Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1.[CH3:18][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:9][C:8]=2[O:16][CH3:17])[CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(Br)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-n2cnc(Br)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-(4-bromo-1H-imidazol-1-yl)-3-methoxybenzoic acid (1.90 g) in toluene (20 mL) and methanol (5 mL) was added trimethylsilyldiazomethane (2M hexane solution, 3.84 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added trimethylsilyldiazomethane (2M hexane solution, 0.96 mL), the mixture was stirred for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (1.32 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:8]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (185 mg, 0.64 mmol) in methylene chloride (6.5 mL) was cooled to 0° C. and was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.35 mL, 0.71 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (142 mg, 1.42 mmol) in tetrahydrofuran (3.23 mL) and N,N-diisopropylethylamine (0.27 mL, 1.55 mmol). The solution was stirred at 25° C. for 5 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethyl-phenyl)-propionamide (127 mg, 53.3%) as a white solid: mp 210-212° C.; EI-HRMS m/e calcd for C18H19F3N2OS (M+) 368.1175, found 368.1170.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[N:14]=3)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.[Pd](Cl)Cl>[CH3:18][C:16]1[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:14]=[C:13]([C:10]2[O:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:3][CH:4]=3)[N:9]=2)[CH:17]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(Br)cc4)co3)cc2C)cc1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CCCCC5)cc4)co3)cc2C)cc1
Temperature: 25 °C
Yield: 11.1 %

Procedure:
A mixture of 4-(4-bromophenyl)-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,3-oxazole (Example 75, 150 mg, 0.37 mmol), piperidine (44 μl, 0.44 mmol), potassium phosphate (156 mg, 0.74 mmol), palladium(II) chloride (3.3 mg, 0.02 mmol) and 2-(dicyclohexylphosphino)-1,1′-biphenyl (9.7 mg, 0.03 mmol) in 1,2-dimethoxyethane (3 ml) was heated to reflux for 18 h. After cooling to rt, the mixture was filtered over a pad of celite. The filtrate was diluted with ethyl acetate and successively washed with 0.1 N aqueous HCl and water. The organic layer was dried (MgSO4), filtered and concentrated to dryness. The crude material was purified by preparative HPLC. The combined product fractions were then further purified by flash chromatography (silica) eluting with cyclohexane/ethyl acetate 5:1 to afford the title compound as a white solid (17 mg, 11%): 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.63 (d, 2H), 7.17 (d, 2H), 7.08 (d, 2H), 6.98 (d, 2H), 6.65 (s, 1H), 5.35 (s, 2H), 3.19 (m, 4H), 2.28 (s, 6H), 1.64-1.52 (m, 6H); ES-MS m/z 413, HPLC RT (Method D) 2.65 min.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Product: Fc1ccc(-c2noc(-c3cccnc3)n2)cc1
Temperature: 25 °C

Procedure:
4-Fluoro-N′-hydroxybenzimidamide (0.154 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.47 (t, J=6.8 Hz, 2H), 7.74-7.70 (m, 1H), 8.20-8.15 (m, 2H), 8.58-8.54 (m, 1H), 8.91-8.89 (dd, J=1.7, 1.7 Hz, 1H), 9.35 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][CH:6]([CH2:23][CH2:24][CH3:25])[C:7]([O:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:30]([C:34]1[N:35]=[C:36]([C:39]2[O:40][C:41]3[CH:47]=[CH:46][C:45](O)=[CH:44][C:42]=3[CH:43]=2)[S:37][CH:38]=1)([CH3:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:30]([C:34]1[N:35]=[C:36]([C:39]2[O:40][C:41]3[CH:47]=[CH:46][C:45]([O:1][CH2:2][C:3]4[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=4[O:5][CH:6]([CH2:23][CH2:24][CH3:25])[C:7]([O:9][CH:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:8])=[CH:44][C:42]=3[CH:43]=2)[S:37][CH:38]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCCC(Oc1ccccc1CO)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of diphenylmethyl 2-[2-(hydroxymethyl)phenoxy]pentanoate (1.70 g), 2-(4-tert-butylthiazol-2-yl)-5-hydroxybenzofuran (2.43 g), and triphenylphosphine (2.44 g) in tetrahydrofuran (40 ml) was added a solution of diethylazodicarboxylate (1.44 g) in tetrahydrofuran (2 ml) under ice-cooling. The mixture was stirred at the same temperature for an hour and at room temperature for an hour. The mixture was concentrated under reduced pressure and the residue was subjected to a column of silica gel (100 g) eluting with a mixed solvent of toluene and n-hexane (7:3) to give diphenylmethyl 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanate (2.16 g).
Reaction SMILES: [C:1]([O:4][C:5](=[CH:10][C:11]1[CH:19]=[C:18]([CH3:20])[C:17]2[C:13](=[CH:14][N:15]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:16]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]>[B-](F)(F)(F)F.CC[C@H]1P(C2C(P3[C@H](CC)CC[C@H]3CC)=CC=CC=2)[C@H](CC)CC1.C1[CH][CH]CC[CH][CH]C1.[Rh].ClCCl>[C:1]([O:4][C@H:5]([CH2:10][C:11]1[CH:19]=[C:18]([CH3:20])[C:17]2[C:13](=[CH:14][N:15]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:16]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(C)=O
Agent: [Rh]
Agent: CC[C@@H]1CC[C@@H](CC)P1c1ccccc1P1[C@H](CC)CC[C@H]1CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(C)=O
Reaction time: 6 h

