Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1cc(NC(=O)c2ccnc(N3CCOCC3)c2)ccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccnc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 80° C. for 16 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-2-morpholinopyridine-4-carboxamide. The reaction mixture was evaporated and the residue was triturated under water. The resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried in a vacuum oven. The material so obtained was purified by column chromatography on an ion exchange column (isolute CBA column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using methanol as eluent. There was thus obtained the title compound (0.493 g) in 58% yield; NMR Spectrum: (DMSOd6) 3.51 (m, 4H), 3.71 (m, 4H), 7.09 (d, 1H), 7.23 (s, 1H), 7.55 (d, 1H), 7.71 (d, 2H), 8.06 (s, 1H), 8.27 (d, 1H), 8.35 (d, 1H), 8.96 (s, 1H), 10.39 (s, 1H), 10.49 (s, 1H); Mass Spectrum: M+H+ 472.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:28][CH2:27][CH2:26][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCOc1ccccc1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCOc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 96.8 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.106 g, 1.050 mmol) and 2-phenoxyethylamine (0.144 g, 1.050 mmol) in MeCN (3 mL) was heated at in a microwave reactor 120° C. for 5 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 65:35 mixture of heptane and EtOAc as eluant to give the title compound (0.262 g, 97%); 1H NMR (500 MHz, CDCl3): δ 7.57-7.54 (m, 2H), 7.49-7.45 (m, 3H), 7.32-7.27 (m, 2H), 7.02-6.97 (m, 1H), 6.86-6.83 (m, 2H), 5.71-5.66 (br m, 1H), 4.46-4.39 (m, 1H), 3.89 (t 2H), 3.27 (q 2H), 1.60 (d 6H); 13C NMR (125 MHz, CDCl3): δ 158.5, 158.2, 135.6, 131.7, 130.0, 129.8, 129.1, 125.1, 121.8, 114.7, 108.0, 65.8, 47.8, 43.6, 20.4; Mass Spectrum: M−H′ 387.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C=O)c(F)c2)cc1

Procedure:
The title compound was prepared by reacting 4-bromo-2-fluoro-benzaldehyde (3 g, 14.8 mmol) with 4-methoxyphenylboronic acid (2.70 g, 17.8 mmol) according to Method B to yield 3.2 g (94%) of white solid: mp 85-86° C.; 1H NMR (DMSO-d6): δ 3.83 (3H, s). 7.06-7.09 (2H, m), 7.70-7.75 (2H, m), 7.79-7.82 (2H, m), 7.88 (1H, t, J=7.96 Hz), 10.22 (1H, s); IR 1681 cm−1; MS (ESI) m/z 231 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14]C)=O.O.[NH2:17][NH2:18]>CO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:17][NH2:18])=[O:14]
Reactant: COC(=O)c1cccc2c(Br)cccc12
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1cccc2c(Br)cccc12
Yield: 65.6 %

