C:27]([O:29][CH3:30])=[O:28])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:31](=[O:34])[C:32]#[CH:33].C(N(CC)C(C)C)(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:6]([N:13]1[CH2:18][CH2:17][C:16]([C:33]#[C:32][CH2:31][OH:34])=[C:15]([C:27]([O:29][CH3:30])=[O:28])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CC=O
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(Cc2ccccc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C1=C(C#CCO)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 13 mL of an N,N-dimethylformamide solution containing 3.6 g of methyl 1-benzyl-4-(((trifluoromethyl)sulfonyl)oxy)-1,2,5,6-tetrahydropyridine-3-carboxylate, 0.75 mL of 2-propine-1-al and 2.2 mL of N,N-diisopropylethylamine, 61 mg of copper(I) iodide, and 0.14 g of bis(triphenylphosphine)palladium(II) dichloride were added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform] to obtain 2.7 g of a brown oily substance, methyl 1-benzyl-4-(3-hydroxy-1-propin-1-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate containing N,N-dimethylformamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:22][C:23]1[C:28]([CH3:29])=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.O.CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:27]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:22])[C:28]=2[CH3:29])=[CH:8][CH:7]=1
Reactant: Cc1nccc(B(O)O)c1C
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)OC(C)(C)C
Yield: 4.4 %

Procedure:
A mixture of 304 mg of (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid methyl ester, 314 mg 2,3-dimethylpyridine-4-boronic acid, 374 mg cupric acetate, and 2 grams of powdered 4 Å molecular seives in 50 mL dry DCM and 0.75 mL TEA was stirred vigorously at rt under an O2 atmosphere for 40 h. The mixture was then poured into water-EtOAc. The organic layer was washed with water and saturated brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM-EtOAc) to provide (S)-2-tert-Butoxycarbonylamino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (18 mg). LCMS (m/z) 401.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C[Si](C)(C)[C:16]([F:19])([F:18])[F:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:1][C:2]1([C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-oxopyrrolidine-1-carboxylate (926 mg, 5.0 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0° C., trimethyl(trifluoromethyl)silane (0.872 mL) and tetrabutylammonium fluoride (TBAF) (176 mg, 0.557 mmol) were added. The ice-bath was removed and the reaction mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl solution (8 mL) was added and stirring was continued. After 15 min TBAF (2.36 g TBAF in 7.5 mL THF) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate, washed with H2O, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum spirit) to give the subtitled compound (800 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([S:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N(C2C=CC=CC=2)C([O:34][C:35](=O)[C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:43]3[C:51]4[C:46](=[CH:47][CH:48]=[C:49]([NH:52][C:53](=[O:60])[CH2:54][CH:55]5[CH2:59][CH2:58][CH2:57][CH2:56]5)[CH:50]=4)[N:45]([CH2:61][CH3:62])[CH:44]=3)=[C:38]([O:63][CH3:64])[CH:37]=2)=O)C=CC=CC=1.P([O-])(O)(O)=O.[K+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH:55]1([CH2:54][C:53]([NH:52][C:49]2[CH:50]=[C:51]3[C:46](=[CH:47][CH:48]=2)[N:45]([CH2:61][CH3:62])[CH:44]=[C:43]3[CH2:42][C:39]2[CH:40]=[CH:41][C:36]([C:35]([CH:20]([S:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)(=[O:19])=[O:18])[C:21]([O:23][CH3:24])=[O:22])=[O:34])=[CH:37][C:38]=2[O:63][CH3:64])=[O:60])[CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Reactant: CCn1cc(Cc2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1cc(Cc2ccc(C(=O)C(C(=O)OC)S(=O)(=O)c3ccccc3)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Temperature: 25 °C

