Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:8][CH2:9][CH3:10])[N:3]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[N:6]([CH2:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:20])[C:5](=[O:7])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:8][CH2:9][CH3:10])[N:3]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: CCCC1(c2ccccc2)N=C(C)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 70 °C
Yield: 55.7 %

Procedure:
(+/−)-2-Methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (541 mg, 2.5 mmol) and 2-bromo-1-(4-nitro-phenyl)-ethanone (707 mg, 2.8 mmol) and potassium carbonate (698 mg, 5 mmol) are dissolved in 5 mL acetone and the reaction mixture is heated at 70° C. for 10 min in the microwave oven (Biotage Initiator). The mixture is cooled to room temperature filtered and the filtrate evaporated. The residue is subjected to flash chromatography (cyclohexane/ethyl acetate-gradient, ethyl acetate 0-100% in 20 min) to yield (+/−)-2-methyl-3-[2-(4-nitro-phenyl)-2-oxo-ethyl]-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (528 mg, 56%). LC/MS at 254 nm; [M+H] 380; Rt 2.959 min.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:24])/[CH:7]=[CH:8]/[C:9]1[CH2:14][CH2:13][C:11](=[O:12])[C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].CCCCC[C@H](O)/C=C/[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(O)=O.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(O)=O)[C@@H](O)C[C@H]1O.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(O)=O)[C@@H](O)C[C@H]1O.CCCCCC(/C=C/[C@@H]1[C@@H](C/C=C\CCCC(O)=O)[C@@H](O)C[C@H]1O)=O.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CC(CCCCC(O)=O)=O)[C@@H](O)C[C@H]1O.CC(OC(CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCC2C=CC=CC=2)[C@H](O)C[C@@H]1O)=O)C.CCCCCC(CC[C@@H]1[C@@H](CC(CCCCC(O)=O)=O)[C@@H](O)C[C@H]1O)=O.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(O)=O)[C@H](O)C[C@H]1O.CCCCC[C@H](O)/C=C/[C@@H]1[C@H](C/C=C\CCCC(O)=O)[C@H](O)C[C@H]1O.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(O)=O)[C@@H](O)C[C@@H]1O.CCCCC[C@H](O)/C=C/[C@H]1C(=O)C=C[C@@H]1C/C=C\CCCC(O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:24])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:11](=[O:12])[CH:13]=[CH:14]1
Reactant: CCCCC[C@H](O)/C=C/C1=C(CCCCCCC(=O)O)C(=O)CC1
Agent: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: CCCCCC(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CCCCCC(=O)CC[C@@H]1[C@@H](CC(=O)CCCCC(=O)O)[C@@H](O)C[C@H]1O
Product: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
Prostaglandins which have been determined to be ineffective or have a low effectiveness in stimulating melanogenesis in melanocytes include: PGB1 ; PGD2 ; PGF1α ; PGF2α ; 15-keto PGF2α ; 6-keto PGF1α ; Latanoprost; 6,15-diketo-13,14-dihydro PGF1α ; 8-iso PGF1β ; 8-iso PGF2β ; 11β-PGF1β ; 11β-PGF2α ; and PGJ2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2([OH:27])[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H][H]>[Pd].CO>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:28])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2([OH:27])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: O=C(NCCO)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(NCCO)c1ccc(OCC2(O)CCNCC2)cc1
Yield: 90.5 %

Procedure:
A mixture of 23 parts of N-(2-hydroxyethyl)-4-[[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methoxy]benzamide and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 16 parts (90.5%) of N-(2-hydroxyethyl)-4-[(4-hydroxy-4-piperidinyl)methoxy]benzamide as an oily residue (int. 81).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)(C1C=CC(C)=CC=1)(=O)=O.[SH:27][C:28]1[NH:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C(N(CC)CC)C.O>C(#N)C>[N:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[NH:32][C:28]=1[S:27][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCOc2nc3ccccc3[nH]2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc2[nH]c(OCCCCCSc3nc4ccccc4[nH]3)nc2c1
Temperature: 25 °C
Yield: 57 %

