Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[Cl:39][C:40]1[CH:48]=[C:47]([C:49]#[C:50][C:51]([O:54][CH3:55])([CH3:53])[CH3:52])[C:43]2[O:44][CH2:45][O:46][C:42]=2[C:41]=1[NH2:56]>CN(C=O)C>[Cl:39][C:40]1[CH:48]=[C:47]([C:49]#[C:50][C:51]([O:54][CH3:55])([CH3:53])[CH3:52])[C:43]2[O:44][CH2:45][O:46][C:42]=2[C:41]=1[NH:56][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COC(C)(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CC(C)(C)OC)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.12 ml) in tetrahydrofuran (1.0M, 1.12 mmol) was added to a solution 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (0.189 g) and 5-chloro-7-(3-methoxy-3-methylbut-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.150 g) in DMF (6 ml) that had been cooled to −15° C. and the mixture was stirred for 3 hours then the reaction was allowed to warm to room temperature. The reaction mixture was quenched into water and saturated ammonium chloride solution was added. The resulting white precipitate was filtered under suction, washing with water, giving a pale tan paste. This was then extracted into dichloromethane, dried over magnesium sulfate and solvents evaporated under reduced pressure to give a tan foam. This was triturated with diethyl ether, giving a white solid. The resulting solid was then gathered by filtration and air-dried. There was thus the title compound (0.225 g) as an off-white solid; NMR Spectrum: (CDCl3) 1.55 (s, 6H), 2.11 (quin, 2H), 2.47 (s(broad), 4H), 2.56 (t, 2H), 3.43 (s, 3H), 3.72 (t, 4H), 4.00 (s, 3H), 4.26 (t, 2H), 6.07 (s, 2H), 6.83 (s, 1H), 7.05 (s, 1H), 7.08 (s, 1H), 7.30 (s, 1H), 8.62 (s, 1H); Mass Spectrum: M+H+ 569/571.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[F:15])[CH3:2].[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[CH:29]O)[C:22](=[O:28])[NH:23]2>>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:29]=[C:21]2[C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[CH3:18])[NH:23][C:22]2=[O:28])=[CH:10][C:9]=1[F:15])[CH3:17]
Reactant: CCN(CC)CCCOc1ccc(N)cc1F
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cccc(C)c32)cc1F
Yield: 49.3 %

Procedure:
In a manner similar to that described in Example 231, 4-(3-diethylamino-propoxy)-3-fluoro-phenylamine (400 mg, 1.1 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (263 mg, 1.5 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (294 mg, 49%).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7](CC#N)=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16][N:17]([CH3:19])[CH3:18]>C1COCC1.O.[Pd](Cl)Cl>[Cl:5][C:6]1[C:7]([CH2:2][C:1]([NH2:4])=[O:3])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16][N:17]([CH3:19])[CH3:18]
Reactant: CN(C)Cc1cccc2cc(Cl)c(CC#N)cc12
Reactant: CC(N)=O
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cccc2cc(Cl)c(CC(N)=O)cc12
Reaction time: 18 h

Procedure:
Palladium(II)-chloride (4.3 mg, 0.024 mmol, 0.1 equiv) and acetamide (60 mg, 1.0 mmol, 4.2 equiv) were added to a solution of (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetonitrile in THF (0.75 ml) and water (0.25 ml). After 18 hours at room temperature, the reaction mixture was adsorbed on silica gel, concentrated to dryness, and purified via two flash columns. Since purification on silica gel failed to remove unreacted acetamide, the resulting mixture was used directly in the next step. MS (ES+): 277 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:15]=2)[C:11]#[N:12])[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:34]=[CH:33][N:32]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:31]=2)[CH2:26][CH2:25]1>>[CH3:22][O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:34]=[CH:33][N:32]([C:35]3[CH:41]=[CH:40][C:38]([NH:39][C:2]4[N:7]=[C:6]([C:8]5[CH:9]=[C:10]([CH:13]=[C:14]([N:16]6[CH2:21][CH2:20][O:19][CH2:18][CH2:17]6)[CH:15]=5)[C:11]#[N:12])[CH:5]=[CH:4][N:3]=4)=[CH:37][CH:36]=3)[N:31]=2)[CH2:26][CH2:25]1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)cc(N2CCOCC2)c1
Reactant: COC1CCN(c2ncn(-c3ccc(N)cc3)n2)CC1
Product: COC1CCN(c2ncn(-c3ccc(Nc4nccc(-c5cc(C#N)cc(N6CCOCC6)c5)n4)cc3)n2)CC1

