Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[N:16]=2)=[CH:4][C:5]([NH:8][C@@H:9]2[CH2:13][CH2:12][C@H:11](O)[CH2:10]2)=[N:6][CH:7]=1.ClC1C(C2C=CC=C(NCC3C=CC=C(F)C=3)N=2)=CC(F)=[N:35]C=1.N[C@@H]1CC[C@H](O)C1.C(N(CC)CC)C>CN1C(=O)CCC1>[NH2:35][C@@H:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[N:16]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:10]1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: O[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Agent: N[C@@H]1CC[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N[C@@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Preparation of (1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentanol: To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (75 mg, 0.226 mmol), was added (1S,3R)-3-aminocyclopentanol (68.6 mg, 0.678 mmol), NMP (0.75 ml) and triethylamine (0.158 ml, 1.130 mmol). The crude reaction mixture was stirred at 100° C. for 18 hr, and the reaction progress followed by LCMS. The crude reaction mixture was cooled, filtered, and purified by prep LC. The product fractions were collected, 50 mL of 1 M NaOH and 50 mL of EtOAc were added. The aqueous layer was removed, the organic layer was washed with 50 mL of saturated salt solution, dried over sodium sulfate, and reduced to constant mass. 28 mg of the desired compound was obtained. LCMS (m/z): 413.1 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, CHLOROFORM-d, 25° C.) δ ppm 1.71 (d, J=14.09 Hz, 1 H) 1.75-1.91 (m, 2 H) 1.97-2.05 (m, 1 H) 2.10-2.16 (m, 1 H) 2.61 (br. s., 1 H) 4.03-4.18 (m, 1 H) 4.39 (tt, J= 4.84, 2.59 Hz, 1 H) 4.55 (d, J= 5.09 Hz, 2 H) 5.19 (br. s., 2 H) 6.41 (d, J= 8.22 Hz, 1 H) 6.55 (s, 1 H) 6.90-7.02 (m, 2 H) 7.05-7.18 (m, 2 H) 7.24-7.34 (m, 1 H) 7.43-7.55 (m, 1 H) 8.07 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[CH3:1][CH:2]([CH2:10][CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=1
Reactant: CCC(C)Cc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCC(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
(+)-2-Methylbutylbenzene, prepared according to the procedure of Example 2, (0.75 mol, 111.0 gm) was added to 200 ml glacial acetic acid. This solution was added dropwise to a mixture of 420 ml 90% fuming nitric acid and 180 ml glacial acetic acid, which had been cooled at -20° C. Maintaining that temperature, the mixture was stirred for one hour and then poured into 2.5 l of ice water. The reaction products were extracted with 2-500 ml portions of petroleum ether (30°-60° C.) and the combined extracts were successively washed with water (2-100 ml portions); 5% sodium hydroxide (2-100 ml portions), 10% sodium hydroxide (2-100 ml portions); and water (3-100 ml portions). The extract was dried over anhydrous calcium sulfate, the solvent was removed under reduced pressure and the resultant light yellow oil fractionated under reduced pressure. The fraction boiling at 158°-160° C. (14 mm Hg) was collected, giving a 38% yield of the product. The structure was confirmed by NMR.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1CCCC1.[CH3:20][C:21]([C:23]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=1O)=[O:22]>CO>[Br:29][C:27]1[CH:28]=[C:23]2[C:24](=[CH:25][CH:26]=1)[O:14][C:11]1([CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1)[CH2:20][C:21]2=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mL of MeOH, 7.97 g of N-Boc-piperidin-4-one, and 3.34 mL of pyrrolidine were added to 8.60 g of 5-bromo-2-hydroxyacetophenone put in a 200-mL flask equipped with a condenser, and the mixture was overnight heated under reflux. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified through silica gel column chromatography (eluted with n-hexane/EtOAc=6/1) to obtain the intended compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:24])=[CH:26][CH:27]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrous pyridine (10 mL) was added dropwise 4-heptylbenzoyl chloride (950 μL) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg) was added and the resulting mixture was stirred overnight at rt. After filtration and rinsing the resin, water (125 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (1051 mg) was obtained as a white solid (90%) in 96.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11]Cl)[N:10]=[C:4]2[CH:3]=1.[NH3:13]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][NH2:13])[N:10]=[C:4]2[CH:3]=1