Procedure:
188 mg of the compound obtained in Example 15a and 75 mg of 2-mercaptobenzimidazole were refluxed for 4 hours in 10 ml of acetonitrile containing 0.1 g of triethylamine. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 100m g of the title compound (yield: 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:16].Cl[CH2:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=1)[C:22]([NH:24][C:25]([C:30]#[N:31])([CH:27]1[CH2:29][CH2:28]1)[CH3:26])=[O:23].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:18][C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=3)[C:22]([NH:24][C:25]([C:30]#[N:31])([CH:27]3[CH2:29][CH2:28]3)[CH3:26])=[O:23])[CH2:14][CH2:15]2)=[O:9])=[CH:4][C:3]=1[F:16]
Reactant: CC(C#N)(NC(=O)c1cccc(CCl)c1)C1CC1
Reactant: Nc1ccc(C(=O)N2CCNCC2)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C#N)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1)C1CC1
Yield: 15.8 %

Procedure:
(4-Amino-3-fluorophenyl)(piperazin-1-yl)methanone (2.74 mmol, 0.612 g), 3-(chloromethyl)-N-(1-cyano-1-cyclopropylethyl)benzamide (2.74 mmol, 0.72 g), sodium iodide (0.548 mmol, 0.082 g) and potassium carbonate (8.22 mmol, 1.136 g) were combined in acetonitrile (25 mL) and heated to reflux for 2 hours. The reaction was concentrated under reduced pressure and the resulting residue taken up in dichloromethane and washed with water. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica column chromatography (eluting with dichloromethane to 4% methanol/dichloromethane) to afford the title compound (195 mg). MS (ESI) m/z 450.3 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:26])=[N:9]2)=[CH:4][CH:3]=1.[O:27]=[C:28]1[NH:32][CH2:31][C@@H:30]([C:33](O)=[O:34])[CH2:29]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH2:21][C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:26][C:33]([C@H:30]3[CH2:29][C:28](=[O:27])[NH:32][CH2:31]3)=[O:34])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cccc(COCC(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1C[C@H](C(=O)Nc2cc(-c3cccc(COCC(F)(F)F)c3)n(-c3ccc(F)cc3)n2)CN1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-(2,2,2-trifluoroethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (43 mg) in N,N-dimethylacetamide (0.4 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (34 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (26 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:6]([CH2:14][OH:15])[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:6]([CH2:14][OH:15])[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2N)C(CO)C(=O)O)cc1
Yield: 53.5 %

Procedure:
A solution of 0.75 g (1.72 mmol) of 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionic acid, tert-butyl ester and 6 ml of trifluoroacetic acid in 6 ml of CH2Cl2 was stirred at room temperature for 3 hours and then concentrated to dryness under vacuum. To the residue was added H2O, CH2Cl2 and 1N NaOH until the aqueous layer reached pH 8. The aqueous layer was then separated, acidified with 2 N citric acid and extracted with ethyl acetate. The extract was washed with H2O, brine and dried Na2SO4. The solvent was removed under vacuum to give 0.35 g (54%) of a solid. Anal. for C17H20N2O6S: Calc'd: C, 53.7; H,5.3; N,7.4; Found: C, 53.0; H,5.3; N,6.9.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[S:19])[N:6]([CH2:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[C:7]=1[NH2:8].[C:21](O)(=O)C.C(N)=N>CS(C)=O>[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[CH2:9][N:6]1[C:7]2[N:8]=[CH:21][NH:1][C:2]=2[C:3](=[O:20])[NH:4][C:5]1=[S:19]
Reactant: CC(=O)O
Reactant: Nc1c(N)n(Cc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Agent: N=CN
Solvent: CS(C)=O
Product: O=c1[nH]c(=S)n(Cc2nc3ccccc3[nH]2)c2nc[nH]c12
Temperature: 70 °C
Yield: 15 %

Procedure:
To a solution of 5,6-diamino-1-(1H-benzimidazol-2-ylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.19 g, 0.65 mmol, obtained from Example 8(c)) in DMSO (2 mL) was added formamidine acetate (0.10 g, 0.98 mmol). The reaction mixture was heated to 70° C. for 2 h. Purification of the crude product using preparative HPLC gave the title compound (0.029 g, 15%) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[C:8]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH2:8]1[C:12]2([O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]2)[CH2:11][CH2:10][CH2:9]1
Reactant: OCC(CO)CO
Reactant: O=C1CCCC1
Product: OCC1COC2(CCCC2)OC1
Yield: 87 %