Procedure:
3-(2-(4-(3-(4-methoxypiperidin-1-yl)-1H-1,2,4-triazol-1-yl)phenylamino)pyrimidin-4-yl-5-morpholinobenzonitrile was obtained by following procedure E using 3-(2-chloropyrimidin-4-yl)-5-morpholinobenzonitrile and 4-(3-(4-methoxypiperidin-1-yl)-1H-1,2,4-triazol-1-yl)aniline. MS (ESI) 538.23 (M+H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]>CN1CCCC1=O>[CH3:4][C:5]1[CH:10]=[C:9]([NH:2][NH2:3])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(NN)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 4 h

Procedure:
5 g of hydrazine hydrate were slowly added dropwise to a solution of 15.9 g of 2-methyl-4-fluoronitrobenzene in 10 ml of N-methylpyrrolidone at room temperature, and the mixture was heated with stirring at 65° C. for 4 hours. The product was precipitated by adding 70 ml of water and was filtered off with suction and then recrystallized from isopropanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Li])CCC.CI>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([CH3:22])=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c(OCCNC(=O)OC(C)(C)C)noc12
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(C)c2c(OCCNC(=O)OC(C)(C)C)noc12
Temperature: -70 °C
Yield: 80 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-methyl-1,2-benzisoxazole (0.15 g) in tetrahydrofuran (5 ml) was added butyl lithium (0.7 ml, 1.6M hexane solution) dropwise with stirring at -70° C. under nitrogen atmosphere, the mixture was stirred at the same temperature for 10 minutes, and then the temperature was raised to 0° C. After cooling the reaction mixture to -70° C., methyl iodide (0.11 g) was added and the temperature was allowed to rise to 0° C. The reaction mixture was poured into ice water (40 ml), extracted with ethyl acetate (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.12 g, 80%) as a colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.[OH:65][CH2:66][C:67](O)=[O:68]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:66](=[O:65])[CH2:67][OH:68])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro-phenyl)-1,3-oxazinan-2-one stirred in anhydrous CH2Cl2 (5 ml) was added HOBT (36 mg, 0.264 mmol), EDCl (52 mg, 0.264 mmol), DIEA (0.5 ml) and hydroxy-acetic acid (50.1 mg, 0.66 mmol) at 0° C. under N2 atmosphere. The solution was stirred at rt overnight. Then the solvent was removed under reduced pressure to give the residue, which was purified by preparative HPLC to afford N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-2-hydroxyacetamide (19.2 mg, 28.6%). 1H NMR (CDCl3): 1.49-1.50 (d, 3H), 2.01-2.13 (m, 1H), 2.14-2.15 (m, 3H), 2.17 (m, 1H), 2.97-2.98 (m, 2H), 3.46-3.52 (m, 4H), 4.01-4.02 (m, 2H), 5.60-5.61 (m, 1H), 6.82-6.88 (m, 2H), 6.98-7.04 (m, 3H), 7.17 (s, 1H), 7.19-7.22 (m, 3H), 7.25-7.27 (m, 3H).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([NH:15][C:16](=[NH:19])[NH:17][CH3:18])=[O:14])[CH3:3].[CH3:20]N(C(OC)OC)C.Cl.CO>>[ClH:1].[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[N:12]1[CH:18]=[N:17][C:16]([NH:19][CH3:20])=[N:15][C:13]1=[O:14])[CH3:11]
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CO
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O
Yield: 47 %

