Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[C:19]([OH:27])[CH:18]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/3=[CH:14]\[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[C:19]([OH:27])[CH:18]=2)=[CH:31][CH:30]=1
Reactant: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(-c4ccc(F)cc4)cc32)cc1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
An amount of (4Z)-6-bromo-4-{[(3-hydroxy-4-propoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.15 g, 0.35 mmol) in 2 mL of N,N′-dimethylformamide is added to 4-fluorophenylboronic acid (0.073 g, 0.52 mmol), 0.02 g (0.03 mmol) of tetrakis(triphenylphosphine)-palladium(0) and 0.4 mL of saturated sodium carbonate solution. The reaction mixture is stirred at 100° C. under N2 for 2 h. Mass spectroscopy suggested the completion of the reaction. Solids were removed by filtration, and solvent is subsequently evaporated under high-pressure vacuum to brown solid. The residue is purified by HPLC to give 0.055 g (35.5% yield) of light brown solid: mp 194-195° C.; MS (ESI) m/z 445.2 (M+H)−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([NH:14][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)NCc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (537 mg, 3.31 mmole) in 7 mL of dry acetonitrile is 0.7 mL (6.62 mmol) of tert-butylamine followed by 457 mg (3.31 mmol) of potassium carbonate. The reaction is heated at 80° C. for 12 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 387 mg (59% yield) of tert-Butyl-(6-chloro-pyridin-3-ylmethyl)-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.16 (s, 9H), 1.60–1.80 (brs, 1H0, 3.72 (s, 2H), 7.26 (d, 1H, J=8.3 Hz), 7.71 (dd, 1H, J=8.3 and 2.5 Hz), 8.33 (d, 1H, J=2.0 Hz); MS 199.2 (M+H).
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(OCC)(=O)C>C(#N)C>[O:38]1[CH2:39][CH2:40][N:35]([CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)[CH2:36][CH2:37]1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCC(CCN3CCOCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
The 4-tosyloxyethyl-N-(4-nitrophenyl)piperidine (2.02 g, 5.0 mmol) obtained in Example 6(2) was dissolved in acetonitrile (20 ml), and potassium carbonate (1.38 g, 10 mmol) and morpholine (0.65 ml, 7.5 mmol) were added thereto, followed by stirring at 80° C. for 15 hours. After the reaction mixture was allowed to cool to room temperature, ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:50 to 1:20), thereby obtaining 4-morpholinoethyl-N-(4-nitrophenyl)piperidine (1.23 g, 77%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH:18][C:19]3[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15]([CH2:17][NH:18][C:19]3[S:20][C:21]([C:24](=[NH:44])[NH2:25])=[CH:22][N:23]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ncc(C#N)s1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ncc(C(=N)N)s1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(5-cyano-thiazol-2-yl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: % of theory, C24H26N8O3S (506.6) Rf value: (silica gel; dichloromethane/methanol=4:1)
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].[Br:13]Br>CC(O)=O>[CH2:1]([C:3]1[NH:4][C:5]2[C:11]([Br:13])=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccc(N)cc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of 1.3 g (7.7 mmol) of 2-ethyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.40 ml of Br2 (7.5 mmol) dropwise and resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (20% isopropanol /EtOAC) to yield 1.5 g (6.3 mmol, 82%) of the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3[nH]nc(I)c23)CC1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (0.219 mL, 1.61 mmol) was added to tert-butyl 4-(3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.575 g, 1.34 mmol) and K2CO3 (0.222 g, 1.61 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 2 hours. Ether (30 mL) and water (10 mL) were added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.59 g, 80%) as a solid. MS APCI (+) m/z 549.7 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.37 (d, J=5.