Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[OH-].[Na+].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][NH2:19]>O.ClCCl>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:19]([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: NCc1ccccn1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: c1ccc(CN(Cc2ccccn2)Cc2ccccn2)nc1
Temperature: 0 °C
Yield: 54.2 %

Procedure:
5.0 g (30.5 mmoles) of 2-picolyl chloride hydrochloride were dissolved in 13 ml of water and 6 ml of 5.3 N NaOH were added to the resulting solution while cooling with ice. The red suspension obtained was cooled to 0° C. and a solution of 1.64 g (15.25 mmoles) of picolylamine in 26 ml of dichloromethane was added. The mixture was heated to room temperature and reacted with another 6 ml of 5.3 N NaOH over a period of several days during which measures were taken to ensure that the pH value did not rise above 9.5. The mixture was then washed twice with 7 ml of 15% NaOH and the organic phase was dried over sodium sulfate. After the drying agent had been removed, the solvent was evaporated off. The brown residue was extracted with ether and the solid obtained was recrystallized from ether. 2.4 g of tris-(2-pyridylmethyl)-amine were obtained.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH2:33]([O:35][C:36]([C:38]1[C:42]([CH:43]=O)=[CH:41][S:40][C:39]=1[NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:37])[CH3:34]>C1COCC1>[CH2:33]([O:35][C:36]([C:38]1[C:42]([CH:43]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:41][S:40][C:39]=1[NH:45][C:46]([O:48][C:49]([CH3:50])([CH3:52])[CH3:51])=[O:47])=[O:37])[CH3:34]
Reactant: CCOC(=O)c1c(C=O)csc1NC(=O)OC(C)(C)C
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C=Cc2ccccc2)csc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
Benzyltriphenylphosphonium bromide (1.30 g, 3.01 mmol) was suspended in anhydrous THF (6 mL) and cooled to 0° C. This was treated with n-butyllithium (1.20 mL, 3.01 mmol, 2.5M in hexanes) by slow addition. It was then stirred at 0° C. for 1.5 hr. Next it was treated with a solution of 2-t-butoxycarbonylamino-4-formyl-thiophene-3-carboxylic acid ethyl ester (0.300 g, 1.00 mmol) dissolved in anhydrous THF (6 mL) by slow addition. The reaction was allowed to stir at room temperature for 1 hr. It was then quenched with sat. NH4Cl (12 mL). This was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with H2O (1×25 mL) and brine (1×25 mL). The extracts were dried (Na2SO4), filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (SiO2, 1 EtOAc/3 hexanes) to afford the title compound (0.3432 g, 92%). MS m/e (CI) 374.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 1.26 (m, 1H), 1.36 (t, 1H), 1.44 (m, 1H), 1.54 (s, 9H), 4.35 (m, 1H), 6.34 (s, 1H), 6.59 (m, 1H), 6.93 (d, 1H), 6.89 (s, 1H), 7.17 (s, 1H), 7.35 (t, 1H), 7.47 (d, 1H), 7.59 (d, 1H), 10.40 (s, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH3:11])[N:5]=1.[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1>>[CH3:11][C:6]1[CH:7]=[C:8]([CH2:14][CH2:13][CH:12]2[CH2:16][CH2:7][CH2:6][N:5]2[CH3:4])[N:9]=[C:4]([NH2:3])[N:5]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(CCC2CCCN2C)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-(−)-1-methyl-2-pyrrolidine (320 mg, 2.78 mmol) in dry THF (10 mL) at 0° C. was added NaH (167 mg, 4.16 mmol). After stirred at RT for 1 h, 2-amino-4-chloro-6-methylpyrimidine (600 mg, 4.16 mmol) in dry THF (10 mL) was added dropwise via the addition funnel. The resulting mixture was heated to reflux under Ar gas for 20 h. The reaction was cooled to RT and quenched with sat. NH4Cl. Solvent was removed. The residue was partitioned between H2O and CHCl3. The organic layer was washed with H2O, brine, dried over MgSO4, and evaporated to dryness. This crude compound was purified in column eluted with CH2Cl2:MeOH=95%:5% to yield the title compound. MS m/z: 223.2 (M+H). Calc'd. for C12H20N4—222.2.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>C1COCC1>[C:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
4-Trifluoromethoxy aniline (3.4 g, 19.21 mmol)was dissolved in THF (25 ml) before pyridine (4.44 ml, 54.88 mmol) was added. 4-Acetyl-benzenesulfonyl chloride (4.0 g, 18.29 mmol) was then added as a solid, and the resulting dark solution was stirred for 10 minutes. The volatiles were then removed, and the resulting residue was suspended in THF. Excess Et3N was then added, and the mixture was stirred for several minutes before the solids were filtered. The mother liquor was then evaporated to a solid which was purified by flash chromatography (EtOAc/hexanes) to yield the desired compound as a white solid. (5.5 g (15.31 mmol, 84%).
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[CH:11]([CH2:13][C:14](O)=[O:15])=[CH2:12]>>[CH3:4][O:3][C:2]1[CH:5]=[C:6]2[C:7](=[CH:8][C:1]=1[O:9][CH3:10])[C:14](=[O:15])[CH2:13][CH:11]2[CH3:12]
Reactant: COc1ccccc1OC
Reactant: C=CCC(=O)O
Product: COc1cc2c(cc1OC)C(C)CC2=O
Temperature: 60 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
A mixture of 19.1 ml (150 mmol) of veratrol and 19.2 ml (225 mmol) of vinylacetic acid in 230 g of 83% polyphosphoric acid was stirred for 15 h at 60° C. and then poured into 500 ml of ice water. After 30 minutes (min) of stirring, the product was extracted three times, each time with 200 ml of ether. The combined organic phases were washed twice, each time with 100 ml of 2N NaOH, once with 100 ml of water and once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and freed from solvent on a rotary evaporator. After recrystallizing the residue (in AcOEt/pentane), 22.8 g (74%) of 5,6-dimethoxy-3-methylindan-1-one were obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[CH:19][C:20]([Br:22])=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1>>[NH2:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:13]3[CH:18]=[C:19]([S:2]([Cl:1])(=[O:5])=[O:3])[C:20]([Br:22])=[CH:21][C:12]=3[CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: Nc1nc2c(c(=O)[nH]1)-c1ccc(Br)cc1CC2
Reactant: O=S(=O)(O)Cl
Product: Nc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)c(Br)cc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
Chlorosulfonic acid(100 g) was added to 3-amino-8-bromo-5,6-dihydrobenzo[f] quinazolin-1(2H)-one(5.20 g,17.8 mmole) and the solution stirred overnight at room temperature. The reaction mixture was poured over ice, the collected solid washed with water, and dried under high vacuum to give 3-amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonyl chloride(7.25 g,90%). 1H NMR (DMSO-d6, 200 MHz) δ: 2.67-2.75 (m, 2H, Ar CH2), 2.81-2.88 (m, 2H, Ar CH2), 7.43 (s, 1H, Ar), 8.23 (br s, 2H, NH2), 8.91(s, 1H, Ar), 9.90-10.50 (v br s, 1H, NH). Anal Calculated for C12H9BrClN3O3S 1/2 H2O.9/20 H2SO4 : C,32.48; H,2.48; N,9.47; S,10.46. Found: C,32.68; H,2.37; N,9.20; S,10.40.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Si:15]([O:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: Cc1c(NC[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC[C@@H]2NCCC[C@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 89 %