Procedure:
To a suspension of 22.8 g. (80.0 mmol) of 1-(2',6'-diethylphenyl)-3-methylamidinourea hydrochloride in CH2CN (100 ml.) are added 19.1 g. (160.0 mmol) of DMF-DMA and the reaction mixture is heated at reflux for 3 hours. The CH3CN is removed under reduced pressure and the residue partitioned between CHCl3 and H2O. The layers are separated and the aqueous layer extracted with CHCl3 (1×100). The combined CHCl3 extracts are washed with H2O (1×100 ml.), dried (MgSO4) and concentrated under reduced pressure to give an off-white solid, which by NMR confirms the desired free base. The solution is dissolved in H2OH and acidified with HCl/MeOH and the MeOH removed under reduced pressure to give an off-white solid which is crystallized from CH3CN to give after vacuum drying over the weekend (105° C., house vacuum) 16.7 g. (71%) of crude product. The material is recrystallized from CH3CN (a hot filtration is necessary to remove some undissolved solid) to give 11.0 g. (47%) of desired product as a white crystalline solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:76]([OH:78])=[O:77])[C:72]([CH3:75])([CH3:74])[CH3:73])=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:76]([OH:78])=[O:77])[C:72]([CH3:73])([CH3:74])[CH3:75])=[O:69])=[O:32])=[CH:34][CH:35]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)[C@@H](NC(=O)CN)C(=O)O
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.006 g, 0.012 mmol) and NMM (0.007 ml, 0.064 mmol) in DMF (3 ml) at RT was added TBTU (0.005 g, 0.016 mmol). The reaction mixture was stirred for 60 min after which glycyl-3-methyl-D-valine (Method 10) (0.003 g, 0.016 mmol) was added. The mixture was stirred for 4 h before the solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.
Reaction SMILES: [OH:1][C:2]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([CH3:26])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=O.[H][H]>C(O)(=O)C.[Pd]>[OH:1][C:2]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([CH3:26])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)CCCCCCCCCc1c(C)cc(OC)c(OC)c1O

Procedure:
A solution of methyl 9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoate (formula II-1 wherein R=H3CO, X=H, Y=OH, n=8, in the form of methyl ester) (0.12 part) in acetic acid (17 volume parts) was shaken with 5% palladium-on-carbon in a current of hydrogen gas at 50°-60° C. The catalyst was removed by filtration and the acetic acid was distilled off under reduced pressure. The residue was subjected to column chromatography on silicic acid (6 parts and elution was carried out with chloroform. The procedure provided methyl 10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoate (formula II-2 wherein R=H3CO, X=H, Y=OH, n=8, in the form of methyl ester) (0.09 part) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][C:13](=[C:15]=[O:16])[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]Br>ClCCl>[C:1]([O:9][CH2:10][CH2:11][CH:12]([Br:17])[C:13](=[C:15]=[O:16])[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=C=O)CCCOC(=O)c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: CC(=C=O)C(Br)CCOC(=O)c1ccccc1

Procedure:
The intermediate, 4-carbonylpentyl benzoate (72 mmol), was dissolved in 75 ml dichloromethane. The temperature of the system was maintained below 5° C., bromine (3.7 ml, 72 mmol) was then slowly added dropwise. After the addition was completed, the stirring was maintained for half an hour, until the color of the reaction system disappears. The product was then washed with water, dried with anhydrous magnesium sulfate, and concentrated, to obtain the intermediate, i.e. 3-bromo-4-carbonylpentyl benzoate, which was directly applied in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][CH3:21])[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[C:34]([NH2:35])=[CH:33][C:32]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:31][N:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:26]1([C:29]2[C:34]([NH:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[S:20][CH3:21])[C:3]=3[CH3:22])=[CH:33][C:32]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:31][N:30]=2)[CH2:25][CH2:24][O:23][CH2:28][CH2:27]1
Reactant: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Nc2cc(N3CCOCC3)cnc2N2CCOCC2)c1C

