Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:27]1(/[CH:33]=[CH:34]/B(O)O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1(/[CH:33]=[CH:34]/[C:2]2[CH:3]=[C:4]([N:8]3[C:12]([CH3:13])=[C:11]([C:14]([N:16]4[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]4)=[O:15])[C:10]([CH3:26])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)/C=C/C1CCCCC1
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(/C=C/C4CCCCC4)c3)c2C)C1
Yield: 40 %

Procedure:
In analogy to the procedure described in Example 14C], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone (Example 30A]) and trans-2-cyclohexylvinylboronic acid gave the title compound in 40% yield as brown gum. MS: 449.3 (MH+).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1=[O:16].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][C:21]=1[S:34]([NH2:37])(=[O:36])=[O:35]>O1CCOCC1>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]2[NH:19][C:3]([C:4]3[C:5](=[O:16])[N:6]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[CH:7]=[CH:8][C:9]=3[OH:10])=[N:37][S:34](=[O:36])(=[O:35])[C:21]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CSC(SC)=C1C(=O)C=CN(CCC(C)C)C1=O
Solvent: C1COCCO1
Product: CC(C)CCn1ccc(O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 457C (2.08 g, 7.29 mmol) was treated with the product of Example 414A (2.00 g, 6.96 mmol) in dioxane (20 mL) at 115° C. for 30 minutes, cooled to 25° C. and concentrated under reduced pressure. A solution of the residue in 4M hydrochloric acid in dioxane (20 mL) was stirred at 25° C. for 18 hours and concentrated under reduced pressure. The residue was triturated with dichloromethane and filtered to give the title compound. The filtrate containing the protected intermediate was concentrated and purified by chromatography on silica gel eluting with 1% methanol in dichloromethane. The protected product was re-subjected to the above deprotection conditions to provide the title compound as its hydrochloride salt (2.02 g, 96%). 1H NMR (300 MHz, DMSO-d6) δ 0.92 (s, 3 H) 0.94 (s, 3 H) 1.58 (m, 3 H) 3.99 (m, 2 H) 6.31 (d, J=7.35 Hz, 1 H) 6.96 (m, 2 H) 7.34 (d, J=8.46 Hz, 1 H) 8.04 (d, J=7.35 Hz, 1 H) 14.04 (s, 1 H) 14.19 (s, 1 H). MS (ESI−) m/z 375 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](F)(F)F)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH2:16].[OH-:17].[Na+]>OS(O)(=O)=O>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)([OH:17])=[O:16]
Reactant: [OH-]
Reactant: O
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc2c(Cl)ccnc2c1

Procedure:
4-Chloro-7-trifluoromethylquinoline (5.0 g, 21.6 mmol) in 100 mL 80% H2SO4 is heated to 200° C. for 24 hours in a sealed tube. The solution is cooled, poured into water and neutralized with sodium hydroxide to pH˜3-4. The precipitated solid is collected, washed with water and dissolved in 2 N sodium hydroxide. The aqueous solution is washed with ethyl acetate then acidified to pH˜3-4. The precipitate is collected, washed with water and dried in a vacuum oven overnight to yield 7-carboxy-4-chloroquinoline as a solid (5.1 g, 24.6 mmol). A portion of this material (2.0 g, 9.6 mmol) is treated with anhydrous THF (200 mL) and DMF (2 mL) and 2 M oxalyl chloride in methylene chloride (14.5 mL, 29 mmol). The resulting suspension is stirred at room temperature for 2 h then treated with methanol (10 mL). After stirring 30 minutes the solution is concentrated and the residue is taken up in methylene chloride. The solution is washed with saturated sodium bicarbonate and dried (sodium sulfate) and concentrated to yield the title compound as a solid (2.1 g, 9.5 mmol). MS m/z: M+=221; 1H NMR (CDCl3, 300 MHz) δ8.6 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.65 (d, 1H), 7.45 (s, 1H), 3.95 (s. 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].C(N(CC)C(C)C)(C)C.[CH2:15]([NH:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[BrH:1].[C:27]1([CH2:26][O:25][CH2:24][CH2:23][N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:2][C:3]([OH:5])=[O:4])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CNCCOCc2ccccc2)cc1
Reactant: O=C(O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Br
Product: O=C(O)CN(CCOCc1ccccc1)Cc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 13.8 g of bromoacetic acid, 200 ml of acetonitrile, 19.0 ml. of N,N-diisopropylethylamine, anmd 26.3 g of N,O-dibenzylethanolamine was heated for 24 hours under reflux. An additional portion of bromoacetic acid (3.5 g) was added, and heating continued for an additional 24 hours. Refrigeration of the resulting mixture caused the precipitation of the title compound as white needles of mp 115°-117° C. after recrystallization from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:12]1)=[O:40]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 68 (175 mg, 0.40 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (110 mg, 0.48 mmol) using Method D to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH:20]([NH:22][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3C1CCCCO1)[CH3:21])=[CH:7]2.C([O-])(O)=O.[Na+]>CO>[N:31]1[C:23]([NH:22][CH:20]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH3:21])=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1
Reactant: Cc1ccccc1-n1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc2cccc(C)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1-n1c(C(C)Nc2ncnc3[nH]cnc23)cc2cccc(C)c2c1=O
Reaction time: 2 h
Yield: 54.1 %