Procedure:
To a solution of methyl 2-acetoxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)acrylate (825 mg, 2.04 mmol) in degassed (by bubbling nitrogen) dichloromethane (20.00 mL) under nitrogen was added solid (−)-1,2-bis-((2R,5R)-2,5-diethylphospholano)benzene-(cyclooctadiene)rhodium(I) tetrafluoroborate (100.00 mg), all at once. The reaction was placed under a hydrogen atmosphere (55 psi), and shaken for 6 h. The reaction was concentrated and purified by column chromatography (25% ethyl acetate/hexanes) to give 700 mg (84%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ −0.03 (s, 9H), 0.94 (t, J=8.2, 2H), 2.07 (s, 3H), 2.61 (s, 3H), 3.11 (dd, J=14.3, 8.9, 1H), 3.20 (dd, J=14.3, 4.6, 1H), 3.64 (t, J=8.5, 2H), 3.72 (s, 3H), 5.26 (dd, J=8.5, 4.6, 1H), 5.72 (s, 2H), 6.93 (s, 1H), 7.33 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.[F:8][CH:9](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:10].[F:25][CH:26]([F:46])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2[CH:37]=[C:38]([CH2:42][CH2:43][CH:44]=O)[CH:39]=[CH:40][CH:41]=2)=[CH:30][CH:29]=1>C1COCC1.C(Cl)Cl>[F:25][CH:26]([F:46])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2[CH:37]=[C:38]([CH2:42][CH2:43][CH:44]=[C:9]([F:10])[F:8])[CH:39]=[CH:40][CH:41]=2)=[CH:30][CH:29]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: O=CCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: FC(F)=CCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of 0.122 mL (0.86 mmol) of diisopropylamine in THF at −78° C. was treated with 0.54 mL (0.54 mmol) of 1.6 M n-BuLI in hexanes, stirred at −78° C. for 0.5 h, treated dropwise with a solution of 0.22 gm (0.86 mmol) of difluoromethyldiphenylphosphine oxide in THF, stirred at −78° C. for 45 min, treated with a solution of 3-[3-(4-difluoromethoxyphenylethynyl)phenyl]propionaldehyde 0.17 gm (0.58 mmol) in THF, stirred at −78° C. for 4 h, warmed to room temperature, stirred at room temperature for 18 h and diluted with CH2Cl2. The organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of this concentrate on silica gel with a gradient of hexanes to 10% EtOAc-hexanes yielded 1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}-phenyl)-4,4-difluorobut-3-ene as an oil, 0.09 gm (52% yield); 1H NMR (400 MHz, CDCl3) δ: 2.29 (m, 2H), 2.66 (t, 2H, J=7.6 Hz), 4.13 (m, 1H), 6.50 (t, 1H, J=73.6 Hz), 7.07 (d, 2H, J=8.8 Hz), 7.13 (m, 1H), 7.26 (d, 1H, J=8.8 Hz), 7.34 (m, 2H), 7.49 (dt, 2H, J=2.1, 2.6, 8.3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[C:26]2=[N:27][CH:28]=[CH:29][N:25]2[N:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[C:26]4=[N:27][CH:28]=[CH:29][N:25]4[N:24]=[CH:23][N:22]=3)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: Clc1ncnn2ccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@H](Nc1ncnn2ccnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Yield: 63.7 %

