Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:3]=1[CH3:22].[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:28]([C:27]1[CH:30]=[CH:31][C:24]([O:23][C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[C:3]=2[CH3:22])=[CH:25][CH:26]=1)=[O:29]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(C=O)cc2)ncnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 39.6 %

Procedure:
To a solution of t-butyl 4-((6-chloro-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate (2.0 gm, 0.00610 mole) and 4-hydroxybenzaldehyde (1.34 gm, 0.00610 mole) in dimethyl formamide (50 mL), Cesium carbonate (4 gm, 0.0122 mole) was added and reaction mixture was stirred for 24 hours at 70° C. Then reaction mixture was cooled, poured into ice cold water and extracted with ethyl acetate. organic extract was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to yield crude product. The crude product so obtained was purified through column chromatography using 15-20% ethyl acetate in hexane to yield 1 gm product as oil.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CCOCC>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[S:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(N=C=S)cc2s1
Solvent: CCOCC
Product: CN1CCN(C(=S)Nc2ccc3nc(C(C)(C)C)sc3c2)CC1

Procedure:
70 g (0.28 mole) of 2-tert.-butyl-6-isothiocyanobenzthiazole are dissolved in 1200 ml of ether and 33 g (0.33 mole) of 4-methylpiperazine are added dropwise, while stirring. The mixture is stirred for 1 hour, filtered and washed first with ether, then with petroleum ether. 2-tert.-butyl-6-[(4-methylpiperazin-1-yl)-thiocarbonylamino]-benzthiazole having a melting point of 176-177° is obtained: ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[C:29]([C:34]([O:36]C)=[O:35])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C
Yield: 79 %

Procedure:
A solution of methyl 6-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylate (0.035 g, 0.061 mmol) in tetrahydrofuran (0.6 mL) was placed in a microwave reaction tube. Methanol (0.3 mL) was added followed by 1N sodium hydroxide (0.092 mL, 0.092 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.027 g, 77.1%) 1H NMR (DMSO-d6): δ 13.03 (s, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 8.15 (d, J=9 Hz, 1H), 8.03 (d, J=9 Hz, 1H), 7.96 (dd, J=2, 9 Hz, 1H), 7.90 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=9, 2H), 7.42 (d, J=8 Hz, 2H), 7.25 (m, 1H), 7.14 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.35 (septet, J=7 Hz, overlapping H2O, 1H), 3.24-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). HRMS C32H27NO4Cl2 m/z 560.1395 (M+H)+cal; 560.1409 (M+H)+Obs.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1.[H][H].[ClH:20]>CO.[OH-].[OH-].[Pd+2]>[ClH:20].[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([CH3:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[C:9]([F:15])[CH:8]=1
Reactant: [H][H]
Reactant: COC(=O)[C@@H](C)COc1ccc(C#N)c(F)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H](C)COc1ccc(CN)c(F)c1
Yield: 95 %

Procedure:
(S)-3-(4-Cyano-3-fluoro-phenoxy)-2-methyl-propionic acid methyl ester (0.14 g) was shaken on a Parr shaker under 50 psi hydrogen for 16 h, using palladium hydroxide on carbon (0.01 g, 30% Pd by wt) in anhydrous methanol (20 mL) and concentrated hydrochloric acid (0.5 mL). The reaction mixture was filtered through sintered glass, and solvents removed in vacuo to afford 0.18 g of a white solid (95% yield).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[CH3:18][O:19][C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21].CCN(CC)CC>CC(O)C.O>[CH3:17][O:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:25]1[CH2:26][CH2:27][CH:22]([C:20]([O:19][CH3:18])=[O:21])[CH2:23][CH2:24]1)[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10]2
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)cc2c1
Reactant: COC(=O)C1CCNCC1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(c2nc3ccc(OC)cc3cc2C(F)(F)F)CC1
Yield: 42.3 %

Procedure:
To a solution of 2-chloro-6-methoxy-3-(trifluoromethyl)quinoline (1.00 g, 3.85 mmol) (see Intermediate 6, Step 8 for synthesis) in IPA (5 mL) was added methyl-4-piperidinecarboxylate (5.50 g, 38.5 mmol) and Et3N (1.17 g, 11.6 mmol). The mixture was heated to reflux for 48 hours. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL×3), the combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (PE/EtOAc=15/1) to give the product (600 mg, yield 43%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[C:6]([CH3:12])=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:15]3[CH:14]=[CH:13][C:3]([O:4][C:5]4[C:6]([CH3:12])=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=4)=[C:2]([F:1])[CH:16]=3)=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: Cc1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)c(C)n1
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: C1COCCO1
Product: Cc1ccc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)cc2F)c(C)n1
Yield: 57.1 %

