Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])=[O:24]>C(#N)C.O>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:23](=[O:24])[CH2:22][NH:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: Nc1cccc(N2CC(=O)NS2(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CN(c2cccc(NCC(=O)c3ccc(Cl)cc3Cl)c2)S(=O)(=O)N1
Temperature: 35 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of 5-(3-amino-phenyl)-1,1-dioxo-[1,2,5]thiadiazolidin-3-one (5 g, 22 mmol) in 37.5 mL of 9:1 v/v acetonitrile-water was added NaHCO3 (4.62 g, 55 mmol). The mixture was stirred at 25° C. while 2-bromo-1-(2,4-dichloro-phenyl)-ethanone (7.1 g, 26.4 mmol) was added. The mixture was stirred for 12-16 hours at 35° C. The mixture was cooled on an ice bath to further precipitate the product, which was then collected by filtration. The filtrate was concentrated under reduced pressure and a second crop of crude product was collected. The combined crude product washed once with 25 mL water and dried, then washed once with 10 mL methyl tert-butyl ether and dried, to provide 6.36 g (70% yield) of 5-{3-[2-(2,4-dichloro-phenyl)-2-oxo-ethylamino]-phenyl}-1,1-dioxo-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O.CCOC(C)=O>CCO>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCCCCOc1ccccc1
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A mixture of 2-(4-phenoxybutyl)1H-isoindole-1,3(2H)-dione (10.10 g, 3.27 mmol) and 25% hydrazine solution in water (2.88 ml, 13.10 mmol) in EtOH (30 ml) was warmed at reflux. After 1.5 h, EtOAc was added and the mixture was extracted with brine. The combined aqueous phases were then re-extracted with EtOAc and all the organic phases combined. These were then extracted with 1N HCl, the acidic aqueous phases combined, basified with 2N NaOH and re-extracted into EtOAc before evaporating to dryness to give the title compound (0.411 mg, 67%) as an oil. 1H NMR (500 MHz CDCl3): δ 7.32-2.26 (m, 2H), 6.95 (t, 1H), 4.00 (t, 2H), 2.80 (t, 2H), 1.90-1.82 (m, 2H), 1.68-1.62 (m, 2H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:29][CH2:28][N:27]([CH:26]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:32][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1-c1cccs1

Procedure:
92 mg (84%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (55 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: C([NH:4]CC1SC=C(CN2CCN([C@@H]([C@@H](C)CC)C(OC(C)(C)C)=O)C2=O)N=1)(C)C.C([O-])(O)=O.[Na+].Cl[C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37]>C(#N)C.O>[C:36]([NH2:4])([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(CNC(C)C)n2)C1=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 141.4 %

Procedure:
A solution of the product of Example 283A (59 mg) in acetonitrile (0.9 mL) and water (0.3 mL) was treated with NaHCO3 (34 mg, 2.4 equivalents) followed by 9-fluorenylmethyl chloroformate (53 mg, 1.2 equivalents) at 25° C. for 1.5 h. The solvents were evaporated and the residue was purified using ethyl acetate:chloroform (1:4) to give 47 mg (40%) of FMOC-amine which was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stirred at 25° C. for 1 h. The solvents were evaporated, and the acid was used directly for the next step.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C.[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Br>C(#N)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([F:38])[CH:40]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:27][CH:28]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (1.898 g, 5.0 mmol) in 25 mL acetonitrile was added to sodium iodide (75 mg, 0.5 mmol) and stirred during the addition of triethylamine (2.5 mL, 1.815 g, 17.94 mmol), followed by 3-fluorobenzyl bromide (1.227 mL, 1.89 g, 10.0 mmol). An immediate turbidity was observed on addition of the 3-fluorobenzyl bromide, thickening to a copious white precipitate over one hour. The flask was sealed under nitrogen and the suspension stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was partitioned between ethyl acetate (40 mL) and saturated sodium bicarbonate solution (10 mL). The supernatant organic layer was separated and the aqueous layer extracted further with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to a pale yellow solid which was dissolved in ethyl acetate (˜7.5 mL) and applied to an intermediate (4×15 cm) Biotage silica column. Elution with ethyl acetate gave fractions containing the product, as evidenced by t.l.c. (silica, EM60F254, 100% EtOAc, Rf=0.78) were evaporated to dryness and dried at room temperature and 2 mm Hg to yield the title compound as white crystals (2.372 g, 97.3%). Calc. for C31H38FN3O: C, 76.35; H, 7.85; N, 8.62; F, 3.90. Found C, 76.32; H, 7.89; N, 8.51; F, 3.90% 1H NMR (CDCl3, 300 MHz); δ 1.06 (d, J=6.1 Hz, 3H); 1.15 (d, J=6.1 Hz, 3H, partially overlapped by br m, 3H); 1.22 (br m, 3H); 1.94 (dd, J=10.8, 8.1 Hz, 1H); 2.02 (dd, J=10.7, 8.2 Hz, 1H); 2.57 (br m, 2H); 2.67 (m, 2H); 3.18 (d, J=13.8 Hz, 1H); 3.28 (br m, 2H); 3.53 (br m, 2H); 3.87 (d, J=13.5 Hz, 1H); 5.15 (s, 1H); 6.90 (br t, J=8.2 Hz, 1H); 7.04 (m, 2H); 7.21 (m, 3H); 7.30 (m, 5H); 7.46 (d, J=8.0 Hz, 2H).
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][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:28]([F:31])([F:30])[F:29])=[C:24]([CH:27]=1)[CH:25]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:28]([F:29])([F:30])[F:31])=[C:24]([CH:27]=1)/[CH:25]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Cl)ccc1C(F)(F)F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0404 mmol) in toluene 5 mL was added 5-chloro-2-(trifluoromethyl)benzaldehyde 51 (84.4 mg, 0.404 mmol) and PTSA (153.9 mg, 0.809 mmol). The reaction was stirred at 120° C. for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 52. The crude 52 was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(5-chloro-2-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 52 was eluted at 28% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:11](C([O-])=O)[NH:12]C([O-])=O)[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1>CO.[OH-].[OH-].[Pd+2]>[NH:11]([C@@H:3]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1)[CH2:2][OH:1])[NH2:12]
Reactant: O=C([O-])NN(C(=O)[O-])[C@H](CO)CC1CCCOC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NN[C@H](CO)CC1CCCOC1
Yield: 100.1 %

