Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([N:31]([CH3:56])[CH2:32][CH2:33][NH:34][C:35](=[O:55])[C@H:36]([CH:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:37][C:38]([O:40][CH3:41])=[O:39])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH3:41][O:40][C:38]([NH:37][C@H:36]([C:35]([NH:34][CH2:33][CH2:32][N:31]([CH3:56])[C@H:10]1[C@H:11]([N:13]([CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])[S:14]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:12][NH:8][CH2:9]1)=[O:55])[CH:42]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:39]
Reactant: COC(=O)N[C@H](C(=O)NCCN(C)[C@@H]1CN(Cc2ccccc2)C[C@H]1N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)NCCN(C)[C@@H]1CNC[C@H]1N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of N-(2-{[(3R,4R)-1-benzyl-4-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl](methyl)amino}ethyl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (168 mg, 0.15 mmol), 1-chloroethyl chloroformate (72 mg, 0.5 mmol) in 1.5 mL of 1,2-dichloroethane was stirred overnight at reflux. The solvent was evaporated, the residue was re-dissolved in MeOH and the mixture was refluxed for 1 hour. MeOH was evaporated and the residue containing compound the deprotected pyrrolidine was used for the next step without additional purification. LC-MS APCI: m/z 695.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]1C2C(=CC=C(O)C=2)N[N:30]=1.N12CCCN=C1CCCCC2>ClCCl>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][P:11]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:1][N:30]=1
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CP(=O)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 497 mg of 50%-pure methylphenylphosphinic acid 4-nitrophenyl ester in 8 ml of dichloromethane is stirred at ambient temperature. A suspension of 403 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol and 268 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene in 12 ml of dichloromethane is added dropwise. The reaction medium is stirred at ambient temperature overnight and then evaporated to dryness under reduced pressure in a rotary evaporator. The reaction crude is purified by flash chromatography on a cartridge of 50 g of silica 15-35 μm. 300 mg of methylphenylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester are collected and recrystallized from ethyl acetate to obtain 220 mg of methylphenylphosphinic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.Br[C:14]1[S:15][CH:16]=[C:17]([Br:19])[N:18]=1.[F:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:28]([CH2:37][CH2:38][CH:39]=[CH2:40])/[CH:29]=[N:30]/[S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32].CO>O1CCCC1>[Br:19][C:17]1[N:18]=[CH:14][S:15][C:16]=1[C@@H:29]([NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[C@H:28]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[F:20])[CH2:37][CH2:38][CH:39]=[CH2:40]
Reactant: C=CCC[C@H](/C=N/[S@](=O)C(C)(C)C)c1cccc(F)c1F
Reactant: Brc1csc(Br)n1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCC[C@@H](c1cccc(F)c1F)[C@H](N[S@](=O)C(C)(C)C)c1scnc1Br
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
To a 250 mL round bottom flask was added tetrahydrofuran (10 mL) and diisopropylamine (1.04 mL, 7.33 mmol) under nitrogen. The flask was cooled down to −20° C. before addition of n-BuLi (2.93 mL, 7.33 mmol). The reaction was stirred at this temperature for 5 min before being cooled to −78° C. 2,4-dibromothiazole (1.782 g, 7.33 mmol) was added at once to the reaction mixture. After stirring at −78° C. for 10 min, (R,E)-N-((S)-2-(2,3-difluorophenyl)hex-5-enylidene)-2-methylpropane-2-sulfinamide (1.1494 g, 3.67 mmol) in 5 mL tetrahydrofuran was added to the reaction mixture via cannula. The reaction was allowed to continue to stir while it was gradually warmed up to −60° C. (4 h). The reaction was cooled down to −78° C. and n-BuLi (2.93 mL, 7.33 mmol) was added at −78° C. The reaction was stirred for 20 min. Methanol (0.44 mL, 11.0 mmol)l was added to quench the reaction. The reaction was stirred at rt for 0.5 h. The solvent was removed under vacuum and the crude mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried (sodium sulfate), filtered and concentrated. Flash chromatography using ethyl acetate in hexane from 0 to 50% to 85% gave the desired product (1.08 g, 62%) as a brown oil, which was solidified upon standing at room temperature overnight: MS (ESI)[M+H+]=479.12. 1H NMR showed a mixture of two diastereomers with a ratio of 3/1 (epimerized 1 from previous reactions).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H]1CCCC[C@@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>O1CCOCC1.O.CCOC(C)=O.[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1cn[nH]c1
Reactant: Fc1ccc(Br)cc1OCc1ccccc1
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2cccn2)cc1OCc1ccccc1
Temperature: 200 °C
Yield: 43 %

Procedure:
To a microwave vial containing 2-benzyloxy-4-bromo-1-fluoro-benzene [CAS: 1036724-54-5] (1500 mg, 5.34 mmol) and (1S,2S)-(+)-1,2-diaminocyclohexane (121.86 mg, 1.07 mmol) in 1,4-dioxane (10 mL) was added copper (I) iodide (203.24 mg, 1.07 mmol), potassium phosphate (2265.3 mg, 10.67 mmol), and 1H-pyrazole (363.26 mg, 5.34 mmol). The vial was sealed and heated in a microwave at 200° C. for 1 hour. The reaction mixture was diluted with water (50 mL) and EtOAc (30 mL), and the organics were separated, washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (25 g, SNAP cartridge), eluting with a gradient of EtOAc:isohexane from 0% to 30%. Fractions containing desired product were combined and concentrated in vacuo to give 1-(3-benzyloxy-4-fluoro-phenyl)pyrazole (D71) (649.1 mg, 2.2984 mmol, 43.1% yield) as a pale orange oil;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH:14]([CH3:16])[CH3:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:23]=[N+:24]=[O:25].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:17])([CH:14]([CH3:15])[CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:7]=1[N+:24]([O-:25])=[O:23]