Procedure:
Methyl 5-bromo-1-naphthoate (D1) (5.32 g, 20 mmol) and hydrazine hydrate (5.7 ml, 100 mmol) were stirred at reflux in methanol (50 ml) for 48 h. After cooling, the solid was filtered off, washed with cold methanol, and dried in vacuo at 60° C., yielding the title compound (3.48 g, 65%) as a grey-brown crystalline powder.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=3)[C:5]([OH:8])=[N:6][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[CH:38]=[C:37]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])[C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][C:29]=3[C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:22][CH:21]=1>CC(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[C:9]([C:4]1[N:3]=[C:2]([C:36]3[C:37]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:28]4[O:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)=[C:30]([C:31]([NH:33][CH3:34])=[O:32])[C:29]=4[CH:35]=3)[CH:7]=[N:6][C:5]=1[OH:8])[NH:10]2
Reactant: Oc1ncc(Br)nc1-c1cc2c(F)cccc2[nH]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc(O)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a degassed solution of 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyrazin-2-ol (prepared using similar method described in Example 1, 1.23 g, 3.98 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (2 g, 3.98 mmol) and K3PO4.3H2O (2.12 g, 7.96 mmol) in IPA (20 mL) and H2O (2 mL) was added Pd2(dba)3 (50 mg) and X-Phos (50 mg) under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 16 h, concentrated in vacuo to remove IPA. The residue was diluted with H2O and extracted with DCM. Then the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (PE:EA=1:2) to give 5-(6-(4-fluoro-1H-indol-2-yl)-5-hydroxypyrazin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (1 g, yield: 41%). 1H-NMR (CDCl3, 400 MHz) δ 8.52 (d, J=4.0 Hz, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.42 (t, J=8.8 Hz, 2H), 7.33˜7.36 (m, 2H), 7.11˜7.18 (m, 2H), 6.80 (dd, J1=10.4 Hz, J2=8.0 Hz, 2H), 3.27 (s, 3H), 3.10 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). MS (M+H)+: 604.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:47][C:48]([F:67])([C:63]([F:66])([F:65])[F:64])[CH2:49][CH2:50][CH2:51]OS(C1C=CC(C)=CC=1)(=O)=O>O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][N:38]([CH2:51][CH2:50][CH2:49][C:48]([F:67])([F:47])[C:63]([F:66])([F:65])[F:64])[CH2:39][CH2:40]3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC(F)(F)C(F)(F)F)cc1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCN2CCN(CCCC(F)(F)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
7-(Methoxymethoxy)-3-(4-methoxymethoxyphenyl)-4-(9-piperazinylnonyl)-3-methylchroman (380 mg, 0.685 mmol), K2CO3 (190 mg, 1.375 mmol) and 4,4,5,5,5-pentafluoropentyl-4-methylbenzenesulfonate (460 mg, 1.384 mmol) were refluxed under acetone for 15 hours. After the mixture was cooled down to room temperature, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the organic solvent was removed under reduced pressure. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to give 238 mg (yield: 48%) of the title compound as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CON(C)[C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)=[CH:22][CH:21]=1.C(O)(=O)C>O1CCCC1>[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:19]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:24][CH:25]=2)=[O:38])=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
To a solution of Lithium diisopropyl amide (1.0M) in tetrahydrofuran was added 4-picoline dropwise (7.55 ml, 5 eq.) at 0° C. under N2. After 30 min the anion was cooled to −78° C. In a separate round bottom flask N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide (5.0, 15.5 mmole) was dissolved in tetrahydrofuran (77 ml, 0.2M) and cooled to −78° C. under N2. 1.2 eq. of the 4-picoline anion was added dropwise to the amide solution. After 45 min, 1 eq. more of the 4-picoline anion was added. After an addition 30 min, acetic acid (40 ml) was added dropwise and the reaction was slowly warmed to ambient temperature. The solid product (acetate salt) was filtered and partitioned between saturated sodium bicarbonate and dichloromethane. The layers were separated, dried magnesium sulfate filtered and concentrated to provide the title compound as a tan solid (4.41 g, 80%). 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=5.8 Hz, 2 H), 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1H), 7.93 (m, 2 H), 7.82 (d, J=8.3 Hz, 1 H), 7.75 (m, 1 H), 7.61 (d, J=8.3 Hz, 1 H), 7.54 (dt, J=7.9, 1.0 Hz, 1 H), 7.23 (m, 2 H) 7.07 (m, 2H), 5.42 (s, 2H), 4.19 (s, 2H); MS: (M+H m/z=355.2).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>N1C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH:10][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[F:13])=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: NNc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: O=C(NNc1ccc(C(F)(F)F)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a stirred solution of 75.0 g of 4-(trifluoromethyl)-phenylhydrazine in 500 ml of dry pyridine, cooled in an ice bath, was added dropwise, under nitrogen, 79.1 g of 2-fluorobenzoyl chloride. Upon completion of the addition, the ice bath was removed and the reaction mixture stirred at ambient temperature for 4 hours. The mixture was poured into water and a precipitate formed. Recrystallization of the precipitate from isopropyl alcohol-water, gave 108 g (84%) of 2-fluorobenzoic acid, 2-(4-(trifluoromethyl)phenyl)hydrazide as a solid. Subsequent recrystallization from isopropyl alcohol-water gave the analytical sample, mp 163°-165°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>C(Cl)Cl.S(=O)(=O)(O)O.CN(C1C=CC=CN=1)C>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH:4][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1F
Agent: CN(C)c1ccccn1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Yield: 88.4 %

