Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[OH:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1ccc(N2CCNCC2)c(O)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(C)cc3O)CC2)c(OC)nc1C
Yield: 52 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-hydroxy-4-methylphenyl)piperazine were reacted by the same way with example 1 to obtain the titled compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C@@H:14]([C:15]#[C:16][Si](C)(C)C)[NH:13][C:12]1=[O:21])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:23].C(=O)([O-])O.[Na+].C(OCC)(=O)C.O>O1CCCC1.O.S([O-])([O-])(=O)=O.[Hg+2]>[C:15]([C@H:14]1[NH:13][C:12](=[O:21])[C@H:11]1[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])(=[O:23])[CH3:16]
Reactant: O=S(=O)(O)O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1C#C[Si](C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)[C@H]1NC(=O)[C@H]1C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.1 %

Procedure:
Cis-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-trimethylsilylethynyl-2-azetidinone (0.24 g) is dissolved in a mixture of tetrahydrofuran (5 ml) and water (1 ml), and mercury sulfate (0.03 g) and concentrated sulfuric acid (0.06 g) are added, followed by stirring at room temperature for 15 hours. After addition of sodium hydrogen carbonate (0.2 g), the reaction mixture is poured into ethyl acetate-water, and the organic layer is separated, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography to give 0.03 g of cis-4-acetyl-3-[1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone.
Reaction SMILES: ClCCCl.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].[Cl-].[Cl-].[Cl-].[Al+3]>CCO>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:19]([C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)=[O:20])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 40 °C

Procedure:
A 2-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with DCE (480.8 mL), chlorobenzene (1) (90.4 mL, 888.5 mmol) and 4-nitrobenzoylchloride (111.4 g, 600.3 mmol), and the resulting mixture stirred and warmed to 40° C. Aluminum trichloride (97.0 g, 720.4 mmol) was added portionwise over 1 h and then the reaction was heated to 60° C. and stirred for 10 h. The reaction was cooled to 20° C., poured into ice-water (2 L) and stirred for 10 min. The resulting aqueous mixture was extracted with DCM (600 mL×2). The combined organic extracts were was washed with deionized water (1 L×3). The solvent was concentrated at 40° C. to remove DCM and then at 66° C. to yield a pale to slight yellowish solid, which was dissolved in hot EtOH (500 mL) at 76° C., stirred for 30 min, and then gradually cooled to 4° C. over 1 h. The resulting solid was collected by filtration to yield (4-chlorophenyl)(4-nitrophenyl)methanone as a slightly yellowish crystalline solid. (ES, m/z) 262 (M+H)+, 284, 286 (M+Na)+
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][Br:29])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(NC1CCCCC1)c1ccc(CBr)c2ccccc12

Procedure:
To a solution of 4-methyl-naphthalene-1-sulfonic acid cyclohexylamide 40 (3.0 g, 10 mmol) in CCl4 (100 mL) was added NBS (2.1 g, 12.0 mmol) and benzoyl peroxide (240 mg, 1.0 mmol), The reaction mixture was heated at reflux overnight. The solid was filtered and the filtrate was concentrated in vacuo. The title compound was a yellow residue (2.5 g, solidified on standing) which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.70 (m, 1H), 8.25 (m, 2H), 7.70 (m, 2H), 7.60 (d, 1H), 4.94 (s, 2H), 4.58 (m, 1H); 3.15 (m, 1H), 1.55 (m, 5H), 1.05 (m, 5H); LC/MS m/z 356 (M+H)+ 382.
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([CH2:35]O)[CH:33]=3)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][NH2:1])[CH:33]=3)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(CO)cc32)CC1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(CN)cc32)CC1
Yield: 105.4 %

