Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:14]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15].C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:5]([CH3:7])=[C:6]1[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)Cc1cc(C)cn1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2[N+](=O)[O-])n1C
Yield: 93.7 %

Procedure:
A solution of 5.7 g (0.032 mole) of ethyl 1,4-dimethylpyrrole-2-acetate and 7.0 g (0.038 mole) of 2-nitrobenzoyl chloride in 130 ml xylene is heated at reflux under nitrogen for 18 hours. The mixture is stirred vigorously over a saturated sodium bicarbonate solution for 3 hours at room temperature. The xylene layer is separated from the aqueous layer, washed with brine, dried and filtered. The filtrate is concentrated in vacuo to give 9.9 g (95%) crude ethyl 1,3-dimethyl-2-(2-nitrobenzoyl)-pyrrole-5-acetate which can be used without further purification in the next step.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[O:47])[NH:37][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([CH3:40])[CH3:39])[CH:31]=4)=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1.CN(C=O)C>C(O)C.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[O:47])[NH:37][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)([CH3:40])[CH3:39])[CH:31]=4)=[CH:20][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1-c1cccc(C(=O)NC(C)(C)c2ccccc2)c1)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
NaOH (500 μL, 0.500 mmol, 1M aq.) was added to a stirring solution of ethyl 2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylate (50 mg, 0.080 mmol) in Ethanol (795 μL) at 60° C. The slurry was allowed to stir overnight. DMF (2 mL) was added along with additional portion of NaOH and the mixture was warmed to 70° C. and allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (49 mg, quant). LC-MS retention time: 2.36 min; m/z (MH+): 601. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH3:10]>C(OC(=O)C)C>[CH3:5][C:6]1[CH:20]=[CH:19][CH:18]=[CH:17][C:7]=1[O:8][CH:9]([C:11]1[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=1)[CH3:10]
Reactant: Cc1ccccc1OC(C)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1OC(C)c1nnc(N=C=O)s1
Reaction time: 8 h

Procedure:
A 500 milliliter, 3-neck flask equipped with a magnetic stirrer, thermometer, dry ice condenser/drying tube and inlet from a phosgene (COCl2) tank via a calibrated rotometer was charged with 50 milliliters of ethylacetate which was saturated with phosgene at 20° C. (approximately 0.5 mole of phosgene) and cooled in an ice bath. An additional 50 milliliters of ethylacetate was added and then 6.8 grams of 5-[1-(2-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole, (prepared above); a cloudy solution formed, the solution was stirred overnight, and then filtered to remove a small amount of insoluble sediment. The clear solution was topped on a roto-vac at 70° C. to form 8.1 grams of a viscous yellow residue of 5-[1-(2-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH3:24])(=[O:23])=[O:22].C(OCC)(=O)C>CN(C=O)C>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: CS(=O)(=O)c1ccc(Cl)cc1CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Product: Cl
Temperature: 25 °C
Yield: 11.9 %

