Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([N:5]5[CH2:6][CH2:7][CH2:8][C@H:4]5[CH2:3][O:2][CH3:1])[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using (s)-2-methoxymethyl-pyrrolidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 481 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=2N)=[CH:5][CH:4]=1.N(OCCCC)=O>C(O)(=O)C.[Cu]>[F:2][C:3]1[CH:8]=[CH:7][C:6]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=3[C:5]=2[CH:4]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(F)cc1
Agent: [Cu]
Agent: CCCCON=O
Agent: Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2sc3ccc(F)cc3c2c1
Temperature: 11 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 55 g. (0.183 mole) of 2-(4-fluorophenylthio)-5-nitroaniline hydrochloride in 450 ml. of acetic acid at 16 to 18° C. is added dropwise 18.6 g. (0.181 mole of n-butyl nitrite during a period of 20 minutes. The solution is then diluted with 1.5 liters of cold (12° C.) of 50 percent aqueous acetic acid. The solution is maintained at 10 to 12° C., and 68 g. of copper powder are added in small portions during a period of 15 minutes. After stirring at 10° to 15° C. for an additional 20 minutes, the mixture is heated and stirred at 50° C. for 1 hour. The mixture is cooled to 5° C. and filtered. The solid residue is washed thrice with 300 ml. of aqueous sodium hydroxide, then thrice with 300 ml. of distilled water. The brown solid is dissolved in hot benzene, filtered and the hot filtrate treated with decolorizing charcoal. The benzene is evaporated to give a residue which is twice recrystallized from benzene to give off-white crystals of 2-fluoro- 8-nitrodibenzothiophene, m.p. 200°-202° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=[O:5].C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.O>[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25])=[O:5]
Reactant: CN(C)C(=O)[C@@H]1CCCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CCCCN1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(2S)—N,N-Dimethyl-2-piperidinecarboxamide hydrochloride (880 mg, 4.567 mmol) was dissolved in a mixture of CH2Cl2 (15 mL) and water (15 mL), and then solid sodium bicarbonate (1.534 g, 18.268 mmol) was added, followed by benzoyl chloride (0.556 mL, 4.795 mmol). After stirring overnight, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-10% methanol/dichloromethane) to provide (2S)—N,N-dimethyl-1-(phenylcarbonyl)-2-piperidinecarboxamide (883 mg, 74%). LCMS: (M+H)+: not detected.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([N:18]([CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[SH:19](=[O:21])=[O:20])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>Cl.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[NH:14]1[CH2:17][CH:16]([N:18]([CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[SH:19](=[O:20])=[O:21])[CH2:15]1
Reactant: O=[SH](=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[SH](=O)N(Cc1cc(F)cc(F)c1)C1CNC1
Yield: 102.9 %

Procedure:
N-Azetidin-3-yl-N-(3,5-difluorophenyl)methylsulfonamide hydrochloride is obtained in the following manner: in a 500-cm3 hydrogenator, a solution of 1 g of N-(1-benzhydrylazetidin-3-yl)-N-(3,5-difluorophenyl)methylsulfonamide in a mixture of 2.5 cm3 of 1M hydrochloric acid and 0.41 cm3 of acetic acid is hydrogenated in the presence of 0.161 g of palladium hydroxide at a hydrogen pressure of 30 bar for 4 hours. The catalyst is removed by filtration on a celite bed and then the filtrate is concentrated to dryness at 40° C. under 2.7 kPa to give 630 mg of N-azetidin-3-yl-N-(3,5-difluorophenyl)methylsulfonamide, melting at 216° C.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6]O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl>[CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][N:33]1[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]2[C:29]1=[O:39])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C=C(/C=C/CO)CC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC=C(C=CCN1C(=O)c2ccccc2C1=O)CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a mixture of (E,E)-4-ethyl-2,4-hexadien-1-ol (1.0 g), triphenylphosphine (2.29 g), phthalimide (1.17 g), and tetrahydrofuran (30 ml) at room temperature was added a solution of diethyl azodicarboxylate (1.52 g) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (hexane-dichloromethane, 2:3) to give 0.42 g of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide as crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([NH2:22])[CH2:8][CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([NH:22][S:44]([C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)=[CH:43][CH:42]=1)(=[O:45])=[O:46])[CH2:8][CH2:9][CH2:10][N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](N)CCCN1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A solution of the title H compound, (2R)-amino-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester (1.02 g, 3.19 mmol) and triethylamine (1.34 mL, 9.61 mmol) in 20 mL of dichloromethane is treated with the title 1 compound, 4′-chlorobiphenyl-4-sulfonyl chloride (0.92 g, 3.19 mmol) at 0° C. After stirring at this temperature for 30 min, then at RT for 16 h, the solution is washed with 35 mL of 2M aqueous HCl and the organic solution is washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Chomatography on silica gel (eluant; ethyl acetate) affords 0.96 g (53%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester as a waxy, white solid: NMR(CDCl3) 1.21 (s, 9H), 1.60-1.68 (br m, 1H), 1.75-1.84 (br m, 3H), 3.68-3.74 (m, 2H), 3.82-3.92 (m, 1H), 5.24 (d, 1H, J=9.2), 7.44 (d, 2H, J=8.6), 7.49 (d, 2H, J=8.6), 7.65 (d, 2H, J=8.5), 7.70-7.74 (m, 2H), 7.83-7.86 (m, 2H), 7.92 (d, 2H, J=8.5); IR 1774, 1712, 1348, 1162; ESI-MS 569 (M++1).
