Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C>[F:26][C:25]([F:28])([F:27])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
Methyl 5-hydroxypyridine-2-carboxylate (Intermediate 224, 0.610 g, 3.59 mmol) was dissolved in DMF (5 mL), cesium carbonate (1.40 g, 4.31 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 g, 4.31 mmol) were added and the mixture stirred at room temperature for 18 h. The mixture was partitioned between EtOAc (50 mL) and water (15 mL) and the aqueous layer extracted with further EtOAc (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude material was purified by FCC, eluting with a gradient of 0-50% EtOAc in heptane to afford the title compound as a white solid (0.652 g, 77%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.40 (1H, d), 8.09 (1H, d), 7.27 (1H, dd), 4.41 (2H, q) and 3.93 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][CH:15]([CH2:23][CH3:24])[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([NH:14][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:23][CH3:24])[CH:20]([CH3:21])[CH3:22]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Product: CCC(NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([I:16])[CH:15]=[C:10]3[N:9]=[C:8]2[NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:4][C:3]=1[O:25][CH3:26].[OH-].[Na+].CC1C=CC(S(O[CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=2)(=O)=O)=CC=1>O1CCCC1.O>[I:16][C:14]1[CH:15]=[C:10]2[N:9]=[C:8]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([O:1][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([C:47]([F:52])([F:53])[C:48]([F:49])([F:50])[F:51])=[CH:45][CH:46]=4)=[C:3]([O:25][CH3:26])[CH:4]=3)[C:11]2=[N:12][CH:13]=1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(C(F)(F)C(F)(F)F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
To a stirred solution of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-36-1) (0.24 g, 0.52 mmol) in tetrahydrofuran (20 mL) was added 5M aqueous sodium hydroxide solution (0.2 mLs, 1.00 mmol). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, and the residue was dissolved in N,N-dimethylformamide (10 mL). The mixture was treated with 4-(perfluoroethyl)benzyl 4-methylbenzenesulfonate (0.40 g, 1.04 mmol), and the mixture was warmed to 80° C. After 3 h, the mixture was allowed to cool to room temperature and was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×40 mL), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to provide 0.090 g of ethyl (6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[N:8][CH:9]=1.I[CH3:15].O>CN(C)C=O>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]([O:13][CH3:15])([CH3:11])[CH3:12])[CH:5]=1
Reactant: CC(C)(O)c1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 46 mg, 1.2 mmol) in N,N-dimethylformamide (4.6 mL) at 0° C. was added a solution of the title compound from Example 22 Step C (100 mg, 0.463 mmol) in N,N-dimethylformamide (4.6 mL). After warming to room temperature and stirring for 1 hour, the solution was cooled back to 0° C. and iodomethane (35 μl, 0.56 mmol) was added. After stirring overnight, the reaction was poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound: LCMS m/z 232.97 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](OB(O)O)=[CH:18][CH:17]=1>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc(OB(O)O)cc1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Reaction time: 5 h
Yield: 56 %

