Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](C(OC)=O)=[CH:16][C:15]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[N:14]2)=[CH:9][CH:8]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:17]=[CH:16][C:15]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[N:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)Nc1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)Nc1ccn(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Yield: 191.9 %

Procedure:
To a solution of (2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)amine (0.90 g, 2.95 mmol) in 20 mL of methylene chloride at ambient temperature was added trimethylaluminum (8.85 mL of a 2.0 M solution in toluene, 17.68 mmol) dropwise. The resulting solution was allowed to stir until no more gas evolution was observed (~15 min). To this solution was added 1-[(4-methoxy)phenyl]-3-(methoxycarbonylamino) -5-(methoxycarbonyl)pyrazole (0.90 g, 2.95 mmol) in 10 mL of methylene chloride. The resulting solution was stirred at 40° C. for 16 h and then was cooled to ambient temperature and quenched by the addition of saturated aq NH4Cl. After diluting with ethyl acetate, the organic layer was washed with 10% aq HCl, saturated aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The solid residue was recrystallized from hexanes/ethyl acetate to afford 1.4 g (82%) of the title compound. LRMS (ES+): 577.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[O:13][N:14]=[C:15]([CH3:16])[C:3]=12.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1>[CH3:16][C:15]1[C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2]=2[N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[O:13][N:14]=1
Reactant: CCOC(=O)c1cnc2onc(C)c2c1Cl
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: Cc1noc2ncc(C(=O)O)c(N3CCN(C)CC3)c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 4-chloro-3-methylisoxazolo[5,4-b]pyridin-5-carboxylate (1.02 g) and 1-methylpiperazine (1.12 ml) in tetrahydrofuran (10 ml) was stirred at room temperature for 1 hr and then concentrated under reduced pressure. The residue was treated with water, the precipitated solid was filtered, washed with water, and dried under high vacuum. This solid was suspended in ethanol (1 ml), added 5N NaOH (11 ml , and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was treated with 5N HCl and purified by ODS column (VARIAN MEGABOND ELUT C18) to give 3-methyl-4-(4-methyl-piperazin-1-yl)isoxazolo[5,4-b]pyridine-5-carboxylic acid as an amorphous solid. A portion of this amorphous solid (417 mg) was dissolved in thionyl chloride (40 ml) and heated at 50° C. for 3.5 hrs. The mixture was concentrated under reduced pressure, the residue was dissolved in THF (20 ml), and reacted with ammonia gas at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, the residue was treated with water, the resulting solid was filtered, washed with water, and dried under high vacuum to give the 3-methyl-4-(4-methylpiperazin-1-yl)-isoxazolo[5,4-b]pyridin-5-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N:52]1([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C)C=O.O>[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[CH2:35][N:55]2[CH2:56][CH2:57][CH2:58][N:52]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53][CH2:54]2)=[O:37])[CH:10]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (400 mg, 0.61 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), potassium carbonate (248 mg, 1.79 mmol, 2.92 equiv), potassium iodide (20 mg, 0.12 mmol, 0.20 equiv), and tert-butyl 1,4-diazepane-1-carboxylate (240 mg, 1.20 mmol, 1.95 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The resulting solution was diluted with 300 mL of water. The resulting solution was extracted with 4×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (20:1˜10:1). The product was obtained as 400 mg (85%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.875-8.887 (d, J=3.6 Hz, 1H), 8.287-8.298 (d, J=3.3 Hz, 1H), 8.253 (s, 1H), 7.936 (s, 1H), 7.772-7.936 (m, 2H), 7.433-7.711 (m, 7H), 7.106-7.146 (dd, J=2.7 Hz, J′=9.0 Hz, 1H), 4.689 (s, 2H), 3.740 (s, 2H), 3.482 (m, 4H), 3.197-3.232 (m, 4H), 2.656-2.693 (m, 4H), 1.720-1.847 (m, 6H), 1.614-1.649 (m, 2H), 1.420-1.459 (m, 9H). MS (ES, m/z): 771 [M+H]+; 793 [M+Na]+.