Procedure:
A mixture of 6.0 g (0.034 mole) of 2,5-difluoro-4-nitroaniline, 6.5 g (0.064 mole) of acetic anhydride, and approximately 0.1 g (0.0008 mole) of dimethylaminopyridine in 300 ml of methylene chloride was stirred and heated at reflux for two hours. The reaction mixture was allowed to cool and stir at room temperature for approximately 18 hours. The solvent was removed from the mixture by distillation under reduced pressure, leaving a residue. To this residue was added 32.5 g (0.318 mole) of acetic anhydride and several drops of concentrated sulfuric acid. This mixture was stirred at room temperature for approximately 18 hours. Approximately 300 ml of water was added to the mixture causing a vigorous exotherm and a solid to form. This solid was collected by filtration. The filter cake was washed with water and was dried under reduced pressure to yield 6.5 g of N-(2,5-difluoro-4-nitrophenyl)acetamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1.C1N=CN([C:18](N2C=NC=C2)=[O:19])C=1>C1COCC1>[O:19]=[C:18]1[N:4]([C:5]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]2)[CH2:3][CH2:2][O:1]1
Reactant: CCOC(=O)C1(NCCO)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(N2CCOC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.6 %

Procedure:
A mixture of ethyl 1-((2-hydroxyethyl)amino)cyclopropanecarboxylate (0.180 g, 1.039 mmol) and CDI (0.177 g, 1.091 mmol) in THF (5 mL) was stirred at room temperature for 15 h, then heated to reflux for 15 h. The solvent was removed and the residue was purified with silica gel chromatography to yield ethyl 1-(2-oxooxazolidin-3-yl)cyclopropanecarboxylate (0.2 g). A solution of LiOH (0.048 g) in water (3 mL) was added to a solution of ethyl 1-(2-oxooxazolidin-3-yl)cyclopropanecarboxylate (0.2 g, 1.004 mmol) in THF (5 mL) and the resulting mixture was stirred vigorously at rt for 16 h. The reaction mixture was then diluted with water and washed with EtOAc. The aqueous layer was then acidified with 1N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to yield Cap L-5 (60 mg). 1H NMR (500 MHz, DMSO-d6) ppm 12.83 (br. s., 1H), 4.30-4.20 (m, 2H), 3.65-3.56 (m, 2H), 1.41-1.33 (m, 2H), 1.25-1.19 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Si:33]([O:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[N:7][CH:6]=1)[CH2:9][O:10][Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)nc1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 1-(6-bromopyridin-3-yl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethanol (1.58 g) and 2,6-lutidine (0.83 mL) in dichloromethane (15 mL) was cooled to 0° C., tert-butyl(dimethyl)silyl trifluoromethanesulfonate (1.31 mL) was added dropwise, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.79 g, yield 84%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:19, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([C:19]#[C:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:23])=[C:12]3[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCO)cc2c1O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CCCO)cc2c1O
Reaction time: 3 h
Yield: 27.4 %

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-2-(3-hydroxy-1-propynyl)-thieno[2,3-b]pyridine-5-carboxamide (Example No.5) (0.300 g) in 1/1 CH2Cl2/CH3OH (70 mL) is hydrogenated over 10% Pd/C (90 mg) at 35 psi. After 3 h, an additional 90 mg of 10% Pd/C is added, and the solution is hydrogenated at 35 psi for 1 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting pale orange solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield and off-white solid which is recrystallized from ethanol to yield 0.083 g (27%) of the title compound as a white, crystalline solid.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]2)[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)N1

