Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:34])[C:5]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([F:25])[CH:12]=1)[CH:8]=[CH:7]2.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[F:34][C:4]1[C:5]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:6]2[C:10](=[CH:2][CH:3]=1)[N:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([F:25])[CH:12]=1)[CH:8]=[CH:7]2
Reactant: Fc1cc(-n2ccc3c(OCc4ccccc4)c(F)cc(Br)c32)ccc1OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Fc1cc(-n2ccc3c(OCc4ccccc4)c(F)ccc32)ccc1OCc1ccccc1
Reaction time: 6 h
Yield: 42.1 %

Procedure:
A solution of 7-bromo-5-fluoro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]-1H-indole (D6) (400 mg, 0.769 mmol) in toluene (10 mL) was degassed by bubbling Argon through for a few minutes and tributylstannane (0.248 mL, 0.922 mmol) was added. The mixture was heated to reflux under argon and AIBN (˜5 mg) was added and refluxing was continued. After 6 hours, another 0.124 mL of Bu3SnH and a few crystals of AIBN were added and the mixture refluxed overnight—only a small amount of further reaction occurred therefore another 0.124 mL of Bu3SnH and a few crystals of AIBN added and refluxing continued, again further reaction occurred but then stopped. Further quantities of Bu3SnH (4×0.124 mL) together with a few crystals of AIBN were added at approx 2 hourly intervals. It was noticed that the reaction proceeded much more with thorough degassing with argon prior to addition of Bu3SnH. After completion of the reaction (˜48 hours total reaction), the toluene was evaporated and ether/20% aqueous ammonia were added. The product was extracted into ether and the extracts were washed with 20% aqueous ammonia (3×). The ether layer was dried over Na2SO4 and concentrated and the product was triturated with hexane to remove high Rf impurities. Chromatography on silica gel (elution with 0-15% diethyl ether in hexane) gave the title compound as a clear gum (D7), (143 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.CO.CN(C=O)C>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:5][CH3:1])=[O:17])[CH3:9])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc([C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.2 %

Procedure:
To 820 mg of tert-butyl[(1S)-1-(3-bromophenyl)ethyl]carbamate were added 113 mg of 1,3-bis(diphenylphosphino)propane, 62 mg of palladium acetate, 0.84 ml of triethylamine, 8 ml of DMF, and 12 ml of methanol, followed by stirring at room temperature for 1 hour. While stirring at room temperature, carbon monooxide was intaken for 10 minutes, followed by stirring at 80° C. overnight under a carbon monooxide atmosphere. 113 mg of 1,3-bis(diphenylphosphino)propane and 62 mg of palladium acetate were added thereto, followed by stirring at 80° C. overnight. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 577 mg of methyl 3-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}benzoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.CO>CN(C=O)C.CCOC(C)=O.[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Agent: O=[Pt]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl

Procedure:
A solution of 2-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)propanamide A29 (1.0 g, 3.1 mmol) in DMF (55 mL) and MeOH (5 mL) was stirred with platinum(II)oxide (0.21 g, 0.94 mmol) under an atmosphere of hydrogen for 120 hours at ambient temperature. The reaction mixture was diluted with EtOAc and filtered through a plug of Celite. The filter cake was washed with EtOAc and the solvents were removed in vacuo to give a crude residue that was purified by silica gel column chromatography (Combiflash Rf, 0-90% EtOAc in cyclohexane), giving the title compound A30 as an off white solid (0.65 g, 64%). LCMS-C: rt 4.98 min; m/z 324 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:12](Cl)[C:13](=[CH2:15])[CH3:14]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:14][C:13](=[CH2:12])[CH2:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: C=C(C)CCl
Reactant: N#CCc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=C(C)CC(C#N)c1ccccc1
Yield: 86.7 %

