Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:12])[CH3:11].N1C=CC=CC=1>[Cl-].[Na+].O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH:10]([CH3:12])[CH3:11])[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: CC(C)N1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(N2CCN(C(C)C)CC2)ncc1Br
Yield: 90.5 %

Procedure:
To a solution of 2,5-dibromo-4-methyl-pyridine (5.0 g, 20 mmol) and isopropyl-piperazine (25.6 g, 200 mmol) were added pyridine (2.06 g, 206 mmol). The reaction mixture was refluxed for 5 h under a nitrogen atmosphere. Brine was added and the mixture was extracted with EtOAc. The organic extract was washed with brine and 0.5 N hydrochloric acid. The acidic layer was made alkaline with Na2CO3 to pH 8 and then extracted with CH2Cl2. The organic extract was dried (Na2SO4) and concentrated to give 5.4 g (90%) of 1-(5-bromo-4-methyl-pyridin-2-yl)-4-isopropyl-piperazine.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][CH:51]=[O:52]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:51]([OH:52])[CH2:50][CH:46]2[CH2:47][CH2:48][CH2:49][O:45]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCC1CCCO1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCO2)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 10.1 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (6.16 g, 24 mmol) in dry tetrahydrofuran (150 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (22.5 mL, 36 mmol) to a 0° C. solution of diisopropylamine (5.4 mL, 38 mmol) in dry tetrahydrofuran (20 mL)] dropwise. The mixture was stirred at −78° C. for 15 min and then treated with (tetrahydro-furan-2-yl)-acetaldehyde (4.9 g, 43 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 30% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-furan-2-yl)-ethanol as a colorless oil (0.9 g, 31%): LC/MS m/e calcd for C19H20N2O4S [M+H]+ 373.45, observed 373.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[C:40]4[CH:47]=[C:46]([CH:48]=O)[NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)=[CH:34][CH:33]=2)=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[C:40]4[CH:47]=[C:46]([CH2:48][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)=[CH:36][CH:37]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(CN4CCOCC4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 0.5 ml of tetrahydrofuran, 10 μl of morpholine and 26 mg of sodium triacetoxyborohydride to the 1-(4-fluorophenyl)-3-[4-(6-formyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]urea synthesized in Example 168, the mixture was stirred overnight at room temperature. The reaction system was subjected to liquid separation and extraction with a tetrahydrofuran-ethyl acetate mixed solvent, and then dried over anhydrous sodium sulfate and concentrated to dryness to obtain 5 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[NH:10][CH:9]=2)=[C:4]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH3:27])[CH:25]=3)[NH:20][CH:19]=2)[C:3]1=[O:28]>CN(C=O)C.[C].[Pd]>[CH3:1][N:2]1[C:3](=[O:28])[CH:4]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH3:27])[CH:25]=3)[NH:20][CH:19]=2)[CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[NH:10][CH:9]=2)[C:6]1=[O:7]
Reactant: Cc1ccc2[nH]cc(C3=C(c4c[nH]c5ccc(C)cc45)C(=O)N(C)C3=O)c2c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]cc(C3C(=O)N(C)C(=O)C3c3c[nH]c4ccc(C)cc34)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.6 %

Procedure:
To a solution of N-methyl-2,3-bis(5-methyl-1H-indol-3-yl)maleimide (150 mg, 0.41 mmol) in DMF (3 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 1-methyl-3,4-bis(5-methyl-1H-indol-3-yl)-2,5-dioxopyrrolodine (109 mg, 72.4%) as a mixture of two isomers (A:B=3:1) as pale red solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:14][CH:13](OS(C)(=O)=O)[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CN(C)C=O>[C:20]([S:22][CH:13]1[CH2:12][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:14]1)(=[O:23])[CH3:21]
Reactant: CCOC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (742 mg, 2.42 mmol) (obtained as described in Reference Example 1(3)) in dimethylformamide (37 ml) was added potassium thioacetate (1.11 g, 9.72 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 3-acetylthio-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (494 mg, yield 71%) as a pale brown solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][S:15][CH2:16][CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(N2CCSCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(N2CCSCC2)c2ccccc2c1=O

Procedure:
The product from Example 91B and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 7.93-8.03 (m, 2H), 7.89 (ddd, J=8.0, 6.2, 1.9 Hz, 1H), 7.34-7.47 (m, 4H), 3.67 (s, 2H), 2.83-2.86 (m, 4H); MS (APCI+) M/Z 415 (M+H)+.
Reaction SMILES: O[CH:2]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]2[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][CH:3]=[CH:2][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]2[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CCC2OC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CC=Cc1ccc(CCC2OC(=O)NC2=O)cc1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A mixture of 5-[2-[4-[1-hydroxy-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]ethyl]-2,4-oxazolidinedione (0.32 g), p-toluenesulfonic acid monohydrate (p-TsOH.H2O) (0.145 g) and toluene (40 ml) was stirred under refluxing conditions for 2 hours. The reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate and water, dried (MgSO4) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:2), 5-[2-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-propenyl]phenyl]ethyl]-2,4-oxazolidinedione (0.235 g, 77%) was obtained, which was then recrystallized from dichloromethane-isopropyl ether to yield colorless needles having a melting point of 175°-176° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN(C)C=O>[O:12]=[C:6]1[NH:7][C:8]2[N:9]=[CH:10][CH:11]=[C:2]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17]4)[C:3]=2[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(F)ccnc2N1
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2c(Oc3ccc4ncc(C(=O)O)cc4c3)ccnc2N1
Temperature: 150 °C