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.68 (d, J=5.2 Hz, 1H), 5.53 (s, 2H), 3.70 (s, 3H), 3.62 (m, 4H), 3.19 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: C(N(CC)CCN[C:7](=[O:34])/[CH:8]=[CH:9]/[C@@H:10]([NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.[CH:37]([NH:40][CH2:41][CH2:42][NH2:43])([CH3:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH:37]([NH:40][CH2:41][CH2:42][NH:43][C:7](=[O:34])/[CH:8]=[CH:9]/[C@@H:10]([NH:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:39])[CH3:38]
Reactant: CCN(CC)CCNC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: CC(C)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCNC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
To a solution of (E)-(S)-4-(3-biphenyl-4-yl-ureido)-5-phenyl-pent-2-enoic acid (Example 19, step A) (0.30 g, 0.78 mmol), N-isopropyl-ethane-1,2-diamine (0.087 g, 0.85 mmol) and HOBt (0.16 g, 1.16 mmol) in DMF (7.8 mL), was added EDCl (0.22 g, 1.16 mmol). The resulting solution was stirred under N2 at rt for 20 h. The solution was diluted with H2O (50 mL) and extracted with 3:1 EtOAc/iPrOH (3×60 mL). The combined organic extracts were washed with 1 N NaOH (1×50 mL) and brine (75 mL), dried (Na2SO4) and filtered, and the solvent was removed. The residue was purified by column chromatography on silica gel using a gradient of 2–10% (MeOH (1% NH4OH)/CH2Cl2 to afford 0.18 g (51%) of the desired product as a white solid. Rf=0.26 (10% MeOH (1% NH4OH)/CH2Cl2). MS (electrospray): mass calculated for C29H34N4O2, 470.27; m/z found, 471.3 [M+H]+, 493.2 [M+Na]+, 941.5 [2M+H]+. 1H NMR (400 MHz, CDCl3): 8.10 (s, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.39–7.33 (m, 5H), 7.31–7.25 (m, 3H), 7.21 (d, J=7.24 Hz, 2H), 6.76 (dd, J=15.3, 5.7 Hz, 1H), 6.25 (d, J=8.3 Hz, 1H), 6.00 (d, J=15.3 Hz, 1H), 4.86–4.79 (m, 1H), 3.46–3.41 (m, 1H), 3.31–3.27 (m, 1H), 2.95–2.85 (m, 2H), 2.77–2.67 (m, 3H), 1.01 (d, J=6.0 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:14]=[CH:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cnc(-c2ccc(F)cc2)nc1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cnc(-c2ccc(F)cc2)nc1

Procedure:
945 mg (4.67 mmol) of 2-(4-fluoro-phenyl)-pyrimidine-5-carbaldehyde, 1544 mg (14.84 mmol) of malonic acid and 4197 mg (49.29 mmol) of piperidine in 50 ml of pyridine were stirred at 125° C. for 17 h. After concentration, water and hydrochloric acid were added, and the solid product was filtered off with suction and dried. Yield: 1.01 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.O1CCOCC1.[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=2[OH:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(B(O)O)c1O
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccnc(Cl)n2)c1O
Temperature: 100 °C

Procedure:
To a solution of 3.0 g (20 mmol) of 2,4-dichloro-pyrimidine in a 10:1 mixture of dioxane:water (220 mL) is added 3.3 g (22 mmol) of 2-hydroxy-3-methyl-phenyl boronic acid followed by 6.0 g (57 mmol) of sodium carbonate. Argon is bubbled through the solution for 15 min then 2.4 g (2.1 mmol) of tetrakis(triphenylphosphine)palladium (0) is added. The reaction is heated overnight at 100° C. then cooled to ambient temperature and filtered through diatomaceous earth. The filter pad is washed with EtOAc then placed on a new receiving flask and washed with a 1:1 mixture of MeOH:DCM. The filtrate is concentrated under reduced pressure to B-16 (1.60 g, 36.0%)
