Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+].Cl>C(O)C.O>[CH:13](=[C:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a 0° C. mixture of 9.66 g (59.6 mmol) of 6-methoxy-1-indanone and 6.32 g (59.6 mmol) of benzaldehyde in 10 ml ethanol was added 9.66 ml of a 4% KOH in ethanol solution. The reaction was stirred 1 hour and then added to 300 ml water and the pH of the quench adjusted to 2 with 1N hydrochloric acid. The resultant mixture was extracted with 3×300 ml ether, and the extracts combined, dried over MgSO4, evaporated and the residue triturated with ether to yield 10.8 g (72%) of present title compound as a solid. 1 -NMR(CDCl3, 300 MHz)delta(ppm): 3.80 (s, OCH3), 3.92 (s, CH2), 7.13 (dd, J=8, 2 Hz, ArH), 7.35 (m, 4ArH and vinyl H) and 7.6 (m, 3ArH).
Reaction SMILES: [CH:1]#[C:2][CH3:3].I[C:5]1[C:10](=[O:11])[NH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:6]=1.[Cl-].O>CS(C)=O.C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(Cl)Cl>[CH3:1][C:2]1[O:11][C:10]2=[N:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:6]=[C:5]2[CH:3]=1
Reactant: C#CC
Reactant: COC(=O)c1cc(I)c(=O)[nH]c1C(=O)OC
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cc(C)oc2nc1C(=O)OC
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Propyne (3.0 mLs, 0.045 mol) is condensed in a graduated cylinder in a dry ice/acetone bath and added to a stirred suspension of dimethyl 1,6-dihydro-5-iodo-6-oxo-2,3-pyridinedicarboxylate (13.48 g, 0.04 mol), cuprous iodide (0.38 g, 0.002 mol) and bis(triphenylphosphine)palladium II) chloride (2.81 g, 0.004 mol) in 150 mLs DMSO and 50 mLs triethylamine at 10° C. After addition of the propyne the reaction mixture is stirred at room temperature for 60 hours. Water is added and the mixture is extracted with ethyl acetate. The ethyl acetate solution is washed with water and dried over anhydrous MgSO4, then concentrated in vacuo to give a mixture of materials. The crude product is isolated by flash column chromatography using 9:1 methylene chloride:ethyl acetate. The fractions containing the title product are concentrated in vacuo and the residue is recrystallized from cyclohexane to give the pure compound mp 115°-118° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][CH2:31][OH:32].CC[O-].[Na+].CCO>CN(C=O)C>[CH2:31]([O:32][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:30]
Reactant: CCO
Reactant: O=C(Nc1cccc(CN2CCOCC2)n1)Nc1csc(-c2ccnc(Cl)c2)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(-c2nc(NC(=O)Nc3cccc(CN4CCOCC4)n3)cs2)ccn1
Reaction time: 2.5 h

Procedure:
To a mixture of 1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea (100 mg, 0.23 mmol, Example 90) and EtOH (50 mL) was added a 21 wt % NaOEt/EtOH solution (0.4 mL, 1.2 mmol) and DMF (2 mL). The mixture was heated to reflux for 15 h then additional 21 wt % NaOEt/EtOH solution (10 mL) were added. After 2.5 h, the reaction was complete as judged by LC/MS. The reaction mixture was concentrated in vacuo then diluted with EtOAc and the solid was filtered off. The filtrate was concentrated in vacuo to afford an orange slushy oil which was purified by silica flash chromatography (5–10% MeOH/CH2Cl2) to afford the title compound as a yellow solid. MS m/z: 441.1 (M+H). Calc'd for C21H24N6O3S: 440.16.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[OH:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CC(N(C)C)=O>[OH:25][C:26]1[C:27]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1ncccc1O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ncccc3O)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.2 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol), 3-hydroxypyridine-2-carboxylic acid (33 mg, 0.24 mmol), dry dimethylacetamide (6 mL), triethylamine (0.07 mL, 0.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (95 mg, 0.25 mmol) were mixed, and the mixture was stirred at room temperature for 24 hours. This reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=1/100), and then washed several times with ethyl acetate to give the title compound (37 mg, yield 42%) as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:24].[NH2:25][OH:26]>C(O)C>[ClH:24].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:25][OH:26])[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC1CN(CC(C)C(=O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Agent: Cl
Solvent: CCO
Product: CC1CN(CC(C)C(=NO)c2ccc(C(C)(C)C)cc2)CC(C)O1
Temperature: 5 °C
Yield: 95.8 %

Procedure:
9.5 g (0.03 mole) of p-tert.-butyl-2-methyl-3-(2,6-dimethyl-morpholin-4-yl)-propiophenone were heated under reflux with 3.6 g (0.05 mole) of hydroxylamine hydrochloride in 80 ml of ethanol for 20 hours. After cooling to 5° C., the mixture was filtered. The filtrate was concentrated, the residue was suspended in dilute sodium hydroxide solution and the suspension was extracted with chloroform. Ethereal hydrochloric acid was added to the organic phase and the reaction product which had precipitated was filtered off. 10.6 g (96% of theory) of p-tert.-butyl-2-methyl-3-(2,6-dimethyl-morpholin-4-yl)-propiophenone oxime hydrochloride of melting point 214° to 16° C. were obtained.