Procedure:
The same procedure as in the step (7a) of Example 7 was repeated using 2-(hydroxymethyl)-1,3-propanediol and cyclopentanone to obtain the title compound (2.8 g, yield: 87%) as yellow oil.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[ClH:22]>C(#N)C.[Cu]>[Cl:22][C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: Cl
Agent: [Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)c1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
In a three-necked flask fitted with a condenser, a suspension of copper II chloride (370 mg, 2.75 mmol) in acetonitrile (5 mL) was treated with tert-butyl nitrite (0.41 mL, 3.44 mmol) and stirred at rt for 10 minutes. A solution of 2-amino-6-trifluoromethylbenzthiazole (500 mg, 2.29 mmol) in acetonitrile (1 mL) was then added dropwise. The mixture was heated at 65° C. for 30 minutes, then cooled and diluted with an excess of 1 N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure. An orange semi-solid (501 mg, 92%) was obtained and used without further purification. 1H NMR (300 MHz, CDCl3) δ 8.10–8.05 (m, 2 H), 7.74 (d, 1 H); LC-MS m/z 238.2 (MH+), ret. time 3.76 min TLC Rf=0.50 (9:1 hexanes/ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=CC=1)[C:5]([NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6].[O:20]1C=CC(C(O)=O)=C1.C(N)/C=C/C1C=CC=CC=1>>[CH2:8]([NH:7][C:5]([C:4]1[CH:3]=[CH:2][O:20][CH:17]=1)=[O:6])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NC/C=C/c1ccccc1)c1cccc(Cl)c1
Reactant: O=C(O)c1ccoc1
Agent: NC/C=C/c1ccccc1
Product: O=C(NC/C=C/c1ccccc1)c1ccoc1

Procedure:
(E)-N-Cinnamyl-3-furancarboxamide may be obtained in the following manner: working as in Example 21 for the preparation of (E)-3-chloro-N-cinnamylbenzamide, but starting with 3-furancarboxylic acid (4 g) and (E)-cinnamylamine (4 g), and after recrystallization in isopropyl ether, (E)-N-cinnamyl-3-furancarboxamide (3.9 g), m.p. 115° C. is obtained.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH3:20]N(C)P(N(C)C)(N(C)C)=O.CI>O>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH3:20])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Agent: [Na]
Solvent: CI
Solvent: O
Product: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 28.2 parts of p-(2-thenoyl)hydratropic acid, sodium salt and 250 parts of hexamethylphosphoramide are added 56.8 parts of methyl iodide at room temperature (slightly exothermic reaction). The whole is stirred at room temperature for 1 hour. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with 140 parts of diisopropylether. The combined extracts are washed with 200 parts of water, dried, filtered and evaporated. The residue is crystallized from 35 parts of diisopropylether at 0° C, washed with cooled ether and dried, yielding methyl p-(2-thenoyl)hydratropate; mp. 62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH:35]=O)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38].[NH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:24])[F:26])(=[O:12])=[O:13])[C:6](=[O:27])[C:5]2([N:39]1[CH2:48][C@H:47]([OH:49])[CH2:46][C@H:40]1[C:41]([N:43]([CH3:44])[CH3:45])=[O:42])[C:28]1[CH:33]=[C:32]([CH2:34][CH2:35][N:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH:31]=[CH:30][C:29]=1[O:37][CH3:38]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CC=O)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Reactant: C1CCNCC1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CCN4CCCCC4)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 38 %

Procedure:
With 600 mg of the compound obtained in Example 219 and 129 mg of piperidine as starting materials, 250 mg of the title compound (light yellow amorphous) was obtained by a similar method to Example 220.
Reaction SMILES: CC1(C)C(C)(C)OBO1.[CH3:10][CH:11]([CH3:17])[CH2:12]/[CH:13]=[CH:14]/[CH:15]=[CH2:16].[CH3:18][O:19][C:20]1[CH:31]=[CH:30][C:23]([CH2:24][O:25][C@@H:26]([CH3:29])[CH:27]=[O:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:18][O:19][C:20]1[CH:31]=[CH:30][C:23]([CH2:24][O:25][C@H:26]([C@H:27]([OH:28])[C@H:14]([CH:15]=[CH2:16])[CH2:13][CH2:12][CH:11]([CH3:17])[CH3:10])[CH3:29])=[CH:22][CH:21]=1
Reactant: C=C/C=C/CC(C)C
Reactant: COc1ccc(CO[C@@H](C)C=O)cc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1=CCCC=CCC1
Solvent: Cc1ccccc1
Product: C=C[C@H](CCC(C)C)[C@@H](O)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.3 %