Procedure:
To a solution of intermediate 12 (2 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (6 ml) was added intermediate 5 (0.51 g, 2 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.231 mg, 0.2 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 3% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 3 (0.445 g, 58%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12]>>[F:9][C:10]([F:17])([F:16])[C:11]([NH:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: NCCc1cccs1
Reactant: CCOC(=O)C(F)(F)F
Product: O=C(NCCc1cccs1)C(F)(F)F
Yield: 86 %

Procedure:
In close analogy to the procedure described above, 2-Thiophen-2-yl-ethylamine is reacted with ethyl trifluoracetate to provide the. title compound.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14][C:15]=2[C:16]([F:19])([F:18])[F:17])=[O:10])=[CH:4][CH:3]=1.C1(C2OC(C(F)(F)F)=C(C(O)=O)N=2)C=CC=CC=1.BrC1N=CC(N)=CC=1.[CH3:52][O:53][C:54]([CH:56]1[CH2:60][CH2:59][CH2:58][CH:57]1[C:61](=[O:77])[C:62]1[CH:67]=[CH:66][C:65](B2OC(C)(C)C(C)(C)O2)=[CH:64][CH:63]=1)=[O:55].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.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.[Pd]>[CH3:52][O:53][C:54]([CH:56]1[CH2:60][CH2:59][CH2:58][CH:57]1[C:61](=[O:77])[C:62]1[CH:63]=[CH:64][C:65]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]=[C:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:14][C:15]=3[C:16]([F:18])([F:19])[F:17])=[O:10])=[CH:6][N:7]=2)=[CH:66][CH:67]=1)=[O:55]
Reactant: COC(=O)C1CCCC1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(Nc1ccc(Br)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Pd]
Agent: Nc1ccc(Br)nc1
Agent: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1CCCC1C(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)cc1
Temperature: 160 °C

Procedure:
2-(4-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-cyclopentanecarboxylic acid methyl ester was prepared through a standard Suzuki coupling procedure by mixing 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide (prepared using a similar coupling procedure as described above from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-bromo-pyridin-3-ylamine), 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-cyclopentanecarboxylic acid methyl ester, palladium tetrakis(triphenylphosphine) and aqueous sodium bicarbonate solution in toluene and ethanol, and heating this mixture to 160° C. under microwave condition for 20 min. Aqueous workup followed by silica gel chromatography separation gave 2-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-cyclopentanecarboxylic acid methyl ester as light yellow solid. LCMS calcd for C30H24F3N3O5 (m/e) 563, obsd 564 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18].O>ClCCl>[CH2:17]([NH:19][C:20]([N:14]1[CH2:13][CH2:12][CH:11]([CH2:10][C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:16][CH2:15]1)=[O:21])[CH3:18]
Reactant: CCN=C=O
Reactant: COc1ccc(F)c(CC2CCNCC2)c1
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)N1CCC(Cc2cc(OC)ccc2F)CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A magnetically stirred solution of 4-[(2-fluoro-5-methoxyphenyl)methyl]piperidine (0.895 g, 4.01 mmol) in anhydrous dichloromethane (15 mL) at 5° C. was treated dropwise with a solution of ethyl isocyanate (0.320 g, 4.41 mmol) in dry dichloromethane (5 mL). The solution was stirred 0.5 h at 5° C., allowed to warm to room temperature and stirred for 48 h. The solution was poured over ice (50g), and treated with water (200 mL) and dichloromethane (250 mL). The layers were separated, the aqueous phase was back-extracted with fresh dichloromethane (3×200 mL), and the combined organic portions were washed with 1N hydrochloric acid solution (350 mL), 5% sodium hydroxide solution (400 mL), water (400 mL), saturated brine (400 mL), dried is (K2CO3), filtered, and concentrated in vacuo. Drying (85° C.) in vacuo gave 1.08 g (92%) of the desired product as a clear oil: IR (film) 3346, 2930, 1622, 1592, 1538, 1498, 1274, 1252; 1214, 1036 cm-1 ; 1H NMR (CDCl3) δ6.90 (t, J=9.0 Hz, 1H), 6.69-6.60 (m, 2H), 4.50 (bt, J=4.7 Hz, 1H), 3.89 (bd, J=13.2 Hz, 2H), 3.74 (s, 3H), 3.27-3.17 (m, 2H), 2.67 (td, J=12.8, 2.4 Hz, 2H), 2.52 (dd, J=7.1, 1.1 Hz, 2H), 1.74-1.61 (m, 1H), 1.62 (bd, J=13.5 Hz, 2H), 1.18 (qd, J=12.0, 4.0 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3)δ57.7, 155.7 (d, J=237.1 Hz), 155.4 (d, J=1.7 Hz, 127.8 (d, J=18.0 Hz), 116.6 (d, J=5.1 Hz), 115.5 (d, J=24.7 Hz), 112.1 (d, J=8.0 Hz), 55.7, 44.1, 37.0, 36.2, 35.7, 31.7, 15.6; MS m/z 295 (M+ +1, free base).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1.[Cl-].[NH4+]>C(OCC)C.O.[Cu]I>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:11]2=[O:18])[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1C=CCCCC1
Reactant: COc1cccc(Br)c1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C2CCCCCC2=O)c1