Procedure:
The compound is prepared by the reaction of 2-bromo-6-methoxynaphthalene (500 mg, 2.11 mmol, 1 eq) with 4-methoxyphenylboric acid (313 mg, 2.12 mmol, 1 eq) according to method A in 5 h. The desired product was precipitated from hexane in a yield of 56% (311 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Reactant: NCc1ccccc1
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:12][N:11]([C:13]2[C:14]3[C:38]([CH3:40])([CH3:39])[C:37](=[O:41])[NH:36][C:15]=3[N:16]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[N:20]=3)[N:18]=2)[CH2:10]1)(C)(C)C>C(OCC)C>[NH2:8][CH:9]1[CH2:10][N:11]([C:13]2[C:14]3[C:38]([CH3:39])([CH3:40])[C:37](=[O:41])[NH:36][C:15]=3[N:16]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[N:20]=3)[N:18]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)C1
Agent: Cl
Solvent: CCOCC
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CC(N)C3)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.66 ml of a 2N solution of hydrogen chloride in diethyl ether was added to 81 mg (0.13 mmol; purity 91%) of tert.-butyl-(1-[2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]azetidin-3-yl)carbamate (example 62A) and it was stirred for 4 h at room temperature. The reaction solution was concentrated by evaporation and purified twice by preparative HPLC (acetonitrile/water (+0.1% trifluoroacetic acid) gradient). The concentrated fractions were dissolved in dichloromethane and washed twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated by evaporation. 31 mg (49% of theor.) of the target compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][C:30](Cl)=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=2)=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:30]3[CH:31]=[CH:32][C:27]([C:26](=[O:37])[NH:25][C:22]4[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=4)=[CH:28][C:29]=3[N+:34]([O-:36])=[O:35])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(S)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(Sc3ccc(C(=O)Nc4ccc(Br)cc4)cc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of the product of Example 59C (39.9 mg, 0.160 mmol) in anhydrous ethanol (2 mL) under a nitrogen atmosphere was treated with the product of Example 49A (56.8 mg, 0.160 mmol) and anhydrous sodium acetate (66 mg, 0.800 mmol) at room temperature, then heated at reflux for 2 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (50 mL) and washed with water (2×25 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel flash chromatography using methylene chloride as eluent afforded the title compound as a yellow solid (77 mg, 85%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (R)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 121.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.98 min, m/z=459.1 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.38 (m, 2H) 1.52-1.61 (m, 1H) 1.76-1.87 (m, 1H) 2.58 (dd, J=12.23, 9.05 Hz, 1H) 2.68-2.78 (m, 1H) 3.34-3.41 (m, 1H) 3.41-3.51 (m, 1H) 3.54-3.62 (m, 1H) 4.72 (d, J=3.67 Hz, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.51 (dd, J=7.95, 4.77 Hz, 1H) 7.83-7.89 (m, 2H) 7.99-8.04 (m, 1H) 8.10 (d, J=2.20 Hz, 1H) 8.58 (d, J=4.65 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 8.79-8.83 (m, 1H) 10.29 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(OCC)C>[O:20]([C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: Oc1ccccc1
Solvent: CCOCC
Solvent: O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccccc1
Yield: 24 %

Procedure:
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine, 13.2 g. of phenol and 3 drops of water was heated at 120° C. under nitrogen gas for 20 hr. The mixture was cooled and dissolved in 100 ml. ethyl ether. The ethereal solution was extracted with 2×50 ml. of 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulfate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallization from cyclohexane gave analytically pure product melting at 101°-104° C. The yield was 24% of theory.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1>>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CCS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 20 %

Procedure:
The title compound (8.9 mg, 20%) was prepared from [4-(ethylsulfonyl)phenyl]boronic acid (21.4 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 446 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:14](=[O:16])[CH3:15])=[CH:10]2)=[CH:5][CH:4]=1.[Cl:19]N1C(=O)CCC1=O.Cl>C(O)(=O)C>[Cl:19][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of 7-trifluoromethyl-2-acetamidonaphthalene (620 mg, 2.45 mmol), N-chlorosuccinimide (326 mg, 2.45 mmol) and 1 M HCl in acetic acid (2.45 mL, 2.45 mmol) in acetic acid (10 mL) is heated at 50° C. under a N2 atmosphere for 1 hour. After cooling to room temperature, the mixture is partitioned between EtOAc and water. The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator to give 1-chloro-7-trifluoromethyl-2-acetamidonaphthalene as an off-white solid.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O.C[N:22](C)C=C(C1C=CN=CC=1)C(C1C=CC(F)=CC=1)=O>>[F:13][C:9]1[CH:8]=[C:7]([C:5]2[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:3][NH:2][N:22]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Reactant: CN(C)C=C(C(=O)c1cccc(F)c1)c1ccncc1
Product: Fc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Yield: 70 %

Procedure:
The reaction was carried out in the same manner as in Example 1-2) except for using 18.3 g (67.7 mmol) of 3-dimethylamino-1-(3-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one obtained in Example 7-1) in place of 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one to obtain 11.3 g of the title compound as a white powder. (Yield: 70%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:19])[C:9]([C:14]([O:16]CC)=[O:15])=[CH:10][NH:11]2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:13]=[C:12]2[C:7]([C:8](=[O:19])[C:9]([C:14]([OH:16])=[O:15])=[CH:10][N:11]2[CH2:21][CH2:22][OH:23])=[CH:6][CH:5]=1)[CH3:2]
Reactant: OCCBr
Reactant: CCOC(=O)c1c[nH]c2nc(OCC)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(=O)c(C(=O)O)cn(CCO)c2n1