Procedure:
(Step 4) A solution of 2-amino-5-chloronicotinamide (210 mg) and 2-(bromomethyl)-4-chloro-1-(methylsulfonyl)benzene obtained in Step 3 (450 mg) in DMF (5 ml) was stirred at 100° C. for 3 hr. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in aqueous sodium hydrogen carbonate solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:1→3:1). The obtained yellow solid was dissolved in methanol, and 2N hydrogen chloride-ethyl acetate solution was added. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol-ethyl acetate to give the title compound (30 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)Nc2ccc3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 191A (91.6 mg, 0.4 mmol) in DMF (4 mL) was added 2-aminoquinoline (64 mg, 0.44 mmol), EDAC (93 mg, 0.48 mmol), HOBT (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][O:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.ClCCl>[CH2:18]([O:9][C:8]([CH:5]1[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[CH2:7][O:6]1)=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: CC1(C)COC(C(=O)O)CO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)COC(C(=O)OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A solution of (5,5-dimethyl-[1,4]dioxan-2-yl)-methanol (657 mg, 4.5 mmol) in 1 M potassium hydroxide solution (6.7 mL, 6.7 mmol) was stirred at 5° C. A solution of potassium permanganate (1.42 g, 9 mmol) in water (10 mL) was added dropwise maintaining the internal temperature below 10° C. The reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 18 h. The reaction mixture was filtered through Celite and the filter pad was washed with water and methanol and the filtrate was evaporated. The residue was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with ethyl acetate and chloroform. The organic extracts were combined and washed with a small volume of brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (694 mg, 4.5 mmol) as a waxy solid. LCMS (m/z) 159.1 [M−H], Tr=0.88 min. A solution of 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (750 mg, 4.7 mmol), oxalyl chloride (600 mg, 0.4 mL, 4.7 mmol) and N,N-dimethylformamide (2 drops) in dichloromethane (15 mL) was stirred at room temperature under nitrogen for 2 h. A solution of benzyl alcohol (508 mg, 0.5 mL, 4.7 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 20 h. Additional benzyl alcohol (0.5 mL, 4.7 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 1:1 to afford the title compound (870 mg, 74%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.19 (s, 3H), 1.32 (s, 3H), 3.43 (d, J=11.4 Hz, 1H), 3.72 (d, J=11.4 Hz, 1H), 3.88-3.92 (m, 2H), 4.21 (dd, J=8.2, 4.7 Hz, 1H), 5.24 (s, 2H), 7.34-7.39 (m, 5H). LCMS (m/z) 273.1 [M+Na], Tr=2.41 min.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(OC2C=CC=CC=2)C=CC=CC=1.[O-]CC.[Na+].C([O:31][C:32](=O)[CH:33]=[C:34]([NH2:36])[CH3:35])C>C(O)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[NH:36][C:34]([CH3:35])=[CH:33][C:32]=1[OH:31])=[O:4])[CH3:7]
Reactant: CCOC(=O)C=C(C)N
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(O)cc(C)[nH]c1=O
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
In a 22 L vessel fitted with a mechanical stirrer and distillation head was charged 2.5 L (16.47 mol) diethyl malonate followed by 4.0 L diphenyl ether. Agitation was started and 1.12 Kg (16.47 mol, 1 eq) of sodium ethoxide was added via a powder funnel. The mixture was gradually, heated to 160° C. and the liberated ethanol was removed via distillation, approximately 950 mL. After 30 min, ethanol distillation ceased and 2.127 Kg (16.47 mol, 1 eq) of 3-amino-but-2-enoic acid ethyl ester was added, and the resulting ethanol formed removed via distillation. After 30 minutes the mechanical stirrer could no longer stir the foamy mass. At this point, external heating was ceased and the mixture allowed to cool to ambient temperature. To the mixture was charged 4 L of methyl-tert-butyl ether (MTBE) and the granular solid broken up with a spatula. The solid was filtered and washed with MTBE. To the solid was then added 100 mL of conc. HCl and 2 L of chloroform to solublize the mixture. The mixture was then taken up three times in 4 L chloroform, and decanted into a 20 L bucket. The combined organic phases were dried over sodium sulfate. The mixture was concentrated in vacuo to afford an orange gummy mass, which was triturated with MTBE and filtered, washing the filter cake with MTBE. The resulting solid was recrystallized from ethanol to afford the desired product as pinkish needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:49][C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][CH:58]=1)[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:55][CH:53]([C:52]2[CH:56]=[CH:57][CH:58]=[C:50]([Br:49])[CH:51]=2)[CH3:54])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(O)c1cccc(Br)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cccc(Br)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 62.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (111 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-bromo-α-methylbenzyl alcohol (75 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (79 mg, yield 584%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2SC)[CH:5]=[CH:6][CH:7]=1.B1([O-])OO1.[OH2:32].O.O.O.[Na+].[CH3:37]O>[Cl-].[Na+].O>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[O:32][CH3:37])[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Reactant: O
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]B1OO1
Product: COc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Yield: 42.2 %

Procedure:
A mixture of 4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (500 mg, 1.182 mmol) and sodium perborate tetrahydrate (700 mg, 3.85 mmol) in Methanol (5 mL) was irradiated in a microwave reactor at 110° C. for 15 min. The reaction was repeated three additional times. The four reaction mixtures were poured into brine and extracted with CH2Cl2 (4×). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified on silica gel (ISCO, 0-7% MeOH in CH2Cl2), but separation failed. The fractions containing product were combined, absorbed onto silica gel and resubmitted for purification on silica gel (ISCO, 0-5% MeOH in CH2Cl2), but again no separation was observed. The residues from the combined fractions were finally purified using Chiralpak IA (101×210 mm, 100% CH3OH, 500 ml/min) to give 4-[(3-chloro-2-methylphenyl)methyl]-5-(methyloxy)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (820 mg, 1.995 mmol, 42.2% yield) as a white powder. LC/MS (ES+): [M+H]+=407.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.36 (d, J=7.83 Hz, 1H), 7.15 (t, J=7.83 Hz, 1H), 6.72 (d, J=7.58 Hz, 1H), 5.34 (s, 2H), 3.85 (s, 3H), 3.60-3.74 (m, 4H), 3.51 (t, J=4.67 Hz, 4H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18]P(=O)(OCC)OCC)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:35])[N:13]2[C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34].[H-].[Na+].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=[C:48]2[CH2:49][CH2:50][N:45]([C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])[CH2:46][CH2:47]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:35])[N:13]2[C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34]
Reactant: CCOP(=O)(Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of diethyl [5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylphosphonate (422 mg, 0.762 mmol) in a mixture of THF (9 mL) and DMF (2 mL) at 0° C. was added sodium hydride (60%, 61 mg, 1.52 mmol). The resulting mixture was stirred at rt for 20 min and then cooled to 0° C. again. To this was added a solution of t-butyl-4-oxo-1-piperidinecarboxylate (310 mg, 1.524 mmol) in THF (2 mL). Then the reaction was stirred at rt for 22 h. The mixture was quenched with brine, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by flash chromatography using 20% acetone/hexane as eluent provided tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylene}piperidine-1-carboxylate as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.48 (s, 9H), 2.24 (brs, 2H), 2.31 (t, 2H, J=5.7 Hz), 3.31 (t, 2H, J=5.5 Hz), 3.45 (t, 2H, J=5.5 Hz), 4.35 (abq, 2H, J=14.4 Hz), 5.10 (s, 1H), 5.96 (s, 1H), 6.21 (s, 1H), 6.74 (s, 1H), 7.30-7.58 (m, 7H). MS (API-ES+): 600 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5[O:31][CH2:30][O:29][C:28]=5[CH:27]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[Cl:44][C:45]1[CH:46]=[C:47]([N:52]=[C:53]=[O:54])[CH:48]=[CH:49][C:50]=1[Cl:51]>C1(C)C=CC=CC=1>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:53]([NH:52][C:47]4[CH:48]=[CH:49][C:50]([Cl:51])=[C:45]([Cl:44])[CH:46]=4)=[O:54])=[CH:3][CH:4]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:21]1)[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1)Nc1ccc(Cl)c(Cl)c1
Reaction time: 24 h