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH2:15])=O)=[N:11][CH:12]=2)[CH:4]([CH3:16])[O:3]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[O:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:15])=[N:11][CH:12]=2)[CH:4]([CH3:16])[O:3]1
Reactant: CC1OC(C)(C)OC1c1ccc(C(N)=O)nc1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC1OC(C)(C)OC1c1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a stirred solution of 5-(2,2,5-trimethyl-1,3-dioxolan-4-yl)2-pyridinecarboxamide (16.4 mg, 0.0695 mmol) in 1,4-dioxane (1 ml) were added pyridine (23 ml, 0.278 mmol) and trifluoroacetic anhydride (20 ml, 0.139 mmol) at room temperature. After stirring at room temperature for 1 h, the mixture was diluted with ethyl acetate (20 ml), washed with sat. NaHCO3 (10 ml×2), dried over Na2SO4, and concentrated in vacuo to give a brown syrup. This was purified by preparative TLC [acetone/hexane (1/4, v/v)] to afford 9.7 mg (64%) of 5-(2,2,5-trimethyl-1,3-dioxolan-4-yl)-2-pyridinecarbonitrile as a solid:1H-NMR (270 MHz, CDCl3) δ8.62 (1H, d, J=1.8 Hz), 7.80 (1 H, dd, J=1.8 and 8.1 Hz), 7.70 (1 H, d, J=8.1 Hz), 5.25 (1 H, d, J=7.0 Hz), 4.67 (1 H, quit. J=6.6 Hz), 1.64 and 1.48 (each 3H, 2 s), 0.82 (3 H, d, J=6.6 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:40]1([OH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:46][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Oc4ccccc4)cc3)oc2C)cc1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
A mixture of 2-(4-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.30 g, 0.614 mmol), potassium phosphate (0.26 g, 1.22 mmol), 2-(di-tert-butylphosphino)biphenyl (0.014 g, 0.0469 mmol) and phenol (0.069 g, 0.733 mmol) in toluene (6 mL) was degassed three times by successive application of vacuum to the reaction vessel followed by nitrogen purge. Palladium (II) acetate (0.007 g, 0.0312 mmol) was added to the reaction and the mixture heated to reflux under nitrogen for 3 h. The reaction was cooled to room temperature, diluted with Et2O, and extracted with water then 1 N NaOH (10 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give 0.316 g of crude 2-methyl-2-(4-{2-[5-methyl-2-(4-phenoxy-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester
Reaction SMILES: Cl.Cl.[C:3]1([C:9]2([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]([O:24][C:25](=[O:31])[N:26]([CH3:30])[CH2:27][CH:28]=O)([CH3:23])([CH3:22])[CH3:21].C(B)#N.[Na].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[CH3:30][N:26]([CH2:27][CH2:28][N:12]1[CH2:11][CH2:10][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][CH2:13]1)[C:25](=[O:31])[O:24][C:20]([CH3:21])([CH3:23])[CH3:22]
Reactant: c1ccc(C2(N3CCCC3)CCNCC2)cc1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN(CCN1CCC(c2ccccc2)(N2CCCC2)CC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
7 g (1 eq) 4-phenyl-4-(pyrrolidin-1-yl)piperidine bishydrochloride were added to a solution of 4.4 g (1.1 eq) tert-butyl-methyl(2-oxoethyl)carbamate in 70 ml methanol under a nitrogen atmosphere and the reaction mixture was stirred for 10 min at 0° C. 3.62 g (2.5 eq) sodium cyanoboron hydride were then added and the mixture was stirred for 30 min at room temperature. The reaction mixture obtained was adjusted to a pH of 5-6 with acetic acid and stirred for 14 h at room temperature. The reaction course was monitored by thin-layer chromatography (10% MeOH/CHCl3). Once the conversion was complete, the methanol was distilled off, saturated NaHCO3 solution was added and the mixture obtained was extracted with chloroform (3×50 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 50% EtOAc/heptane). 8 g (89%) of product were obtained in the form of a red oil.
