Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]1([CH3:24])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][C:9]([CH3:24])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: Cc1ccccc1-c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccnc(Cl)c2)cc1
Yield: 44 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (10.0 g, 41.8 mmol), p-tolylphenylboronic acid (5.68 g, 41.8 mmol), Pd(Ph3P)4 (1.45 g 1.25 mmol), sodium carbonate (13.3 g, 125 mmol), DME (300 mL) and water (75 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and the extracted with ethyl acetate. The the ethyl acetate layer was dried on Na2SO4, vacuum distilled and recrystalized to give 2-chloro-4-(p-tolyl)pyridine (3.75 g, 18.4 mmol, 44% yield).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.C(=O)=O.CC(C)=O.[C:49]1([CH2:55][CH2:56][CH2:57][CH2:58][CH:59]=[O:60])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@@H:15]([CH3:16])[C@H:59]([OH:60])[CH2:58][CH2:57][CH2:56][CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCCCc1ccccc1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=C=O
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)CCCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 68.8 %

Procedure:
4-(S)-Benzyl-3-propionyl-2-oxazolidinone (8.4 g, 36 mmol) is dissolved in CH2Cl2 (60 mL), cooled in an ice bath and to this is added 1 M dibutyl boron triflate in CH2Cl2 (40 mL, 40 mmol) over 5 minutes. Then triethylamine (6.3 mL, 45 mmol) is added dropwise at a rate that kept the reaction temperature <3° C. The ice bath is then replaced by dry-ice/acetone and 5-phenylpentanal (7.8 g, 48 mmol) in CH2Cl2 (20 mL) is added over 5 minutes. This mixture is stirred 20 minutes at -78° C. and then for 1 hour at 0° C. The reaction is quenched by the addition of pH 7 phosphate buffer (40 mL), followed by MeOH (120 mL). Then a mixture of MeOH (80 mL) and 30% hydrogen peroxide (40 mL) is added at a rate that kept the reaction temperature <10° C. The reaction is stirred 1 hour and then concentrated in vacuo (bath temperature <30° C.). The residue is extracted into ether (3×200 mL) and the combined ether layers are washed with NaHCO3 (200 mL), brine (200 mL) and dried over MgSO4 and then concentrated in vacuo. The crude product is purified by column chromatography (silica, 10% petroleum ether in CH2Cl2 then a second purification using 45% ether in petroleum ether) to yield 4-(S)-benzyl-3-(3-(R)-hydroxy-2-(S)-methyl-7-phenylheptanoyl)oxazolidin-2-one (9.8 g, 70%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.14 (m, 10H), 4.73-4.65 (m,1H), 4.24-4.15 (m, 2H), 3.96-3.91 (m, 1H), 3.79-3.71 (m, 1H), 3.27-3.21 (dd, J=13.4, 3.3 Hz, 1H), 2.88 (d, J=3.0 Hz, 1H), 2.78 (dd, J=13.3, 9.5 Hz, 1H), 2.62 (t, J=7.5 Hz, 2H), 1.70-1.34 (m, 6H), 1.25 (d, J=6.8 Hz, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16]>CCCCCC.COCCOC>[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:16]/[C:15]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
After 903 mg (20.7 mmol) of 55% sodium hydride were washed with hexane, it was suspended in 60 ml of 1,2-dimethoxyethane, and 4.63 g (20.7 mmol) of triethyl phosphonoacetate were added dropwise thereto while the suspension was stirred at 0° C. under nitrogen atmosphere. After 15 minutes, 2.00 g (11.5 mmol) of 4-(trifluoromethyl)benzaldehyde were added to the resulting mixture at the same temperature, followed by stirring of the mixture for 15 minutes. Ethyl acetate was added to the reaction mixture and the resulting mixture was washed with water. After drying, an oily residue obtained by evaporation of the solvent was subjected to column chromatography using silica gel and eluted with 4% ethyl acetate-hexane to obtain the title compound having a melting point of 31 to 32.5° C. in a yield of 98%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[C:13]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-3-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 470.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17](I)[N:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/B(O)O)=[CH:34][CH:33]=1.O>COC.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]>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17](/[CH:39]=[CH:38]/[C:35]4[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=4)[N:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: O
Product: Cc1nc(-c2cncc(/C=C/c3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Reaction time: 12 h
Yield: 64.9 %