Procedure:
(S)-1-(6-Fluoro-1-pyrid-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.066 g, 0.26 mmol), 4-chloroimidazo[2,1-f][1,2,4]triazine (WO2010/014930) (0.040 g, 0.26 mmol) and diisopropylethylamine (0.090 mL, 0.52 mmol) in isopropanol (2 mL) was heated to 60° C. in a sealed tube for 0.5 h. The reaction mixture was cooled and diluted with EtOAc (20 mL) and washed with water (2 mL) The organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-10% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 322 as a white solid, (62 mg, 63%). LCMS (Method C): RT 3.78 min [M+H]+ 375.04. 1H NMR δ (ppm) (DMSO-d): 9.13 (1H, d, J=7.61 Hz), 8.57 (1H, dd, J=4.90, 1.81 Hz), 8.01-7.98 (2H, m), 7.93 (1H, s), 7.74-7.73 (2H, m), 7.55 (1H, d, J=1.12 Hz), 7.44-7.44 (1H, m), 7.15-7.15 (2H, m), 5.92 (1H, dq, J=7.11 Hz), 1.65 (3H, d, J=6.87 Hz)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)CCC.[F-].[Cs+]>CCOC(C)=O.[Cu]I.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>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=[C:2]([C:24]2[S:28][CH:27]=[N:26][CH:25]=2)[CH:7]=1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3cncs3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (189 mg, 0.668 mmol), 5-(tributylstannyl)thiazole (250 mg, 0.668 mmol), CuI (32 mg, 0.17 mmol), CsF (304 mg, 2.00 mmol), and Pd(PPh3)4 (39 mg, 0.033 mmol). The vial was capped with a septum screw-cap and then placed under N2 atmosphere. To the vial was added degassed DMF (4 mL). The vial was placed in an 80° C. heating block with stirring for 1 hour. The vial was cooled to room temperature and then opened, and to the solution was added an additional charge of 5-(tributylstannyl)thiazole (85 mg, 0.23 mmol) and Pd(PPh3)4 (39 mg, 0.033 mmol). The vial was capped, placed under N2 atmosphere, and then placed in a 80° C. heating block with stirring for an additional 1 hour. The reaction mixture was cooled to room temperature and then transferred to a 125 mL separatory funnel. The mixture was diluted with EtOAc (50 mL) and then washed with saturated aqueous NaCl (“brine”, 50 mL). The aqueous phase was extracted with EtOAc (25 mL). The combined organics were washed with brine (25 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford a dark liquid. This material was subjected to silica gel chromatography to afford 5-(4-chloro-6-(4-isopropoxyphenyl)pyridin-2-yl)thiazole as a pale orange liquid (122 mg, 55%). 1H-NMR: (400 MHz, CDCl3-d) δ 8.87 (s, 1H), 8.40 (s, 1H), 8.04-7.98 (m, 2H), 7.60 (d, J=1.5 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.04-6.98 (m, 2H), 4.65 (spt, J=6.1 Hz, 1H), 1.39 (d, J=6.3 Hz, 6H); MS: MS m/z 331.1 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH:18]1[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cnc(Cl)c(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cnc(C2CNCCN2C(=O)OC(C)(C)C)c(C)n1
Yield: 87.1 %

Procedure:
Under a nitrogen stream, to a mixture of 2-chloro-3,5-dimethylpyrazine (2.8 g), 1-Boc-piperazine (3.7 g), palladium(II) acetate (225 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (953 mg) and sodium tert-butoxide (2.7 g) was added toluene (40 mL), and the mixture was stirred with heating under reflux for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give (3,5-dimethylpyrazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5 g). The obtained (3,5-dimethylpyrazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5 g) was dissolved in chloroform (15 mL), 4N hydrogen chloride/ethyl acetate (15 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (100 mL), and the precipitate was collected by filtration to give the title compound (3.3 g).
Reaction SMILES: [C:1]1([P:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][C:10](=O)[CH2:9][C:8]2([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20].[B-]C#N.[Na+].Cl>CO>[CH2:18]([NH:21][CH:10]1[CH2:11][C:12]([CH3:14])([CH3:13])[P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([CH3:17])([CH3:16])[CH2:9]1)[CH2:19][CH3:20]
Reactant: CC1(C)CC(=O)CC(C)(C)P1c1ccccc1
Reactant: CCCN
Agent: Cl
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNC1CC(C)(C)P(c2ccccc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.9 %