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[C:6]1[CH:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:3][C:2]2=1.[H-].[Na+].Br[CH2:19][C:20]#[N:21].O>CN(C=O)C>[C:20]([CH2:19][N:3]1[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:6]2[CH:7]3[CH2:10][CH:1]([CH2:9][CH2:8]3)[C:2]1=2)#[N:21]
Reactant: CCOC(=O)c1cc2c([nH]1)C1CCC2C1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(n1CC#N)C1CCC2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Into a solution of 167c (3.0 g, 14.6 mmol) in anhydrous DMF (30 mL) was added NaH (880 mg, 22 mmol). The mixture was stirred at room temperature for 30 minutes. 2-Bromoacetonitrile (3.5 g, 29.3 mmol) was added and the resulting mixture was heated at 65° C. for 1 hour. It was then stirred at room temperature overnight. After reaction water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase was evaporated under reduced pressure to dryness. The residue was purified by silica-gel column chromatography eluting with 20:1 methylene chloride/methanol to afford 167d as a brown solid (2.6 g, 72%). MS: [M+H]+ 245.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:2]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][CH:16]=2)[N:13]([C:23](=[O:25])[CH3:24])[CH2:12][CH2:11][CH2:10]3)[CH:2]=1
Reactant: c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCCc2cc(-c3cccnc3)cnc21
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
6-Pyridin-3-yl-1,2,3,4-tetrahydro-[1,8]naphthyridine (41 mg, 0.19 mmol) is dissolved in 2 mL of DCM and pyridine (0.19 mL, 2.3 mmol) is added into the solution. Then acetyl chloride (0.08 mL, 1.2 mmol) is added. The mixture is stirred for 0.5 hrs and saturated aqueous NaHCO3 (2 mL) is added along with water (3 mL). The mixture is extracted with EtOAc (3×10 mL) and the organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 37 mg of the titled product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:14][C:15](=O)[C@@H:16]([C@@H:30]1[C@:47]2([CH3:48])[C@H:33]([C@H:34]3[C@H:44]([CH2:45][CH2:46]2)[C@:42]2([CH3:43])[C:37]([CH2:38][C@@H:39]([O:56][CH:57]4[CH2:62][CH2:61][CH2:60][CH2:59][O:58]4)[CH2:40][C@@H:41]2[O:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][O:51]2)=[CH:36][CH2:35]3)[CH2:32][CH2:31]1)[CH2:17][CH2:18][C@@H:19]([F:29])[C:20]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH3:21])C>CCOCC>[O:51]1[CH2:52][CH2:53][CH2:54][CH2:55][CH:50]1[O:49][C@@H:41]1[C@@:42]2([CH3:43])[C:37](=[CH:36][CH2:35][C@@H:34]3[C@@H:44]2[CH2:45][CH2:46][C@@:47]2([CH3:48])[C@H:33]3[CH2:32][CH2:31][C@@H:30]2[C@H:16]([CH2:15][OH:14])[CH2:17][CH2:18][C@@H:19]([F:29])[C:20]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH3:21])[CH2:38][C@@H:39]([O:56][CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][O:58]2)[CH2:40]1
Reactant: CCOC(=O)[C@H](CC[C@@H](F)C(C)(C)OC(C)OCC)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 0.34 g. (0.0090 mole) of lithium aluminum hydride and 17 ml. of tetrahydrofuran at 0° C. was added 4.26 g. of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-oic acid ethyl ester in 60 ml. of tetrahydrofuran. The mixture was heated at 50° C. for 1.5 hr, recooled to 0° C., and diluted with 200 ml. of ether. The mixture was then quenched with the dropwise addition of 0.68 ml. of water and 0.55 ml. of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 0.5 hr and was filtered. The solids were triturated with ether and filtered. Evaporation of solvent afforded [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol, [α]D25 +7° (c 1.1, CHCl3).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: N[C@@H]1CCc2ccccc21
Product: Clc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 125 °C
Yield: 33.9 %

Procedure:
A stirred mixture of 2,6-dichloro-quinoline (4.8 g, 24 mmol) and (R)-1-aminoindane (6.5 g, 48 mmol) was heated in a sealed tube for 16 h at 125° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane) yielded (6-chloro-quinolin-2-yl)-(R)-indan-1-yl-amine as a yellow solid (2.4 g, 34%), MS 295.1 [(M+H)+].