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1([NH:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([C:33]2[C:34]([CH3:41])=[C:35]([CH:39]=O)[NH:36][C:37]=2[CH3:38])=[O:32])[CH2:23][CH2:22]1>N1CCCCC1.C(O)C>[CH:21]1([NH:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([C:33]2[C:34]([CH3:41])=[C:35](/[CH:39]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:36][C:37]=2[CH3:38])=[O:32])[CH2:22][CH2:23]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (27 mg), 4-((S)-2-cyclopropylaminomethyl-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (25 mg) and piperidine (1 drop) in ethanol (2mL) was stirred at rt for 4 hours, the precipitate was collected by vacuum filtration and purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:13]([NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[O:15])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1nnn[nH]1
Reactant: COc1nc2ccccc2nc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1nc2ccccc2nc1C(=O)Nc1nnn[nH]1

Procedure:
3Methoxy-2-quinoxalinecarboxylic acid (1.5 g) and N,N-carbonyldiimidazole (1.2 g) in tetrahydrofuran (50 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.7 g) in dimethylformamide (5 ml) was added and the solution was heated under reflux for 1 hour. The crystalline solid was collected and stirred with dilute hydrochloric acid (25 ml., 2N) and the solid was filtered off and dried. It had m.p. 260° (d) (45%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+:11]([O-])(O)=O>C(O)(=O)C.C(O)C.[Pd]>[NH2:11][C:7]1[C:8]([OH:10])=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: O=[N+]([O-])O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cc(N)c(O)cc1F

Procedure:
This was prepared from 2-fluoro-4-hydroxy-benzonitrile by nitration (concentrated nitric acid in acetic acid at 40° C.) followed by hydrogenation in ethanol over 10% palladium/carbon.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].CCN(C(C)C)C(C)C.[CH2:27](Cl)[O:28][CH3:29]>C(Cl)Cl>[CH3:27][O:28][CH2:29][O:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5]
Reactant: COCCl
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(OC2CCCCO2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
To a solution of 2-hydroxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (10.4 g, 44.0 mmol) in DCM (100 mL) at 0° C. was added DIPEA (11.5 mL, 66.0 mmol) followed by MOMCl (5.0 mL, 66.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (hexane:EtOAc 70:30) to give 2-methoxymethoxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (10.0 g, 81%). 1H NMR (400 MHz, CDCl3): δ 10.52 (s, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 5.51 (t, J=3.2 Hz, 1H), 5.25 (q, J=6.8 Hz, 2H), 3.87-3.81 (m, 1H), 3.65-3.61 (m, 1H), 3.51 (s, 3H), 2.57 (s, 3H), 2.04-1.58 (m, 6H). MS (ESI) m/z=281 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[F:6][C:7]([F:13])([F:12])[C:8](OC)=[O:9]>CO>[F:6][C:7]([F:13])([F:12])[C:8]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:9]
Reactant: COC(=O)C(F)(F)F
Reactant: NCCCO
Solvent: CO
Product: O=C(NCCCO)C(F)(F)F
Yield: 102 %

Procedure:
3-Amino-1-propanol (10.0 mL, 0.131 mol) and methyl trifluoroacetate (65 mL, 0.646 mol) in methanol (200 mL) were refluxed for 1.5 h, cooled and concentrated to give 2,2,2-trifluoro-N-(3-hydroxypropyl)-acetamide (22.87 g, quantitative) as a light yellow oil which was used without purification. NMR CDCl3 δ 7.45 (br s, 1H), 3.77 (t, J=5.5 Hz, 2H), 3.53-3.42 (m, 2H), 2.45 (s, 1H), 1.83-1.75 (m, 2H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)(C)=O.[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:42])[C:25](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][C:21]=2[F:43])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[CH:13]1([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:42])[C:25]([CH:35]4[CH2:8][CH:36]4[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:22][C:21]=2[F:43])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a 6 ml DMSO suspension of 200 mg of 60% sodium hydride was added 1.1 g of trimethylsulfoxonium iodide, followed by stirring for 30 minutes. To the reaction mixture was added 242 mg of ethyl (2E)-3-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]acrylate, followed by stirring at room temperature for 1 hour and at 60° C. for 1 hour. To the reaction mixture was added water, followed by extraction with diethyl ether. The organic layer was washed with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 55 mg of ethyl 2-[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]cyclopropanecarboxylate.