Procedure:
8-Methyl-3-(1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-2-o-tolylisoquinolin-1(2H)-one 4105 (180 mg, 0.36 mmol) was dissolved in MeOH (HCl) (50 mL) and stirred for 2 h. Aqueous NaHCO3 solution was added to the reaction mixture and the pH value was adjusted to 9. The mixture was then filtered and the filtrate was concentrated in vacuo to afford the desired product, 3-(1-(9H-purin-6-ylamino)ethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one 4106 (80 mg, 54% yield) as a yellow solid.
Reaction SMILES: [Cl-].C[N:3]([CH3:14])[CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[N+:7](C)C.Cl.[CH2:16]([N:23]1[CH2:28][CH2:27][N:26](C(N)=N)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:14]2[N:3]=[CH:4][C:5]([C:10]([F:11])([F:12])[F:13])=[CH:6][N:7]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CN(C)C=C(C=[N+](C)C)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of (3-Dimethylamino-2-trifluoromethyl-allylidene)-dimethyl-ammonium chloride ([176214-18-9], 0.60 g) in acetonitrile (10 mL) was added 4-Benzyl-piperazine-1-carboxamidine hydrochloride ([7773-69-5], 0.66 g) and triethylamine (0.87 mL) and the reaction mixture was stirred for 3 hours at room temperature. After such time the reaction mixture was concentrated in vacuo and purified by column chromatography to yield the title compound as a light yellow solid (0.79 g). MS (m/e): 323.4 (M+H+).
Reaction SMILES: IC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[I:34])=[S:45])=[CH:28][C:27]=1[F:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccccc1I
Agent: O=C(N=C=S)c1ccccc1I
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4I)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (86 mg, yield 90%).
Reaction SMILES: C([O:8][CH2:9][C:10](Cl)=[O:11])C1C=CC=CC=1.[C:13]1([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[OH:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Si](Cl)(C(C)C)C(C)C)(C)C.N1C=CN=C1>CN(C)C=O.CCCCC>[OH:11][CH2:10][C:9]([O:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: O=C(Cl)COCc1ccccc1
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C(CO)O[C@@H]1CCCC[C@H]1c1ccccc1
Yield: 95 %

Procedure:
To obtain 1c(-), a solution of (-)-(1R,2S)-2-phenyl-1-cyclohexyl hydroxyacetate (851 mg, 3.63 mmol) was prepared through esterification of benzyloxyacetyl chloride with (-)-(1R,2S)-2-phenyl-1-cyclohexanol followed by hydrogenolysis. Then, triisopropylsilyl chloride (840 mg, 4.36 mmol) and imidazole (618 mg, 9.08 mmol) in dimethylformamide (DMF) (1.7 mL) was stirred at room temperature for 12-20 hours. The mixture was poured into pentane (25 mL), and washed with water and brine. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was subjected to a purification on a short silica gel column using hexane/chloroform (3/1) as the eluant to give pure 1c(-) (1.35 g, 95% yield) as a colorless oil.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.[CH3:13][NH2:14]>>[CH3:13][NH:14][C@@H:11]1[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: CN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A one necked round bottom flask equipped with a stir bar was charged with glucose (40.0 g, 0.22 mole) and 2.0M methylamine (116.5 ml, 0.23 mole). The mixture was stirred overnight at room temperature (20°-21° C.). A sample was taken and analyzed by gas chromatography after acetylation.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[C:11]([N:6]1[C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=4[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=3)=[CH:3][C:4]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:13])[CH3:12]
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCCOc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(C)=O)ncc1Cl
Yield: 60.2 %

Procedure:
1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (97 mg, 0.47 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide (167 mg, 0.494 mmol), and 10-Camphorsulfonic acid (16 mg, 0.070 mmol) in Isopropyl alcohol (4 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was neutralized with MP-carbonate (0.3 mmol) and purified on silica gel (ISCO, 2×12 g, 0-100% EtOAc:Hex) to afford 2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide as a light brown foam (144 mg, 60%). MP=196-199° C.; LCMS: 509 (M+H); 1H-NMR (DMSO): 9.50 (s, 1H), 9.21 (s, 1H), 8.99 (m, 1H), 8.20 (s, 1H), 7.49 (m, 3H), 7.34 (s, 1H), 7.16 (m, 1H), 7.06 (m, 1H), 4.55 (m, 1H), 4.34 (m, 1H), 4.01 (d, 2H, J=2.3 Hz), 3.55 (m, 1H), 3.11 (t, 1H, J=2.3 Hz), 2.62 (m, 1H), 1.95 (m, 1H), 1.72 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[OH:27][C:28]1[C:32]([CH:33]=[O:34])=[CH:31][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:33]([C:32]1[C:28]([O:27][CH2:2][C:3]2[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])[O:12][C:13]=3[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=2)=[N:29][N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=1)=[O:34]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 3-[4-{(4-chloromethyl-2-methoxyphenoxy)methyl}-5-methyl-1,3-oxazol-2-yl]benzonitrile (4.32 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (2.0 g), anhydrous potassium carbonate (1.47 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl)-2-methoxyphenoxy}methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (5.30 g, yield 96%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[NH2:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:27](Cl)(=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[NH:18][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cnccc2N)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccncc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 12.5 %