Reactant: ClCc1cn2ccc(Br)cc2n1
Reactant: N
Solvent: CO
Product: NCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 7-Bromo-2-chloromethyl-imidazo[1,2-a]pyridine (0.325 g, 1.326 mmol) in methanol (5 mL), NH3 gas is purged at 0° C. for 30 minutes. The reaction is allowed to stir at room temperature for 16 hours. The solvent is concentrated to afford the title compound (0.315 g). 1H-NMR (400 MHz, DMSO-d6) δ: 4.15 (s, 2H), 7.12-7.15 (dd J1=1.96 Hz, J2=7.24 Hz, 1H), 7.90 (s, 1H), 8.03 (s, 1H), 8.32 (bs, 2H), 8.61 (d, J=7.2 Hz, 1H). LC-MS (m/z): [M+H]=225.9.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CN(C=O)C.O[N:18]=[C:19]([NH2:30])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1>O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][N:18]=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=2)[NH2:30])=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(N)=NO)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(N)=NOC(=O)c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
1,1′-Carbonydiimidazole (2.37 g, 14.6 mmol) was added to a solution of 4-hydroxymethylbenzoic acid (2.00 g, 13.1 mmol) and DMF (50 mL) and stirred at room temperature for 1 hour. N′-Hydroxy-4-isobutylbenzamidine (2.54 g, 13.2 mmol) was added and stirred for 16 hours. The reaction mixture was diluted with water, causing a white solid to precipitate, filtered, washed with water, and dried to give the title compound (3.08 g, 72% yield) as a crude white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(c2ccc(F)cc2)CC1
Agent: Cl
Product: O=C(CN1CCN(c2ccc(F)cc2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 27.7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(4-fluorophenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 218, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(4-fluorophenyl)piperazin-1-yl)acetamido)propanamide (13.3 mg, 27.7%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 8.01 (d, 1H), 7.60 (d, 2H), 7.26-7.30 (m, 5H), 7.19-7.25 (m, 2H), 6.98-7.01 (m, 6H), 6.92-6.95 (m, 2H), 4.70 (m, 1H), 4.52 (s, 2H), 3.72-3.80 (m, 2H), 3.07 (m, 6H), 2.59-2.65 (m, 4H). MS (EI) for C34H34F2N4O4. found 601.6 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C@H:6]([C:25]([N:27]1[C@@H:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][O:29][C:28]1=[O:39])=[O:26])[C@@H:7]([CH:9]1[CH2:13][CH:12]([O:14][CH2:15][CH:16]=[CH2:17])[CH2:11][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:8].C([C@H]1COC(=O)N1C(=O)CCC1C=C(F)C=C(F)C=1)C1C=CC=CC=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.CCN(C(C)C)C(C)C.C(O[C@H]1CN(C(OC(C)(C)C)=O)[C@@H](C=O)C1)C=C>C(Cl)Cl>[F:43][C:41]1[CH:40]=[C:4]([CH:3]=[C:2]([F:1])[CH:42]=1)[CH2:5][C@H:6]([C:25]([N:27]1[C@@H:31]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:30][O:29][C:28]1=[O:39])=[O:26])[C@@H:7]([C@H:9]1[CH2:13][C@@H:12]([O:14][CH2:15][CH:16]=[CH2:17])[CH2:11][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[OH:8]
Reactant: C=CCOC1CC([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: C=CCO[C@@H]1C[C@H](C=O)N(C(=O)OC(C)(C)C)C1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Agent: O=C(CCc1cc(F)cc(F)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Step A (5): 2R,4R)-tert-butyl 2-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-4-(allyloxy)pyrrolidine-1-carboxylate. To a solution of (S)-4-benzyl-3-(3-(3,5-difluorophenyl)propanoyl)oxazolidin-2-one (Preparation B, 1.47 g, 4.27 mmol) in CH2Cl2 (15 ml) at −78° C. was added Bu2BOTf (5.12 ml, 5.12 mmol, 1M in CH2Cl2) and Hunig's base (1.12 ml, 6.41 mmol). The resulting mixture was brought to 0° C. and stirred for 30 min. The mixture was again cooled to −78° C. and a solution of (2R,4R)-tert-butyl 4-(allyloxy)-2-formylpyrrolidine-1-carboxylate (Step A (4), 1.09 g, 4.27 mmol) in CH2Cl2 (10 ml) was added dropwise. When the addition was complete, the mixture was stirred at −78° C. for 5 min., then was allowed to warm to rt. After stirring at rt for 4 h. the mixture was concentrated in vacuo. Flash chromatography (silica gel, 0-75% ethyl acetate/hexane) gave 1.22 g (48%) of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-4-(allyloxy)pyrrolidine-1-carboxylate as a slightly yellow oil: 1H NMR (CDCl3, 300 MHz) δ 1.49 (9H, s), 2.03-2.22 (2H, m), 2.31 (1H, d, J=12 Hz), 2.98 (1H, dd, J=3, 15 Hz), 3.07 (1H, t, J=12 Hz), 3.42-3.57 (3H, m), 3.97-4.11 (8H, m), 4.57 (2H, brd s), 5.17-5.30 (2H, m), 5.81-5.94 (1H, m), 6.61 (1H, t, J=9 Hz), 6.90 (2H, brd s), 7.00 (2H, brd s), 7.26 (3H, m). HPLC retention time: 2.04 min (method A). MS (ESI) (M+H)+ 601.37.