Procedure:
Under ice cooling, a solution of diethyl azodicarboxylate (4.6 g) in tetrahydrofuran (20 ml) was added dropwise into a solution of 1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-hydroxymethylindoline (7.9 g), triphenylphosphine (6.9 g) and phthalimide (3.9 g) in tetrahydrofuran (250 ml) and the resultant mixture was stirred at room temperature for 3 hr. After concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system). Then hydrazine hydrate (3.6 g) and ethanol (150 ml) were added thereto followed by healing under reflux for 2 hr. After ice cooling, the resulting crystalline precipitates were filtered off and the filtrate was concentrated under reduced pressure to give the title compound (8.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[C:27]([CH3:29])[C:6]([C:7]([NH:9][CH2:10][CH2:11][C@H:12]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:21][C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH2:16][CH2:15]2)[CH3:13])=[O:8])=[C:5]([CH3:30])[N:4]=1)#[N:2].Cl.[NH2:32][OH:33]>CCO.C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[OH:33][NH:32][C:1]([C:3]1[CH:28]=[C:27]([CH3:29])[C:6]([C:7]([NH:9][CH2:10][CH2:11][C@H:12]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:21][C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH2:16][CH2:15]2)[CH3:13])=[O:8])=[C:5]([CH3:30])[N:4]=1)=[NH:2]
Reactant: NO
Reactant: Cc1cc(C#N)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=N)NO)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Yield: 77 %

Procedure:
To a solution of 6-cyano-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (208 mg, 0.49 mmol) in EtOH (3 ml) was added hydroxylamine HCl (190 mg, 2.73 mmol) and NaHCO3 (239 mg, 2.84 mmol) and the reaction heated to reflux overnight. The mixture was diluted with CH2Cl2 (25 ml) and water (10 ml) and saturated aqueous NaHCO3 (20 ml). The aqueous layer was extracted with CH2Cl2 (2×5 ml) and the combined organic extracts were dried (Na2SO4) and concentrated to afford 6-(N-hydroxycarbamimidoyl)-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (173 mg) as a beige foam.
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][C@H:13]2[CH2:17][C@H:16]([C:18](=[O:33])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C:27]4=[O:32])=[CH:22][CH:21]=3)[N:15]([C:34](=[O:43])[NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[CH2:14]2)=O)=CC=1)([O-])=O>CO>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([NH:35][C:34]([N:15]2[CH2:14][C@@H:13]([OH:12])[CH2:17][C@@H:16]2[C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)=[O:33])=[O:43])=[CH:37][CH:38]=1
Reactant: O=C(O[C@H]1C[C@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
8.3 0.075 ml of 1N sodium hydroxide solution is added with ice cooling to the solution of 50 mg (0.082 mmol) of (3S,5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl 4-nitrobenzoate in 2 ml of methanol, and the reaction mixture is stirred for 15 minutes. The precipitate is filtered off and washed with 2 ml of methanol and dried, giving 35 mg (93%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide as colourless crystals, ESI 459, m.p. 243° (decomposition).
Reaction SMILES: [NH2:1][N:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]1=[NH2+:10].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[Cl:24][CH2:25][C:26](OC)=O.C(=O)([O-])[O-].[K+].[K+]>CCO>[Cl:24][CH2:25][C:26]1[N:10]=[C:3]2[C:4]([CH3:9])=[CH:5][CH:6]=[C:7]([CH3:8])[N:2]2[N:1]=1
Reactant: COC(=O)CCl
Reactant: Cc1ccc(C)n(N)c1=[NH2+]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(C)n2nc(CCl)nc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
A suspension of 1-amino-3,6-dimethylpyridin-2(1H)-iminium-2,4,6-trimethylbenzenesulfonate (crude product from the previous step, 8.2 mmol), methyl 2-chloroacetate (1.78 g, 16.4 mmol) and potassium carbonate (2.26 g, 16.4 mmol) in EtOH (30 mL) was stirred at 80° C. for 16 h. After cooled to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with 20% v/v EtOAc in PE) to give the title compound (920 mg, yield 36%, 2 steps). ESI MS: m/z 196, 198 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 7.24 (d, J=7.2 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 4.85 (s, 2H), 2.74 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[O:25][C:24]2[C:17](=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=O)[O:16]1.CO.[BH4-].[Na+]>C(O)=O>[O:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:18]([CH2:19][NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17]=2[O:16][CH2:15]1
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: O=Cc1cccc2c1OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: c1ccc(Oc2ccccc2NCc2cccc3c2OCO3)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
A mixture of 2-phenoxy-phenylamine (410 mg, 2.22 mmol) and 2,3-(methylenedioxy)-benzaldehyde (500 mg, 3.33 mmol) was heated at 90° C. for 2 h under nitrogen. The reaction was cooled to 0° C. and MeOH (4 mL) was added, followed by NaBH4 (253 mg, 6.70 mmol) in portions over 20 min. The mixture was stirred at room temperature for 24 h. Formic acid (0.4 mL was added and the mixture stirred for 15 min. The solvents were removed in vacuo, the residue quenched with saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×30 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with petroleum spirit (A) and ethyl acetate (B) (5% B, 80 g, 4.0 CV, 60 mL/min) to afford 360 mg (51%) of N-(benzo[1,3]dioxol-4-ylmethyl)-N-(2-phenyloxy-phenyl) amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>O.C(#N)C>[C:54]1([NH:53][C:17]([C:15]2[CH:14]=[CH:13][C:5]3[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:2]([Cl:1])=[N:3][C:4]=3[CH:16]=2)=[O:19])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: Nc1ccccc1
Reactant: COCCOCn1c(Cl)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCn1c(Cl)nc2cc(C(=O)Nc3ccccc3)ccc21
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
To a solution of 2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid (0.235 g, 0.825 mmol) and acetonitrile (4 mL) was added HATU (0.408 g, 1.07 mmol). The resulting suspension was stirred at 23° C. for 5 min, treated with DIPEA (0.428 mL, 2.48 mmol) and stirred for an additional 20 minutes. The reaction mixture was then treated with aniline (90.0 μL, 0.990 mmol) and stirred for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-70% EtOAc/hexanes) to yield the titled compound (0.265 g, 89%) as a mixture of regioisomers. MS (ESI/CI): mass calcd. for C18H18ClN3O3, 359.1; m/z found, 360.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 10.26 (d, J=7.5 Hz, 2H), 8.32 (dd, J=3.6, 1.5 Hz, 2H), 7.99 (dd, J=8.6, 1.6 Hz, 1H), 7.94 (dd, J=8.5, 1.6 Hz, 1H), 7.87-7.73 (m, 6H), 7.41-7.32 (m, 4H), 7.16-7.02 (m, 2H), 5.75 (d, J=8.6 Hz, 4H), 3.67-3.61 (m, 4H), 3.43 (ddd, J=6.3, 4.7, 3.1 Hz, 4H), 3.19 (d, J=1.5 Hz, 6H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][N:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCNC2)cc1OC1CCCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
460 mg of 3-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine and 214 mg of triethylamine were dissoved in 15 ml of dichloromethane and cooled in an ice bath. During agitation, 229 mg of ethyl chloroformate was added in drops. After dropping, agitation was continued for 1 hour at a room temperature. Thereafter, the agitated solution was poured into ice water and then extracted with dichloromethane. After organic layers were cleaned by water and dried over magnesium sulfate, it was concentrated under a reduced pressure. The residue was purified by means of the silica gel column chromatography to obtain 92 mg of Compound No. 4 in Table 1.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:10]1)=[O:5])C.[OH-].[Na+]>O.CO>[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:10]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 74.4 %