Procedure:
To a solution of 3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (600 mg, 1.3 mmol) in toluene (20 mL) were added ethyldiisopropylamine (0.454 mL, 2.6 mmol) and 3,4-dichlorophenylisocyanate (270 mg, 1.4 mmol), and the resulting solution was stirred for 1 day under reflux. The reaction solution was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=1:19), and then recrystallized from ethyl acetate to thereby yield 280 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)[C:12]=2[OH:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:26]([C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[O:29])[NH2:27]>C(O)(C)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:27][NH:26][C:28]([C:30]3[CH:31]=[CH:32][C:33]([S:36]([NH:39][CH3:40])(=[O:37])=[O:38])=[CH:34][CH:35]=3)=[O:29])[C:12]=2[OH:25])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNS(=O)(=O)c1ccc(C(=O)NN)cc1
Reactant: Cn1nc(C(=O)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(C(=O)NN=C(c2ccccc2)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 21.9 %

Procedure:
[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl)methanone (0.254 mmol, 85 mg), 4-(hydrazinocarbonyl)-N-methylbenzenesulfonamide (0.254 mmol, 58 mg) and p-tosylic acid monohydrate (30 mol %, 13 mg) were dissolved in isopropyl alcohol (8.5 mL) and stirred at 100° C. for 19 hours. Then, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (30.3 mg, yield 22%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([C:19](=[O:24])N(OC)C)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[C:26]([NH:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[CH3:39])([CH3:29])([CH3:28])[CH3:27]>>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])[C:19](=[O:24])[CH2:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[C:31](=[O:40])[NH:30][C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C(=O)NC(C)(C)C)c(C)c1
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Product: Cc1ccc(C(=O)NC(C)(C)C)c(CC(=O)[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)c1

Procedure:
Using general procedure 2 with [(R)-1-(methoxy-methyl-carbamoyl)-2-(2,4,5-trifluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.4 g, 4.1 mmol) and N-tert-Butyl-2,4-dimethyl-benzamide (2.5 g, 12 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(N)cc2)CC1
Temperature: 25 °C
Yield: 97 %

Procedure:
To the solution of 1-tert-butoxycarbonyl-4-(4-nitrobenzyl)piperidine (4.53 g, 14.2 mmol) in methanol-tetrahydrofuran (1:1, 100 mL) were added activated carbon (2 g) and anhydrous ferric chloride (250 mg). To the mixture was added hydrazine monohydrate (5.64 mL), and the mixture was heated for 26 hours under ref lux. The reaction mixture was cooled to room temperature, the activated carbon was filtered off. The activated carbon was washed with metahnol. The filtrate and washings were combined, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=2/3) to give the titled compound (4 g) as colorless powdery crystals.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>>[CH3:5][C:3]1[CH2:4][CH:7]2[C:6](=[O:12])[O:11][C:9](=[O:10])[CH:8]2[CH2:1][CH:2]=1
Reactant: C=CC(=C)C
Reactant: O=C1C=CC(=O)O1
Product: CC1=CCC2C(=O)OC(=O)C2C1

Procedure:
reacting isoprene and maleic anhydride to form 4-methyl-1,2,3,6-tetrahydrophthalic anhydride;