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:28]([O-])=O)=[C:12]([CH:15]=[C:16]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH3:20])[CH:17]=3)[C:13]#[N:14])[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=[O:35])C.[NH4+]>CO.C1COCC1.[Zn]>[NH2:28][C:11]1[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[CH:17][C:16]([NH:18][C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH3:20])=[CH:15][C:12]=1[C:13]([NH2:14])=[O:35]
Reactant: C[C@H](Nc1cc(C#N)c([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)c(C(N)=O)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (S)-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)-2-nitrobenzonitrile (Method 97; 4.20 g, 10.0 mmol) and zinc dust (3.40 g, 52 mmol) in MeOH-THF (1:1, 100 ml) was slowly added saturated ammonium chloride (40 ml). The reaction mixture was stirred at 25° C. for 1 hour, to which was then added saturated ammonium acetate solution (50 ml). The resulting mixture was stirred for another 30 minutes. Zn dust was removed by filtration and washed with EtOAc (200 ml). The organic layer was separated, washed with brine (100 ml), dried over sodium sulfate, and concentrated. The crude product was used directly for the next step without further purification. MS: Calcd: 394; Found: [M+H]+ 395.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH3:11])(=[O:9])[CH2:7][CH3:8].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:8]#[C:7][C:6]([O:10][CH3:11])=[O:9])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.57N hexane solution, 6.4 ml) was added dropwise to a solution of methyl propionate (893 μl) in tetrahydrofuran (50 ml) at −78° C. After stirring for 30 minutes, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) in tetrahydrofuran (10 ml) was added, and the mixture was gradually warmed to room temperature and stirred overnight. A saturated aqueous solution (50 ml) of ammonium chloride and ethyl acetate (50 ml) were added to the reaction mixture to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate 3:1) to obtain the title compound (1.78 g) as a pale yellow caramel-like substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:2]1.O[C@H:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]>CO>[OH:18][C@@H:17]1[C@@H:19]([OH:20])[C@H:21]([OH:22])[C@@H:23]([CH2:25][OH:26])[O:24][C@H:16]1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:2]1
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: COC(=O)CC1CNc2ccccc21
Solvent: CO
Product: COC(=O)CC1CN([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc21
Temperature: 70 °C
Reaction time: 60 h
Yield: 87.7 %

Procedure:
To a solution of indoline 75 (8.5 g, 44.2 mmol) in MeOH (150 mL) was added α-D-glucose (27 g, 146 mmol) at room temperature. The mixture was stirred at 70° C. for 60 h, cooled to room temperature and concentrated in vacuo to remove solvent. The residue was purified by silica column chromatography to provide the titled compound 76 (13.7 g, 88%). MH+354.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:15]1([C:18](=[S:20])[NH2:19])[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:18]([CH:15]2[CH2:17][CH2:16]2)[S:20][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-Chloro-2-oxo-3-phenyl-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=0.99 min; [M+H]+=260.5.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:5][CH2:4][CH2:3][CH2:8][CH3:7])[C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=3)=[CH:5][CH:4]=2)[S:25]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Product: CCCCCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Yield: 180.6 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 320 mg (0.8 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)benzamide with 100 mg (0.8 mmol) of 2,4-thiazolidine dione, 350 mg (87%) of the expected product are obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([OH:24])=[O:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=O)C>CO>[O:1]([C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccccc1Sc1cccc(Oc2ccccc2)c1