Reaction SMILES: CS(O[CH2:6][C:7]#[CH:8])(=O)=O.[Cl:9][C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[N:19]([CH3:27])[C:18]=2[Cl:28])=[C:12]([F:29])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(CC(C)C)=O>[Cl:9][C:10]1[C:15]([O:16][CH2:8][C:7]#[CH:6])=[CH:14][C:13]([C:17]2[C:21]([Cl:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[N:19]([CH3:27])[C:18]=2[Cl:28])=[C:12]([F:29])[CH:11]=1
Reactant: Cn1c(Cl)c(-c2cc(O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: C#CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C#CCOc1cc(-c2c(Cl)c(C(F)(F)F)n(C)c2Cl)c(F)cc1Cl
Temperature: 80 °C
Yield: 39.9 %

Procedure:
2-propinyl methanesulfonate (0.35 g; 2.6 mmoles) is added to a mixture of 3-(4-chloro-2-fluoro-5-hydroxyphenyl) -2,4-dichloro-1-methyl-5-trifluoromethyl pyrrole (0.9 g; 2.5 mmoles) and potassium carbonate (0.33 g; 2.39 mmoles) in methylisobutylketone (10 ml). The mixture is heated to 80° C. for 3 hours. The reaction mixture is poured into water (10 ml), extracted with ethyl ether (3×20 ml), the ether phase is washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated in a rotavapor. The raw product obtained (1.0 g) is chromatographed on silica gel, eluating with n-hexane/ethyl acetate 90:10. 0.40 g of solid white product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:29]1([CH2:39][NH2:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>O1CCCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:40][CH2:39][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: NCc1cccc2ccccc12
Reactant: COC(=O)CCCCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC(=O)NCc1cccc2ccccc12
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a solution of suberic acid monomethyl ester 6c (376 mg, 2.0 mmol) in anhydrous tetrahydrofuran (5 ml) under argon atmosphere triethylamine (0.36 ml, 2.6 mmol) was added and the resulting solution was cooled in ice bath. To the mixture iso-butylchloroformate (0.3 ml, 2.3 mmol) was added and the reaction was stirred for 20 min, then a solution of 1-naphthylmethylamine 1/89 (314 mg, 2 mmol) in tetrahydrofuran (1.5 ml) was added. The mixture was stirred at ice bath temperature for 15 min and for 1 h at room temperature, diluted with brine (50 ml) and extracted with ethyl acetate (3×25 ml). The organic phase was washed with brine, 5% NaHCO3, brine, saturated KH2PO4, and brine. The organic layer was dried (Na2SO4) and the solvent was evaporated. The residue was purified on silica gel (20 g) with chloroform-ethyl acetate as eluent to give the title compound 7/89, yield 85.4%. 1H NMR (CDCl3, HMDSO) δ: 1.12-1.81(m, 8H); 2.16(t, J=8.0 Hz, 2H); 2.25(t, J=8.0 Hz, 2H); 3.63(s, 3H); 4.87(d, J=6.0 Hz, 2H); 5.61(br s, 1H); 7.32-7.63(m, 4H); 7.67-8.09(m, 3H).