Procedure:
A solution of 77G (170mg, 0.34 mmol) in 5% TFA/DCM (5 mL) was stirred at rt for 5 h and LC-MS showed completion. The mixture was concentrated and the residue was dissolved in EtOAc (30 mL), washed with saturated sodium bicarbonate solution (15 mL), brine (10 mL), dried (MgSO4) and evaporated to give desired product 77H (121 m, 89%) as a white solid: Rf (10% MeOH/DCM) 0.39; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 3.2 min (100%); MS (ES) m/z 344.1 [M+H]+; HRMS calcd for C20H33N3OSiCl 394.2081, Found 394.2080.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7](=[N:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[O:16][C:17]([C:20](=O)[NH:21][NH:22][C:23]([NH2:25])=[NH:24])=[CH:18][CH:19]=2)[N:14]=1)[NH2:8].O>[OH-].[NH4+]>[NH2:24][C:23]1[N:25]=[C:20]([C:17]2[O:16][C:15]([C:13]3[N:14]=[C:10]([N:9]=[C:7]([NH2:8])[NH2:6])[S:11][CH:12]=3)=[CH:19][CH:18]=2)[NH:21][N:22]=1
Reactant: N=C(N)NNC(=O)c1ccc(-c2csc(N=C(N)N)n2)o1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(N)=Nc1nc(-c2ccc(-c3nc(N)n[nH]3)o2)cs1
Yield: 60.1 %