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[O:11][N:10]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1.O1CCCC1.[C:24](=[O:26])=[O:25]>CCCCCC>[NH2:6][C:7]1[O:11][N:10]=[C:9]([CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:24]([OH:26])=[O:25])[N:8]=1
Reactant: Nc1nc(Cc2ccccc2)no1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1nc(C(C(=O)O)c2ccccc2)no1
Reaction time: 2 h

Procedure:
260 g. (0.507 mole + 20%) of a 15% solution of butyl lithium in n-hexane is cooled to -60° under nitrogen. At this temperature a solution of 27.6 g. of 5-amino-3-(phenylmethyl)-1,2,4-oxadiazole in 300 ml. of absolute tetrahydrofuran is added dropwise with stirring over a period of about 21/2 hours. The reaction mixture is stirred for an additional 30 minutes. Then over a period of 2 hours a proportionate stream of carbon dioxide is passed through the mixture. The cold bath is removed and the reaction mixture is permitted to come to room temperature. This mixture is concentrated in a rotary evaporator, the residue is treated with water and adjusted to pH 8. The aqueous solution is extracted with ether and the aqueous phase is acidified with 2N hydrochloric acid. The precipitate is filtered under suction and reprecipitated twice by dissolving in dilute sodium hydroxide solution and acidifying with dilute hydrochloric acid. 7.4 g. of 5-amino-α-phenyl-1,2,4-oxadiazole-3-acetic acid are obtained, m.p. 163°-164° (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1>NCCCCO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:14]=3[N:13]=[C:12]([NH:8][CH2:20][CH2:19][CH2:14][CH2:15][OH:21])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Agent: NCCCCO
Product: Cc1ccccc1-n1ccc2c(NCCCCO)nc3c(OCC(F)(F)F)cccc3c21
Temperature: 180 °C
Yield: 138 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,β-trifluoroethoxypyrrolo[3,2-c]quinoline(600 mg, 1.5 mmol), prepared by the procedures of Step 1 and Step 2 in the Example 34, was added in 4-amino-1-butanol(10 ml) in the pressure tube, and refluxed at 180° C. for 3 hours. After removing the excess 4-amino-butanol by distillation under reduced pressure, the residue was diluted in dichloromethane(20 ml), and washed with water(15 ml) for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 459 mg of desired compound as solid in 69% of yield.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[C:21]([F:37])=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27](=[O:35])OC4C=CC=CC=4)[CH:25]=3)[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1)=[O:5])#[N:2].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CS(C)=O>[C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[CH:25]=[C:24]([NH:26][C:27]([NH:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:35])[C:23]([F:36])=[CH:22][C:21]=3[F:37])[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1)=[O:5])#[N:2]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Oc3ccccc3)c(F)cc2F)cc2cnc(NC(=O)CC#N)cc21
Reactant: Nc1ccccc1
Solvent: CS(C)=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(NC(=O)CC#N)cc21
Yield: 12.4 %

Procedure:
A solution of phenyl (5-(7-(2-cyanoacetamido)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (400 mg, 0.80 mmol) and aniline (158 mg, 1.6 mmol) in DMSO (3 mL) was heated at 60° C. overnight and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA) to afford 2-cyano-N-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (50 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 8.92 (s, 1H), 8.78 (s, 1H), 8.20-8.16 (m, 2H), 8.11 (s, 1H),7.49-7.39 (m, 4H), 7.29-7.25 (m, 2H), 6.96 (t, J=7.2 Hz, 1H) 4.26-4.21 (q, J=6.8 Hz, 2H), 4.09 (s, 2H),1.30-1.26 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 503.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][CH:6]=1)=[O:4].[CH:16]([NH2:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:17][CH:16]([NH:19][CH:6]=[C:5]1[C:14](=[O:15])[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:7][CH2:2][C:3]1=[O:4])[CH3:18]
Reactant: O=C(CBr)c1coc2ccccc2c1=O
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)NC=C1C(=O)COc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A mixture of 8.0g (0.03 mole) of 3-(bromoacetyl)chromone, 3.78g (0.064 mole) of isopropylamine, 200ml of methylene chloride and 30g of powdered anhydrous potassium carbonate was stirred at room temperature for 4 hours. The solids were filtered and the dark filtrate was filtered through layer of silica gel. This filtrate was concentrated to dryness. Recrystallization from ether gave 5.0g (68%) of product; m.p. 89°-91°. Recrystallization from isopropyl ether gave pure product; m.p. 92°-93°.