Procedure:
A mixture of 3-[2-(3-ethoxycarbonylpropyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (13.7 g) and sodium hydroxide (2.73 g) in a mixture of water (8.6 ml) and methanol (96 ml) was refluxed for 2 hours and then the solvent was evaporated in vacuo. The residue was dissolved in water, and the aqueous solution was acidified with hydrochloric acid, and extracted with chloroform. The extract was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and n-hexane to give 3-[2-(3-carboxypropyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (9.48 g).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH:13]1[CH:14]=[CH:15][C:16]([NH:23][C:24]2[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:30])=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=1.[ClH:32].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH:13]1[CH:14]=[CH:15][C:16]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:18]=1.[ClH:32]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(N)O
Reaction time: 3 h

Procedure:
In 2 ml of dichloromethane, 1019 mg of the Boc-aminopropanol-diclofenac obtained above was dissolved, and 8 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring for 3 hours. After 150 ml of diethyl ether was added thereto for precipitation, the precipitate was dried under reduced pressure. The titled compound was obtained at a yield of 791 mg (90%). The structure was identified by 1H-NMR.
Reaction SMILES: C(S([C:6]1[N:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:11][CH:12]=2)[N:7]=1)(=O)=O)C.[NH2:30][C:31]1[CH:40]=[CH:39][C:34]2[NH:35][C:36](=[O:38])[NH:37][C:33]=2[CH:32]=1>C(#N)C>[O:38]=[C:36]1[NH:35][C:34]2[CH:39]=[CH:40][C:31]([NH:30][C:6]3[N:15]=[CH:14][C:13]4[C:8](=[CH:9][C:10]([O:16][CH:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]5)=[CH:11][CH:12]=4)[N:7]=3)=[CH:32][C:33]=2[NH:37]1
Reactant: CCS(=O)(=O)c1ncc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nc3c2)CC1
Yield: 50 %