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline (75.0 mg, 0.22 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-(methylsulfanyl)phenyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 7.83 (1H, d, J=12.1 Hz), 7.64 (1H, d, J=9.0 Hz), 7.61 (1H, d, J=2.7 Hz), 7.64 (1H, d, J=9.4 Hz), 7.43-7.50 (1H, m), 7.37-7.42 (1H, m), 7.34 (1H, td, J=7.2, 1.2 Hz), 7.25-7.30 (1H, m), 7.03 (1H, ddd, J=13.5, 8.5, 2.5 Hz), 6.42 (1H, br. s.), 3.92 (4H, br. s.), 3.73-3.83 (4H, m), 3.39 (2H, br. s.), 3.03-3.12 (4H, m), 2.85-3.03 (2H, m), 2.41 (3H, s), 1.97 (3H, s). Mass Spectrum (ESI) m/e=564.3 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH:5]1[C:10]1[C:15](F)=[CH:14][C:13]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=O)=[C:12]([N+:26]([O-])=O)[CH:11]=1)(=[O:3])[CH3:2].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[C:1]([N:4]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH:5]1[C:10]1[C:15]([O:36][C:33]2[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=2)=[CH:14][C:13]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[NH:26][C:12]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(C)CCC1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Reactant: Cc1ccc(O)cn1
Product: CC(=O)N1C(C)CCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(C)nc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using N-(4-(1-acetyl-5-methylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyridine-2-carboxamide obtained in Example 545 and 6-methylpyridin-3-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18]O)[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Se:39]C#N)([O-:32])=[O:31].C(P(CCCC)CCCC)CCC.[Na+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18][Se:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N+:30]([O-:32])=[O:31])[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCO)[C@H]1Oc1ccccc1
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CC[Se]c2ccccc2[N+](=O)[O-])[C@H]1Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-hydroxyethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (227 mg, 0.557 mmol) in anhydrous THF (5.6 mL) at 0° C. (ice water bath) were added 1-nitro-2-selenocyanatobenzene (177 mg, 0.780 mmol) and tributylphosphine (223 μl, 0.891 mmol). The resulting solution was stirred for 3 h and then treated with additional 1-nitro-2-selenocyanatobenzene and tributylphospine (53 mg and 67 μL, respectively). The reaction was stirred for an additional 1 h, then poured into 20 mL sat. NaCl solution and extracted with 3×20 mL EtOAc. The organic extracts were combined, dried over MgSO4, filtered, and concentrated to provide a brown oil, which was purified by column chromatography on SiO2 (2→20% acetone/hexanes) to provide the title compound as a bright yellow solid (294 mg, 89%): 1H NMR (400 MHz, CDCl3) δ 8.24 (dt, J=8.2, 1.0 Hz, 1H), 7.36-7.19 (m, 5H), 7.00-6.92 (m, 1H), 6.92-6.84 (m, 2H), 5.16-4.98 (m, 2H), 4.21 (t, J=8.5 Hz, 2H), 3.05-2.76 (m, 2H), 2.30 (dt, J=13.2, 6.7 Hz, 1H), 1.94 (tdq, J=28.6, 14.1, 8.4, 6.4 Hz, 3H), 1.78-1.64 (m, 2H), 1.60 (d, J=4.5 Hz, 1H), 1.45 (s, 9H), 1.30 (d, J=6.5 Hz, 3H), 1.27-1.13 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 173.23, 159.12, 154.89, 146.86, 133.45, 133.21, 129.76, 128.95, 126.41, 125.29, 121.34, 115.33, 80.99, 79.97, 74.59, 52.99, 43.60, 34.00, 29.99, 28.58, 28.33, 24.24, 19.15, 18.29; ESIMS m/z 593.2 ([M+Na]+).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH3:17])[C:6]([NH:8][CH2:9][C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[CH3:17][CH:5]([C:6]([NH:8][CH2:9][C:10]([F:15])([F:16])[C:11]([F:12])([F:14])[F:13])=[O:7])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.8 g (6.5 mmol) 2-Methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid ethyl ester in 40 ml of tetrahydrofurane, 20 ml of water and 1.09 g (26 mmol) of lithium hydroxide were added and the mixture was stirred overnight at room temperature. After concentration in vacuo water (50 ml) was added and the mixture was extracted with dichloromethane (three times 30 ml). The aqueous phase was acidified with 8 N hydrochloric acid and extracted with dichloromethane (three times 30 ml).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:12]([NH2:14])=O)[C:4](=[O:11])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2>P(Cl)(Cl)(Cl)=O>[C:12]([C:3]1[C:4](=[O:11])[N:5]2[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]2)=[CH:1][CH:2]=1)#[N:14]
Reactant: NC(=O)c1ccc2ccccn2c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2ccccn2c1=O

