Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27](OCC)=O)[CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]2[NH:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:11]=2)[CH:22]=1)#[N:20]
Reactant: CCOC(=O)c1cc(C#N)ccn1
Reactant: NCC(N)(c1ccc(F)cc1)c1ccc(F)cc1
Product: N#Cc1ccnc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)CN2)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The mixture of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine(153 mg) and 4-cyano-2-ethoxycarbonylpyridine(95 mg) was stirred at 180° C. for 2 hours. The obtained oily compound was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=3:2) to give the objective compound (103 mg).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][CH3:21])=[O:18])=[O:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
Magnesium chloride (221 mmol) and triethylamine (752 mmol) were added to a solution of diethyl malonate (375 mmol) in toluene (250 ml) and the reaction mixture was maintained for 1 h at 25° C. A solution of 2-chloronicotinoyl chloride (313 mmol) in toluene (80 mL) was added dropwise over the course of 2 h. The reaction mixture was maintained at rt for 3.5 h and was quenched with cold (0° C.) water (500 mL). The resulting solution was extracted with ethyl acetate (500 mL) and the organic layers combined. The organic layer was washed with brine (3×300 mL), dried (sodium sulfate), and was concentrated to provide diethyl 2-(2-chloronicotinoyl)malonate in 85% yield as a brown oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH:13]=[CH2:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:15].[Na+].OO.[Cl-].[Na+]>O1CCCC1.C(O)C>[Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: C=CC1CC1CO[Si](C)(C)C(C)(C)C
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC1CC1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-vinylcyclopropylmethyl t-butyldimethylsilyl ether (17.1 g, 81 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to 0° C. A borane-dimethylsulfide complex (2.5 g, 33 mmol) was added thereto, and the mixture was stirred for one hour. Ethanol (38 ml), 3N sodium hydroxide (38 ml) and 30% hydrogen peroxide (18.2 ml) were added thereto, and the mixture was stirred for 30 minutes. The saturated sodium chloride aqueous solution was added thereto, and the product was extracted with ethyl acetate, then dried over anhydrous magnesium sulfate and concentrated. Then, it was purified by silica gel column chromatography to obtain 2-(2-hydroxyethyl)cyclopropylmethyl t-butyldimethylsilyl ether (15.0 g, yield: 81%).
Reaction SMILES: Cl.C(OCC)(=O)C.[C:8]12([NH:18][C:19](=[O:32])[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23][CH3:24])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[C:8]12([NH:18][C:19](=[O:32])[CH2:20][NH:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2
Reactant: CCCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCNCC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
Next, a 4 N solution of hydrogen chloride in ethyl acetate (55 ml, 0.22 mol) was added to 2-[N′-(t-butoxycarbonyl)-N′-propylamino]acetic acid N-(1-adamantyl)amide (7.68 g, 21.9 mmol), and the mixture was stirred at room temperature for one hour. The resulting crystals were filtered off with ethyl acetate and washed with ethyl acetate to give 5.97 g (95%) of the titled compound as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH2:36])(=[O:35])=[O:34]>C1C=CC=CC=1>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33](=[O:35])(=[O:34])[NH2:36])=[O:14])=[CH:18][CH:19]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
A benzene (30 ml) solution containing 4.00 g (14.1 mmol) of 3-(4-trifluoromethylbenzyloxy)benzoic acid and 3 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.66 g (15.4 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 5.10 g (yield: 80.0%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([NH:30][CH:31]=[O:32])[CH:29]=1)[NH:26][C:25](=[O:33])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:33])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[CH:29][C:28]=4[NH:30][CH:31]=[O:32])=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: O=CNc1cc(F)cc2c1NC(=O)C2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3c(NC=O)cc(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 79 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide 20c obtained from step 3 of Example 20 as starting materials to obtain (Z)—N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide 26 (71 mg, yield 79%) as a red solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH:24]1([C:30]#[CH:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]#[C:31][C:2]2[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)nc1
Reactant: C#CC1CCCCC1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(C#CC2CCCCC2)nc1
Yield: 25 %

Procedure:
The title compound was synthesized as described for Example 179 a) in 25% yield, starting from 2-(2-(6-bromopyridin-3-yl)ethylsulfonamido)benzenesulfonamide and cyclohexylacetylene. Purification by column chromatography using a gradient of 10-60% ethyl acetate in heptane as the eluent.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH:8]=1.[CH3:38][NH2:39].C(O)C>O1CCCC1>[CH3:38][NH:39][CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:37])([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH:8]=1
Reactant: CN
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c1cccc(OCC=CCBr)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CNCC=CCOc1cccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1-bromo-4-[3-(perfluoro-n-octyl)phenoxy]but-2-ene (12.9 g) in tetrahydrofuran (20 mL) is added to a solution of 40 wt % methyl amine (20 mL), ethanol (20 mL) and tetrahydrofuran (20 mL) at 40° C. The mixture is stirred at ambient temperature for 2 hr. and extracted in the normal fashion. The resulting oil is Kugelrohr distilled to give N-methyl-4-[3-(perfluoro-n-octyl)phenoxy]but-2-enamine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[C:8]([CH2:13][C:14]1[N:18]3[N:19]=[C:20]([CH2:23][CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=1)=[C:7]([F:25])[CH:6]=2.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([CH2:13][C:8]3[C:9]([F:12])=[C:10]4[C:5](=[CH:6][C:7]=3[F:25])[N:4]=[CH:3][C:2]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)=[CH:11]4)=[N:15][N:16]=2)[N:19]=1)[CH3:24]
Reactant: CCc1ccc2nnc(Cc3c(F)cc4ncc(Br)cc4c3F)n2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCc1ccc2nnc(Cc3c(F)cc4ncc(-c5cnn(C)c5)cc4c3F)n2n1
Yield: 64.1 %

Procedure:
To a mixture of 3-bromo-6-(6-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (86 mg, 0.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.21 mmol, 44 mg) and cesium carbonate (0.6 mmol<195 mg) in 1,4-dioxane (2 mL) at reflux was added [2-[(D-N)methyl]phenyl-c](tricyclohexylphosphine)trifluoroacetato-O-(SP-4-3)-palladium (Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22, 987) (0.5 mol %, 0.1 μmol, 0.1 mg). After 30 min the reaction mixture was filtered through a pad of silica gel (2 g) eluting with dichloromethane/methanol (17/3, 12 mL). The filtrate was concentrated onto silica gel and purified via flash column chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound as an off white solid (52 mg, 60% yield). Analytical data presented in Table 2.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:25]=[C:24]([CH3:26])[C:17]([O:18][CH2:19][CH:20]([OH:23])[CH2:21]O)=[C:16]([CH2:27][CH3:28])[CH:15]=3)[N:10]=2)[CH:6]=[C:5]([CH2:29][CH3:30])[N:4]=1.CC[N:34](C(C)C)C(C)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N>C1COCC1.CO>[NH2:34][CH2:21][CH:20]([OH:23])[CH2:19][O:18][C:17]1[C:24]([CH3:26])=[CH:25][C:14]([C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH2:29][CH3:30])[N:4]=[C:3]([N:2]([CH3:31])[CH3:1])[CH:8]=3)[O:13][N:12]=2)=[CH:15][C:16]=1[CH2:27][CH3:28]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(CC)c3)no2)cc(N(C)C)n1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(CC)c3)no2)cc(N(C)C)n1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of rac-3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol (78 mg, 0.183 mmol) and DIPEA (47 mg, 0.365 mmol) in THF (5 mL) is added methanesulfonylchloride (23 mg, 0.201 mmol) at 0° C. The mixture is stirred at 0° C. for 3 h (Mesylate: LC-MS: tR=0.88 min; [M+1]+=505.12) before it is added to 7 N NH3 in methanol (10 mL). The mixture is stirred at 65° C. for 16 h. The solvent is removed in vacuo and the crude product is purified on prep. TLC plates with DCM containing 5% of methanol and 10% of 7 N NH3 in methanol to give rac-1-amino-3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phen-oxy}-propan-2-ol as a yellow resin. This material is dissolved in DCM and to the solution glycolic acid (29 mg, 0.375 mmol) and DIPEA (70 mg, 0.540 mmol) is added. The mixture is cooled to 0° C. before TBTU (71 mg, 0.221 mmol) is added. The mixture is stirred at 0° C. for 1 h before it is diluted with EA (100 mL), washed twice with sat. aq. NaHCO3-solution (25 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 7:3 to give rac-N-(3-{4-[5-(2-dimethylamino-6-ethyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (32 mg) as a yellow resin; LC-MS: tR=0.76 min; [M+1]+=484.19.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C:25]5([CH2:31][CH2:30][NH:29][CH2:28]5)[CH2:24]4)=[C:19]([F:32])[CH:18]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C:25]5([CH2:31][CH2:30][N:29]([CH2:33][C:34]([OH:35])([CH3:37])[CH3:36])[CH2:28]5)[CH2:24]4)=[C:19]([F:32])[CH:18]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: O=c1c2ccc(OCC3CC3)cc2ccn1-c1ccc(N2CCC3(CCNC3)C2)c(F)c1
Product: CC(C)(O)CN1CCC2(CCN(c3ccc(-n4ccc5cc(OCC6CC6)ccc5c4=O)cc3F)C2)C1

Procedure:
According to Method U, 6-cyclopropylmethoxy-2-[4-(2,7-diaza-spiro[4.4]non-2-yl)-3-fluorophenyl]-2H-isoquinolin-1-one was reacted with 2,2-dimethyl-oxirane. In this way the product was obtained with molecular weight 505.64 (C30H36FN3O3); MS (ESI): 506 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1>N1C=CC=CC=1>[C:1]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[CH:10]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Oc1cccc(Br)c1
Solvent: c1ccncc1
Product: CCCCC(=O)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pentanoyl chloride (12.7 g) was added dropwise to 3-bromophenol (9.0 g) in pyridine (50 ml), and the reaction mixture was stirred at room temperature for 1 hour. Work-up as described in Example 12 gave 3-bromophenyl pentanoate.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:16])([F:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([CH3:36])[N:34]=[C:33]([C:37]3[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:44])[N:32]=2)=[CH:27][C:26]=1[Cl:45]>O>[Cl:44][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]=1[C:33]1[N:32]=[C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][O:14][C:11]3[CH:10]=[CH:9][C:8]([C:7]([F:15])([F:16])[F:6])=[CH:13][CH:12]=3)=[C:26]([Cl:45])[CH:27]=2)[N:35]([CH3:36])[N:34]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 4-trifluoromethyl phenol (0.77 g) and potassium carbonate (0.72 g) and 5-(4-bromomethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (1.60 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.50 g of desired compound (refractive index: 1.5961).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=O)[CH3:13].[O-]CC.[Na+]>C(O)C.CCOCC>[C:15]([C:16]1[O:11][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[C:8](=[O:9])[CH:10]=1)([O:14][CH2:12][CH3:13])=[O:21]
Reactant: CC(=O)c1ccc(C)cc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cc(=O)c2ccc(C)cc2o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of 10.7 g (71.25 mmoles) of 2-hydroxy-4-methylacetophenone and 31.24 g (214 mmoles) of diethyloxalate in 25 ml of ethanol is added dropwise to a solution of sodium ethoxide (formed by adding 6.55 g of sodium metal to 120 ml of ethanol). The mixture is refluxed for 4 hours, cooled to 0° C. and diluted with 500 ml of ether. The precipitate which forms on standing overnight is filtered off and redissolved in water and the solution acidified (pH approximately 1) with 1 N hydrochloric acid. The mixture is extracted with ethyl acetate which is dried and concentrated in vacuo. The residue is dissolved in 100 ml of ethanol and 3 ml of concentrated hydrochloric acid. This solution is refluxed for 1.5 hours, then concentrated in vacuo. The residue is poured into ice water and the precipitate which formed on standing overnight is filtered off and dissolved in ethyl acetate. The ethyl acetate solution is dried and concentrated in vacuo. The residue is purified by flash column chromatography through silica gel and recrystallization from ether/hexanes to give 8.75 g of 2-carboethoxy-7-methyl-4-oxo-4H-1-benzopyran as a white crystalline solid having an m.p. of 62°-4° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:15]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:13]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:44])[CH:42]=[CH2:43]>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:41](=[O:44])[CH:42]=[CH2:43])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:17]=1
Reactant: C=CC(=O)Cl
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(OCCO)cc3O)n2)c(C)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCOc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Temperature: 27.5 °C
Yield: 88.8 %

Procedure:
22.1 g (0.05 mol) of 2-(2-hydroxy-4-hydroxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine (prepared as described in U.S. Pat. No. 3,244,708, Example 18), are dissolved in 300 ml of tetrahydrofurane at 40° C. and 21 ml (0.15 mol) of triethylamine are added. A solution of 5.05 ml (0.053 mol) of acrylic acid chloride in 20 ml THF is added dropwise with stirring and with cooling the reaction mixture to 25-30° C. After further stirring of two hours the precipitated ammonium salt is filtered off, the filtrate is evaporated and the residue recrystallized from toluene-hexane mixture to obtain 22 g (88.7% yield) of 2-(2-hydroxy-4-acryloyloxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine as slightly yellow crystals (compound No. 25), m.p. 128-129° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:14][C:15]1[C:22]([F:23])=[C:21]([C:24]([F:27])([F:26])[F:25])[C:20]([F:28])=[C:19]([F:29])[C:16]=1[CH2:17]Br>>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:17][C:16]2[C:19]([F:29])=[C:20]([F:28])[C:21]([C:24]([F:25])([F:27])[F:26])=[C:22]([F:23])[C:15]=2[F:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1[N+](=O)[O-]
Yield: 64.4 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-nitrobenzoic acid (1.03 g, 5.65 mmole) and 2,3,5,6-tetrafluoro-4-trifloromethylbenzyl bromide (1.01 g, 6.04 mmole)(ACROS, 33074-0010), 1.50 g (76.3% yield) of 2-nitro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22]>ClCCl>[F:19][C:20]([F:26])([F:25])[S:21]([O:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)c1ncccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-hydroxypyridine-2-carboxylate (80 g, 523 mmol) in anhydrous dichloromethane (250 ml) was added triethylamine (58.2 g, 575 mmol). The solution was cooled to 0° C., and trifluoromethanesulfonyl chloride (97 g, 575 mmol) was added dropwise. The reaction suspension was allowed to stir at 0° C. for 1 h, and it was then warmed to rt to stir for 4 h. The solid triethylammonium chloride was removed via filtration, and the filtrate was concentrated in vacuo to yield methyl 3-{[(trifluoromethyl)sulfonyl]oxy}pyridine-2-carboxylate as an oily residue (148.6 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[C:21]4[C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=4[CH2:19][CH2:18][C@H:17]([NH:32][C:33](=[O:35])[CH3:34])[C:16]=3[CH:36]=2)=[O:10])=[CH:5][CH:4]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[O:40]1[CH2:41][CH2:42][N:37]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]4[C:21]5[C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=5[CH2:19][CH2:18][C@H:17]([NH:32][C:33](=[O:35])[CH3:34])[C:16]=4[CH:36]=3)=[O:10])=[CH:5][CH:4]=2)[CH2:38][CH2:39]1
Reactant: C1COCCN1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)c3ccc(CCl)cc3)cc1[C@@H](NC(C)=O)CC2
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)c3ccc(CN4CCOCC4)cc3)cc1[C@@H](NC(C)=O)CC2
Yield: 86 %

Procedure:
Using an analogous procedure to that described for Example 16, N-[(5S)-3-(4-chloromethylphenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide was reacted with morpholine to give N-[(5S)-3-(4-{morpholinomethyl}phenylcarbonyloxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:19])=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cn(-c2ccc(C(=O)O)cc2)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cn(-c2ccc(C(=O)Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.3 %

Procedure:
To a suspension of 4-(4-methylimidazol-1-yl)benzoic acid (0.80 g) in dichloromethane (25 ml) was added oxalyl chloride (0.50 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure to yield 4-(4-methylimidazol-1-yl)benzoyl chloride (1.02 g), which was utilized without further purification.