Procedure:
To the solution of 1-((2S)-1-hydroxy-3-(tetrahydro-2H-pyran-3-yl)propan-2-yl)hydrazine-1,2-dicarboxylate (14.68 g, 0.0332 mol) in methanol (250 mL) was added Pd(OH)2/C (1.47 g). The reaction flask was degassed and filled with H2. When the reaction was over, the mixture was filtered through celite, and the filter cake was washed with MeOH (2×20 mL). The combined organic solvent was dried over Na2SO4, and concentrated in vacuo to give (2S)-2-hydrazinyl-3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (5.79 g, 94%), which was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][Si:30]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:29][C@@H:28]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:27]1>>[C:36]([Si:30]1([C:32]([CH3:35])([CH3:34])[CH3:33])[O:29][C@@H:28]([CH2:40][C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:27][C@@H:26]([CH2:25][CH2:24][N:23]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:31]1)([CH3:38])([CH3:37])[CH3:39]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)O[Si](C(C)(C)C)(C(C)(C)C)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)O[Si](C(C)(C)C)(C(C)(C)C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-di-t-butyl-1,3,2-dioxasilinan-4-yl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].S(=O)(=O)(O)O.[O-:16][C:17]#[N:18].[Na+]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:17]([NH2:18])=[O:16]
Reactant: N#C[O-]
Reactant: COc1ccccc1CN
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccccc1CNC(N)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To an aqueous solution (13 ml) containing 2-methoxybenzylamine (13.7 g, 0.1 mol.) was added dropwise dilute sulfuric acid (prepared from 2.8 ml of conc. sulfuric acid and 6.7 ml of refined water) at room temperature. After completion of the dropwise addition, an aqueous solution (70 ml) containing sodium cyanate (7.65 g, 0.12 mol.) was added to the reaction mixture at room temperature taking 15 minutes. The suspension obtained as reaction mixture was heated at 80° C. for one hour. The reaction mixture was cooled, then resulting crystalline precipitates were collected by filtration, followed by recrystallization from ethanol to give 17 g (yield 94%) of colorless prisms.
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([O-])=O.C(=O)(O)[O-].[Na+]>CO>[N:14]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH2:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccccc1N1CCCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1ccccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.8 %

Procedure:
Concentrated hydrochloric acid (1.50 ml, 18.0 mmol) and anhydrous tin dichloride (1.45 g, 7.64 mmol) were sequentially added at 0° C. to a methanol (10 ml) solution of 1-(2-nitrophenyl)piperidine (315 mg, 1.52 mmol) obtained as described in Referential Example 18-1. The resulting mixture was warmed to room temperature and stirred for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=15/1). Thus, 2-(1-piperidinyl)aniline (238 mg, 88.8%) was yielded as a pale yellow oily material.
Reaction SMILES: [C:1]1([NH:7][C:8](SC)=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH:21]1[O:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:22]1>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:23]2[CH2:24][CH2:25][O:26][CH:21]([CH2:20][NH:19][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:22]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(C#N)=C(Nc1ccccc1)SC
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Product: CCOC(=O)C(C#N)=C(NCC1CN(Cc2ccc(F)cc2)CCO1)Nc1ccccc1
Yield: 66 %

Procedure:
This compound was synthesized from ethyl 3-phenylamino-3-methylthio-2-cyanoacrylate and 2-aminomethyl-4-(p-fluorobenzyl)morpholine according to the same procedure as in Example 8. Yield=66%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:32]1[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]1
Reactant: OC1CCNCC1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCN2CCC(O)CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 4-hydroxy-piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>C(OCC)(=O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C=C(N)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(C)cc1
Yield: 47 %