Procedure:
To a freshly prepared Grignard solution of 5.83 g of magnesium shavings and 28.7 ml of 1-bromo-3-methoxybenzene in 675 ml of anhydrous diethylether at 20° C., with stirring, were added first 20.95 g of copper(I) iodide, then dropwise a solution of 15.2 g of cyclohept-2-enone (80%) in 175 ml of anhydrous diethylether. After complete addition, the mixture was heated for 45 min under reflux. Then the product was decomposed by the dropwise addition of 85 ml of a saturated ammonium chloride solution. After diluting with 200 ml of water, the organic phase was separated and the aqueous phase was extracted twice using 100 ml of diethylether each time. The combined organic phases were washed once each with saturated solutions of sodium hydrogen carbonate and sodium chloride, dried over sodium sulfate and evaporated under vacuum. The residue was purified on a chromatography column using diethylether/n-hexane=1/4, finally 1/1, as eluant and 16.5 g (68.6% of theory) of the title compound was thus obtained as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[S:9][C:10]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=C(C(O)=O)[N:12]=1>ClCCl.CN(C)C=O>[Cl:7][C:8]1[S:9][C:10]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[C:1]([C:2]([Cl:4])=[O:3])[N:12]=1
Reactant: O=C(O)c1nc(Cl)sc1CCc1cccc(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc(Cl)sc1CCc1cccc(Cl)c1

Procedure:
Oxalyl chloride (1.75 ml) was added to a solution of the product from step (iii) (3.14 g) in dichloromethane (30 ml) at room temperature containing 2 drops of dimethylformamide. After 4 h the volatiles were removed under reduced pressure to leave the subtitle product. Used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=12.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.Cl.[OH-].[Na+]>O>[Cl:20][C:21]1[N:22]=[C:23]([NH2:28])[N:24]=[C:25]([NH:8][C:6]2[CH:5]=[CH:4][C:3]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[C:18]([CH3:19])[C:11]=34)=[C:2]([F:1])[CH:7]=2)[CH:26]=1
Reactant: Cc1c[nH]c2nccc(Nc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Nc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Temperature: 100 °C