Procedure:
A flask, under nitrogen, was charged with a mixture of 12.4 grams (0.05 mole) of 1-phenyl-2,2,6,6-tetra methyl-4-phosphorinanone, 17.7 grams (0.30 mole) of n-propylamine, 1.89 grams (0.03 mole) of sodium cyanotrihydroborate, 20 mls of 5N methanolic hydrochloric acid and 150 mls of methanol. The mixture was stirred at ambient temperature for three days and then treated with 20 mls of conc. hydrochloric acid. The reaction mixture was concentrated in vacuo and 30 mls of water and 25 mls of diethylether were added. The layers were separated and to the aqueous layer was added 8 grams of solid sodium hydroxyde. The resultant basic mixture was extracted sequentially with five 25 ml portions of diethylether. The combined extracts were dried over anhydrous sodium sulfate, the solvent removed in vacuo and the residue distilled under reduced pressure to give 11.2 grams (77% yield) of colorless liquid, b.p. 140°-144° C. (0.1 mm Hg)
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].CCN(CC)CC>C(Cl)Cl>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]

Procedure:
Combine phenyl boronic acid (7.32 g, 60 mmol), 4-methyl-3-nitrophenol (4.5 g, 30 mmol), and Cu (oAC)2-H2O (6 g, 30 mmol) in 30 mL CH2Cl2 and treat with 6 g 4A molecular sieves powder. Add Et3N (15.18 g, 150 mmol) dropwise, and stir the reaction at ambient temperature for 8 days. Dilute with 100 mL CH2Cl2 and filter through celite and concentrate to dryness. Purification by chromatography using 2% EtOAc in hex anes gave the desired product as a yellow oil.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[S:6]([CH3:9])(=[O:8])=[O:7])(O)=[O:2].[Cl-].C[NH3+].C1C=CC2N(O)N=[N:43][C:41]=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:41][NH:43][C:1]([CH2:4][N:5]([C:10]1[CH:11]=[CH:12][C:13]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=1)[S:6]([CH3:9])(=[O:7])=[O:8])=[O:2]
Reactant: CS(=O)(=O)N(CC(=O)O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 18 from (Z)-3-{1-[4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, methylammonium chloride, HOBt, TBTU and N-ethyl-N,N-diisopropylamine in DMF.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN(C)CCCN
Product: CN(C)CCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and 3-dimethylamino-propylamine comparable as in Example A. A colorless, crystalline product with a melting point of 107° to 108° C. was obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]2([C:31]#[N:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[N:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[F:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[C:13]1[C:12]([CH2:25][C:26]2([C:31]#[N:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][N:14]=1
Reactant: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2CC2(C#N)CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(CO)cc2CC2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a solution of 1-((5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanecarbonitrile (514 mg) in THF (10 mL) was added a THF solution (1 M, 2.2 mL) of tetrabutylammonium fluoride, and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (355 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[C:9]([O:22]C)[C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[C:9]([OH:22])[C:8](=[O:24])[NH:7][C:6]=2[CH:25]=1
Reactant: COc1c(-c2ccc([N+](=O)[O-])cc2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2ccc([N+](=O)[O-])cc2)c1O
Reaction time: 1 h
Yield: 91.6 %

Procedure:
8-Chloro-3-methoxy-4-(4-nitrophenyl)-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (125 mg) was dissolved in dichloromethane (10 mL). To this was added boron tribromide (1M in dichloromethane 1 mL). This suspension was stirred for one hour. Saturated sodium bicarbonate (5 mL) was then added, and this mixture stirred for 2-3 minutes. The mixture was then adjusted to pH 3 by addition of 6N HCl. This suspension was stirred for 40 minutes, then vacuum filtered and the collected solid washed with water and crystallized from dimethylformamide (2 mL) and water (6 mL) to yield the title compound (110 mg, 91%) as an off white solid; mp 310°-312° C.; NMR: 11.90 (s,1, NH), 10.7 (broad s,1, OH), 8.26 (dd,2, J=6.9, 2.0), 7.92 (d,1, J=8.7), 7.51 (m,3), 7.34 (dd,1, J=8.7, 2.0); MS: m/z=345(M+1). Analysis for C16H9ClN2O5 : Calculated: C, 55.75; H, 2.63; N, 8.13; Found: C, 55.49; H, 2.54; N, 8.05