Procedure:
A solution of potassium bis(trimethylsilyl)amide (7.1 ml of a 0.8M solution in toluene) was added to a solution of methyl 2-(phenylsulfonyl)acetate (1.24 g) in tetrahydrofuran (THF) (9.0 ml) at -78° C. This mixture was then added to a solution of 4-[5-(2-cyclopentylacetamido)-1-ethylindol-3-ylmethyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride (E) (600 mg) in THF at -78° C. The reaction solution was allowed to warm to room temperature overnight and saturated potassium dihydrogen phosphate (20 ml) was then added. The mixture was made acidic to pH 4 with the addition of 1N HCl and partitioned with ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (41 g) using chloroform as the eluent. The title compound was obtained as an oil which was crystallized from methyl t-butyl ether/hexane to give a pale yellow solid (64.5 mg, 10%); mp 78°-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[N:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[N:15][CH:16]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Nc2ccc(Cl)c(Cl)c2)cn1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
A mixture of 3,4-dichloroaniline (1.127 g, 6.95 mmol) and methyl 5-chloropyrazine-2-carboxylate (0.6 g, 3.48 mmol) in dioxane (32 mL) was heated at 100° C. for 7 days, then cooled to room temperature and concentrated. The residue was triturated with methanol and filtered. The brown filter cake was washed with methanol and dried to yield methyl 5-(3,4-dichlorophenylamino)pyrazine-2-carboxylate (0.53 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.44 (1H, s), 8.81 (1H, d, J=1.26 Hz), 8.30 (1H, d, J=1.51 Hz), 8.21 (1H, d, J=2.26 Hz), 7.46-7.73 (2H, m), 3.58 (2H, s). LCMS: R.T.=4.07; [M+H]+=298.12.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=3)=[CH:18][CH:19]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A solution of 62 mg (0.21 mmol) of the crude (RS)-[1-(4-hydroxy-phenyl)-5-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester in 3 ml of 2-butanone is treated with 0.031 ml (0.23 mmol) of 3-fluorobenzyl-bromide and 59 mg (0.42 mmol) of potassium carbonate and the mixture is stirred at 50° C. for 18 h. For the working-up, the reaction mixture is diluted with ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 2:1 mixture of n-hexane and ethyl acetate as the eluent. There are obtained 61 mg (72% of theory) of (RS)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester as a white solid. MS: m/e=401 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25]C(OC(C)(C)C)=O)=[CH:20][CH:19]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O1CCOCC1>>[CH:1]1([O:6][C:7](=[O:33])[C@@H:8]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][NH2:25])=[CH:22][CH:23]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
(S)-2-[4-(tert-Butoxycarbonylamino-methyl)-benzylamino]-3-phenyl-propionic acid cyclopentyl ester was treated with 4M HCl in dioxane (1 mL, 0.25 mmol) and stirred at r.t. for 1 h. The mixture was evaporated to dryness and partitioned between EtOAc (20 mL) and water (20 mL). Saturated sodium bicarbonate (20 mL) was added to the aqueous layer which was then extracted with EtOAc (3×20 mL). The organic layers were combined, dried (Na2SO4) and evaporated to dryness to give the desired product (263 mg, 79% over 2 steps). m/z 353 [M++H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.C(Cl)(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCCCCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(OCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.15 %

Procedure:
A solution of N-(4-hydroxyphenyl)-acetamide (paracetamol) (1) (1.50 g, 0.01 mol) and 1,5-dibromopentane (9) (10.0 ml) in ethyl methyl ketone (25.0 ml) containing potassium carbonate (5.0 g) was stirred for 8 hr at room temperature. The reaction mixture was filtered, residue washed with ethyl methyl ketone and solvent evaporated under reduced pressure to get the residue. The residue was dissolved in chloroform (200.0 ml), washed with 5% sodium hydroxide solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(5-bromo-pentoxy)-phenyl]-acetamide (11) (2.15 g, 72.15%), mp 110-111° C.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1>[OH-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:14][CH:15]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C=CC(=O)C(=O)O)cc1
Temperature: 0 °C

Procedure:
Sodium pyruvate (24.2 g, 0.22 mol) was dissolved in 200 ml 1N aqueous sodium hydroxide at 20° C. To this solution there was added anisaldehyde (27.4 g, 0.20 mol) at 0.2 ml/min. The solution was aged twenty-four hours at 20° C., cooled at 0° C. and acidified with 6N NCl to pH 1.0 while maintaining a temperature of 0° C. The 4-(p-methoxyphenyl)-2-oxo-3-butenoic acid product was then extracted with 500 ml ethyl acetate and isolated as a yellow solid by concentration under vacuum. The yield by HPLC analysis was 88%.
Reaction SMILES: O=C1NC(=O)NC2NN=CC1=2.[CH2:12]([N:14]1[C:19]2[N:20]([CH3:23])[N:21]=[CH:22][C:18]=2[C:17](=[O:24])[NH:16][C:15]1=[O:25])[CH3:13].[Br:26][CH2:27][CH2:28][CH2:29]Br>>[Br:26][CH2:27][CH2:28][CH2:29][N:16]1[C:17](=[O:24])[C:18]2[CH:22]=[N:21][N:20]([CH3:23])[C:19]=2[N:14]([CH2:12][CH3:13])[C:15]1=[O:25]
Reactant: BrCCCBr
Reactant: CCn1c(=O)[nH]c(=O)c2cnn(C)c21
Agent: O=c1[nH]c(=O)c2cn[nH]c2[nH]1
Product: CCn1c(=O)n(CCCBr)c(=O)c2cnn(C)c21

