Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(OCC)(=O)C>C1CCCCC1>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: NC(=O)CBr
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Agent: Cl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: NC(=O)CN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 143, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide. The crude product was subjected flash chromatography (SiO2, gradient 50 to 100% ethyl acetate in cyclohexane). Pure fractions were combined and concentrated in vacuo and the resultant residue dissolved in DCM and treated with 4M HCl in dioxane then diethyl ether. The resultant precipate was collected by filtration to give 178 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H); 8.48-8.43 (m, 1H); 8.30 (s, 1H); 8.05 (s, 1H); 7.85 (td, J=8.75, 5.93 Hz, 1H); 7.74-7.63 (m, 2H); 7.41-7.34 (m, 1H); 7.22 (d, J=2.30 Hz, 1H); 7.10 (dd, J=8.45, 2.35 Hz, 1H); 6.97 (d, J=8.39 Hz, 1H); 4.22 (t, J=5.00 Hz, 2H); 3.98 (d, J=4.37 Hz, 2H); 3.60 (t, J=12.26 Hz, 2H); 3.24-3.13 (m, 2H); 3.06 (t, J=4.95 Hz, 2H); 2.69-2.61 (m, 1H); 1.87 (s, 4H). LCMS: RT=7.46 min, M+H+=506
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1F)[C:5]([O:7]C)=[O:6].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(F)c(Br)c1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(Br)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
Methyl 3-bromo-4-fluorobenzoate (Preparation 122, 500 mg, 2.15 mmol), 3,4-dichlorophenol (350 mg, 2.15 mmol) and caesium carbonate (1.4 g, 4.29 mmol) were stirred in dimethylsulfoxide (10 mL). The reaction mixture was heated to 120° C. and stirred overnight under an atmosphere of nitrogen. A 1M aqueous solution of sodium hydroxide was added and the mixture extracted with ethyl acetate. The aqueous phase was acidified and extracted with ethyl acetate. The organic phase from the second extraction was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (30%-100% ethyl acetate in heptane) to afford the title compound as a white solid (244 mg, 31%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1ccccc1Br
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1cccc2[nH]ccc12
Temperature: 75 °C
Reaction time: 15 h
Yield: 63.9 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.431 g, 10.0 mmol), and 2-bromofluorobenzene (1.75 g, 10.1 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (0.347 g, 0.30 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30.0 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.35 g (64%) of the product 4-(2-fluoro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.[CH:28]1C=C[C:31]2[N:36]([OH:37])N=[N:34][C:32]=2[CH:33]=1.CC1ON=CC=1N>CN(C)C=O.O>[CH3:28][C:33]1[O:37][N:36]=[CH:31][C:32]=1[NH:34][C:11](=[O:13])[C:10]1[CH:14]=[C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:9]=1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: Cc1oncc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: Cc1oncc1NC(=O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 100 mg, 0.30 mmol), EDC (115 mg, 0.60 mmol), and HOBT (92 mg, 0.60 mmol) in dimethylformamide (2 ml) was stirred in air at room temperature for 1 h, then 5-methyl-4-isoxazolamine (may be prepared as described in Description 93; 100 mg, 1.02 mmol) was added in one charge. The reaction mixture was stirred at 25° C. overnight. The solution was heated at 35° C. for 7 hours, then diluted with water (30 ml) and extracted with ethyl acetate (80 ml×3). The organic phase was washed with brine (60 ml×2), dried over anhydrous MgSO4, and concentrated. The residue was purified by chromatography (silica gel, 20 g, eluent: dichloromethane/methanol=60:1, 600 ml). The crude product was washed with methanol (2 ml×2), filtered, and dried in vacuum to yield the title compound. 23 mg.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.[C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23](=O)[CH2:24]Br)=[CH:21][CH:20]=1)#[N:18].C(Cl)Cl>CC(O)C>[C:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]2[N:6]=[C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]3[CH:24]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: COC(=O)c1cccc(N)n1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)cn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
NaHCO3 (1.0 eq.) was added to a solution of (A1) in i-PrOH (0.5 M), then 4-cyanophenacyl bromide (1.2 eq.) was added and the resulting reaction mixture was stirred at RT for 18 h, then heated to reflux for another 18 h. After cooling down, the solvent was reduced in vacuo and the residue partioned between sat. aq. NaHCO3 and DCM. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was triturated with hot EtOH and filtered to yield (31%) the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 9.31 (1H, s), 8.26 (2H, d, J=8.3 Hz), 8.00 (1H, d, J=9.0 Hz), 7.91 (2H, d, J=8.3 Hz), 7.85 (1H, d, J=7.0 Hz), 7.45 (1H, dd, J=9.0, 7.0 Hz), 4.00 (3H, s). MS (ES+) C16H11N3O2 requires: 277, found: 278 (M+H)+.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([C:27]1[N:28]=[CH:29][N:30]2[CH:34]=[CH:33][S:32][C:31]=12)=O.C(OCC)(=O)C>CO>[CH3:24][O:23][C:21]([CH:20]=[CH:25][C:27]1[N:28]=[CH:29][N:30]2[CH:34]=[CH:33][S:32][C:31]=12)=[O:22]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ncn2ccsc12
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ncn2ccsc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.1 %