Procedure:
Part A. To a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (250 mg, 0.55 mmol, 1.0 equiv) in dimethyl ether (3 mL) was added Na2CO3 (175 mg, 1.65 mmol, 3.0 equiv), trans-2-(4-fluorophenyl)vinyl boronic acid (274 mg, 1.65 mmol, 3.0 equiv), PdCl2(dppf) (40 mg, 0.06 mmol, 0.1 equiv) and water (0.4 mL) in a sealed tube. The reaction vessel was immersed in an oil bath preheated to 100° C. After stirring for 12 hr, the reaction mixture was cooled and the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 10:90, v/v] to give 2-{6-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (160 mg, 65%). MS (M+H)+=449.1, Rt=1.64 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1=[O:24])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(C(C)C)CC)(C)C.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([S:46]([NH:1][CH2:2][CH:3]([C:11]2([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[O:24])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:48])=[O:47])=[CH:44][CH:45]=1
Reactant: CC(C)CC1(C(CN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC(C(=O)OC(C)(C)C)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A cold (0° C.) solution of tert-butyl α-(1-aminomethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (337 mg, 0.867 mmol) in dry CH2Cl2 (3 mL) is treated with diisopropylethylamine (240 μL, 1.30 mmol) and 4-methoxybenzenesulfonyl chloride (215 mg, 1.30 mmol). The solution was allowed to slowly warm to room temperature, stirring overnight under N2. After diluting with CH2Cl2 (25 mL), the solution is washed with dilute NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 460 mg of a yellow oil. The oil was purified by silica gel chromatography (20 g SG; 25% EtOAc/hexane) to provide 383 mg (79%) of the desired material as a white amorphous solid:
Reaction SMILES: Cl.[OH:2][NH2:3].C(=O)(O)[O-].[Na+].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]>CO>[OH:2][N:3]=[C:14]([C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([CH2:10][OH:9])[CH:12]=1)[NH2:15]
Reactant: N#Cc1cccc(CO)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1cccc(CO)c1
Temperature: 25 °C
Yield: 105.7 %

Procedure:
Hydroxyl amine hydrochloride (2.29 g, 32.9 mmol) and sodium bicarbonate (5.52 g, 65.8 mmol) were added to 3-(hydroxymethyl)benzonitrile (2.19 g, 16.4 mmol) and methanol (30 mL) and stirred at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo to give the title compound (2.88 g, 100% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:17](/[CH:18]=[CH:19]/[N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)(=O)C.CCCCCC>C1COCC1.CN1C(=O)CCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]([C:17]3[C:12]([CH3:11])=[C:13]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:14]=[CH:15][CH:16]=3)[CH2:19][N+:20]([O-:22])=[O:21])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 6 h
Yield: 61.4 %

Procedure:
A mixture of 6-bromo-1H-indole (2.82 g, 14.41 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (3.0 g, 9.61 mmol) was dissolved in THF (50 mL) and NMP (0.5 mL). The THF was removed under vacuum, and the residue was heated at 120° C. for 16 hr and then at 125° C. for 6 hr. Upon cooling to room temperature, the mixture was dissolved in THF (50 mL). The resulting solution was diluted with ethyl acetate (250 mL), washed with water (3×80 mL) and brine (60 mL), and dried over anhydrous MgSO4. The desired product (3.00 g, 5.90 mmol, 61.4% yield) was isolated as a beige solid by ISCO (300 g silica gel, 25-60 ethyl acetate/hexane).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])=[CH:4][C:3]=1[F:25].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])O.[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[C:18]([O:17][C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:23]=[CH:24][C:2]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[C:3]([F:25])[CH:4]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Br)c(F)c1
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2cccnc2)c(F)c1
Yield: 91.3 %

Procedure:
t-Butyl 2-[(4-bromo-3-fluorobenzoyl)amino]phenylcarbamate (Method 63, 205 mg, 0.5 mmol), 3-pyridine boronic acid (74 mg, 0.6 mmol), tetrakis(triphenylphosphine) palladium (104 mg, 0.09 mmol), 1,2-dimethoxyethane (3 ml) and a saturated aqueous solution of sodium hydrogen carbonate (3 ml) were stirred at 80° C. under an atmosphere of argon for 48 hours. The cooled mixture was partitioned between ethyl acetate and water. The aqueous layer was removed using Varian Chem Elut column (CE1010) and the resulting solution was then concentrated under reduced pressure and purified by flash column chromatography, eluting with ethyl acetate/isohexane (25-75%), to give the title compound (186 mg, 91%). Mass Spectrum: M+H+ 408.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24](OC)=[O:25])=[CH:6][CH:5]=2.[ClH:28].[NH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33]>C(=O)([O-])O.[Na+]>[ClH:28].[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24]([NH:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[O:25])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Reactant: CS(=O)(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)CCNC(=O)c1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Yield: 36 %