Procedure:
A mixture of 4H-quinolizin-4-one-3-carboxamide (1.0 g) and phosphorus oxychloride (50 ml) was refluxed for one hour. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in aqueous sodium bicarbonate solution and chloroform. The chloroform extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was chromatographed on silica gel (30 g) eluting with chloroform-methanol (50:1) to give 3-cyano-4H-quinolizin-4-one, which on recrystallization from ether gave crystals (800 mg), mp. 198°-200° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([N+]([O-])=O)=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1CCC[CH2:23]1>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[NH:22][CH:23]=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(OCCOCc2ccccc2)c1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(COCCOc2ccc3[nH]ccc3c2)cc1
Temperature: 120 °C
Yield: 22 %

Procedure:
5 (2-Benzyloxy-ethoxy)-2-nitro-toluene (12.4 g, 43.0 mmol), N-N-dimethylformamide dimethyl acetal (6.55 g, 51.6 mmol) and pyrrolidine (3.68 g, 51.6 mmol) were dissolved in N-N-dimethylformamide (25 mL). The mixture was heated to 120° C. for 16 h. The solvent was evaporated under vacuum and the crude reaction was dissolved in 70% ethyl acetate/methanol (250 mL). The reaction was placed in a Parr Hydrogenator under a hydrogen atmosphere for 16 h with 10% palladium on carbon [10% w/w] (3.00 g) at 50 psi. The reaction was filtrated over celite and the crude mixture was purified via column chromatography with silica gel eluting with hexane/ethyl acetate to give the title compound (22% yield). 1H NMR (CDCl3) δ 7.27-7.41 (m, 6H), 7.19 (t, 1H, J=2.5 Hz), 7.13 (d, 1H, J=2.3 Hz), 6.91 (dd, 1H, J=2.5, 8.8 Hz), 6.48 (m, 1H), 4.67 (s, 2H), 4.21 (m, 2H), 3.87 (m, 2H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH:7]([C:9]([O-:11])=[O:10])[CH2:6][NH:5][CH2:4]2)[CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:2]1[C:3]2([CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][NH:5][CH2:4]2)[CH2:1]1
Reactant: O=C([O-])C1CNCC2(CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CNCC2(CC2)C1

Procedure:
The above product of tert-butyl (6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylate was stirred in 8 mL of 50% TFA in methylene chloride solution (v/v) for 4 hours. After removal of solvent, the residue was dried under high vacuum overnight to give (6S,7S)-6-((4-phenyl)piperazin-1-yl)carbonyl)-5-azaspiro(2,5)octane-7-carboxylic acid. LC-MS: m/z 344.1 (M+H)+.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: OCCCCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1ccc2ccc(CCCCCCCl)cc2o1

Procedure:
Preparation can be carried out analogously to Synthetic Example 1 using 16.2 g (100 mmol) 7-Hydroxycoumarin, 14.3 g (105 mmol) 6-chlorohexanol, 28.8 g (110 mmol) triphenylphosphine and 47.9 g (110 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene to yielded 7-(6-chlorohexyl) coumarin.