Procedure:
Methyl triphenylphosphoranylideneacetate (500 mg) was added to a solution of 150 mg of 7-formylimidazo[5,1-b]thiazole in 15 ml of methanol. The mixture was stirred at room temperature for 15 min. Ethyl acetate was added thereto. The mixture was washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 228 mg of 7-(2-methoxycarbonylvinyl)imidazo[5,1-b]thiazole (a mixture of geometrical isomers).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:27])/[CH:24]=[CH:25]/[CH3:26])=[CH:16][CH:15]=1>C(O)C.COCCOCCOC>[CH2:7]([O:6][C:4]([CH:3]1[CH:25]([CH3:26])[CH2:24][C:23](=[O:27])[N:22]([CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[C:2]1=[O:10])=[O:5])[CH3:8]
Reactant: C/C=C/C(=O)NCCc1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: COCCOCCOC
Solvent: CCO
Product: CCOC(=O)C1C(=O)N(CCc2ccc(F)cc2)C(=O)CC1C

Procedure:
Sodium (1.5 g, 65.1 mmol) was dissolved in ethanol (50 mL) and the solution was concentrated under vacuum. The residue was suspended in toluene (50 mL) and bis(2-methoxyethyl)ether (30 mL). Diethyl malonate (4.0 mL, 26.5 mmol) was added, followed by a suspension of trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (5.00 g, 24.1 mmol) in bis(2-methoxyethyl)ether (20 mL). The mixture was heated at reflux for 6 hours. The cooled mixture was washed with 1.0 N aqueous hydrochloric acid, then with water, and dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography, eluting with 25% ethyl acetate in hexane, to provide a pale yellowish oil which slowly crystallized (5.81 g, 75%). This appeared to be a mixture of cis and trans isomers (approximately 15% cis). 1H NMR (300 MHz, CDCl3) δ7.20 (m, 2H), 6.99 (t, J=9 Hz, 2H), 4.28 (m, 2H), 4.00 (m, 2H), 3.66 (d, J=5 Hz, 0.15H), 3.27 (d, J=10 Hz, 0.85H), 2.82 (m, 3H), 2.53 (m, 1H), 2.33 (dd, J=17, 10 Hz, 1H), 1.34 (m, 3H), 1.09 (d, J=7 Hz, 3H). Mass spec (AP+) m/z 322.0 (M+H+, 100%).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([Na])[CH:14]=CC=[CH:11][CH:10]=1.C(Cl)C=C>C1(C)C=CC=CC=1.O>[C:3]1([CH2:11][CH2:10][CH:9]=[CH2:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ccccc1
Reactant: [Na]c1ccccc1
Agent: [Na]
Solvent: C=CCCl
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCCc1ccccc1
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
In 220 g of toluene, 20.3 g (0.883 mol) of sodium dispersion was reacted with 46.5 g (0.413 mol) of chlorobenzene, to prepare phenyl sodium. The resultant toluene slurry was stirred for 2.5 hours under heat reflux. The thus-obtained black slurry was cooled, and then a toluene (40 g) solution containing 31.6 g (0.413 mol) of allyl chloride was added to the cooled slurry, keeping the reaction temperature in the range of from -10° C. to 0° C., and then the reaction mixture was allowed to stand, for aging, for 30 minutes at room temperature. After the reaction was completed, the reaction mixture was subjected to hydrolysis with 350 ml of water in the range of 5 to 20° C., and then the resultant organic layer was washed with 300 ml of water twice, according to a usual manner. Toluene was removed therefrom by atomospheric distillation, and the residual orange oil was subjected to distillation under reduced pressure in the same manner as in Example 7. As a result, 39.4 g (0.298 mol, yield 72.2%) of 4-phenyl-1-butene was given (purity 98.3%), and 6.3 g of a residue remained.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]([Cl:11])=[N:4][N:3]=1.[Br-].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Zn+])=[CH:16][CH:15]=1>>[Cl:11][C:5]1[C:6]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:2]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2c1CCC2
Reactant: Fc1ccc(C[Zn+])cc1
Agent: [Br-]
Product: Fc1ccc(Cc2nnc(Cl)c3c2CCC3)cc1

Procedure:
Compound 45 is prepared analogous to compound 44 starting from of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (compound 39) and para-fluorobenzyl zinc bromide.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCl>[CH:1]1([C:6]2[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=2[O:12][C:28]([O:30][CH3:31])=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCc1ccc(O)c(C2CCCC2)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(OC(=O)OC)c(C2CCCC2)c1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of ethyl 3-(3-cyclopentyl-4-hydroxy-phenyl)propanoate (857 mg, 3.27 mmol) and triethylamine (911 μL, 6.53 mmol) in dichloromethane (5 mL) under a N2 atmosphere at 0° C. was added methyl chloroformate (463 mg, 377 μL, 4.90 mmol) dropwise. After 1 h, the reaction mixture was partitioned between dichloromethane/water, separated and the aqueous layer was extracted once more with dichloromethane. The combined organics were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-30% ethyl acetate/hexanes) provided ethyl 3-(3-cyclopentyl-4-methoxycarbonyloxy-phenyl)propanoate (920 mg, 88% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.20 (d, J=1.7 Hz, 1H), 7.09-7.03 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 3.03-2.96 (m, 1H), 2.83 (t, J=7.6 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.77-1.72 (m, 2H), 1.66-1.58 (m, 2H), 1.54-1.47 (m, 2H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13](OCC)=O)[CH:9]([CH3:18])[CH2:8]1)=[O:5].[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][N:37]=[C:36]([NH2:39])[CH:35]=2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:39][C:36]2[CH:35]=[C:34]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[NH:38][N:37]=2)[CH:9]([CH3:18])[CH2:8]1)=[O:5]
Reactant: CCOC(=O)C1CCC(NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1C
Reactant: Nc1cc(-c2ccc(F)cc2)[nH]n1
Product: CC1CC(NC(=O)c2cc(C(F)(F)F)ccc2Cl)CCC1CNc1cc(-c2ccc(F)cc2)[nH]n1

Procedure:
The title compound is prepared analogously to Example 1 by replacing trans-4-(2-chloro-5-trifluoromethyl-benzoylamino)-cyclohexane carboxylic acid methyl ester (Ex. 1 Step 2) with ethyl 4-(2-chloro-5-(trifluoromethyl)benzamido)-2-methyl cyclohexane carboxylate (Ex. 1.35 step 2) and by replacing 2-amino-3-picoline (Ex. 1 step 4) with 5-(4-fluorophenyl)-1H-pyrazol-3-amine. [MH]+ 509.40.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16](=[O:21])[CH2:17][N:18]([CH3:20])[CH3:19])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1>CN1CCCC1=O.[OH-].[Na+]>[CH3:19][N:18]([CH3:20])[CH2:17][C:16]([NH:15][C:13]1[N:14]=[C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:31]([C:30]4[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=4)=[O:32])[CH:24]=[CH:23][CH:22]=3)=[N:11][N:10]2[CH:12]=1)=[O:21]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: CN(C)CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)CN(C)C)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]-N2,N2-dimethylglycinamide (196 mg, 0.6 mmol) in N-methylpyrrolidone (5.0 mL) was added 1,3-dimethylpyrazole-5-carbonyl chloride (270 mg, 1.7 mmol), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→460/40) and precipitated from ethyl acetate to give the title compound (131 mg, 49%) as a white powder. melting point 210° C.
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH2:49]([NH2:54])[C:50]([CH3:53])([CH3:52])[CH3:51]>C(O)(=O)C>[CH2:49]([N:54]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1)[C:50]([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)CN
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC(C)(C)Cn1cnc2c(-c3ccccc3)csc2c1=O
Yield: 35.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), neopentylamine (0.117 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 45.8 mg (0.15 mmol, 35.7% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1Cl
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 30.0 g (0.176 mol) of o-chlorophenylacetic acid and 40 ml of thionyl chloride was stirred for 18 hours. The volatiles then were removed in vacuo to give 32.76 g (99.0%) of o-chlorophenylacetyl chloride as a transparent, pale yellow, mobile liquid.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([Cl:12])[Cl:11]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:9][Si:10]([Cl:12])([Cl:11])[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([Si:10]([Cl:12])([Cl:11])[Cl:9])[CH3:8])=[CH2:1]
Reactant: Cl[SiH](Cl)Cl
Reactant: C1=CCCCCC=C1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C=C(CCCCC(C)[Si](Cl)(Cl)Cl)[Si](Cl)(Cl)Cl
Temperature: 180 °C
Yield: 10 %

Procedure:
As in Example 1, 1,3-cyclooctadiene (1.00 g, 9.24 mmol), trichlorosilane (5.01 g, 36.99 mmol) and tetrabutylphosphonium chloride (0.27 g, 0.92 mmol) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180° C. for 20 hours. The resulting mixture was distilled to yield 0.35 g (yield: 10%) of 2,7-bis(trichlorosilyl)-1-octene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)O1>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.O1CCOCC1>[C:19]1([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
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: C1COCCO1
Product: O=C(Nc1cccnc1)c1cc(-c2cccnc2)ccc1OCc1ccccc1
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 200 mg, 0.52 mmol), 1,4-dioxane (2 ml), 1M sodium carbonate (1.04 ml, 1.04 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (107 mg, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (36.2 mg, 0.03 mmol). The vial was sealed and heated to 100° C. for 30 min under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified using the MDAP. Some impurities persisted and the mixture was re-purified using MDAP to yield the title compound. 17 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[C:5]([NH:8][C:9]2[CH:10]=[C:11]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH2:24](O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[N:21]=[CH:24][N:8]([C:9]3[CH:10]=[C:11]([N:15]4[CH2:19][CH2:18][CH2:17][C:16]4=[O:20])[CH:12]=[CH:13][CH:14]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCCN1c1cccc(Nc2ncc(Br)cc2[N+](=O)[O-])c1
Reactant: CCO
Product: O=C1CCCN1c1cccc(-n2cnc3cc(Br)cnc32)c1

Procedure:
1-[3-(6-Bromo-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]pyrrolidin-2-one was prepared from 1-[3-(5-bromo-3-nitropyridin-2-ylamino)phenyl]pyrrolidin-2-one as described in Example 1. Oxalate salt, white crystals, m.p. 194-195° C. (from ethanol); δH (360 MHz, d6-DMSO) 2.10 (2H, quin, J 7), 2.56 (2H, t, J 8), 3.92 (2H, t, J 7), 7.58-7.65 (2H, m), 7.78-7.81 (1H, m), 8.19 (1H, s), 8.52-8.54 (2H, m), 8.93 (1H, s); m/z (ES+) 357 and 359 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([CH3:32])[C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2C(=O)NC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(C)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
390 mg (1 mmol) of 3-(4-methoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester were solubilized in 5 mL of DMF under nitrogen before adding 61 mg (1.5 mmol) of sodium hydride in mineral oil 60%. The reaction mixture was agitated for 5 minutes before the addition of 70 μL (1.1 mmol) of iodomethane. After 2 hours of agitation at room temperature, the reaction mixture was quenched with 20 mL of water and then extracted with diethyl ether (2×20 mL). The organic layers were dried over sodium sulfate, filtrated and evaporated in vacuo to give quantitatively 3-(4-methoxy-benzyl)-1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (404 mg) as a yellowish oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])[CH:2]=[CH2:3].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCNc1cccc(CCC(=O)OCC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCNc1cccc(CCC(=O)O)c1

Procedure:
A 4 g. sample of ethyl 3-(allylamino)hydrocinnamate is hydrolyzed with 1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected, dried in vacuo and crystallized from acetone to yield the title compound as white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>>[C:8]([C:4]1[CH:3]=[C:2]([N:13]2[CH2:14][CH2:15][O:11][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: O=C1NCCO1
Reactant: CC(=O)c1cccc(Br)c1
Product: CC(=O)c1cccc(N2CCOC2=O)c1

Procedure:
The title compound was prepared in quantitative yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 1-(3-bromophenyl)ethanone and 1,3-oxazolidin-2-one.