Procedure:
Provided one of the residues R1 or R2 is an alkylcarbonylalkyl group, profitably one can proceed in the way, that the corresponding 4,5,6,7-tetrahydro-4,6-dioxo-pyrazolo-[3,4-d]-pyrimidine is alkylated with a ω-ω'-dibromalkane to ω-alkyl derivative which is treated with acetoaceticester and the reaction product is subjected to a ketone decomposition reaction. For example by such a reaction with the 7-ethyl-4,5,6,7-tetrahydro-1-methyl-4,6-dioxo-1H-pyrazolo-[3,4-d]-pyrimidine with 1,3-dibromopropane, the 5-(3-bromopropyl)-7-ethyl-4,5,6,7-tetrahydro-1-methyl-4,6-dioxo-1H-pyrazolo-[3,4-d]-pyrimidine is obtained, which upon acetoaceticester condensation and subsequent ketone decomposition yields the 7-ethyl-4,5,6,7-tetrahydro-1-methyl-4,6-dioxo-5-(5-oxo-n-hexyl)-1H-pyrazolo-[3,4-d]-pyrimidine. The alkylcarbonyalky rest can also be introduced by direct alkylation reaction of the appropriate 4,5,6,7-tetrahydro-4,6-dioxo-pyrazolopyrimidine, preferably as a sodium salt, with an alkylcarbonylalkylhologenide, preferably a chloride or a bromide. For example a 5-oxo-n-hexyl group can be introduce by using 1-bromohexanone-5.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH3:8].C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:8][C:3]1[S:4][C:5]([Cl:7])=[CH:6][C:2]=1[Cl:1]
Reactant: Cc1sc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Cl)c(CBr)s1
Temperature: 0 °C
Yield: 55.3 %

Procedure:
A solution of 3,5-Dichloro-2-methyl-thiophene (1.3 grams, 7.8 mmole), NBS (1.4 grams, 7.8 mmole) and benzoyl peroxide (0.065 g) in carbon tetrachloride (40 ml) was refluxed for 18 hours. The mixture was cooled to 0° C., diluted with 40 ml hexane and filtered. The filtrate was concentrated to an oil which was purified via flash chromatography on silica using hexane as eluent to give an oil (1.06 g). MW 245.95; MS (m/e) 246 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[N:13]([CH3:23])[C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][C:17]([F:22])=[CH:16][CH:15]=3)(=[O:11])=[O:10])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[N:13]([CH3:23])[C:14]4[C:19]([C:20]=3[CH3:21])=[CH:18][C:17]([F:22])=[CH:16][CH:15]=4)(=[O:11])=[O:10])=[C:4]([C:24]([F:25])([F:27])[F:26])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C)c2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2C(F)(F)F)n(C)c2ccc(F)cc12
Yield: 58.2 %

Procedure:
This product was prepared in analogy to Example 2 starting from 5-fluoro-1,3-dimethyl-1H-indole-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.100 g), 4-pyridineboronic acid (0.040 g) in 1,2-dimethoxyethane (5.0 ml), ethanol (1.0 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.025 g) to obtain the title compound (0.058 g) as a brownish foam. MS (ISN): 462.4 (M−H)−
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]2=[N:7][NH:8][CH:9]=[C:5]2[CH2:4][CH2:3]1.[CH2:11]=[O:12].C(N(CC)CC)C>CC(C)=O>[CH3:1][C:2]1([CH3:10])[C:6]2=[N:7][N:8]([CH2:11][OH:12])[CH:9]=[C:5]2[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2c[nH]nc21
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CCc2cn(CO)nc21
Temperature: 130 °C
Reaction time: 5 h
Yield: 15.1 %

Procedure:
The mixture of 1.68 g of 6,6-dimethyl-2,4,5,6-tetrahydrocyclopenta [c] pyrazole, 0.41 g of paraformaldehyde and 0.2 g of triethylamine was stirred at 130° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure. Hexane was added to the residue, and then crystalline was formed. The crystalline was collected to obtain 0.31 g of {6,6-dimethyl-5,6-dihydrocyclopenta [c] pyrazole-2 (4H)-yl} methanol.
Reaction SMILES: C(O[CH:5]1[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:8][CH:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6]1)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([CH:7]1[CH2:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH:5]=[CH:6]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1Cc2sccc2C(OC(C)=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C=Cc2ccsc2C1
Yield: 56.7 %

Procedure:
A mixture of 4-acetoxy-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene (2.34 g), tosic acid monohydrate (0.13 g), and toluene (50 ml) was stirred at reflux for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and brine, and dried over MgSO4, and then evaporated in vacuo. After evaporation of the filtrate, the resulting oil was purified by chromatography on silica gel (CHCl3 -MeOH as eluent) to give 6-ethoxycarbonyl-6,7-dihydrobenzo[b]thiophene (1.03 g) as an oil.