Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[C:16]([O:34][CH3:35])[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:37]1C=C(S(Cl)(=O)=O)C=C[C:42]=1Cl>>[CH2:37]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[C:16]([O:34][CH3:35])[CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:42]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1CCN2S(=O)(=O)c1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3,4-Dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 539.27 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 3,4-dichloro-benzenesulfonyl chloride and yielded 4-{[1-(3,4-dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11]/[C:12]/2=[CH:15]\[C:16](Cl)=[O:17])=[CH:7][CH:6]=1>ClCCl.C(OCC)(=O)C>[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11]/[C:12]/2=[CH:15]\[C:16]([N:2]([CH3:3])[CH3:1])=[O:17])=[CH:7][CH:6]=1
Reactant: O=C(Cl)/C=C1\CCCc2ccc(F)cc21
Reactant: CNC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
Dimethylamine (3 ml, 0.045 mol, Kodak) was added to a chilled (ice bath) solution of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl chloride (2.3 g, 0.010 mol) in dichloromethane (35 ml). The reaction was warmed to 25° C. and stirred for 1.5 h. The volatiles were removed by spin evaporation in vacuo to give a beige residue. This residue was dissolved in ethyl acetate (200 ml), washed with deionized water (50 ml), and the organic layer was concentrated by spin evaporation in vacuo. The residue was chromatographed on Silica Gel 60 using a step gradient from ethyl acetate-hexanes/1:5 to ethyl acetate. Fractions containing (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide were combined and concentrated by spin evaporation in vacuo to a white solid. Recrystallization from dichloromethane-hexanes gave 1.62 g (70%) of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide as a white crystalline solid; m.p., 66°-70° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[N:11]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(=O)OC(C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:12]2[N:13]=[C:14]([O:16][CH2:17][C:18]([F:20])([F:21])[F:19])[N:15]=[C:10]([NH:9][C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]3)[N:11]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(Nc2nc(Nc3ccc(C(=O)NCCCCN)cc3)nc(OCC(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 4-(4-(1-(ethoxycarbonyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (100 mg) in DMF (5 mL) was added tert-butyl 4-aminobutylcarbamate (64.0 mg), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (109 mg) and iPr2NEt (0.119 mL). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. The residue was dissolved in dichloromethane (5.00 mL) and 2 mL of TFA. The mixture was stirred at r.t. for 3 hours. All solvents were removed under vacuum and the residue was purified by prep. HPLC to give ethyl 1-(4-(4-(4-aminobutylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropanecarboxylate (80 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:20])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: C1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added piperidine (0.13 ml, 1.29 mmol) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (113 mg, 46% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H29Cl N2 O2, 376.9, found, 377.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47 (d, J=2.1 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.34 (dd, J=7.9, 1.7 Hz, 1H), 3.70 (s, 2H), 3.54-3.48 (m, 2H), 3.32-3.26 (m, 2H), 3.02-2.93 (m, 1H), 2.75-2.67 (m, 2H), 2.65-2.51 (m, 6H), 1.78-1.71 (m, 4H), 1.63-1.44 (m, 6H); 100 MHz 13C NMR (CDCl3) δ 173.5, 146.3, 135.4, 133.9, 130.8, 126.5, 123.7, 72.9, 56.7, 54.3, 46.8, 43.5, 41.0, 28.4, 26.8, 25.8, 24.7, 23.7.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:15](OC)=[O:16])[C:8](=[CH:13][CH:14]=1)[C:9](OC)=[O:10])[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH2:9][OH:10])=[C:7]([CH2:15][OH:16])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OC)c(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1ccc(CO)c(CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl 4-(allyloxy)phthalate [prepared according to Inouye, M.; Tsuchiya, K.; Kitao, T. Angew. Chem. 1992, 104, 198–200 (See also Angew. Chem., Int. Ed. Engl., 1992, 204–205)] (9.9 g, 38 mmol) was dissolved in THF (40 mL) and cooled to 0° C. before the dropwise addition of lithium aluminium hydride (1M in THF, 77 mL, 77 mmol) over 10 min. The mixture was then allowed to stir at room temperature for 3 h before being quenched cautiously by the addition of water (1.4 mL) followed by 2M NaOH (1.4 mL). Excess MgSO4 was then added followed by water until a granular precipitate formed (ca. 5 mL). The mixture was then filtered and evaporated to a brown oil (7.1 g, ca. 95%). 1H NMR showed the material to be of ca. 85% purity. It was used directly in the next stage without further purification; δH (CDCl3, 400 MHz) 2.63 (1H, brs), 2.91 (1H, brs), 4.52 (2H, m), 4.67 (4H, m), 5.26 (1H, dd), 5.38 (1H, dd), 5.97–6.09 (1H, m), 6.80 (1H, dd), 6.92 (1H, d), 7.22 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:31]=[CH:30][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>>[C:35]([CH2:34][CH2:33][S:32][CH:22]1[C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:30]=[CH:31][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:37])=[O:36]
Reactant: O=C(O)CCS
Reactant: COc1ccc2c(c1)COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2O
Product: COc1ccc2c(c1)COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-hydroxy-8-methoxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.Cl>C(#N)C>[C:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:10][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2CNC(C)(C)C)CC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CC#N
Product: CN1CCN(c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2CNC(C)(C)C)CC1
Yield: 47.3 %

Procedure:
3-[(tert-butylamino)methyl]-4-(4-methylpiperazin-1-yl)aniline (60 mg, 0.22 mmol) and 4,7-dichloroquinoline (43 mg, 1 eq) were refluxed overnight in 10 mL of acetonitrile with 0.43 mL of HCl 1M. The reaction mixture was then evaporated and purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH/18/210.1) to yield expected compound as a pale yellow solid (45 mg, 47% yield). m/z (ESI) 438.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:15])C=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].I([O-])(=O)(=O)=O.[Na+]>O.C(OCC)C>[OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[O:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(CC(=O)C=O)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(O)c1ccc(CC=O)cc1
Reaction time: 2 h

Procedure:
A biphasic mixture of 3-[4-(1-hydroxy-1-methylethyl)phenyl]propane-1,2-dial (5.44 g, 25.9 mmol) in water (85 mL) and diethyl ether (170 mL) was charged with sodium periodate (11.07 g, 51.7 mmol) and stirred vigorously for two hours. The reaction mixture was then partitioned between diethyl ether (50 mL) and saturated aqueous sodium thiosulfate (50 mL), and the layers were separated. The aqueous layer was extracted with diethyl ether (2×100 mL), and the combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated. To remove water left over, the concentrated material was dissolved in dichloromethane (70 mL), washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: O[CH2:2][C@H:3]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Li+]>C1COCC1>[CH:18]1[C:13]([C@H:3]2[CH2:2][O:12][C:6]3[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=3[CH2:4]2)=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=1
Reactant: OC[C@@H](Cc1ccc(O)cc1O)c1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1ccc([C@H]2COc3cc(O)ccc3C2)cc1
Temperature: 25 °C

Procedure:
To a mixture of alcohol of formula (9) (50 g) and triphenyl phosphine (151 g) in THF (2.5 L) diisopropyl azodicarboxylate (116.5 g) in THF (500 mL) was added at 15-20° C. and maintained at that temperature for 1-2 hours. About 5% lithium hydroxide solution (1000 mL) was added into the reaction mass and extracted with MTBE (3×750 mL) to remove the organic impurities. The pH of the aqueous layer was adjusted to 1-4 by dilute hydrochloric acid (250 mL). The reaction mass was maintained at RT for 5-6 hours and the product was filtered off. The crude product was taken with IPA (7.5 vol) and added water (22.5 vol). The reaction mass was then maintained at RT for 12-14 hours. The solid was filtered and dried at 50-55° C. for 10-12 hours to afford the title compound.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:8]2[C:9](=[O:11])[CH:10]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:16][C:15]1[C:7]2=[N:6][C:5](/[CH:4]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][C:9](=[O:11])[N:8]2[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(=O)n2cccc(C)c2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccn2c(=O)cc(/C=C/c3ccccc3)nc12
Yield: 26.6 %

Procedure:
To a solution of 1.1g of sodium methoxide and 25ml of absolute methanol is added 1.1g of 2,9-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one, followed by 2.2g of benzaldehyde. The mixture is heated and stirred under reflux for 15 hours and concentrated on a rotary evaporator in vacuo at 45°C. The residual material is distributed between 100ml of chloroform and 50ml of water. The two solutions are separated and the chloroform solution is washed with saturated aqueous sodium chloride, dried, filtered, and the filtrate concentrated. The residual material is recrystallized from 100ml of cyclohexane to yield 0.44g of the title compound, melting point 150°-152°C.
Reaction SMILES: CCCCCC.C([Li])CCC.[C:12]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[N:21]=[C:20]([C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)[N:19]=2)=[CH:14][CH:13]=1.Br[C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)=[N:54][CH:55]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[C:12]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[N:21]=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([C:50]4[CH:51]=[CH:52][C:53]([C:56]5[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=5)=[N:54][CH:55]=4)=[CH:38][CH:37]=3)[N:19]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Reactant: Brc1ccc(-c2ccncc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2ccc(-c3nc(-c4ccc(-c5ccccc5)cc4)nc(-c4ccc(-c5ccc(-c6ccncc6)nc5)cc4)n3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
Under a stream of argon, 2.2 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 60 ml of tetrahydrofuran cooled to −78° C. in which 1.62 g of 2,4-bis(4-biphenylyl)-6-(4-bromophenyl)-1,3,5-triazine obtained in Reference Example 3 had been dissolved. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 30 ml portion of tetrahydrofuran prepared by dissolving 0.71 g of 5-bromo-2,4′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=1:1) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 5-{4-[4,6-bis(4-biphenylyl)-1,3,5-triazin-2-yl]phenyl}-2,4′-bipyridyl (1.00 g, yield 54%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:13].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][C:2](=[O:13])[N:3]([CH2:21][CH2:22][CH2:23][Cl:24])[C:4]1=[O:12]
Reactant: O=C1Cc2ccccc2CC(=O)N1
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2CC(=O)N1CCCCl

Procedure:
A quantity of 3.5 gm (0.020 mol) of 1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione is suspended in 30 ml of dimethylformamide and mixed with 2.5 gm of potassium tert.butoxide with stirring. After ten minutes, the solution obtained is added dropwise to 3.5 ml of 1-bromo-3-chloropropane in 20 ml of dimethylformamide while being cooled with ice. After one hour the mixture is poured onto ice water. A short time later the greasy precipitate crystallizes. The precipitate is subjected to suction filtration, dissolved in acetone, precipitated again with water, suction filtered, and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH2:11][C:10]([C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=3)([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=2)[O:4][C:3]=1[CH:25]=O.[CH:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH2:11][C:10]([C:16]3[CH:17]=[C:18]([Cl:24])[C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=3)([C:12]([F:14])([F:13])[F:15])[O:9][N:8]=2)[O:4][C:3]=1[CH2:25][NH:32][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: NC(=O)C1CC1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1C=O
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1CNC(=O)C1CC1
Temperature: 110 °C
Yield: 78.3 %

Procedure:
A mixture of 3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-carbaldehyde (100 mg), cyclopropanecarboxamide (61 mg), trifluoroacetic acid (54 μl) and triethylsilane (112 μl) in toluene (2 ml) is refluxed at 110° C. After 4 hours 30 minutes the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield cyclopropanecarboxylic acid {3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-ylmethyl}-amide (91 mg, compound 3.1 in Table 3) as a white solid. MS (HPLC/MS): 495 (MH+). Retention time: 2.08 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[CH3:25][O:26][CH2:27][CH2:28][CH:29]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:29][CH2:28][CH2:27][O:26][CH3:25]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: COCCC=O
Product: COCCC=NOCCC1=C(C)/C(=C/c2ccc(SC)cc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-methoxypropanal by the method of Example 1.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Br[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>C1COCC1>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][CH2:33][C:19]([C:20]#[N:21])([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH3:39]
Reactant: N#CC(CCCOC1CCOCC1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C#N)(CCCOC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Potassium hexamethyldisilazide (0.5 M in toluene, 285 mL, 0.143 mol) was added dropwise to a solution of (4) (39 g, 0.119 mol) in THF (240 mL) under nitrogen and stirred at room temperature for 1 hour. A solution of ethyl 3-bromopropionate (22.8 mL, 0.178 mol, 1.5 eq) in THF (45 mL) was added to the reaction mixture all at once. After stirring at room temperature for 4 hours, the reaction was quenched with saturated NH4Cl solution (20 mL). The organic solution was dried over MgSO4, and solvent is evaporated. The crude oil was purified by flashed chromatography (hexane-AcOEt/8:1) to give light yellow oil (48.03 g, 94.4% yield).
Reaction SMILES: O([CH2:9][CH2:10][O:11][CH3:12])S(C(F)(F)F)(=O)=O.COCCO.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:40]2[CH:44]=[C:43]([C:45](=[O:47])[CH3:46])[N:42]=[C:41]2[CH3:48])C=CC=CC=1>C(Cl)Cl>[CH3:12][O:11][CH2:10][CH2:9][N:42]1[C:43]([C:45](=[O:47])[CH3:46])=[CH:44][N:40]=[C:41]1[CH3:48]
Reactant: COCCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: COCCO
Product: COCCn1c(C(C)=O)cnc1C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 2-methoxyethyl triflate (prepared on a 6 mmole scale from 2-methoxyethanol and trifluoromethanesulphonic anhydride by the method published in Synthesis 1982 85) in DCM (20 ml) was added dropwise to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 1.5 g, 4 mmol) in DCM (5 ml) and the mixture was stirred for 40 hours at ambient temperature. The volatiles were removed by evaporation to give a solid (2.4 g) which was purified by flash chromatography on silica gel eluting with DCM/MeOH (100:0 increasing in polarity to 95:5) to yield the title compound (660 mg, 88%) as a solid NMR (CDCl3) 1.31 (s, 3H), 1.49 (s, 3H), 2.02 (s, 3H), 2.43 (m, 2H), 3.31 (m, 2H), 6.87 (s, 1H); m/z 183.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([O:18][CH3:19])(=[O:17])[CH2:12][CH2:13][C:14]([O-])=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]([NH:9][NH:10][C:14](=[O:15])[CH2:13][CH2:12][C:11]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)[O-]
Reactant: NNC(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
The mixture of benzhydrazide (1.5 g, 11.0 mmol), butanedioic acid, monomethyl ester (2.0 g, 15 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.4 g, 12 mmol), N,N-diisopropylethylamine (3.8 mL, 22 mmol) and 4-dimethylaminopyridine (0.87 g, 7.2 mmol) in DMF (30 mL) was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed by brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography to yield the desired product (900 mg, 32.6%). LCMS calculated for C12H15N2O4(M+H): 251.1; found: 251.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][NH:7][CH2:8][C:9]#[CH:10].CN(C1C=CC=CN=1)C.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:6][N:7]([CH2:8][C:9]#[CH:10])[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCNC
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#CCN(C)S(C)(=O)=O
Reaction time: 15 h

Procedure:
Methansulfonylchloride (1.12 mL, 14.5 mmol) was added to a stirred solution of N-methylpropargylamine (1.22 mL, 14.5 mmol) and dimethylaminopyridine (35 mg, 0.30 mmol) in pyridine (10 mL) at room temperature. After aging for approximately 15 h, the reaction mixture was poured into ethyl acetate and washed successively with 1N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo, to afford the title compound (i-4), which was used without further purification.