Procedure:
Under a strict nitrogen atmosphere an oven-dried round-bottomed flask with a magnetic stir bar was charged with bis(1,5-cyclooctadiene)nickel(0) (0.297 grams (g), 1.080 millimole (mmol)) and tricyclohexylphosphine (0.379 g, 1.35 mmol). Anhydrous toluene (40 milliliters (mL)) followed by 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.34 ml, 57.5 mmol) and (E)-6-methylhepta-1,3-diene (11.9 g, 54.0 mmol), prepared according to the procedure disclosed in Wang, Y.; West, F. G. Synthesis 2002, 99-103, were added to the flask and the reaction was allowed to stir at room temperature for 20 hours (h), as described in the diene hydroboration conditions reported in Ely, R. J.; Morken, J. P. J. Am. Chem. Soc. 2010, 132, 2534-2535. To the mixture was added a solution of (S)-2-((4-methoxybenzyl)oxy)propanal (10.49 g, 54.0 mmol) in anhydrous toluene (5 mL) at −20° C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 40 h, then quenched with MeOH and stirred for an additional 2 h. The crude mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (SiO2; gradient, hexanes/ethyl acetate) to yield the title compound as a colorless oil (11.3 g, 69%): IR (neat) 3467, 2925, 2868, 1513, 1247 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.27-7.22 (m, 2H), 6.90-6.85 (m, 2H), 5.51-5.38 (m, 1H), 5.08-4.96 (m, 2H), 4.52-4.40 (m, 2H), 3.80 (s, 3H), 3.66 (ddd, J=9.2, 3.1, 2.1 Hz, 1H), 3.59-3.49 (m, 1H), 2.26-2.20 (m, 1H), 2.04-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.59-1.43 (m, 1H), 1.29-1.14 (m, 2H), 1.13 (d, J=6.2 Hz, 3H), 1.10-0.99 (m, 1H), 0.87 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.19, 138.56, 130.59, 129.22, 116.59, 113.82, 75.89, 74.46, 70.11, 55.29, 47.18, 36.05, 28.57, 28.23, 22.98, 22.42, 12.17; ESIMS m/z 329.2 ([M+Na]+).
Reaction SMILES: [Br-].[NH2:2][C:3]1[C:12](Cl)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[CH2:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=O.C([OH:24])C>>[O:24]=[C:12]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:2]=[C:3]12
Reactant: CCO
Reactant: CCOC(=O)C(=O)C[n+]1c(N)c(Cl)nc2ccccc21
Agent: [Br-]
Product: CCOC(=O)c1cn2c(n1)c(=O)[nH]c1ccccc12
Reaction time: 2 h

Procedure:
A suspension of 6.5 g of the product of Step A in 500 ml of ethanol was refluxed with stirring for 2 hours and the resulting clear yellow solution was concentrated and cooled in a refrigerator. The mixture was filtered and then 3.70 g of white crystalline product was crystallized from ethanol to obtain ethyl 4,5-dihydro-4-oxoimidazo-[1,2-a]-quinoxaline-2-carboxylate in the form of shiny crystals melting at 292°-293° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:25]4)=[N:22][CH:23]=2)=[N:3][C:2]([C:43]2[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 63.2 %

Procedure:
Following general procedure II, (S)-tert-Butyl 1-{5-[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-ylamino]pyridin-2-yl}piperidin-3-ylcarbamate (131 mg, 0.25 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (102 mg, 0.38 mmol) to afford the desired product (100 mg, 63%) as an orange red solid. ESI MS m/z 633 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CO.[C].[Pd]>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:4]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccc1Cl
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)nc2)ccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.8 %

Procedure:
To a solution of tert-butyl {2-chloro-5-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (13.5 g, 36.9 mmol) in methanol (500 mL) was added palladium carbon (50% water-containing product, 2.96 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 17 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→75/25) to give the title compound (7.29 g, 59%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35]>>[O:22]=[C:10]1[NH:11][C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[CH:15]=[CH:16][C:17]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:34]([C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=3)(=[O:36])=[O:35])[CH:7]=[CH:6][CH:5]=2)[C:9]1=[O:23]
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4ccc5ccccc5c4)c2)c1=O)CCCC3
Yield: 19 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 2-naphthalenesulfonyl chloride (33 mg, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 9 mg, yield 19%).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])=[O:20]
Reactant: O=C=NCCCc1cccs1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Product: O=C(NCCCc1cccs1)n1cc(F)c(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-Fluorouracil (3.30 g.) was added to the solution of 3-(2-thienyl)propyl isocyanate and stirred at 100° C. for 2 hours. The resultant mixture was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized from ethanol to give colorless plate 1-[N-[3-(2-thienyl)propyl]carbamoyl]-5-fluorouracil (2.3 g.).