Procedure:
5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Int-28, 120 mg, 0.72 mmol), 6-hydroxyquinoline-3-carboxylic acid (1.5 mg, 0.794 mmol), and cesium carbonate (706 mg, 2.17 mmol) were weighed into a microwave vial. N,N-Dimethylformamide (3.5 mL) was added and the vial was sealed and heated in a microwave at 150° C. for 4 h. The vial was opened and water was added (5 mL). The resulting clear solution was neutralized by the addition of 1N HCl and washed with ethyl acetate. The washed aqueous phase was acidified to pH 3 and pure product was collected by suction filtration. LC-MS: (FA) ES+ 336; 1H NMR (400 MHz, d6-DMSO) δ ppm 13.55 (s, 1H), 10.60 (s, 1H), 9.27 (d, J=2.1 Hz, 1H), 8.94 (d, J=1.9 Hz, 1H), 8.17 (d, J=9.1 Hz, 1H), 8.07-8.02 (m, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.74 (dd, J=9.1, 2.8 Hz, 1H), 6.52 (d, J=5.7 Hz, 1H), 2.92 (t, J=7.7, 7.7 Hz, 2H), 2.54 (dd, J=8.3, 7.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[CH:16][N:15]=2)=[CH:24][CH:23]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(/C=C/c2ccc(F)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2)nc1
Reaction time: 20 h
Yield: 61.3 %

Procedure:
5-[(4-fluorophenyl)sulfonyl]-2-[(E)-2-(4-fluorophenyl)vinyl]-pyridine (Example 2, 0.42 g, 1.18 mmol) was taken up in ethanol (5 mL) and ethyl acetate (5 mL) and palladium (10% wt. on activated carbon, 60 mg) was added. The suspension was shaken in a Parr apparatus at 20 psi hydrogen for 6 hours, followed by 40 psi hydrogen for 3 days. The catalyst was removed by filtration and the solvent removed in vacuo. The residue was taken up in acetic acid (25 mL) and platinum(IV) oxide (20 mg) was added. The suspension was stirred under a balloon of hydrogen for 20 hours. Further platinum(IV) oxide (20 mg) was added and stirring under hydrogen continued for 24 hours. The catalyst was removed by filtration and most of the solvent removed in vacuo. The residue was partitioned between ethyl acetate and 4N sodium hydroxide solution. The organic phase was dried over MgSO4 and concentrated in vacuo while loading onto silica. Eluting through a plug of silica using 20% ethyl acetate/isohexane gave the title compound as a yellow solid (0.26 g, 61%). δH (500 MHz, d6 DMSO): 9.04 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=2.4, 8.3 Hz), 8.09–8.07 (2H, m), 7.49–7.45 (3H, m), 7.22–7.19 (2H, m), 7.04 (2H, t, J=8.8 Hz), 3.11–3.09 (2H, m), 2.98–2.95 (2H, m); m/z (ES+) 360 [MH+].
Reaction SMILES: N1C=C[C:3](B(O)O)=N1.Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([N:27]1[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]1)=[O:26])[C:15](=[O:36])[CH:14]=[C:13]2[CH2:37][CH2:38][CH2:39][OH:40].BrC1C=C2C(=CC=1)CN(C(N[C:54]1[CH:59]=[CH:58][C:57]([C:60](=[O:65])NCCC)=[CH:56][CH:55]=1)=O)C2>>[C:60]([C:57]1[CH:58]=[C:59]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([N:27]2[CH2:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:35]2)=[O:26])[C:15](=[O:36])[CH:14]=[C:13]3[CH2:37][CH2:38][CH2:39][OH:40])[CH:54]=[CH:55][CH:56]=1)(=[O:65])[CH3:3]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: OB(O)c1cc[nH]n1
Reactant: O=C(NCCCCn1c(=O)cc(CCCO)c2cc(Br)ccc21)N1Cc2ccccc2C1
Product: CC(=O)c1cccc(-c2ccc3c(c2)c(CCCO)cc(=O)n3CCCCNC(=O)N2Cc3ccccc3C2)c1