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:20]=[C:21]([CH:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:4]1([CH:3]=[CH:2][C:1]([NH:27][CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH:20]=2)[CH3:26])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CC(N)c1cccc(Oc2ccccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1ccccc1)c1cccc(Oc2ccccn2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of cinnamic acid (0.11 mmol), 1-[3-(pyridine-2-yloxyl)phenyl]-ethylamine (16.3 mg, 0.11 mmol), EDAC.HCl (42 mg, 0.22 mmol), DMAP (13 mg, 0.11 mmol) and Et3N (0.1 mL, 0.44 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title compound.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]([F:31])([F:30])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:38]([O:42][C:43](=[O:46])[CH2:44]Br)([CH3:41])([CH3:40])[CH3:39]>CC(C)=O>[C:38]([O:42][C:43](=[O:46])[CH2:44][N:3]([CH2:1][CH3:2])[S:4]([C:7]([F:30])([F:31])[C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC(=O)OC(C)(C)C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
20 g (37.94 mmol) of N-ethylperfluorooctylsulfonamide and 15.73 g (113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone, and 14.80 g (75.87 mmol) of bromoacetic acid-tert-butyl ester is added in drops at 60° C. It is stirred for 3 hours at 60° C. Salts are filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: hexane/dichloromethane/acetone=10:10:1). After the product-containing fractions are concentrated by evaporation, the residue is recrystallized from methanol/ether.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[NH2:14][NH2:15]>C(O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([NH:14][NH2:15])=[O:2])[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: NN
Solvent: CCO
Product: NNC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (44.7 mmol) and hydrazine (447 mmol) in ethanol (100 mL) was stirred at 80° C. for 18 h. After it was cooled to room temperature and concentrated in vacuo, the crude product was purified by crystallization in ethanol to give (3,4-dichloro-phenyl)-acetic acid hydrazide (43 mmol).
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)n(C)c2c1
Product: Cc1ccn2c(C)c(-c3ccc4oc(=O)n(C)c4c3)nc2c1
Yield: 46 %

Procedure:
5-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzoxazolinone (1.35 g) was prepared in the substantially same manner as that of Example 4 from 5-(2-bromopropionyl)-3-methyl-2-benzoxazolinone (2.84 g) and 2-amino-4-methylpyridine (3.24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:17][CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:21]=1
Reactant: CCC(CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of Step G (75 mg, 0.21 mmol) and NMM (42 mg, 0.42 mmol) in DCM (3 mL) was added methanesulfonyl chloride (36 mg, 0.38 mmol). Then the mixture was stirred at room temperature for 3 h, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=3/1) to afford the title compound as colorless oil. LC/MS m/z=435.1[M+H]+.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][C:8](O)=[O:9])(=[O:3])[CH3:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:22])=O>CN(C)C=O>[C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][C:8]([Cl:22])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)CCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)CCC(=O)Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
46.5 g (0.29 mol) of 4-acetoxypentanoic acid are dissolved at room temperature in 230 ml of abs. toluene, and then 0.2 ml of abs. Dimethyl formamide is added. Then 32.6 ml (0.38 mol) of oxalyl chloride are added dropwise such that the evolution of gas remains under control. When the dropwise addition is complete, the reaction mixture is heated to 50° C. and stirred for 1 hour at this temperature. The orange-red reaction solution is concentrated by evaporation. Distillation of the residue gives 42.2 g of 4-acetoxypentanoic acid chloride as a colorless liquid of b.p.34 110°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[CH:24][NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][CH:24]=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.8 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol to give 63 mg (51%) of the title compound as a yellow solid. 