Solvent: CO
Product: COC(=O)Cc1ccccc1Sc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Mercaptophenylacetic acid was prepared by a method described in the chemical literature (see D. Papa et al, J. Org. Chem., 1949, 24, 723, R. H. Glauert and F. G. Mann, J. Chem. Soc., 1952, 2127 and references therein). 2-Mercaptophenylacetic acid (1.68 g) was added to a stirred solution of sodium hydroxide (0.8 g) in methanol (10 ml), (compare D. C. Atkinson et al, J. Med. Chem., 1983, 26, 1361). The resulting orange solution was stirred at room temperature for 90 minutes then concentrated under reduced pressure, removing the final residues of methanol by azeotroping with toluene, to leave a yellow solid. Cuprous chloride (0.2 g) and a solution of 3-phenoxybromobenzene (2.49 g, prepared from 3-phenoxyphenol and triphenylphosphine dibromide by the method described by J. P. Schaefer et al, Org. Synth., Coll. Vol.5, 142) in DMF (10 ml) were added successively to a stirred solution of this yellow solid in DMF (20 ml). The resulting mixture was heated at 95° C. for 11/2 hours, at 125° C. for 2 hours, and then at reflux for a further 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydroxide then washed with ether (×3). The aqueous solution was acidified with concentrated hydrochloric acid and extracted with ether (×3). These extracts were washed with water, dried and concentrated to give a purple oil (2.2 g) consisting mainly of 2-(3-phenoxyphenylthio)phenylacetic acid. A solution of this oil in methanol (20 ml) was added to acidic methanol [prepared by carefully treating methanol (30 ml) with acetyl chloride (3.5 ml)] and the resulting mixture was stirred for 90 minutes at room temperature. The reaction mixture was concentrated and the residue was partitioned between ether and aqueous sodium bicarbonate. The organic layer was separated and washed successively with aqueous sodium hydroxide (×2) and water (×3) then dried and concentrated to give crude methyl 2-(3-phenoxyphenylthio)phenylacetate (2.06 g) as a purple oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[CH:36][N:35]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:43][C:40]5([C:37]6[CH:38]=[CH:39][N:34]=[N:35][CH:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: NC1(c2ccnnc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.184 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.093 g, 0.920 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5 eq). The reaction mixture was to stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent and further purified by prep HPLC. Yield: 0.053 g (52.42%). 1H NMR (400 MHz, CD3OD): δ 9.21-9.16 (m, 2 H), 8.01-7.94 (m, 2H), 7.81 (br. s., 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.17 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.38 (s, 3H), 1.75 (s, 4H). 19F NMR (376.51 MHz, CD3OD): δ −77.43 (TFA), −112.62. LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.N[C:12](N)=[O:13]>O>[Cl:1][C:2]1[C:7]2[NH:8][C:12](=[O:13])[NH:9][C:6]=2[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1N
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)nc(Cl)c2[nH]1
Temperature: 165 °C
Reaction time: 4 h

Procedure:
A mixture of 2,6-dichloro-3,4-dihydropyridine-3,4-diamine (500 mg, 2.8 mmol) from Step B and urea (1.0 g, 16.8 mmol) was stirred as a melt at 165° C. for 4 h, then cooled and H2O (100 mL) was added. The aqueous mixture was heated at reflux until all solid dissolved and the solution was allowed to cool and aged for 18 h. The precipitate was isolated by filtration to give the title compound. MS: m/z=204 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[O:13]([CH2:12][CH2:11][N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCOc1ccccc1
Reactant: O=Cc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cnn(CCOc2ccccc2)c1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
Sodium hydride (60%, 6.3 g, 1.0 eq) was added to a solution of 1H-pyrazole-4-carbaldehyde (15 g, 156 mmol) in DMF (150 ml) at 0° C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using a hexane/EtOAc gradient (10:1 to 0:100). Pure fractions were combined and evaporated under reduced pressure to yield 1-(2-phenoxyethyl)-1H-pyrazole-4-carbaldehyde (24 g, 71%).