Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[C:35](=[O:37])[CH3:36])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(=O)Cl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from example 1 (142 mg) was dissolved in DCM (5 mL) and TEA (0.065 mL) was added. The reaction mixture was cooled to 0° C. Acetyl chloride (0.029 mL) was added and the reaction mixture stirred for 30 min. The solvents were evaporated and the residue was taken up in MeOH and purified by RPHPLC to afford the title compound (40 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)(=[O:22])C.ClC(Cl)C.OO>[Cl-].[Cl-].[Cl-].[Ti+3].O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[O:22])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc(Sc2ccc(C(C)=O)cc2)cc1
Agent: [Ti+3]
Agent: OO
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(S(=O)c2ccc(C(C)=O)cc2)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a 300 mL four-necked flask, 20.0 g (0.107 mole) of diphenyl sulfide and 140.0 g of chlorobenzene were fed, and the resulting mixture was stirred and allowed to dissolve. To the resulting solution, 31.5 g (0.236 mole) of aluminum chloride was added, and the resulting mixture was cooled to 10° C., followed by addition of 17.7 g (0.225 mole) of acetyl chloride dropwise thereto while keeping a temperature of not more than 20° C., and allowing the resulting mixture to react by stirring thereof at 10° C. for 2 hours. The reaction solution was added to a mixture of 1000 g of ice water and 1000 mL of methylene chloride with stirring at a temperature of not more than 30° C. The methylene chloride layer was washed 3 times with 1000 mL of water and concentrated under reduced pressure, followed by addition of 1000 mL of methanol to the resultant, collection of the yielded crystals by filtration and drying thereof to obtain 19.67 g of bis(4-acetylphenyl)sulfide. The yield was 68%. To a 100 mL four-necked flask, 6.22 g (0.023 mole) of bis(4-acetylphenyl)sulfide, 60.0 g of acetic acid and 40 g of dichloroethane were fed, and the resulting mixture was allowed to dissolve under heat. To the resulting solution, 0.18 g (0.001 mole) of 20% aqueous solution of titanium trichloride was added, and 2.07 g (0.018 mole) of 30% aqueous hydrogen peroxide solution was added thereto dropwise, followed by stirring the resulting mixture for 2 hours. To this mixture, 100 mL of water was added, and the resulting mixture was cooled to 10° C., followed by collection of yielded crystals by filtration. These crystals were washed with 30 mL of methanol and collected by filtration, followed by drying thereof to obtain 6.39 g of bis(4-acetylphenyl)sulfoxide. The yield was 97%. By following the same procedure as in Example 1 except that 5.73 g (0.020 mole) of bis(4-acetylphenyl)sulfoxide was used instead of bis(hydroxyphenyl)sulfoxide, the compound No. 8 was obtained. The yielded amount was 3.98 g, and the yield was 26%.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:20][S:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10]CC1(CCC)OCCO1.ClC1C=C[N+]([O-])=C(C)C=1C.[F:42][CH2:43][C:44]1(CO)[O:48][CH2:47][CH2:46][O:45]1>>[Na:1].[F:42][CH2:43][C:44]1([CH2:10][O:9][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:20][S:21]([C:23]3[NH:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)=[O:22])[C:3]=2[CH3:2])[O:48][CH2:47][CH2:46][O:45]1
Reactant: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCO1
Reactant: OCC1(CF)OCCO1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Product: Cc1c(OCC2(CF)OCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 8.2 %

Procedure:
The same procedure as in the steps (3c) to (3h) of Example 3 was repeated using 4-chloro-2,3-dimethylpyridine 1-oxide and (2-(fluoromethyl)-1,3-dioxolan-2-yl)methanol to obtain the title compound (140 mg, 6 steps 8.2%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[CH2:22][C:23]([N:52]=[N+:53]=[N-:54])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(CC(=O)O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CC(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