Procedure:
To a mixed solution of 1,580 g (13.5 mol) of phenylacetonitrile, 11.3 g (5.0 mmol) of triethylbenzylammonium chloride, and 1,200 ml of 50% aqueous sodium hydroxide was added dropwise 410 g (4.5 mol) of methallyl chloride over 2 hours, while vigorously stirring and maintaining the temperature at 20°-30° C. After the addition, the mixture was stirred at the same temperature for one hour. 1,700 ml of water was added to the reaction mixture and the mixture was separated into an organic layer and a water layer. The organic layer was washed twice with 300 ml of saturated brine, once with 50 ml of 10% hydrochloric acid, and further twice with 100 ml of saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated from the organic layer. The residue was distilled under reduced pressure to obtain 670 g (3.9 mol) of the target Compound (IV) at a yield of 87% for the feed methallyl chloride.
Reaction SMILES: [Br:1][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])[CH2:5]2.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([Br:24])[C:22]=1[OH:23])[CH:18]=O.N1CCCCC1>C(O)(C)C>[Br:1][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:18]\[C:17]1[CH:16]=[C:15]([Br:14])[C:22]([OH:23])=[C:21]([Br:24])[CH:20]=1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: O=C1Cc2cc(Br)ccc2C(=O)N1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/c1cc(Br)c(O)c(Br)c1
Temperature: 95 °C
Yield: 99.6 %

Procedure:
6-Bromo-4H-isoquinoline-1,3-dione (0.12 g, 0.5 mmol), 3,5-dibromo-4-hydroxybenzaldehyde (0.14 g, 0.5 mmol), and piperidine (0.075 mL, 0.75 mmol) were dissolved in i-propanol (2 mL). After heating at 95° C. for 3 h, it is cooled, and the solid is filtered and washed with I-propanol, ether and hexane to yield 0.25 g (99.6%) solid; mp 167-168° C.; HRMS (ESI) m/z 499.8 (M−H)−1.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[OH:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([OH:16])=[CH:18][CH:19]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccc(O)cc1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)cc2)C(=O)OC1=O

Procedure:
To a boiling solution of 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 200 ml. of methanol is added 2.18 g. (0.02 m.) of p-hydroxyaniline. The resulting mixture is refluxed overnight and filtered to yield 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 223°-225° C. Both the mono-and di-sodium salts are prepared upon treatment of the dione with sodium methoxide in methanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].O[Li].O>O.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2cccc(C#N)c2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(COc2ccnn2-c2cc(C(=O)O)ccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-[5-[(3-cyanophenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (1.0 eq) and LiOH.H2O (3.0 eq) in a mixture of water (2 mL) and THF (2 mL) was stirred at room temperature for 30 min. Diluted with another 2 mL water, and the mixture was washed with ethyl acetate twice (6 mL×2). The water phase was acidified with 1N HCl (pH=3), filtered and dried the solid to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ 5.36 (2H, s), 6.03 (1H, s), 7.61-7.64 (2H, m), 7.77-7.78 (1H, m), 7.82-7.84 (2H, m), 7.96 (1H, s), 8.09 (1H, s), 8.69 (1H, d, J=4.4 Hz), 13.92 (1H, s). LCMS (mobile phase: 10%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=2.106 min. [M+H] Calc'd for C17H12N4O3, 321. Found, 321.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1.C(Cl)Cl>[CH3:14][O:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:9]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
3-nitro-5-methoxybenzoic acid (900 mg; 4.57 mmol; 1 eq; commercially available IMPAMEX) is dissolved in THF (5 mL) at room temperature. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g; 5.48 mmol; 1.2 eq) and 1-hydroxybenzotriazole hydrate (987 mg; 7.3 mmol; 1.6 eq) are added in DCM (20 mL). The reaction mixture is stirred at room temperature for 25 min before adding morpholine (795.44 mg; 9.13 mmol; 2 eq). After 3 h, the reaction mixture is quenched with water and the organic phase recovered and washed with citric acid (5%). The aqueous phase is extracted with DCM. The organic phase is dried over MgSO4, and the solvent is evaporated under reduced pressure to afford 1.2 g (99%) as a yellow solid. The next step is carried out directly on the crude material. LC/MS: (ES+): 267.3; (ES−): 265.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[C:5]2[N:14]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]3)[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][C@H:18]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][C:4]=2[CH:3]=1.[CH3:37][N:38](C=O)C>[C-]#N.[C-]#N.[Zn+2].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].ClCCl>[CH:10]1([CH2:9][O:8][C:6]2[C:5]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:4]=3[CH:3]=[C:2]([C:37]#[N:38])[N:7]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CN(C)C=O
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(OCC4CCC4)c32)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C#N)nc(OCC4CCC4)c32)CC1
Temperature: 140 °C