Procedure:
A solution of tert-butyl 4-(2-(ethylsulfonyl) quinazolin-7-yloxy)piperidine-1-carboxylate (1 eq) and 5-amino-1,3-dihydro-benzimidazole-2-one (5 eq) in acetonitrile was heated in sealed tube at 110° C. for 48 h. The product was filtered, washed and dried. A brown solid, yield 50%. ES/MS m/z 477.5 (MH+).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.CC(C)([O-])C.[Na+].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C=O)C>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][N:20]1[C:16](=[O:26])[C:17]2[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19]1=[O:21]
Reactant: Cn1ccnc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccnc1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
The compound (83.50 g) obtained in Example 10-2 was suspended in DMF (250 ml) and added with sodium t-butoxide (49.00 g) at −30° C. The solution was further added with a potassium phthalimide salt (95.0 g) and then the whole was stirred at 70° C. for 2 hours. After completion of the reaction, the resultant was added into water (800 ml). The precipitated crystal was filtrated, washed with water, and dried, thereby obtaining the subject compound (101.5 g) as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[CH:7]=[C:6]([C:19]([O:21]CC)=[O:20])[C:5]2=[O:24].[CH2:25]([NH:27][C:28]([NH:30][C:31]1[CH:36]=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)=[O:29])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+]>O1CCOCC1.O.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>[CH2:25]([NH:27][C:28](=[O:29])[NH:30][C:31]1[N:32]=[CH:33][C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH:7]=[C:6]([C:19]([OH:21])=[O:20])[C:5]3=[O:24])=[C:35]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[N:41]=2)[CH:36]=1)[CH3:26]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(C[C@@H]2CCCNC2)c2ccc(I)cc2c1=O
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C[C@@H]2CCCNC2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a solution of (R)-ethyl 6-iodo-4-oxo-1-(piperidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate (Intermediate 108, 200 mg, 0.42 mmol, 1 equiv.) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 17, 151 mg, 0.42 mmol, 1 equiv.) in 1,4-dioxane (4.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (48.5 mg, 0.04 mmol, 0.1 equiv.) followed by a solution of cesium carbonate (205 mg, 0.63 mmol, 1.5 equiv.) in water (1.5 mL). This was stirred at 100° C. for 2 h. 2 M lithium hydroxide (0.629 mL, 1.26 mmol, 3 equiv.) was then added and the mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water, and the precipitate that formed was collected by filtration, washed with water and hexanes and dried under vacuum. Purification via reverse phase HPLC (C18, 0-95% acteonitirile/water gradient) gave (R)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1-(piperidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (92.5 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[N:28]=[C:27]([CH:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)[O:26][N:25]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]4[N:28]=[C:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[O:26][N:25]=4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1noc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1noc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
1,1-Dimethylethyl 4-[3-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carboxylate (12.3 g, 20.4 mmol) was dissolved in MeOH (100 ml) and HCl (4M in dioxane; 65 ml) was added. The solution was stirred at room temperature for 10 min and concentrated to half the initial volume. Ethyl ether was added to the suspension obtained and the precipitate was collected by filtration, washed with ether and concentrated to dryness to give 8 g of N-(3,4-dichlorophenyl)-6-(methyloxy)-7-{[(5-piperidin-4-yl-1,2,4-oxadiazol-3-yl)methyl]oxy}quinazolin-4-amine (78% yield). 1H NMR (400 MHz; DMSO-d6): 1.61 (qd, 2H), 1.94 (m, 2H), 2.07-2.19 (br s, 1H), 2.57 (td, 2H), 2.95 (dt, 2H), 3.17 (m, 1H), 3.97 (s, 3H), 5.44 (s, 2H), 7.40 (s, 1H), 7.63 (d, 1H), 7.85 (s, 1H), 7.87 (dd, 1H), 8.23 (d, 1H), 8.54 (s, 1H), 9.64 (s, 1H); MS (EI) for C23H22Cl2N6O3: 501.07 (MH+)