Reaction SMILES: Cl[B:2]([CH:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:25][Al](C)C.[Cl-].[NH4+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCCCCC>[CH3:25][B:2]([CH:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Al](C)C
Reactant: ClB(C1CCCC1c1ccccc1)C1CCCC1c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Product: CB(C1CCCC1c1ccccc1)C1CCCC1c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Chloro-bis-(2-phenyl-cyclopentyl)-borane from preparation 1 was diluted with 60 mL of dry hexanes under nitrogen. The solution was cooled to 0° C. and a 2M solution of trimethylaluminum in hexanes (5.8 mL) was added dropwise causing the reaction to turn orange. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. During this time a red-brown mass precipitated out of solution, leaving a yellow supernatant. The hexane supernatant was transferred via cannula to a nitrogen flushed separatory funnel containing 50 mL of saturated aqueous ammonium chloride. The organic phase becomes colorless and was transferred via cannula to a dry flask containing sodium sulfate for drying. The solution was then transferred via cannula to a dry, nitrogen-flushed flask and the solvent removed under aspirator vacuum and nitrogen. The clear oil was used directly without further characterization.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH:27]1([CH2:34]O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([CH2:34][I:25])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: II
Reactant: OCC1CCCCCC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICC1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of triphenylphosphine (24.59 g; 92.8 mmol) and imidazole (6.40 g; 93.1 mmol) in methylene chloride (100 mL) cooled to 0° C. and Iodine (23.52 g; 92.7 mmol) was added portionwise over a 10 minute period. A solution of cycloheptane methanol (9.14 g; 71.3 mmol) dissolved in methylene chloride (50 mL) was then added over a 5 minute period. The cooling bath was removed and the mixture allowed to warm to room temperature and stirred overnight. The mixture was diluted with methylene chloride, washed with water and the organic layer dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed (eluent:hexanes) to give 15.35 g (93%) of cycloheptylmethyl iodide as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[OH:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.CCN(CC)CC>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:13][CH2:14][C@H:10]([OH:9])[CH2:11]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O[C@H]1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O[C@H]1CCN(c2ccc(Br)cn2)C1
Yield: 72.6 %

Procedure:
Heat 5-bromo-2-fluoro-pyridine (10.33 g, 57.39 mmmol) in THF (50 mL) with (S)-3-hydroxypyrrolidine (5.00 g, 57.39 mmol) and Et3N (9.2 mL, 68.87 mmol) in a microwave reactor at 120° C. for 45 min. Dilute with EtOAc (150 mL), and wash with saturated NaHCO3 (2×50 mL) and water (100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 100% EtOAc to give 10.13 g (72%) of the title compound. MS/ES m/z (79Br) 244.0 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:15][O:16][C:17]1[CH:45]=[CH:44][C:20]([CH2:21][S:22][C@@H:23]2[CH2:27][N:26]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[C@H:25]([C:41]([OH:43])=O)[CH2:24]2)=[CH:19][CH:18]=1.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH:55]([CH3:59])[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C(#N)C.O1CCCC1>[CH3:15][O:16][C:17]1[CH:45]=[CH:44][C:20]([CH2:21][S:22][C@@H:23]2[CH2:27][N:26]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:29])[C@H:25]([C:41]([N:56]3[CH2:57][CH2:58][N:53]([C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:54][CH:55]3[CH3:59])=[O:43])[CH2:24]2)=[CH:19][CH:18]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3C)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
3.41 ml of triethylamine and 3.03 ml of pivaloyl chloride were added dropwise to a solution of 9.99 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 100 ml of dry acetonitrile, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 20 minutes. A solution of 5.38 g of 1-t-butoxycarbonyl-3-methylpiperazine in 50 ml of dry tetrahydrofuran was then added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed, in turn, with a 1N aqueous solution of oxalic acid, with water and with an aqueous solution of sodium chloride. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and cyclohexane ranging from 1:1 to 3:2 by volume as the eluent, to give 8.56 g of the title compound, as an amorphous solid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11](=O)[CH:10]([CH2:16][C:17]([OH:19])=O)[CH2:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:21][NH2:22]>C(O)C>[N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11]2=[N:21][NH:22][C:17](=[O:19])[CH2:16][CH:10]2[CH2:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CC1Cc2cc(-n3ccnc3)ccc2C1=O
Solvent: CCO
Solvent: O
Product: O=C1CC2Cc3cc(-n4ccnc4)ccc3C2=NN1
Yield: 48 %

Procedure:
A solution of 1.48 g of 2,3-dihydro-5-(1H-imidazol-1-yl)-1-oxo-1H-indene-2-acetic acid and 0.38 g of 85% hydrazine hydrate in 15 ml of ethanol is heated to reflux for three hours. The reaction mixture is filtered, the residue is washed with ethanol and purified by crystallization from ethanol to give 0.7 g of the product, 2,4,4a,5-tetrahydro-7-(1H-imidazol-1-yl)-3H-indeno[1,2-c]pyridazin-3-one, mp 263°-264° dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([O:14][CH2:15][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: O=C(O)COc1ccc(-c2ccccc2F)nn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: O=C(COc1ccc(-c2ccccc2F)nn1)N1CCCCC1

Procedure:
20 mg (0.08 mmol) of [6-(2-fluoro-phenyl)-pyridazin-3-yloxy]-acetic acid, 10.3 mg (0.12 mmol) of piperidine, 27.8 mmol (0.24 mmol) of NEM and 29.1 mg (0.089 mmol) of TOTU in THF were stirred at room temperature for 3 h. After filtration and evaporation, the product was purified by RP18 chromatography. Yield: 7 mg.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[C:6](=[O:16])[NH:7][N:8]([CH2:13][CH2:14][OH:15])[C:9]=1[CH:10]([CH3:12])[CH3:11].[CH3:21][C:22]([O:24][CH2:25][C@H:26]1[O:31][C@H:30](Br)[C@H:29]([O:33][C:34]([CH3:36])=[O:35])[C@@H:28]([O:37][C:38]([CH3:40])=[O:39])[C@@H:27]1[O:41][C:42]([CH3:44])=[O:43])=[O:23].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[OH:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[C:6]([O:16][C@@H:30]2[O:31][C@H:26]([CH2:25][O:24][C:22](=[O:23])[CH3:21])[C@@H:27]([O:41][C:42](=[O:43])[CH3:44])[C@H:28]([O:37][C:38](=[O:39])[CH3:40])[C@H:29]2[O:33][C:34](=[O:35])[CH3:36])=[N:7][N:8]([CH2:13][CH2:14][OH:15])[C:9]=1[CH:10]([CH3:12])[CH3:11]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)c1c(Cc2ccccc2O)c(=O)[nH]n1CCO
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2nn(CCO)c(C(C)C)c2Cc2ccccc2O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
To a solution of 4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-isopropyl-1,2-dihydropyrazol-3-one (90 mg), acetobromo-α-D-glucose (161 mg) and benzyl tri(n-butyl)ammonium chloride (101 mg) in dichloromethane (5 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.81 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane 1/1—ethyl acetate) to give the title compound (35 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[O:10])[C:2]1C=CC=C[CH:3]=1.Cl.[H][H].ClC(OCC=C)=O.[OH-].[Na+].[Cl-].[Na+]>[Pd].O1CCCC1.O.C(OCC)(=O)C.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][C@H:12]1[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[O:10])[CH:2]=[CH2:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](Cn2ccnc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: C=CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1Cn1ccnc1
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A mixture of (2S,4R)-1-benzyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (8.60 g), conc. hydrochloric acid (1.76 ml), methanol (80 ml) and 10% palladium on carbon (50% wet) (4.50 g) was stirred for 6 hours under atmospheric pressure of hydrogen residue. The residue was dissolved in a mixture of tetrahydrofuran (22 ml) and water (22 ml). To the solution was added dropwise allyl chloroformate (2.5 ml) under ice-cooling, keeping pH 9-10 with 4N sodium hydroxide and then the mixture was stirred at the same condition for 30 minutes. To the reaction mixture were added sodium chloride (1.0 g) and ethyl acetate (10 ml). The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-(imidazol-1-yl)methyl-4-methanesulfonyloxypyrrolidine (5.85 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27](OCC)=O)[CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]2[NH:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:11]=2)[CH:22]=1)#[N:20]
Reactant: CCOC(=O)c1cc(C#N)ccn1
Reactant: NCC(N)(c1ccc(F)cc1)c1ccc(F)cc1
Product: N#Cc1ccnc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)CN2)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The mixture of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine (153 mg) and 4-cyano-2-ethoxycarbonylpyridine (95 mg) was stirred at 180° C. for 2 hours. The obtained oily compound was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=3:2) to give the objective compound (103 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(OCl)(C)(C)C.[CH3:22][S:23][CH:24]([CH3:30])[C:25](OCC)=[O:26].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:2]=1[NH:1][C:25](=[O:26])[C:24]2([CH3:30])[S:23][CH3:22])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(C)SC
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1(C)C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 3.94 g. (0.02 mole) of 2-aminobenzophenone in methylene chloride at -65° C. was treated with 2.16 g. (0.02 mole) of t-butylhypochlorite. After 15 min. 2.96 g. ethyl α-(methylthio)propionate was added dropwise and stirring continued for 1 hr. At the end of this time 2.02 g. of triethylamine (0.02 mole) was added dropwise and the reaction solution was allowed to warm to room temperature. This was followed by treatment with 1N hydrochloric acid and stirred for 15 min. The methylene chloride solution was then separated and stripped under vacuum. The yellow oil residue was triturated with isopropyl ether and 3 g. of a yellow solid was filtered off (51%). Recrystallization from absolute ethanol gave a cream color solid, m.p. 135°-137° C.