Procedure:
7-Ethoxy-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester (3.6 g), 2-bromoethanol and potassium carbonate (7.5 g) in dimethylformamide (50 ml) (4.95 ml) were stirred and heated on a steam bath for 16 hours. The solid was filtered off and the filtrate evaporated. The residue was crystallized from dimethylformamide. This ester (2.0 g) and aqueous sodium hydroxide (40 ml, 2N) were heated on a steam bath for 3 hours, cooled and acidified to pH 2 with aqueous hydrochloric acid. The solid was collected and crystallized from ethanol, m.p. 219.5°-220° (24%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[NH:14][C:13]2[N:12]=[C:11]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:10]=[C:9](N)[C:8]=2[N:7]=1)=[O:5])[CH3:2].C(Br)(Br)[Br:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[NH:14][C:13]2[N:12]=[C:11]([S:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[N:10]=[C:9]([Br:29])[C:8]=2[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]c1=O
Reactant: BrC(Br)Br
Product: CCOC(=O)c1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]c1=O

Procedure:
The sub-titled compound was prepared from the product of example 36, step (a) (2 g) and bromoform (40 ml) using the method of Example 3, step (b).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:14]([I:15])[C:9]=2[O:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:14]([I:15])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)COc2c(I)cc(C(=O)OC)cc21
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: NCCO
Product: CCCCN1CCOc2c(I)cc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 91.5 %

Procedure:
A solution of Methyl 4-butyl-8-iodo-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (680 mg) and 9-BBN (900 mg) in tetrahydrofuran (30 mL) was heated at reflux for 1.5 h. The mixture was cooled to room temperature, ethanolamine (0.22 mL) was added, and the resulting solution was concentrated under reduced pressure. The residue was washed with hexanes, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica, 10% ethyl acetate/hexanes) afforded 600 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.75, 7.28, 4.34, 3.86, 3.36, 3.28, 1.58, 1.40, 0.96.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=1[NH2:16]>O>[Cl:13][C:14]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]2[C:15]=1[N:16]=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:4]=[C:5]2[OH:7]
Reactant: Nc1cc(F)ccc1Cl
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: O
Product: Oc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Temperature: 150 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
A solution of ethyl 4,4,4-trifluoroacetoacetate (commercially available, 4 mL, 27.3 mmol, 1.05 eq.) in polyphosphoric acid (22 mL) was heated to 100° C. 2-chloro-5-fluoroaniline (3.78 g, 26.0 mmol, 1 eq.) was added slowly to the stirred hot solution. The resulting reaction mixture was further heated to 150° C. and then stirred at that temperature overnight (approximately 18 hours). The reaction was cooled to room temperature and water was added carefully. The resulting light brown precipitate was collected by vacuum filtration, washed with water and dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous MgSO4 and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 3.54 g (51% yield) of the desired product as an off-white solid; MP=141-142; MS (ES) m/z (relative intensity): 266 (M+H)+ (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]#[N:16])[C:6]2=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Product: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Temperature: 0 °C

Procedure:
A stirred mixture of 20 g of 1,4-dihydro-6,7-dimethoxy-4-oxo-3-quinolinecarbonitrile and 87 ml of phosphorous oxychloride was refluxed for 2 h, cooled, and evaporated free of volatile matter. The residue was stirred at 0° C. with dichloromethane-water as solid sodium carbonate was added until the aqueous layer was pH 8. The organic layer was separated, washed with water, dried and concentrated. Recrystallization from dichloromethane gave a solid, mp 220-223° C.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:4]=1.Cl.Cl.[NH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][N:34]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:5]1[N:4]=[C:3]([NH:29][CH2:30][CH2:31][NH:32][C:33]2[N:34]=[CH:35][C:36]([C:37]#[N:38])=[CH:39][CH:40]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.13 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-methylpiperidin-4-yl)[1,2,4]triazolo-[1,5-c]pyrimidine hydrochloride (Example 49A), 30 mg (0.15 mmol) of 6-[(2-aminoethyl)amino]pyridin-3-carbonitrile hydrochloride (Example 2A) and 0.13 ml (0.76 mmol) of N,N-diisopropylethylamine were initially charged in 1.5 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 25 mg (37% of theory) of the product as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:31]=[C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]2)[NH:33]1>>[O:31]=[C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:38][CH2:39][CH:40]([C:43]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]4[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]5[N:17]=[C:18]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[O:19][C:20]=5[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=4)[CH2:3][CH2:2]3)=[O:44])[CH2:41][CH2:42]2)[NH:33]1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(O)C1CCC(c2noc(=O)[nH]2)CC1
Product: O=C(Nc1ccc(C2CCN(C(=O)C3CCC(c4noc(=O)[nH]4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarbonyl]-piperidin-4-yl}-phenyl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (202 mg, 0.49 mmol) and 4-(5-Oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarboxylic acid (104 mg, 0.49 mmol) as an off white solid (13 mg, 4%). LCMS calcd for C31H30F3N5O5 (m/e) 609, obsd 610 (M+H).