Reaction SMILES: [C:1]([O-])(=[O:4])[CH2:2]C.[CH2:6]([NH+:13]1[CH2:18][CH2:17][C:16]([C:30]2[NH:34][N:33]=NN=2)([N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OC(=O)C)(=O)C>[CH2:6]([N:13]1[CH2:14][CH2:15][C:16]([C:30]2[O:4][C:1]([CH3:2])=[N:33][N:34]=2)([N:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:20](=[O:23])[CH2:21][CH3:22])[CH2:17][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnn[nH]2)CC[NH+](Cc2ccccc2)CC1
Reactant: CCC(=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)N(c1ccccc1)C1(c2nnc(C)o2)CCN(Cc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A 100 ml r.b. flask was charged with 1-benzyl-4-(1H-tetrazol-5-yl)-4-(N-phenylpropionamido)piperidinium propionate (6.04 g, 13 mmol) and acetic anhydride (50 ml). The resulting mixture was stirred at 110° C. for 2 hours and concentrated in vacuo. The crude was dissolved in CH2Cl2 (100 ml), washed with 5% Na2CO3 (100 ml), dried over Na2SO4 and concentrated in vacuo. The resulting residue was chromatographed (SiO2, EtOAc/Hex 1:1) to give the product (4.20 g, 10.4 mmol) as a viscous oil: NMR (60 MHz, CDCl3) δ0.90 (t, 3H, CH3CH2CO), 2.61 (s, 3H, oxadiazolyl CH3), 3.46 (s, 2H, benzyl CH2), 7.33 and 7.52 (2bs, 10H, phenyl H's). ##STR26##
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11][O:12][C:13](N2C=CN=C2)=[O:14])[CH:7]=1.[N:20]1([C:26](=[O:28])[CH3:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11][O:12][C:13]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:28])[CH3:27])[CH2:21][CH2:22]2)=[O:14])[CH:7]=1
Reactant: O=C(OCc1cc(-c2ccco2)on1)n1ccnc1
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)OCc2cc(-c3ccco3)on2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.2 %

Procedure:
To a solution of 30 mg of imidazole-1-carboxylic acid 5-furan-2-yl-isoxazol-3-ylmethyl ester in 1 mL of methylene chloride was added 16 mg of 1-piperazin-1-yl-ethanone. After stirring at room temperature for 4 hrs, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography to afford 30 mg of the title compound. (Yield: 79%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[O:19])=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(O)(=O)C>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[O:19])=[CH:15][CH:16]=2)[NH:11][N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccn2)c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1C(=O)c1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Yield: 71 %

Procedure:
A solution of 2-{1-[3-((E)-2-Pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-yl]-methanoyl}-benzoic acid (402 mg, 0.805 mmol) (synthesis described below), ethylene diamine (215 μL, 3.22 mmol), and 1M TBAF in THF (6.44 ml, 6.44 mmol), was stirred in a 90° C. oil bath for 4 hr. The crude reaction mixture was quenched with acetic acid (386 μL, 6.44 mmol), diluted with ethyl acetate (100 mL), extracted 1M sodium bicarbonate solution (2×20 ml), brine (5×20 ml), dried magnesium sulfate, filtered, and concentrated to a 3 mL volume. The resulting crude material was purified by preparative C18 reverse phase column chromatography, giving 211 mg of the title compound as a yellow solid (71% yield). 1H NMR (DMSO-d6) δ 13.50 (bs, 1H), 8.68 (d, J=5.27 Hz, 1H), 8.29 (d, J=8.86 Hz, 1H), 8.13–7.90 (m, 4H), 7.81–7.43 (m, 7H).
Reaction SMILES: [C:1]1([C:7](=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>ClCCl>[C:1]1([CH:7]([NH:13][CH:10]2[CH2:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccccc1
Reactant: NC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(NC1CC1)c1ccccc1

Procedure:
To a solution of 1-phenylethanone (1 eq.) in dichloromethane (0.17 M) was added cyclopropylamine (3 eq.) and magnesium sulfate (9 eq.). The resulting mixture was stirred at reflux for 2 days. The insolubles were then filtered off and the filtrate evaporated in vacuo. The resulting residue was taken up in methanol (0.2 M) and added sodium borohydride (1.5 eq.). The reaction mixture was then stirred at RT overnight. After quenching with 1 N aq. HCl, the volatiles were removed in vacuo. The resulting residue was partitioned between 1 N NaOH and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH2:17][NH2:18]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:18][CH2:17][CH2:16][NH2:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CN(C)C=O
Product: NCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-bromo-4-chloro-3-nitroquinoline (143.8 g, 0.5 mol) in 800 mL warm DMF was added to a stirred solution of ethylenediamine in 200 mL DMF at room temperature; the reaction was stirred at room temperature overnight. The reaction was quenched with 2 L water and stirred for an additional hour. Additional water was added, and the mixture was stirred overnight. A precipitate formed and was isolated by filtration and air-dried overnight on the filter funnel to provide N1-(7-bromo-3-nitroquinolin-4-yl)ethane-1,2-diamine as a yellow solid.