To 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)butanoic acid (C41) (1.77 g, 4.52 mmol) in toluene (18 mL) was added triethylamine (0.82 mL, 5.88 mol) and diphenyl phosphorazidate (1.05 mL, 4.98 mmol) and the solution was stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was loaded onto a Celite® cartridge and purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent to afford the title compound as a clear oil (0.223 g, 12% yield): 1H NMR is consistent with a mixture of carbonyl azide and isocyanate. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.28-8.03 (m, 2H), 7.88-7.66 (m, 2H), 7.48-7.30 (m, 4H), 3.60-3.40 (m, 2H), 3.08 (q, J=6.9 Hz, 1H), 2.81-2.49 (m, 1H), 1.37 (dd, J=10.4, 7.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 417 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[CH:6][C:7]([CH2:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[S:3])[NH2:2].I[CH3:21]>O1CCCC1>[CH:16]1([C:5]2[C:4]([C:1](=[NH:2])[S:3][CH3:21])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:14][CH3:15])[CH:6]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: CCc1cc(C2CCC2)c(C(N)=S)cc1C(=O)OC
Reactant: CI
Solvent: C1CCOC1
Product: CCc1cc(C2CCC2)c(C(=N)SC)cc1C(=O)OC
Reaction time: 15 h
Yield: 114.2 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate (compound 181.6, 1.50 g, 5.41 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). This was followed by the addition of iodomethane (3.80 g, 26.8 mmol, 5.00 equiv) dropwise with stirring. The resulting solution was stiffed at 25° C. for 15 h, then concentrated in vacuo. This resulted in 1.80 g (97%) of the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25](COCC[Si](C)(C)C)[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CC1>>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[NH:25][C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(-c2ccccc2)c2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CCC4)c3)c(-c3ccccc3)c12
Yield: 84.2 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 145 mg (0.261 mmol) of 2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-3-phenyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 34-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water was added to the obtained concentrate, and the mixture was extracted with ethyl acetate. The organic layer after separation was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained solid was dissolved by adding ethyl acetate, followed by addition of diisopropyl ether and hexane, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain 93 mg of the title compound as a beige solid. (Yield: 84%)
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].C([Li])CCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C.C(OCC)(=O)C>C1COCC1>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[C:3]([CH3:9])=[N:4]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1nn(C)c(C)c1Br
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A solution of 4-bromo-1,3,5-trimethyl-1H-pyrazole (1 g, 5.3 mmol) in anhydrous THF (20 mL) cooled to −78° C. under a nitrogen atmosphere was treated dropwise with n-butyl lithium (4.2 mL, 1.6 M in hexane) and stirred at room temperature for 20 minutes. Then, 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.7 mL, 8.3 mmol) was added dropwise at −78° C. and allowed to warm to ambient temperature overnight. Ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was concentrated and chromatographed on silica gel eluting with 40% ethyl acetate in hexanes to provide the title compound as white crystals (996 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 1.29 (s, 12 H), 2.33 (s, 3 H), 2.37 (s, 3 H), 3.69 (s, 3 H); (DCl/NH3) m/z 237 (M+H)+.