Procedure:
Starting materials: methyl 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxylate and 2-aminoethylmethylsulfone hydrochloride, but the reaction mixture was after cooling diluted with a saturated sodium hydrogen carbonate solution (10 mL) and concentrated in vacuo. The residue was suspended in methanol/dichloromethane (1:1) and silica gel (˜2 g) was added. The mixture was re-concentrated in vacuo, resulting in a fine yellow powder that was purified on a silica gel column using dichloromethane/methanol/aqueous NH3, (100:10:1), as the eluent to afford the title compound as a base in 36% yield: 1H NMR (DMSO-d6, 300 MHz) δ 14.70 (br s, 1H), 11.42 (br s, 1H), 10.71 (s, 1H), 8.73 (br s, 1H), 8.22 (s, 1H), 8.06 (d, J=9.3 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.25 (s, 2H), 3.98-3.92 (m, 2H), 3.85-3.67 (m, 4H), 3.44-3.29 (m, 4H), 3.12-3.00 (m, 5H); MS (ES) m/z 459 (M++1). The base was converted to the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.Cl.Cl.[NH2:30][CH:31]1[CH2:34][NH:33][CH2:32]1.CN1CCCC1>CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH:31]([NH2:30])[CH2:32]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(N)C4)c(F)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To 210 mg of N,N-dimethylformamide were added 50 mg of 5-amino-1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour, and concentrated under reduced pressure. The procedure of adding 2 ml of diisopropylether to the residue, stirring and decanting was repeated twice. 2 ml of ethanol and 40 mg of N-methylpyrrolidine were added to the residue, and the mixture was allowed to stand overnight, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 26 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]2=[O:17].[NH2:19][CH:20]1[CH:28]=[CH:27][CH:26]([CH3:29])[CH:25]2[CH:21]1[CH2:22][NH:23][CH2:24]2.N12CCN(CC1)CC2>CS(C)=O>[NH2:19][CH:20]1[CH:28]=[CH:27][CH:26]([CH3:29])[CH:25]2[CH:21]1[CH2:22][N:23]([C:3]1[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:17])[C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]3[CH2:12][CH3:13])=[CH:5][CH:4]=1)[CH2:24]2
Reactant: CC1C=CC(N)C2CNCC12
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(F)c(Cl)c21
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N3CC4C(C)C=CC(N)C4C3)c(Cl)c21

Procedure:
270 mg (1 mmol) of 8-chloro-1-ethyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid together with 180 mg (1.2 mmol) of 4-amino-7-methyl-1,3,3a,4,7,7a-hexahydroisoindole and 224 mg (2 mmol) of 1,4-diazabicyclo[2.2.2]octane are heated for three hours at 100° C. in 10 ml of dimethyl sulphoxide.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-difluoro-ethyl)-oxazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyloxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:36]=1.[CH3:37][N:38](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:37]([C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25][NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([C:21]([F:23])([F:22])[F:24])[C:6]=2[CH:36]=1)#[N:38]
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(C#N)ccc32)cc1

Procedure:
A solution of N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (1.0 g, 1.76 mmol), zinc cyanide (414 mg, 3.53 mmol) and tetrakis(triphenyl phosphine)palladium (102 mg, 0.088 mmol) in DMF (4.5 mL) was stirred at 100° C. for 3 hours. The temperature of the solution was brought to room temperature and the solution was diluted with ethyl acetate, which was washed sequentially with an aqueous citric acid solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1), whereby the objective compound (873 mg, 96%) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1.ClCCl>[NH2:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:8][CH:7]=3)=[CH:10][N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CNC(=O)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of trans-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.119 mmol) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0° C. then treated with benzoyl chloride (19 mg, 0.13 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The solvents were removed under reduced pressure then the residue was purified by preparative reverse phase chromatography to give trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzyl)benzamide (50 mg) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.08(t, 1H), 8.13(s, 1H), 7.91(m, 2H), 7.4-7.54(m, 8H), 6.0(bs, 2H), 4.53(m, 3H), 2.30-2.40(m, 5H), 2.15(s, 3H), 1.85-1.89(m, 10H), 1.43-1.46 (m, 2H); RP-HPLC (Hypersil HS C18, 5μm, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 18.20 min.; MS:MH+ 524.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][CH2:12][C:11](=O)[CH2:10][S:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[NH2:21][CH:11]1[CH2:12][S:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[S:9][CH2:10]1
Reactant: [BH3-]C#N
Reactant: Cc1ccc(C2SCC(=O)CS2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C2SCC(N)CS2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
22.4 g (0.1 mol) of 2-(4-methylphenyl)-1,3-dithian-5-one and 77.1 g (1.0 mol) of ammonium acetate were stirred in 250 ml of methanol with the addition of 37.5 g of molecular sieve (3 Å) for 30 minutes and 6.30 g (0.1 mol) of sodium cyanoborohydride were then added in portions at 20° C. The mixture was stirred at room temperature for 48 hours, diluted with methanol and filtered. The filtrate was concentrated and the residue was taken up in dilute hydrochloric acid/toluene. The hydrochloric acid phase was rendered basic with concentrated sodium hydroxide solution and extracted with ether. This gave 2.2 g of product as a colorless oil (9.8% of theory), which was reacted without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[C:28]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 11 h
Yield: 32.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (59.4 μL, 0.835 mmol), and the mixture was stirred at room temperature for 11 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane) to give the title compound (109 mg, 33%) as a pale-yellow solid.