Procedure:
A suspension of 2-(diaminomethyleneamino)-4-(5-guanidinocarbamoylfuran-2-yl-)thiazole sulfate (1.70 g) in concentrated ammonium hydroxide (17 ml) was refluxed with stirring. Additional ammonium hydroxide (8.5 ml) was added twice. After refluxing for 8 hours, water was added to the mixture and the resulting precipitate was collected by filtration, followed by recrystallization from aqueous N,N-dimethylformamide to afford 4-[5-(3-amino-1H-1,2,4-triazol-5-yl)furan-2-yl]-2-(diaminomethyleneamino)thiazole (0.73 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH:18]=[CH2:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26]O>[Pd]>[C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH:18]([CH3:26])[CH3:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Reactant: CO
Agent: [Pd]
Product: CC(C)c1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 2-(3,5-diphenylpyridazin-4-yl)-4-vinyloxazole (70 mg, 0.20 mmol) in methanol (5 mL), 10% Pd/C (35 mg, wt/wt) was added and the resulting reaction mixture was stirred at rt under hydrogen atmosphere for 2 h. The reaction mixture was filtered through celite bed, washed with methanol and evaporation of solvent under reduced pressure gave the crude product which was purified by column chromatography to furnish 2-(3,5-diphenylpyridazin-4-yl)-4-isopropyloxazole (compound 23) (25 mg, 95%) as pale yellow gummy liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:15])[CH2:11][N+:12]([O-:14])=[O:13].[CH:16](OC(=O)C)=O>O>[N+:12]([C:11]1[C:10](=[O:15])[C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[O:1][CH:16]=1)([O-:14])=[O:13]
Reactant: COc1ccc(C(=O)C[N+](=O)[O-])c(O)c1
Reactant: CC(=O)OC=O
Solvent: O
Product: COc1ccc2c(=O)c([N+](=O)[O-])coc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-Nitro-7-methoxy-4H-1-benzopyran-4-one was prepared by the addition of 1-(2-hydroxy-4-methoxyphenyl)-2nitro ethanone (2.11 g, 0.01m), prepared in Example 8, and sodium formate (0.68 g, 0.01m) to stirred acetic-formic anhydride (25 ml). The reaction was warmed to 80° C. and allowed to return to room temperature. After stirring at least an additional 1 hour, cold water (100 ml) was added. The product was filtered off, washed with fresh portions of water and sucked dry. Recrystallization from ethyl acetate gave yellow crystals (1.7 g, 77.5%), m.p. 185°-87° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.[I:40]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:37][Si:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:38])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:40])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (5 g, 8.65 mmol) in DMF (15 mL) was added N-iodosuccinimide (1.86 g, 8.27 mmol) and the resulting mixture was allowed to stir at room temperature for 1 hour. The mixture diluted with EtOAc (100 mL), washed with water (20 mL). The aqueous layer was extracted with EtOAc (20 mL) once, and combined organic layer was washed with water (20 mL) three times, brine once and dried (MgSO4). After concentration, the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hex (0-30%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (4.55 g, 75%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:24]([F:25])=[C:23]([NH2:26])[C:9]2[C:10](=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:27])(=[O:3])[CH3:2].[Br:28][CH2:29][CH2:30][C:31](O)=[O:32].Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:24]([F:25])=[C:23]([NH2:26])[C:9]2[C:10](=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:31](=[O:32])[CH2:30][CH2:29][Br:28])=[C:16]([F:21])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Reactant: O=C(O)CCBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCBr)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-amino-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (1.51 g, 4.00 mmol) in dimethylformamide (40 mL) were added 3-bromopropionic acid (3.06 g, 20.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.83 g, 20.0 mmol), and the mixture was stirred at room temperature for 45 minutes. Water was added thereto and the mixture was extracted with ethyl acetate. Purification by silica gel column chromatography (6:1 chloroform/acetate) gave 7-(acetoxymethyl)-5-amino-2-[4-[(3-bromopropionyl)amino]-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (554 mg, 27%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])=[O:3].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.N1CCCC1>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:2](=[O:3])[CH2:1][C:17]3([O:12][C:5]=2[CH:6]=1)[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]3
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc(C(C)=O)c(O)c1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)OC1(CCN(C)CC1)CC2=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 98.7 %

Procedure:
To a stirred solution of 2-hydroxy-4-methoxyacetophenone (4.08 g, 24.58 mmol) in anhydrous methyl alcohol (60 cm3) under an atmosphere of dry nitrogen was added 1-methyl-4-piperidinone (3 cm3, 24.58 mmol) followed by pyrrolidine (4 cm3, 47.92 mmol) and the solution was heated to reflux. After 7 h, a further portion of 1-methyl-4-piperidinone (0.6 cm3, 4.76 mmol) was added and the mixture was heated to reflux for a further 4.5 h. It was then allowed to cool to room temperature before the volatile fractions were removed under reduced pressure. The resulting oil was treated with dichloromethane (100 cm3), washed with water (5×100 cm3), dried over anhydrous sodium sulfate to afford a dark viscous oil (6.33 g, 24.25 mmol) which partially crystallised on standing over a long period of time.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Br.Br.Br.[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][NH:37][CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]>>[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][N:37]([CH2:5][C:4]6[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=6)[CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=Cc1cccc(O)c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3cccc(O)c3)C4)n[nH]c2c1
Yield: 62 %