1H NMR (360 MHz, DMSO-d6) δ 13.29 (br s, 1H, NH), 11.73 (br s, 1H, NH), 9.16 (br s, 1H), 8.31 (s, 1H), 7.72 (dd, J=2.7 & 6.5 Hz, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.43 (m, 1H), 7.40 (s, 1H), 7.34 (t, J=9.05 Hz, 1H), 3.49 (m, 4H, 2×CH2), 2.29 (m, 4H, 2×CH2), 2.19 (s, 3H, CH3), 2.18 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)O1.FC(F)(F)S(O[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[S:47][CH:48]=[CH:49][N:50]=2)[N:41]=1)(=O)=O>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].C(Cl)Cl.COCCOC>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[C:42]1[N:41]=[C:40]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]2)[CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Oc1cccc(-c2nccs2)n1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(B4OC(C)(C)C(C)(C)O4)cc23)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: N[C@H]1CCCN(c2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)C1
Yield: 40 %

Procedure:
A solution of (S)-tert-butyl 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 6-(thiazol-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.5 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.15 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 100° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by RP HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (S)-1-(6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-yl)piperidin-3-amine (40%). LC/MS=388.1 (M+H), LC=2.02 min.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([OH:11])[CH:7]=[CH:8][CH2:9][OH:10].N1C=CC=CC=1>C1COCC1>[CH3:5][O:4][C:2](=[O:3])[O:10][CH2:9][CH:8]=[CH:7][CH2:6][O:11][C:2]([O:4][CH3:5])=[O:3]
Reactant: OCC=CCO
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)OCC=CCOC(=O)OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine methyl chloroformate (7.04 g, 80.0 mmol) in THF (70 mL) and add dropwise to a ice-water cold solution of 2-buten-1,4-diol (majority Z form) (19.7 g, 208 mmol) and pyridine (16.5 g, 208 mmol) in THF (150 mL). Warm the mixture to room temperature and stir for 20 hours. Remove the pyridine salt by filtration and concentrate the filtrate to a residue. Dissolve the residue with CH2Cl2 and wash sequentially with 1 N HCl and brine. Dry the organic layer over Na2SO4 and concentrate the solvent in vacuo to give a residue. Purification by chromatography using hexanes: EtOAc=12:1 as the eluents give the title compound: 1H NMR (CDCl3): δ5.82–5.79 (m, 2H), 4.75 (d, J=4.8 Hz, 4H), 3.79 (s, 6H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:34])([F:33])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]([NH:19][C:20](=[O:32])[N:21]([CH3:31])[C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[N:8]=1.[CH3:35]I>C1COCC1>[CH3:35][N:19]([C:9]1[N:8]=[C:7]([O:6][CH2:5][C:4]([F:3])([F:33])[F:34])[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=1)[C:20](=[O:32])[N:21]([CH3:31])[C:22]1[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1
Reactant: CI
Reactant: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)N(C)c1ccc(C(F)(F)F)s1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (18 mg, 0.36 mmol) in anhydrous THF (3 mL) was added a solution of the 3-(4,6-bis(2,2,2-trifluoro ethoxy)pyrimidin-2-yl)-1-methyl-1-(5-(trifluoromethyl)thiophen-2-yl)urea (2) (150 mg, 0.30 mmol). The reaction was stirred for 10 minutes after which time gas evolution had subsided. To the reaction was added methyl iodide (51.2 mg, 0.36 mmol). The reaction was stirred at ambient temperature for 2 h. The reaction was quenched with H2O (5 mL) and extracted with t-butyl ethyl ether (3×5 mL). The organics were combined and extracted with an equal amount of H2O. The organics were dried (MgSO4), filtered and concentrated to afford crude product. The crude material was purified by silica gel chromatography (5% EtOAc in pet ether) to afford 3-methyl-3-(4,6-bis(2,2,2-trifluoro ethoxy)pyrimidin-2-yl)-1-methyl-1-(5-(trifluoromethyl)thiophen-2-yl)urea (6) as an off white solid (31 mg, 20%), mp 113-114° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.35-7.24 (m, 1H), 6.73 (d, J=4.2 Hz, 1H), 5.88 (s, 1H), 4.76 (q, J=8.7 Hz, 4H), 3.35 (s, 3H), 3.28 (s, 3H); ESIMS m/z 513 ([M+H]+).