Procedure:
A solution of N3-(4-tert-butylbenzoyl)-3,4-pyridinediamine (400 mg, 1.49 mmol), pyridine (0.264 mL), and p-anisoyl chloride (0.254 mL, 1.49 mmol) in toluene (12 mL) was heated at reflux for 3 h. The mixture was filtered and the filtrate poured into a mixture of ethyl acetate and water. The organic layer was washed three times with water, once with saturated sodium chloride solution, dried, and filtered. Concentration in vacuo and purification of the residue by recrystallization (methanol/ethyl acetate/hexanes) followed by flash chromatography (silica gel, ethyl acetate/methylene chloride) yielded 75 mg (13%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC([CH:13]=[O:14])=CC=1.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH3:16]>CN(C=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:18]1([C:15]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:13]=[O:14])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccncc1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=CC=C(c1ccccc1)c1ccncc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Pyridine (0.6 g, 7.5 mmol) and Cobalt (ii) acetate (1.3 g, 7.5 mmol) were dissolved in DMF to produce a blue solution of the complex to which was added 4-pyridine carboxaldehyde (5 g, 46.7 mmol) and acetophenone (6.2 g, 51.4 mmol). The resulting mixture was stirred for 18 hours at 90° C. Most of the DMF was evaporated in vacuo and the residue was purified by flash chromatography (silica gel) with 30% EtoAc/Hexane to afford the titled compound, white solid (5 g). ESP+ (Mass Spec) m/z 210 (MH+).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12]CC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:19][O:20][P:21]([CH2:25]C(=O)CC(O[Si](C(C)(C)C)(C)C)CCC)(=[O:24])[O:22][CH3:23]>>[CH3:19][O:20][P:21]([CH2:25][C:10](=[O:12])[CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH2:15][CH2:16][CH2:17][CH3:18])(=[O:24])[O:22][CH3:23]
Reactant: CCCC(CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)CP(=O)(OC)OC
Yield: 61 %

Procedure:
Dimethyl (3-((tert-butyldimethylsilyl)oxy)-2-oxoheptyl)phosphonate 6 (1.56 g) was prepared in 61% yield using compound 5 according to the procedures described for compound 3 (see Schemes 1 and 2).
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([I:10])[C:5]([CH3:11])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>O1CCOCC1>[I:10][C:6]1[C:5]([CH3:11])=[CH:4][N:3]=[C:2]2[NH:13][N:14]=[CH:8][C:7]=12
Reactant: NN
Reactant: Cc1cnc(F)c(C=O)c1I
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc2[nH]ncc2c1I

Procedure:
2-fluoro-4-iodo-5-methyl-pyridine-3-carbaldehyde (510 mg, 1.924 mmol) was dissolved in dry Dioxane (10 mL) and Hydrazine monohydrate (288.9 mg, 280.8 μL, 5.772 mmol) was added in one portion
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.ClC(Cl)(Cl)S(O[CH2:53][C:54]([F:57])([F:56])[F:55])(=O)=O>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:53][C:54]([F:57])([F:56])[F:55]
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1[nH]c(=O)n2CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
100 mg (0.266 mmol) of the compound from example 33 and 73 mg (0.266 mmol) of BEMP were initially charged in 9 ml of dimethylformamide, and a solution of 75 mg (0.266 mmol) of 2,2,2-trifluoroethyl trichloromethanesulfonate in 1 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 60 mg of the title compound were obtained (47% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of ethyl 3-hydroxybenzoate (0.200 g; 1.20 mmol), benzeneboronic acid (0.294 g; 2.41 mmol), copper acetate (0.437 g; 2.41 mmol) and pyridine (0.195 mL; 2.42 mmol) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent 5 to 35% ethyl acetate in heptane) to yield 0.222 g (76%) of the title compound as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:17]([NH2:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C(N([CH2:39][CH3:40])CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:16]([C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[C:17]([NH:19][C:40]2[CH:39]=[CH:4][CH:3]=[CH:2][CH:1]=2)=[O:18])[C:30]([C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[O:31])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(C)C(=O)C(=Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Reactant: O=Cc1ccc(F)cc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Product: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
Step B—A solution of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (2 mmol), 2-(4-benzyloxyphenylmethylene)-4-methyl-3-oxopentanamide (8 mmol), 4-fluorobenzaldehyde (8 mmol) and triethylamine (1 mL) in EtOH (100 mL) is heated at reflux. The progress of the reaction is monitored by tlc. When the reaction is complete, the solvent is removed under reduced pressure and the residue is dissolved in EtOAc. The solution is washed with dilute HCl, then dried and evaporated. The residue is chromatographed to afford 2-[1-(4-benzyloxyphenyl)-2-(4-fluorophenyl)-2-oxoethyl]-4-methyl-3-oxo-N-phenylpentanamide, 14 (R=4-benzyloxy).