Procedure:
To a solution of 6-chloro-4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine (120 mg, 0.23 mmol) in DMF (1.5 mL) was added Zn(CN)2 (83 mg, 0.70 mmol), and the mixture was deoxygenated by purging with nitrogen for 10 minutes. Pd(dppf)Cl2 dichloromethane adduct (57.7 mg, 0.07 mmol) was added and the reaction was again deoxygenated for 5 minutes. The reaction flask was sealed and the mixture was heated at 140° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc (50 mL), and the organic layer was separated. The organic layer was washed with water (2×50 mL) followed by saturated brine solution (2×30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (40% EtOAc/petroleum ether) to yield 4-(cyclobutylmethoxy)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCI calc'd. for C30H37N5O2 [M+H]+ 500. found 500.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[N:14]([C:15]4[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=4)[NH2:18])[CH:13]=[CH:12][N:10]3[N:11]=2)[CH:2]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28])#[N:23]>>[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:37])([F:38])([F:34])([F:35])[F:36])[CH:32]=1)[C:27]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([N:14]2[C:9]3[N:10]([N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[CH:12]=[CH:13]2)[CH:16]=1)=[O:28])#[N:23]
Reactant: Nc1cccc(-n2ccn3nc(-c4cccnc4)cc23)c1
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: N#Cc1cc(C(=O)Nc2cccc(-n3ccn4nc(-c5cccnc5)cc34)c2)cc(S(F)(F)(F)(F)F)c1

Procedure:
Analogously to the process described in Example 26, 100 mg (0.363 mmol) of the compound of Example 62A and 117 mg (0.363 mmol) of the compound of Example 23A gave 62 mg (32% of theory) of the title compound. In this case, the reaction time was about 15 h.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[O:3]1.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl>[Br:25][C:5]1[C:6](=[O:7])[C:2]([CH3:17])([CH3:1])[O:3][C:4]=1[C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a 0° C. stirred solution of crude 2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one (170 mg, 0.73 mmol, 1 eq) in CHCl3 (10 mL) was added NBS (259 mg, 1.45 mmol, 2 eq), and the reaction mixture was then stirred at RT for 2 h. The chloroform was removed and the crude material was then purified via silica gel column chromatography eluting with 10% EtOAc in hexanes to afford 4-bromo-2,2-dimethyl-5-(4-nitrophenyl)furan-3(2H)-one (100 mg, 44%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Br)c2)CC1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A solution of 3-bromo-5-iodopyridine (13.0 g, 45.8 mmol), tert-butyl piperazine-1-carboxylate (8.53 g, 45.8 mmol), copper(I) iodide (0.871 g, 4.57 mmol), K3PO4 (19.46 g, 91.68 mmol), 1,2-ethanediol (5.1 mL, 91 mmol) in isopropyl alcohol (80 mL) in a sealed tube was heated at 80° C. in an oil bath for 2 days. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the solution was washed with saturated NaHCO3, dried (MgSO4) and concentrated. Purification by flash chromatography on silica gel (20% EtOAc/hexanes to 30% EtOAc/hexanes) afforded 5.75 g (37%) of desired product. MS calculated for C14H20BrN3O2: (M+H) 343; found 342.0, 344.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C.CC#N>[N:5]1[CH:6]=[CH:7][C:2]([CH:10]=[CH:9][C:8]([O:12][CH3:13])=[O:11])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OC
Reactant: Brc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1ccncc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93152.5 %