Procedure:
19 mg (70 μmol) of 2-fluoro-N1-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 17 mg (10 μmol) of 4,6-dichloropyrimidine-2-amine are suspended in 3.5 ml of water. 100 μI of 1 M hydrochloric acid are added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7M ammonia) 100:1 to 10:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[O:22])[CH2:17][CH2:16]2)[C:12]([Cl:34])=[CH:11][N:10]=1.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[O:22])[CH2:19][CH2:20]2)[C:12]([Cl:34])=[CH:11][N:10]=1)(=[O:38])[CH:36]=[CH2:37]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of 4-(2-((2-aminophenyl)amino)-5-chloropyrimidin-4-yl)-N-(3-(trifluoromethyl)phenyl)piperazine-1-carboxamide (0.043 mmol) in DCM (0.5 mL) was added acryloyl chloride (0.004 mL, 0.052 mmol) and DIEA (0.018 mL, 0.11 mmol) and the mixture was stirred at 0° C. for 1 h. The crude reaction mixture was loaded onto silica gel and purified using 0-7% MeOH/DCM gradient to give the title compound (10 mg, 43%). MS (ES+) C25H23ClF3N7O2 requires: 545. found: 546 [M+H]+.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C([Li])(C)(C)C.[Br:18][C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[N:28]([C:31]1[N:36]=[C:35]([C:37](OC)=[O:38])[CH:34]=[C:33]([CH3:41])[N:32]=1)[CH2:29][CH3:30]>CCOCC.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[N:28]([CH2:29][CH3:30])[C:31]1[N:36]=[C:35]([C:37]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][CH:8]=[CH:7]3)=[O:38])[CH:34]=[C:33]([CH3:41])[N:32]=1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCN(c1nc(C)cc(C(=O)c2ccc3[nH]ccc3c2)n1)c1ccc(C(C)C)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a suspension of potassium hydride (35% in oil, 0.16 g, 1.4 mmol), washed with hexanes and decanted twice, in anhydrous ether (5 mL), cooled to 0° C. under a nitrogen atmosphere was added a solution of 5-bromoindole (0.27 g, 1.4 mmol) in anhydrous ether. After being stirred for 30 min., the reaction mixture was cooled to −78° C. and transferred via cannula to a pre-cooled (−78° C.) mixture of t-butyl lithium (1.7 M in pentane, 1.6 mL, 2.7 mmol) in dry ether (5 mL). The resulting white suspension was stirred at −78° C. for 30 min and a solution of methyl 2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate (Example 18) (0.5 g, 1.25 mmol) in anhydrous ether (5 mL) was added dropwise. After quenching the reaction mixture as in Example 87; it was extracted three times with ethyl acetate, followed by two washings of the combined organic layers with a saturated NaHCO3 solution, drying over MgSO4, filtration and concentration in vacuo to give a dark brown oil. Column chromatography (ethyl acetate: hexanes::1:4) afforded the title product, a light brown solid (140 mg, 24% yield, Rf 0.2): mp 77-79° C.; NMR (DMSO-d6, 400 MHz, 90° C.): 11.6-11.35 (br s, 1H), 8.30 (s, 1H), 7.75 (dd, 1H, J=8, 1), 7.55 (d, 1H, J=1), 7.4-7.35 (m, 2H), 7.35-7.25 (m, 2H), 6.9 (s, 1H), 6.60-6.55 (m, 1H), 4.1-3.7 (m, 2H), 2.95-2.8 (m, 1H), 2.4 (br s, 3H), 1.25-1.1 (m, 9H); Anal (C25H25BrN4O): C, 62.90; H, 5.28; N, 11.74; Br, 16.74; Found: C, 63.13; H, 5.60; N, 11.37; Br, 16.80.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[O:20]=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([N:24]3[CH2:25][CH2:26][C:21](=[O:20])[CH2:22][CH2:23]3)=[O:19])[CH:16]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: O=C1CCNCC1
Product: CCc1cc(-c2cncc(C(=O)N3CCC(=O)CC3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-oxo-piperidine to afford the title compound. MS: m/e=340 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cc(F)c(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,4,5-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.55 (td, J=10.3, 6.4 Hz, 1 H), 7.64 (ddd, J=8.1, 5.0, 0.8 Hz, 1 H), 8.23 (ddd, J=10.3, 8.6, 6.4 Hz, 1 H), 8.56 (dt, J=8.1, 1.9 Hz, 1 H), 8.75 (dd, J=5.1, 1.7 Hz, 1 H), 9.29 (d, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
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]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH:29]=[C:28]([C:31]2[CH:32]=[C:33]([NH2:37])[CH:34]=[N:35][CH:36]=2)[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[O:25]1[CH2:26][CH:27]=[C:28]([C:31]2[CH:32]=[C:33]([NH:37][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]([CH3:23])(=[O:22])=[O:21])[C:3]=3[CH3:24])[CH:34]=[N:35][CH:36]=2)[CH2:29][CH2:30]1
Reactant: Nc1cncc(C2=CCOCC2)c1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cncc(C2=CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (50.0 mg, 0.140 mmol) and 5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine in toluene to give N-(5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.23 (2H, d, J=2.2 Hz), 8.20 (1H, dd, J=8.0, 1.2 Hz), 7.75-7.82 (1H, m), 7.68 (1H, td, J=7.7, 1.4 Hz), 7.50 (1H, ddd, J=9.3, 2.5, 1.3 Hz), 7.42 (1H, dd, J=7.6, 1.2 Hz), 7.15 (1H, d, J=13.7 Hz), 7.01-7.11 (2H, m), 6.22 (1H, dt, J=2.9, 1.4 Hz), 4.28 (2H, q, J=2.6 Hz), 3.89 (2H, td, J=5.4, 2.1 Hz), 3.14 (3H, s), 2.33-2.58 (2H, m), 1.86 (3H, s). Mass Spectrum (ESI) m/e=508.1 (M+1).