Reaction SMILES: [N:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)=[N+]=[N-].Cl.[NH2:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>C(O)C.C(O)C.O>[O:15]=[C:14]1[NH:16][C:17](=[O:18])[CH2:19][N:13]1[N:12]=[CH:9][C:7](=[O:8])[CH:6]=[CH:5][C:4]#[N:1]
Reactant: NN1CC(=O)NC1=O
Reactant: [N-]=[N+]=Nc1ccc(C=O)o1
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#CC=CC(=O)C=NN1CC(=O)NC1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
A solution of 5-azido-2-furaldehyde (240 mg, 1.75 millimole (mmole)) in 20 milliliters (ml) of ethanol was added dropwise over 10-20 minutes to a solution of 1-aminohydantoin hydrochloride (320 mg, 2.1 mmole) in 25 ml of ethanol:water (4:1) and the mixture was chilled in an ice bath. The reaction mixture turned into a yellow-orange suspension within thirty minutes and was gradually heated to about 60° C. to form a complete solution. The heating continued for another 24 hours after which time it was allowed to cool and evaporated to dryness. The dark residue was triturated with 4-5 portions (15 ml each) of acetonitrile to obtain a suspension which was then filtered through a filter paper. The filtrate was evaporated to dryness. The residue was dissolved in 3 ml of acetone and streaked on two preparative silica gel TLC plates (EM Science, Cat # 5717-7) and developed with ethyl acetate: petroleum ether (3:1). The fast moving major band (Rf around 0.51) detected under UV light was stripped, and the silica gel was ground to a fine powder and eluted with acetone. The acetone eluent was evaporated to give a pale yellow solid which showed a homogeneous single spot on TLC (137 mg, 0.67 mmole, 38% yield). Alternatively the crude reaction product can be purified by silica gel column chromatography and further recrystallized from 30% ethyl acetate/hexanes to give the pure desired product (mp 171-173° C.). Elemental analysis supported a molecular formula of C8H6N4O3. 0.15 EtOAc. The structure of compound 1 was established by 1H and 13C NMR analysis as shown in FIGS. 1-4. 1H NMR analysis of 1 revealed that the acrylonitrile moiety has a trans (E)-configuration (coupling constant J=16.5 Hz). MALDI-TOF mass spectral analysis confirmed structure 1 with the M+1 peak of 207.22
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][CH:3]=1.[F-:17].[K+].C(OCC)(=O)C.O>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:17][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][CH:3]=1
Reactant: [F-]
Reactant: N#Cc1nc(Cl)cnc1Sc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1nc(F)cnc1Sc1ccccc1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 53.6 %

Procedure:
In 3.6 mL of dimethyl sulfoxide was dissolved 0.20 g of 6-chloro-3-(phenylsulfanyl)-2-pyrazinecarbonitrile. After adding 0.42 g of potassium fluoride and 0.16 g of tetra-n-butylammonium bromide successively, the mixture thus obtained was stirred at 50-60° C. for 2.5 hours. The reaction mixture was poured into a mixture of 20 mL of ethyl acetate and 20 mL of water, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: toluene:n-hexane=1:2] to obtain 0.10 g of 6-fluoro-3-(phenylsulfanyl)-2-pyrazinecarbonitrile as a light yellow-colored oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:17]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22]([OH:24])([CH3:32])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-c1cnc(C)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)(C)O)n2)ccc1-c1cnc(C)o1
Reaction time: 0.08 h

Procedure:
1-(2-(3-Methoxy-4-(2-methyloxazol-5-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidin-4-yl)ethanone (64 mg, 0.15 mmol) was dissolved in THF (5 mL) and was added slowly to a solution of methylmagnesium bromide (3 M in THF, 0.391 mL, 1.17 mmol) in THF (5 mL). The mixture was stirred for 5 min. The mixture was cooled on ice bath and ammonium chloride (sat, aq, 5 mL) was added. The mixture was stirred for 5 min. The mixture was extracted with EtOAc (×2). The solvents were evaporated and the residue was purified by column chromatography eluting with a gradient of methanol in DCM to give the title compound as a solid, 46 mg (69%).