Procedure:
A mixture of 4-bromopyridine (40.6 g, 0.25 mmol), palladium acetate (1.16 g, 5.14 mmol), tri-(O-tolyl)phosphine (3.14 g, 10.3 mmol), CH3CN (129 mL), triethylamine (64.3 mL, 0.46 mmol) and methyl acrylate (46.8 mL, 0,514 mmol) was sealed in a bomb and placed in an oil bath at 120° C. for 4 hours. The mixture was cooled to 0° C., the bomb was vented, and the slurry thus obtained was partitioned between CH2Cl2 /water. The aqueous phase was separated, extracted with CH2Cl2 (2×200 mL) and the combined organic layers were dried over MgSO4. The solvent was removed in vacuo to afford 38 g of methyl 3-(4-pyridyl)propenoate.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C.[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][N:34]([C:37](Cl)=[O:38])[CH2:35][CH:36]=2)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:40][C:24]([F:23])([F:41])[C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]3[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]3[Cl:1])=[O:38])[CH2:33][CH:32]=2)=[CH:29][CH:30]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C(Cl)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@](O)(COC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methyl)-propyl-4-nitroimidazole prepared in Example 10 (0.74 g, 3.11 mmol) and triethylamine (1.74 ml, 12.42 mmol) were added to a suspension of 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carbonylchloride (0.60 g, 2.07 mmol) in toluene (36 ml) followed by stirring at 100° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.32 g, yield 31%) as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[N:3]=1.[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[CH3:9][O:8][C:7]1[C:2]([CH:13]=[CH2:14])=[N:3][C:4]([N+:10]([O-:12])=[O:11])=[CH:5][CH:6]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1nc([N+](=O)[O-])ccc1OC
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a solution of 1.0 g (4.3 mmol) 2-bromo-3-methoxy-6-nitropyridine (J. Lombardino, J. Med. Chem. 1981, 24, 39–42) in 25 ml of toluene was added 1.9 ml (6.4 mmol) of tri-n-butyl-vinyltin and a catalytic amount of bis(triphenylphosphine-palladium(II) chloride, and the reaction was refluxed under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature and the solvent evaporated. The residue was chromatographed on silica using chloroform as the elutant. Appropriate fractions were combined to yield 0.63 g of 3-methoxy-6-nitro-2-vinyl-pyridine as an oil. TLC: Rf=0.5 (5:1 hexane/ethyl acetate). 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.35 (d, 1H), 7.10 (m, 1H), 6.55 (d, 1H), 5.65 (d, 1H), 4.0 (s, 3H). Mass spectrum: m/e=181.1 (p+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH3:1][C@@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:7]1
Reactant: C[C@H]1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C[C@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(S)-methylpiperazine (2.62 g, 26.2 mmol) in dichloromethane (100 mL) was trityl chloride (7.30 g, 26.2 mmol) added and the mixture was stirred at ambient temperature for 1.5 h. The organic phase was washed (×1) with 1 M aqueous K2CO3, water, and brine. Drying (MgSO4) and solvent removal in vacuo furnished a quantitative yield of the title compound as a glassy oil which solidified upon standing. This material was used directly in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:7]=1[C:16]#[N:17])=[O:4].C(=O)(O)[O-:19].[Na+]>S(=O)(=O)(O)O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:7]=1[C:16](=[O:19])[NH2:17])=[O:4]
Reactant: CCN(CC)c1nsc(NC(=O)NC)c1C#N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCN(CC)c1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C

Procedure:
A stirred mixture of 8.5 g of 1-methyl-3-(4-cyano-3-(diethylamino)-5-isothiazolyl)urea in 17 ml of concentrated sulfuric acid was heated at 100° during 11/4 hours. The reaction mixture was poured into 250 ml of stirred ice-water. The mixture became unstirrable and was then carefully poured into 1 liter of saturated sodium bicarbonate solution. The mixture was stirred during one and a quarter hours, filtered cold, and washed with cold water. The collected solid was recrystallized twice from ethanol to give 5.3 g of 1-methyl-3-(4-carbamoyl-3-(diethylamino)-5-isothiazolyl)urea; m.p. 195°-197°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: CC([O:4][C:5]([C:7]1[N:44]=[CH:43][C:10]2[N:11]([CH2:26][C:27](=[O:42])[CH2:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:41])[CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:45][O:46][CH3:47])=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3)=[O:6])C.[OH-].[Na+].Cl>CO>[CH2:19]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:26][C:27](=[O:42])[CH2:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:41])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]1[CH:43]=[N:44][C:7]([C:5]([OH:6])=[O:4])=[C:8]([CH2:45][O:46][CH3:47])[C:9]2=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(OCc3ccccc3)ccc1n2CC(=O)CCCCN(C)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1c(C(=O)O)ncc2c1c1cc(OCc3ccccc3)ccc1n2CC(=O)CCCCN(C)CCc1ccccc1
Yield: 64.9 %

Procedure:
350 mg of 6-benzyloxy-4-methoxymethyl-9-{6-[N-methyl-N-(2-phenylethyl)-amino]-2-oxohexyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester (0.55 mmol) is mixed in 10 ml of methanol with 1 ml of 2N aqueous sodium hydroxide solution and held at 40° C. until the reaction is completed. Then, the reaction mixture is acidified with dilute hydrochloric acid, and the precipitated product is suctioned off. It is washed with water and then with diethyl ether, dried in a vacuum, and 212 mg of 6-benzyloxy-4-methoxymethyl-9-{6-[N-methyl-N-(2-phenylethyl)-amino]-2-oxohexyl}-9H-pyrido-[3,4-b]-indole-3-carboxylic acid is obtained as a yellow, amorphous powder.