Procedure:
The title compound was prepared as described in Example 280, substituting 3-acetylphenylboronic acid for 1H-pyrazol-3-ylboronic acid and N-(4-(6-bromo-4-(3-hydroxypropyl)-2-oxoquinolin-1(2H)-yl)butyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.24 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.87-7.79 (m, 2H), 7.58 (t, J=7.7 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.28 (s, 4H), 6.71 (s, 1H), 4.74 (s, 4H), 4.41 (t, J=7.4 Hz, 2H), 3.82 (t, J=6.0 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H), 3.12-2.99 (m, 2H), 2.68 (s, 3H), 2.10-1.96 (m, 2H), 1.96-1.83 (m, 2H), 1.79-1.72 (m, 2H); MS (APCI(+)) m/e 538 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][NH2:35]>C1COCC1.CCOC(C)=O>[CH3:34][NH:35][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 65.7 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available methylamine (2 M in THF, 2.05 ml, 4.1 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 65%) as a white solid. MS (ISP) 484.2 [(M+H)+]; mp 176° C.
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:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ccc(C2CCNC2)nc1
Product: Nc1c(F)c(N2CCC(c3ccccn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 91 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.97 g, 2.9 mmol) and 2-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.12 g, 91%) as a bright yellow solid, mp 206°-208° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([NH:22][C:23]([N:25]4[C:29]5[N:30]=[CH:31][N:32]=[C:33](Cl)[C:28]=5[CH:27]=[CH:26]4)=[O:24])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(=O)C.[F:39][C:40]([F:49])([F:48])[C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].Cl>C(O)CCC>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([NH:22][C:23]([N:25]4[C:29]5[N:30]=[CH:31][N:32]=[C:33]([NH:44][C:43]6[CH:45]=[CH:46][CH:47]=[C:41]([C:40]([F:39])([F:48])[F:49])[CH:42]=6)[C:28]=5[CH:27]=[CH:26]4)=[O:24])[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)c1cccc(NC(=O)n2ccc3c(Cl)ncnc32)c1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCCCO
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1cccc(NC(=O)n2ccc3c(Nc4cccc(C(F)(F)F)c4)ncnc32)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [3-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-amide resin(50 mg, 0.05 mmol), prepared as in reference 1, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-trifluoromethyl-aniline (31 μL, 0.25 mmol), or only mixed with HCl salt of 3-trifluoromethyl-aniline (50 mg, 0.25 mmol), and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together and concentrated. The residue is purified by preparative HPLC to give 4-(3-trifluoromethyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [3-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-amide (19.0 mg, yield 64%). 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.16 (s, 1H), 10.09 (s, 1H), 8.69 (s, 1H), 8.31 (s, 1H), 8.22 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.92 (d, J=3.9 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.63 (d, J=6.9 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.13 (d, J=4.0 Hz, 1H), 6.95 (d, J=9.0 Hz, 2H), 3.74 (t, J=4.6 Hz, 4H), 3.08 (t, J=4.7 Hz, 4H); ESIMS m/z 602.20 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH:14]([CH3:16])[CH3:15].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH:14]([CH3:16])[CH3:15])[CH2:20][CH2:19]1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1ccc(CBr)c(OC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCC(O)CC2)c(OC(C)C)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
A mixture of methyl 4-(bromomethyl)-3-isopropoxybenzoate (2.0 g, 6.96 mmol), 4-hydroxypiperidine (1.06 g, 10.4 mmol), potassium carbonate (1.44 g, 10.4 mmol) and N,N-dimethylformamide (20 mL) was stirred at 70° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (1.77 g, yield 83%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH:17][C@@H:18]2[CH2:22][CH2:21][N:20](CC3C=CC=CC=3)[CH2:19]2)=[O:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([NH:17][C@@H:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)=[O:16])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)N[C@@H]2CCNC2)CC1

Procedure:
To a solution of {4-[3-((R)-1-Benzyl-pyrrolidin-3-yl)-ureido]-cyclohexyl}-carbamic acid tert-butyl ester in ethanol under an inert atmosphere of argon is added palladium hydroxide on carbon. The reaction mixture is purged with argon and placed under an atmosphere of hydrogen for over night. The mixture is filtered and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo to yield the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[O:22])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: O=C(CCCCl)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3)c1ccncc1
Yield: 18.4 %

Procedure:
The title compound (0.080 g, 18%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 4-chloro-1-(4-pyridinyl)-1-butanone (0.36 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 1.68-2.18 (m, 7H), 2.20-2.65 (m, 5H), 2.69 (t, J=6.4 Hz, 2H), 2.72-2.82 (m, 1H), 2.92-3.08 (m, 3H), 3.15-3.28 (m, 2H), 6.62 (t, J=7.5 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.89 (d, J=7.4 Hz, 1H), 7.70-7.80 (m, 2H), 8.75-8.82 (m, 2H) ppm.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([Cl:22])[CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=2[CH3:8])=[C:17]([Cl:22])[CH:16]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Product: Cc1c(Nc2ccc(Br)cc2Cl)c(C(=O)O)cn(C)c1=O

Procedure:
The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 4-bromo-2-chloroaniline instead of 2-fluoro-4-iodoaniline. The title compound is used for the next reaction without further purification.