Reaction SMILES: [CH2:1]([CH:11]([C:17]([O:19]CC)=O)[C:12]([O:14]CC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O-]CC.[Na+].[NH2:26][C:27]([NH2:29])=[O:28]>C(O)C>[CH2:1]([CH:11]1[C:12](=[O:14])[NH:29][C:27](=[O:28])[NH:26][C:17]1=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NC(N)=O
Reactant: CCCCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCC1C(=O)NC(=O)NC1=O

Procedure:
To a solution of diethyl decylmalonate of step a) in 40 ml of ethanol are added 2.72 g of sodium ethoxide and then 1.8 g of urea. The reaction mixture is refluxed for 2 hours, then the precipitate is filtered and redissolved in 40 ml of water. The resulting aqueous solution is acidified with 6 N hydrochloric acid. The solid which separates is recovered by filtration and dried under vacuum at 40° C. overnight, to give 2.152 g of the product. m.p. 190° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[CH3:22])=O)(C)(C)C.BrC[CH2:25][CH2:26][CH2:27][C:28]12[CH2:39][CH2:38][CH2:37][C:35]3[C:36]1=[C:31]([CH:32]=[CH:33][CH:34]=3)[NH:30][C:29]2=[O:40].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.Cl>[CH3:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:20][CH3:21])[CH:9]([CH3:22])[N:8]([CH2:6][CH2:25][CH2:26][CH2:27][C:28]13[CH2:39][CH2:38][CH2:37][C:35]4[C:36]1=[C:31]([CH:32]=[CH:33][CH:34]=4)[NH:30][C:29]3=[O:40])[CH2:17][CH2:16]2
Reactant: COc1cc2c(cc1OC)C(C)N(C(=O)OC(C)(C)C)CC2
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1OC)C(C)N(CCCCC13CCCc4cccc(c41)NC3=O)CC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-t-Butoxycarbonyl-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline (190 mg, 0.61 mmol) was dissolved in hydrochloric acid methanol solution (4 ml) and stirred at room temperature for 2.5 hours. The residue obtained by evaporating the solvent from the reaction solution under a reduced pressure was dissolved in anhydrous N,N-dimethylformamide (2 ml), and the solution was mixed with 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indole-2-one (190 mg, 0.61 mmol) and potassium carbonate (250 mg, 1.8 mmol) and stirred at room temperature for 14 hours. The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 200 mg (0.46 mmol, 76% in yield) of the title compound.
Reaction SMILES: CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:22]1([CH3:40])[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH:23]=1.[C:41]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([CH3:53])[C:50](O)=[O:51])=[CH:45][C:44]=1[F:54])#[N:42].C(N(CC)CC)C>>[C:41]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([CH3:53])[C:50]([NH:35][CH2:34][C:33]2[C:28]([C:24]3[CH:23]=[C:22]([CH3:40])[CH:27]=[CH:26][CH:25]=3)=[N:29][C:30]([C:36]([F:37])([F:39])[F:38])=[CH:31][CH:32]=2)=[O:51])=[CH:45][C:44]=1[F:54])#[N:42]
Reactant: CC(C(=O)O)c1ccc(C#N)c(F)c1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)c(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (1.5 equiv), 1-hydroxybenzotriazole (1.5 equiv), and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (1 equiv) are added to a solution of 2-(4-cyano-3-fluorophenyl)propanoic acid (5 equiv) drop-wise triethylamine (2.5 equiv). The reaction mixture is stirred overnight at room temperature. The reaction is quenched with water and extracted with ethyl acetate. The extracted organic layer is dried over magnesium sulfate. After evaporate solvent, purified by column chromatographic purification (ethylacetate:hexane) afforded 2-(4-cyano-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)[N:4]=1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:53]([O:52][C:50]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:32])([F:33])[F:1])=[N:4]2)[CH:10]=1)(=[O:25])=[O:26])=[O:51])[CH2:54][CH2:55][CH3:56]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccc(C(F)(F)F)n3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 3-[3-(3-trifluoromethylpyrazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (43.5 mg, 0.087 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (25.8 mg, 0.174 mmol) and butyl chloroformate (110.7 μL, 0.87 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (40-100% CH3CN in water) to give the title compound in 88% yield, over two steps, (41.6 mg, 0.076 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].Br[CH:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19])=[O:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8])[O:10][CH:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19])=[O:14]
Reactant: Cc1cc(O)cc(C)c1C
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1cc(C)c(C)c(C)c1

Procedure:
In a similar procedure to Example 3 Stage 2, 3,4,5-trimethylphenol was reacted with 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide to give the title product as a colourless gum. 1H NMR (CDCl3) δ: 1.61(6H, s); 1.80(3H, s); 2.11(3H, s); 2.26(6H, s); 3.40(3H, s); 3.82(2H, m); 4.53(1H, t); 6.62(2H, s); 6.66(1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:31][CH:30]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ncnc2cc1OCc1ccccc1
Temperature: 50 °C
Yield: 75.5 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxy-quinazoline (100 mg, 0.333 mmol), K2CO3 (345 mg, 2.49 mmol) and N-(4-hydroxy-phenyl)-benzamide (106 mg, 0.499 mmol) in DMA was heated at 50° C. for 18 hours. The reaction was cooled and partitioned between ice water and EtOAc. The aqueous was extracted twice with EtOAc and the combine organic washed with water, brine, dried and concentrated. The residue was purified by column chromatography (30-100% EtOAc:Heptane) to provide the title compound as a cream solid (120 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17]O>OS(O)(=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(-c2ccccc2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)cc(-c2ccccc2)c1
Yield: 94 %

Procedure:
A solution of 3-methyl-5-phenylbenzoic acid (3.5 g; 16.5 mmol) and concentrated H2SO4 (30 drops) in methanol (25 ml) was heated at reflux overnight. After evaporation to dryness, the residue was extracted with ether. The organic phase was evaporated and purified by flash chromatography eluting with petroleum ether/ethyl acetate (90/10) to give methyl 3-methyl-5-phenylbenzoate as an oil. Yield=94%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[Br-].[CH3:25][C:26]1[N:31]=[C:30]([Zn+])[CH:29]=[CH:28][CH:27]=1.C1COCC1>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]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Cc1cccc([Zn+])n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Yield: 47 %

Procedure:
Using a procedure similar to Example 32, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.60 g, 1.53 mmol) and PdCl2(dppf) (0.056 g, 0.076 mmol) and 0.5 M solution of 6-methyl-2-pyridylzinc bromide in THF (6.0 mL, 3.06 mmol) furnish the title compound (0.29 g, 0.72 mmol, 47%). 1H NMR (CDCl3), δ 0.89 (t, J=7.5 Hz, 6H), 1.73-1.93 (m, 4H), 2.16 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 2.58 (s, 3H), 3.31-3.40 (m, 1H), 6.67 (s, 1H), 7.00 (d, J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 8.56 (t, J=7.7 Hz, 1H). LC/MS (m/z): calcd. for C24H28N4 (M+H)+: 405.7; found: 405.2.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)C>[C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:25][CH:22]([CH3:24])[CH3:23])#[N:2]
Reactant: CCCCCC(=O)Nc1ccc(OCC2CO2)c(C#N)c1
Reactant: CC(C)N
Solvent: CCO
Product: CCCCCC(=O)Nc1ccc(OCC(O)CNC(C)C)c(C#N)c1

Procedure:
Ten grams (0.035 mol) of 1-(2-cyano-4-hexanoylamino-phenoxy)-2,3-epoxypropane were dissolved in 100 ml of ethanol and, after the addition of 8.3 gm (0.14 mol) of isopropylamine, the mixture was refluxed for one hour. The solvent was evaporated in vacuo, and the remaining residue solidified. It was recrystallized twice from acetonitrile. The white crystalline base was recovered by suction filtration and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].[O-]CC.[Na+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(CC#N)ccc1F
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(C#N)=Cc2ccccc2)ccc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 4-fluoro-3-methoxyphenylacetonitrile (10.8 g, 65.4 mmol) in 200 ml EtOH was added a sodium ethoxide 21% solution in EtOH (26.9 ml, 71.9 mmol). Benzaldehyde was added (6.64 ml, 65.4 mmol) and stirred at room temperature over night. The white precipitate was filtered and washed with diethylether and dried to obtain 14.23 g of pale yellow crystals (86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25]S(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH3:33][CH:34](O)[CH3:35]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][CH:34]([CH3:35])[CH3:33])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Reactant: CC(C)O
Product: CCOC(=O)c1c(OC(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C) and propan-2-ol. Off white solid. LC-MS (ESI): 418 (M+H)+.