Procedure:
Upon heating a solution of 6 g of 4-methylbenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6 hours, 2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 119° C (ethyl acetate/petroleumether) is obtained.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:30])[N:16]([CH2:18][C:19]3[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([F:40])[C:37]=1[CH2:38][OH:39].C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:30])[N:16]([CH2:18][C:19]4[C:20]([CH3:29])=[N:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:34]2[CH:33]=[C:32]([F:31])[C:37]([CH2:38][OH:39])=[C:36]([F:40])[CH:35]=2)=[CH:13][CH:12]=1
Reactant: OCc1c(F)cc(B(O)O)cc1F
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3cc(F)c(CO)c(F)c3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 90 °C

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (60 mg, 0.12 mmol) in THF (2 mL) at room temperature under argon was added 3,5-difluoro-4-hydroxymethylphenylboronic acid (68.0 mg, 0.36 mmol), Pd(dppf)Cl2.CH2Cl2 (9.8 mg, 0.011 mmol), and K3PO4 (77 mg, 0.36 mmol). The resulting suspension was purged of oxygen by bubbling with argon for 15 min, sealed in a vial under argon, heated at 90° C. for 12 h, and then cooled to room temperature. Analysis by HPLC/MS indicated that starting material was still present and one major new product had formed. The reaction mixture was diluted with EtOAc and washed once with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes). Pooling of the desired fractions, washing with saturated aq. NaHCO3 solution to eliminate any possible boronic acid contaminant, drying the organic phase (MgSO4), filtering and evaporation provided the title compound as a yellow solid, 24 mg, 36%. HPLC/MS: retention time=3.66 min, [M+H]+=561. 1H NMR (CDCl3): δ 7.85 (d, J=7.1 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.28 (m, 2H), 7.08 (m, 2H), 6.81 (d, J=7.7 Hz, 2H), 6.63 (d, J=7.1 Hz, 1H), 5.23 (s, 2H), 4.75 (d, J=2.8 Hz, 2H), 2.74 (s, 3H), 2.01 (t, J=5.5 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[OH:24][CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27](=O)[O:26]1.CN(C)C=O>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:27]4[C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25](=[O:24])[O:26]4)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: O=C1OC(O)c2ccccc21
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Solvent: CN(C)C=O
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C4OC(=O)c5ccccc54)CC3)cc21
Yield: 99 %

Procedure:
A mixture of 1-ethyl-1,4-dihydro-6-fluoro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid 0.5 g, 3-hydroxyphthalide 0.24 g and dimethylformamide 5 ml was heated at 100°-110° C. for 3 hours under stirring. After cooling, ethanol was added, and the insoluble matters were collected by filtration. The precipitates obtained were washed with ethanol and dried. 0.70 g (99%) of 1-ethyl-1,4-dihydro-6-fluoro-4-oxo-7-(4-phthalidyl-1-piperazinyl)quinoline-3-carboxylic acid was obtained as colorless powders.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].Cl[CH2:12][CH:13]1[O:17][CH2:16][O:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C>[O:17]1[CH:13]([CH2:12][NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:3]=2[CH2:1][CH3:2])[CH2:14][O:15][CH2:16]1
Reactant: CCc1cc(Cl)ccc1N
Reactant: ClCC1COCO1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: CCc1cc(Cl)ccc1NCC1COCO1

Procedure:
2-Ethyl-4-chloroaniline (0.3 mole), 5-chloromethyl-1,3-dioxolane (0.3 mole), potassium carbonate (0.3 mole) and tetraethylammonium chloride (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of 6 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxolan-5-ylmethyl)-2-ethyl-4-chloroaniline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N+:17]([O-])([O-:19])=[O:18].[Na+]>S(=O)(=O)(O)O>[N+:17]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3]2)([O-:19])=[O:18]
Reactant: CCOC(=O)C(C)c1cc2ccccc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
Ethyl 2-(1H-indol-2-yl)propanoate (0.91 g, 4.2 mmol) was dissolved in concentrated sulfuric acid (3.9 mL) and cooled to −10° C. (salt/ice-mixture). A solution of sodium nitrate (0.36 g, 4.2 mmol) in concentrated sulfuric acid (7.8 mL) was added dropwise over 35 min. Stirring was continued for another 30 min at −10° C. The mixture was poured into ice and the product was extracted with ethyl acetate. The combined organic phases were washed with a small amount of sat. aq. sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2-(5-nitro-1H-indol-2-yl)propanoate (0.34 g, 31%).
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.O.[N+]([O-])([O-])=[O:15].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)(=O)C>[O:15]=[C:12]1[C:2]2[S:1][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cc2c(s1)CCCC2
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc2c(s1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (3.00 g, 16.5 mmol), acetic acid (40 mL) and water (40 mL). A solution of ammonium cerium(IV) nitrate (36.1 g, 65.9 mmol) in acetic acid (40 mL) was added dropwise, and the reaction was stirred at room temperature for 1 h. After this time, the reaction mixture was poured into water (200 mL) and extracted with methylene chloride (3×200 mL). The organic extracts were combined, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to afford 16 in 72% yield (2.35 g) as a yellow solid: mp 174-175° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.60 (bs, 1H), 7.68 (s, 1H), 2.86 (t, 2H, J=6.0 Hz), 2.59 (t, 2H, J=6.0 Hz), 2.08 (quintet, 2H, J=6.0 Hz).