Procedure:
A solution containing 0.65 g of hydantoin, 0.92 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 g of ammonium acetate in 15 ml of acetic acid was refluxed overnight. The product was filtered and washed with acetic acid and 2-propanol. Yield 0.56 g (42%), mp >350° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:22]([O-])=O)=[C:5]([CH3:21])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:8]=1.O.NN>CCO>[NH2:22][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)[C:5]=1[CH3:21]
Reactant: Cc1[nH]c([N+](=O)[O-])c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1[nH]c(N)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Yield: 33.6 %

Procedure:
[4-(2,4-Dimethyl-5-nitro-1H-pyrrol-3-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine (45 mg, 0.14 mmol) was dissolved in EtOH (3 mL) and 10% Pd(C) catalyst (10 mg) was added, followed by hydrazine hydrate (48 μL of a 55% w/w aq solution, 0.84 mmol). The mixture was heated at reflux for 18 h. The cooled mixture was filtered through a pad of Celite filter aid and the filtrate was evaporated in vacuo. The residue was purified by SiO2 chromatography (20:1 EtOAc/2 M ammonia in MeOH) to afford the title compound (14 mg) as a yellow solid. M.p. 227–231° C. MS: [M+H]+=397.8 (C16H16FN5 requires 297.3). 1H-NMR (CDCl3) δ: 1.98 (s, 3H, CH3), 2.37 (s, 3H, CH3), 4.86 (br. s, 2H, NH2), 6.65 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 7.03 (t, 2H, J=8.3 Hz, Ph-H), 7.49 (br. s, 2H, NH), 7.58–7.61 (m, 2H, Ph-H), 8.53 (d, 1H, J=4.9 Hz, pyrimidinyl-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:24]4[CH2:28][CH2:27][CH2:26][C:25]4=[O:29])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Agent: [H-]
Agent: [Na+]
Product: O=C1CCCN1c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1

Procedure:
To a solution of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (4.8 g, 0.015 mol) in pyrrolidon (20 ml) is added sodium hydride (1.93 g, 0.06 mmol of a 75% dispersion in oil) in several portions. The reaction temperature is slowly raised to +150° C. After 30 minutes the heating bath is removed and the mixture is poured onto crushed ice. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is separated, dried over magnesium sulfate, filtered and evaporated under reduced presssure. The residue is purified by silicagel chromatography and recrystallized from ethyl acetate to give the title compound, m.p. 165–166° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[N:26]1[C:31]2[CH2:32][CH2:33][NH:34][CH2:35][C:30]=2[C:29](=[O:36])[NH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:34]3[CH2:33][CH2:32][C:31]4[N:26]=[CH:27][NH:28][C:29](=[O:36])[C:30]=4[CH2:35]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: O=c1[nH]cnc2c1CNCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCc4nc[nH]c(=O)c4C3)n2n1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 52 mg, 0.151 mmol), 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (78 mg, 0.395 mmol), and N,N-diisopropylethylamine (60 mg, 0.467 mmol) in DMF (0.5 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a white solid (26.9 mg, 39%). 1H NMR (DMSO-d6) δ: 8.13 (br. s., 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (s, 1H), 6.18 (s, 1H), 5.18 (s, 1H), 4.49 (br. s., 2H), 4.10 (t, J=6.7 Hz, 2H), 2.87 (t, J=6.7 Hz, 2H), 2.40 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 460.2 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:39](O)=[O:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:39]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)=[O:40]
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Reactant: O=CO
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCN(C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To it were added formic acid (25 mg, 0.55 mmol), DIEA (200 μL, 1.10 mmol) and then PyBOP (115 mg, 0.22 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-5-(4-(1-formylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (496), as HCl salt (37 mg). LC-MS (ESI): m/z (M+1) 536.2. UV: λ=261, 329, 337 nm.