Procedure:
The title compound was prepared from 3-hydroxy-benzaldehyde (24.2 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 18. The crude material was purified by HPLC Method A to afford 39.6 mg of the title compound.
Reaction SMILES: [CH2:1](O)[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[Br:36][CH2:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC#CCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCC#CCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of oct-3-yn-1-ol (1.26 g, 10.0 mmol) in DMF (25 mL) was added triphenylphosphine (2.92 g, 11.2 mmol). The solution was cooled to 0° C. and NBS (1.92 g, 10.8 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (150 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 1-bromo-oct-3-yne (1.35 g, 71%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.40 (2H, d, J=7.2 Hz), 2.78 (2H, m), 2.15 (2H, m), 1.22 (4H, m), 0.88 (3H, t, J=6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 82.83, 77.05, 31.18, 30.63, 23.68, 22.20, 18.67, 13.89.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:18][NH3+:19].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]1([CH2:7][C:8](=[N:19][OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH3+]O
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 1,3-diphenyl-2-propanone (5.0 g, 24 mmol) and hydroxylammonium chloride (3.3 g, 48 mmol) in a mixture of absolute ethanol (30 ml) and water (10 ml) was carefully added a solution of sodium carbonate (13.2 g, 96 mmol) in water (30 ml). The resulting mixture was stirred at room temperature for 16 h. The precipitated compound was collected and washed with water (3×15 ml) and dried to give 4.9 g of 1,3-diphenyl-2-propanone oxime.
Reaction SMILES: [C:1]12([C:12]3[C:11]([OH:13])=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][CH2:5][CH2:4]1)[CH2:3][CH2:2]2.CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[C:1]12([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:13][C:20]3[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=3)[O:6][CH2:5][CH2:4]1)[CH2:3][CH2:2]2
Reactant: Oc1cccc2c1C1(CCO2)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Oc2cccc3c2C2(CCO3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2,3-dihydrospiro[chromene-4,1′-cyclopropan]-5-ol (Intermediate 221, 63 mg, 0.358 mmol) in DMF (3 ml) K2CO3 (74.1 mg, 0.536 mmol) and 2-chloro-5-nitropyrimidine (86.0 mg, 0.536 mmol) were added and the reaction mixture was stirred at rt for 1 h. DMF was then evaporated under high vacuum, water was added and the reaction mixture was extracted with AcOEt (three times). Collected organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents affording the title compound (91 mg).
Reaction SMILES: CC(C)=O.N[C:6]1([O:15]O)[CH2:11][CH:10]([CH3:12])[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7]1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[CH3:12][CH:10]1[CH2:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6](=[O:15])[CH2:11]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: CCO
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 1 h

Procedure:
Acetone (11.6 g.) in ethanol (50 c.c.) was stirred at below 0°C and 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g; 80% pure) added. After stirring for ca. 1 hour the solid had dissolved. To the solution was added magnesium sulphate and it was stored at 0°C overnight. Filtration and distillation gave acetone and dihydroisophorone (probably containing some symmetrical amino-peroxide ##STR19## and a product (2.2 g.), b.p. 75° - 78°C/ 1.0 mm, had a peroxide equivalent 239.4 and gave N, 6.3% an elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3F)cccc2c1N
Yield: 65.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (125 mg, 0.40 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (136 mg, 0.80 mmol) were reacted to afford the title compound (93 mg, 66% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.56 (bs, 1H), 7.88 (dd, J=8.2, 1.5 Hz, 1H), 7.69-7.77 (m, 2H), 7.43 (t, J=8.3 Hz, 1H), 6.76-6.86 (m, 2H), 3.86 (s, 3H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.65 (apparent sextet, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=355 (M+H) HPLC 1.79 min.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:26])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:12](=[O:13])[CH2:11][C@H:10]1O.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][C@@H:14]1[C@@H:9](/[CH:8]=[CH:7]/[C@@H:6]([O:26][C:27](=[O:29])[CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH:10]=[CH:11][C:12]1=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C/CCCC(=O)OC
Solvent: c1ccncc1
Product: CCCCC[C@@H](/C=C/[C@H]1C=CC(=O)[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O
Temperature: 35 °C
Reaction time: 40 h

Procedure:
A mixture of 2.4 g of PGE2 methyl ester, 30 ml of acetic anhydride and 6 ml of pyridine was stirred at 35° C. for 40 hours. After concentration under reduced pressure, the residue was dissolved in diethyl ether, washed with water, and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 2.56 g of (5Z,13E)-(15S)-9-oxo-15-acetoxyprosta-5,10,13-trienoic acid methyl ester having the following physical characteristic: