Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[Cl:10][C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=2)=[O:18])=[C:15]([F:32])[C:14]([OH:33])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=2)=[O:18])=[C:15]([F:32])[C:14]([O:33][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(O)c2F)cc1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2c(Cl)ccc(OCc3cccc(Cl)c3)c2F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
3-Chlorobenzylbromide (28 μl, 0.24 mmol) was added to a suspension of ethyl (4-{[(6-chloro-2-fluoro-3-hydroxyphenyl)carbonyl]amino}phenyl)acetate (80 mg, 0.228 mmol) and potassium carbonate (38 mg, 0.273 mmol) in dimethylformamide (3 ml) and the reaction was stirred at room temperature for 4 hrs. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic layer was separated, dried (Na2SO4) and the solvent evaporated to afford the title compound as a colourless oil (91 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([NH:32][CH2:33][C:34]([CH3:42])([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH3:35])[N:3]=1>[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([NH:32][CH2:33][C:34]([CH3:42])([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)[CH3:35])[N:3]=1
Reactant: CC(C)(CNc1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F)N1CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)(CNc1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F)N1CCOCC1
Yield: 48.4 %

Procedure:
[(2R)-3-[2-(2-Chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.169 g, 0.28 mmol) and Pd(OH)2 (0.017 g) were treated as described in General Procedure E, Part D, to provide [(2R)-3-[2-(2-chloro-5-fluoro-6-{[2-methyl-2-(4-morpholinyl)propyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a white solid (0.070 g, 49%). LCMS: (M+H)+=516.3.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:19]([C:22]1[CH:23]=[C:24](F)[CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])([O-:21])=[O:20]>C1COCC1.C(OCC)(=O)C>[C:6]([O:5][C:3]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[CH:26][C:27]([N+:28]([O-:30])=[O:29])=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[CH2:12][CH2:11]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.096 g, 2.4 mmol) was added in several portions to a solution of N-Boc-4-piperidine ethanol (0.550 g, 2.4 mmol) in THF (20 ml). To this mixture was added a solution of 3,4-dinitrofluorobenzene (0.372 g, 2.0 mmol) and the resultant mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (60 ml) and the aqueous phase back extracted with ethyl acetate (3×50 ml). The combined organics were washed with brine (50 ml), dried (MgSO4) and reduced in vacuo. The resulting residue was subjected to column chromatography eluting with a 0-50% gradient of ethyl acetate in petroleum ether. 4-[2-(3,4-dinitro-phenoxy)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester was obtained as a yellow oil (0.361 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[OH:14][C:15]1[CH:19]=[C:18]([N:20]2[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[S:17][C:16]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:14][C:15]2[CH:19]=[C:18]([N:20]3[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][C:23]=4[N:22]=[CH:21]3)[S:17][C:16]=2[C:29]([O:31][CH3:32])=[O:30])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example B11, 110.5 mg of 4-fluoro-2-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[C:27]1([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49]([OH:51])=O)=[C:46]([CH3:48])[N:47]=3)[C:39]2=[O:52])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>>[C:27]1([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:49]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:51])=[C:46]([CH3:48])[N:47]=3)[C:39]2=[O:52])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1nc(N2CCN(Cc3nccc4ccccc34)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3nccc4ccccc34)C2=O)sc1C(=O)NCc1cccnc1
Yield: 43 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(isoquinolin-1-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)-pyridine, the title compound was obtained as a colorless solid in 43% yield: mp 151-153° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.53 (d, J=3.0 Hz, 1H), 8.45 (d, J=6.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.86 (d, J=6.0 Hz, 1H), 7.74-7.63 (m, 4H), 7.31-7.28 (m, 1H), 6.06 (br s, 1H), 5.12 (s, 2H), 4.59 (d, J=6.0 Hz, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.61 (t, J=6.0 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 459.3 (M+1).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:26][C:25](OS(C(F)(F)F)(=O)=O)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21]C[CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[Cl-].[Li+].[C:37](=[O:40])([O-])[O-].[Na+].[Na+].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([C@H:25]2[CH2:26][C@@:4]3([CH3:5])[C@@H:6]([CH2:7][CH2:8][C:3]3=[O:2])[C@H:15]3[C@H:24]2[C@@H:23]2[C:18]([CH2:17][CH2:16]3)=[CH:19][C:37](=[O:40])[CH2:21][CH2:22]2)=[CH:47][CH:46]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(B(O)O)cc1
Reactant: C[C@]12CC(OS(=O)(=O)C(F)(F)F)=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]1CC13OCCOC12OCCO3
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]32)cc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
17,17-bis-(ethylenedioxy)-11-trifluoromethylsulfonyloxy-5,9(11)-estradiene is dissolved in a mixture of 360 ml of toluene and 170 ml of ethanol and mixed in succession with 2.5 g of palladiumtetrakistriphenylphosphine, 3.6 g of lithium chloride, 55 ml of 2 molar sodium carbonate solution and 7.2 g (46.8 mmol) of 4-methoxyphenyl boronic acid. The reaction mixture is then stirred for two hours at 95° C., cooled to room temperature and mixed with saturated sodium chloride solution. The organic phase is separated, washed in succession with 5% sodium hydroxide solution and water, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane. 19.2 g of the title compound is obtained as white foam.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[Br:7][C:8]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:9]=1[CH2:10][NH:11][C:12]([NH:14][NH2:15])=[S:13].[CH3:21]O>OS(O)(=O)=O>[Br:7][C:8]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:9]=1[CH2:10][NH:11][C:12]([NH:14][N:15]=[C:2]([CH3:4])[C:1]([O:6][CH3:21])=[O:5])=[S:13]
Reactant: NNC(=S)NCc1cc(F)ccc1Br
Reactant: CC(=O)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)=NNC(=S)NCc1cc(F)ccc1Br

Procedure:
To a solution of pyruvic acid (352 mg, 4.00 mmol) in methanol (15 mL) was added N-(2-bromo-5-fluorobenzyl)hydrazinecarbothioamide (14, 1.112 g, 4.00 mmol) followed by conc. H2SO4 (5 drops). The mixture was heated at reflux for 7 h. Most of the solvent was evaporated. The residue was taken into EtOAc (150 mL), washed with water, saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give methyl 2-(2-(2-bromo-5-fluorobenzylcarbamothioyl)hydrazono)propanoate (15). MS: m/z, 362 (100%, M+1), 364 (100%), 384 (60%, M+23), 386 (60%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=[O:17]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=[O:17])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1C(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: COc1ccccc1C(=O)COC(=O)CCNC(=O)OC(C)(C)C

Procedure:
The product was obtained starting from 3-(tert-butoxycarbonylamino)propanoic acid (400 mg, 2.11 mmol) and 2-bromo-1-(2-methoxyphenyl)ethanone (484 mg, 2.11 mmol) according to the method described in example 7, step 1 as black oil (786 mg, 2.1 mmol, 99.2%). MS: M=238.2 (M-Boc+H)+
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]([N:23]1[CH:27]=[CH:26]N=C1)(N1C=CN=C1)=[S:17].N1C=CN=C1.N[C:34]1[CH:39]=[CH:38]C=C[C:35]=1[CH2:40][C:41]([NH2:43])=[O:42]>C(#N)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([NH:23][C:27]2[CH:26]=[CH:38][CH:39]=[CH:34][C:35]=2[CH2:40][C:41](=[O:42])[NH2:43])=[S:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)Cc1ccccc1N
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNC(=S)Nc2ccccc2CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving 1-N-Boc-4-aminomethylpiperidine (869 mg, 4.06 mmol) in acetonitrile (10 mL), a solution of thiocarbonyldiimidazole (794 mg, 4.46 mmol) and imidazole (82.9 mg, 1.22 mmol) in acetonitrile (15 mL) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 4 hours. After then adding 2-(2-aminophenyl)acetamide (670 mg, 4.46 mmol) thereto, the mixture was stirred overnight at 60° C. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (methylene chloride/methanol=65:1→49:1) to obtain the title compound.
Reaction SMILES: [Na].[C:2]([C:5]1[O:6][C:7](O)=[CH:8][CH:9]=1)([OH:4])=[O:3].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.CN([CH:24]=[O:25])C>>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:4][C:2]([C:5]2[O:6][C:7]([CH2:24][OH:25])=[CH:8][CH:9]=2)=[O:3])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(O)o1
Agent: [Na]
Product: COc1ccc(COC(=O)c2ccc(CO)o2)cc1
Temperature: 70 °C

Procedure:
A mixture of the sodium salt of 2-carboxy-5-hydroxyfuran (3.33 g, 20.28 mmol), 4-methoxybenzyl chloride (3.29 g, 21.0 mmol) and DMF (20 mL) was heated at 70° C. for 5.5 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate and concentrated to afford 6.3 g of crude product. The crude product was combined with 2.7 g of crude product from a similar experimental run and the mixture was purified by column chromatography on silica gel eluting with 2.5% EtOAc/CH2 Cl2 to 50% EtOAc/CH2Cl2 to afford 5.63 g of 2-(4-methoxyphenylmethyl oxycarbonyl)-5-hydroxymethylfuran.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[F:11])#[N:2].[CH2:12]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]([CH2:24]O)[CH2:22][OH:23])[CH2:17][CH2:16]1)[CH2:13][CH3:14]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[O:23][CH2:22][CH:21]([C@H:18]3[CH2:17][CH2:16][C@H:15]([CH2:12][CH2:13][CH3:14])[CH2:20][CH2:19]3)[CH2:24][O:8]2)=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: CCC[C@H]1CC[C@H](C(CO)CO)CC1
Product: CCC[C@H]1CC[C@H](C2COC(c3ccc(C#N)c(F)c3)OC2)CC1

Procedure:
A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde and 4.0 g of 2-(trans-4-n-propylcyclohexyl)-propane-1,3-diol is reacted analogously to Example 5. 2-(4-Cyano-3-fluorophenyl)-5-(trans-4-n-propylcyclohexyl)-1,3-dioxane is obtained. The following compounds are prepared analogously:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([C:12]#[N:13])[N:9]([CH3:11])[CH:10]=1)(=[O:4])=[O:3].[H][H]>[Pd].CO>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][NH2:13])[N:9]([CH3:11])[CH:10]=1)(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: Cn1cc(NS(C)(=O)=O)cc1C#N
Agent: [Pd]
Solvent: CO
Product: Cn1cc(NS(C)(=O)=O)cc1CN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 22-7 (150 mg) and 10% palladium/carbon (catalytic amount), together with methanol (10 ml), were poured into reactor and the reactor was filled with hydrogen gas, followed by stirring at room temperature for 24 hours. After the completion of the reaction, the resulting mixture was filtered through celite and concentrated under reduced pressure. The following procedure was carried out using the obtained residue which was not purified.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:38])([F:37])[CH2:16][CH2:17][CH2:18][S:19]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:24]=1)(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1([Pd-4](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:38][C:15]([F:14])([F:37])[CH2:16][CH2:17][CH2:18][S:19]([O:22][C:23]1[CH:24]=[CH:25][N:26]=[C:27]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:28]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(CCCC(F)(F)F)Oc1ccnc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: c1ccc([Pd-4](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cc(OS(=O)(=O)CCCC(F)(F)F)ccn2)cc1

Procedure:
42.2 mg (0.24 mmol) of 4-tert-butylbenzeneboronic acid, 90 mg (0.22 mmol) of 2-trifluoromethylsulfonyloxy-4-pyridinyl 4,4,4-trifluoro-1-butanesulfonate (Example 40A), 12.5 mg (0.01 mmol) of tetrakisphenylpalladium(0) and 68.6 mg (0.65 mmol) of sodium carbonate are heated in 5 ml of dioxane at 80° C. under argon for 2 hours. The reaction mixture is cooled, mixed with 0.5 ml of water and filtered through a cartridge packed with 3 g of Extrelut NT3 (Merck) and thoroughly washed with dichloromethane, and the solvent is distilled off under reduced pressure. The residue is purified by preparative HPLC and chromatography on silica gel (toluene).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])[CH:4]=[CH2:5].[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])/[CH:4]=[CH:5]/[C:28]1[CH:27]=[N:26][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:30][CH:29]=1
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Reactant: Brc1ccc(Nc2ccccc2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(Nc2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (from Example 76 (a)) was taken up in propionitrile (50 mL). To this solution was added with stirring 2-phenylamino-5-bromopyridine (1.3 g, 5.2 mmole), DIEA (1.8 mL, 10 mmole), Pd(OAc)2 (112 mg, 05 mmole) and P(o-tol)3 (304 mg, 1.0 mmole). The reaction was purged with argon then stirred at reflux for 16 h. After cooling to room temperature the reaction was concentrated to dryness under vacuum. Flash chromatography on silica gel (5% methanol/CHCl3) followed by a second flash column on silica gel (50-70% EtOAc/CHCl3) left a residue that was triturated with EtOAc/petroleum ether. Filtration and drying under vacuum gave the title compound (1.42 g, 69%) as an off-white powder: MS (ES) m/e 396.20 (M+H)+.
Reaction SMILES: [Li+].[Cl-].P([CH2:11][C:12]#[N:13])(OCC)(OCC)=O.C1CCN2C(=NCCC2)CC1.[C:25]([O:29][C:30](=[O:42])[NH:31][C@H:32]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:33]=O)([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C:25]([O:29][C:30](=[O:42])[NH:31][C@@H:32](/[CH:33]=[CH:11]/[C:12]#[N:13])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](/C=C/C#N)Cc1ccccc1
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
To a stirred suspension of LiCl (1.0 g, 24 mmol) in dry ACN (200 mL) under nitrogen at rt, was added (EtO)2POCH2CN (4.2 g, 24 mmol), DBU (3.0 g, 20 mmol) and compound 31d (5.0 g, 20 mmol). Almost all of the salt soon dissolved and the reaction completed in 1.5 h. The reaction was quenched with citric acid, and the mixture was extracted with EA three times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EAc=5:1) to give compound 31e (4.2 g, 77% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[CH3:1][O:2][C:3]([C@H:4]1[NH:5][C@H:23]([C:22]2[CH:17]=[CH:18][C:19]3[O:27][CH2:26][O:25][C:20]=3[CH:21]=2)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1

Procedure:
The same method but starting from L-tryptophan methyl ester and piperonal gave the cis and trans isomers of the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[O:20]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:21]1
Reactant: O=C(Nc1nc2c(Br)cccn2n1)c1ccccc1
Reactant: OB(O)c1ccoc1
Product: O=C(Nc1nc2c(-c3ccoc3)cccn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure and work up described for example 56 but starting from N-(8-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B9), 159 mg; 0.50 mmol; 1.0 eq.) and furan-3-boronic acid (112 mg; 1.0 mmol; 2.0 eq.) as a white powder (80 mg, 52%). HPLC, Rt: 3.26 min. (purity 99.6%). LC/MS, M+(ESI): 305.0, M−(ESI): 303.1.
Reaction SMILES: [OH:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C1(CC#[N:21])C=CC=CC=1>O1CCOCC1>[OH:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: O=C(Cl)c1cc(I)cc(I)c1O
Reactant: N#CCc1ccccc1
Solvent: C1COCCO1
Product: NC(=O)c1cc(I)cc(I)c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.9 parts of 2-hydroxy-3,5-diiodobenzoyl chloride and 3.7 parts of 4-amino-2-(trifluoromethyl)-α-[3-trifluoromethyl)phenyl]benzeneacetonitrile in 60 parts of 1,4-dioxane is stirred and refluxed for 10 minutes. The reaction mixture is evaporated. The residue is boiled in methylbenzene for 10 minutes. After cooling to room temperature, the precipitated product is filtered off, yielding N-[4-{α-cyano-α-[3-trifluoromethyl)phenyl]methyl-}3-(trifluoromethyl)phenyl]-2-hydroxy-3,5-diiodobenzamide; mp. 206.3° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].BrCC(O)=O.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[C:19]([NH2:24])[N:18]=1.[CH3:25][C:26]([CH3:28])=O>Cl.CO>[NH2:16][C:17]1[N:18]=[C:19]([NH2:24])[C:20]2[CH:28]=[C:26]([CH:8]=[O:9])[CH:25]=[N:23][C:21]=2[N:22]=1
Reactant: Nc1cc(N)nc(N)n1
Reactant: CC(C)=O
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(O)CBr
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(N)c2cc(C=O)cnc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus oxychloride (27.5 ml, 46.0 g, 300 mmol) was added over 15 minutes with stirring to N,N-dimethylformamide (11.0 g, 150 mmol), which was cooled with an ice bath. After stirring at room temperature for 1 hour, the reaction mixture was treated with bromoacetic acid (13.9 g, 100 mmol). The resulting solution, protected by a calcium chloride tube was heated at 92° C. for 10 hours and evaporated to dryness in vacuo. The colored oil (~30 g) was dissolved in water (1000 ml), and the solution was neutralized with 50% sodium hydroxide to pH 7. After addition of 2,4,6-triaminopyrimidine (5.00 g, 40.0 mmol), the solution was refluxed for 3 hours and filtered hot through a fluted filter. The filtrate was cooled and the solid that precipitated was collected by filtration and dried in vacuo over P2O5 : yield, 2.53 g (33%). Mass spectrum, m/e 189 (M+). HPLC [ 0.1 M NH4OAc (pH 3.6) --CH3OH (9:1)] indicated that this product was 86% pure. A sample (200 mg) was dissolved in 0.1 N HCl (15 ml) and diluted with acetone (225 ml) to precipitate impure III: yield, 91 mg. The filtrate was evaporated to dryness under reduced pressure and the residue was dried in vacuo over P2O5 to give compound III: yield, 128 mg; mp, gradual darkening and decomposition with white sublimate when taken to 360° C. λmax nm (ε×10-3): 0.1 N HCl --258 (16.4), 317 (9.12), 326 sh (8.42); pH 7-263 (15.0), 316 (10.1), 345 (10.8); 0.1 N NaOH --254 (13.2), 267 (13.5), 3.16 (8.56), 347 (10.0). 1H-NMR (CF3CO2D, 6% w/v), 9.48 s, 9.75 s (5 --CH, 7 -- CH), 10.21 s (6 --CHO).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:17][N:18]([C:20]3[N:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O([CH2:42][C:43]([F:46])([F:45])[F:44])S(C(F)(F)F)(=O)=O>>[C:1]([O:5][C:6]([N:8]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:17][N:18]([C:20]3[N:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc(Cl)nn3)nc2-c2ccc(F)cc2)ccn1
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2cn(-c3ccc(Cl)nn3)nc2-c2ccc(F)cc2)ccn1
Yield: 52.4 %

Procedure:
The reaction was carried out in the same manner as in Example 3-1) except for using 5.60 g (12.0 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-1-(6-chloropyridazin-3-yl)-3-(4-fluorophenyl)-1H-pyrazole obtained by the same reaction as in Example 2-3), and using 4.18 g (18.0 mmol) of 2,2,2-trifluoroethyl triflate in place of methyl iodide to obtain 3.45 g of the title compound as a pale grayish white powder. (Yield: 52%)