Reactant: COC(=O)CC(C)(c1ccc(Cl)cc1)C(C)C
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC(C)(c1ccc(Cl)c([N+](=O)[O-])c1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.3 g (9.03 mmol) of methyl 3-(4-chlorophenyl)-3,4-dimethylpentanoate were dissolved in 50 ml of dichloromethane and cooled to 0° C. 1.44 g (10.8 mmol) of nitronium tetrafluoroborate were then added a little at a time. After the addition had ended, the reaction solution was initially stirred at 0°-10° C. for 1 h. The mixture was then slowly warmed to room temperature and stirred at this temperature for another 2 h. The reaction mixture was then added to about 50 ml of water, the phases were separated and the organic phase was dried over magnesium sulphate. The solution was concentrated by evaporation and the residue obtained was then purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 2.3 g (85% of theory) of the target compound.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1F>CN(C=O)C.CCOC(C)=O>[C:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Br:17])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: Fc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Br)CC1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a slurry of NaH (60% dispersion in oil, 5.9 g, 148.5 mmol, 3.0 eq.) in DMP (40 mL) at 65° C. under N2 was added a solution of N-boc-4-hydroxy piperidine (10 g, 49.5 mmol, 1.0 eq.) in DMF (50 mL). After stirring for about 2 hours, a solution of 1-bromo-2-fluoro benzene (11.0 mL, 99.0 mmol, 2.0 eq.) in DMF (10 mL) was added dropwise. The resulting mixture was stirred at 65° C. overnight. The mixture was diluted with EtOAc (250 mL) and washed with water (100 mL) and brine (100 mL). The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (250 g SiO2, linear gradient, 40 mL/min, 0% to 30% EtOAc/Hexane over 20 minutes and 30% EtOAc for 13 minutes) afforded title compound (14.2 g, 39.8 mmol, 81%). LRMS (electrospray): 358.0.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.O[NH:40][C:41](=[NH:43])[CH3:42]>ClCCl.CN(C)C=O>[CH3:42][C:41]1[N:43]=[C:28]([C:27]2[CH:31]=[CH:32][C:24]([CH2:23][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([C:22]5[C:13](=[CH:14][C:15]6[O:20][CH2:19][CH2:18][O:17][C:16]=6[CH:21]=5)[O:12][CH2:11]4)[C:2]3=[O:1])=[CH:25][CH:26]=2)[O:29][N:40]=1
Reactant: CC(=N)NO
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(CN3C(=O)C4(COc5cc6c(cc54)OCCO6)c4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (0.75 g, 1.7 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.50 mL, 5.77 mmol) and N,N-dimethylformamide (2 drops, catalytic amount). The mixture was stirred for 16 h at ambient temperature and concentrated in vacuo. The residue was dissolved in pyridine (1 mL) and transferred into a 10 mL microwave reaction vessel with pyridine rinses (2×1 mL). To this solution was added N-hydroxyacetamidine (0.25 g, 3.4 mmol) and the reaction mixture was irradiated at 170° C. for 30 min in a microwave reactor. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo and the residue was purified by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes, followed by recrystallization from dichloromethane/diethyl ether to afford 1′-[4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.50 g, 63%) as a colorless solid: mp 177-178° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.26-7.13 (m, 2H), 7.06-6.98 (m, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.49 (s, 1H), 6.21 (s, 1H), 5.14 (d, J=16.0 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.87 (d, J=16.0 Hz, 1H), 4.66 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 174.9, 167.8, 155.3, 144.7, 141.7, 138.4, 132.2, 128.9, 128.6, 128.0, 124.1, 123.8, 123.8, 120.8, 111.5, 109.1, 99.5, 80.1, 64.5, 63.9, 58.1, 43.9, 11.7; MS (ES+) m/z 467.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([NH2:65])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[Cl:64])=[N:56][C:52]=2[CH:51]=1.ClCl>CN(C)C=O.ClCCl.CO>[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=3[Cl:64])[NH:65][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: NC(c1nc2cc(Cl)ccc2[nH]1)c1ccccc1Cl
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(C(=O)NC(c2nc3cc(Cl)ccc3[nH]2)c2ccccc2Cl)ccc1C(=O)N1CCCC1
Yield: 63 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and C-(5-chloro-1H-benzimidazol-2-yl)-C-(2-chlorophenyl)methylamine in dimethylformamide. Yield: 63%; Rf value: 0.?? (silica gel; dichloromethane/methanol=95:5); C27H24Cl2N4O2 (507.42); mass spectrum: (M−H)-=505/507/509 (chlorine isotope).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:12]2[C:13]3=[N:14][NH:15][C:16](=[O:24])[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]=43)[NH:23][CH:11]2[C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)=[CH:30][CH:29]=1
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
To a solution of the crude 8-(4-(diethoxymethyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (3.0 g, 6.53 mmol) in water (10 mL) was added hydrochlorichttp://newsearchch.chemexper.com/cheminfo/servlet/org.dbcreator.MainServlet?sort=%3E%7Eentry.intValue&query=structure_structureID%3D4635571&target=entry&action=PowerSearch&onclick=1&from=0&history=off&forGroupNames=&style=&realQuery=rn.value%3D%22CF3COOH%22+elsor+entry.catalogID%3D%22CF3COOH%22+elsor+iupac.value%3D%22CF3COOH%22+elsor+mf.value%3D%22CF3COOH%22+elsor+%28iupac.value%3D%7E%22CF3 COOH%22+or+catalog.description%3D%7E%22CF3COOH%22%29&format=ccd&searchTemplate=rn.value%3D %3F+elsor+entry.catalogID%3D%3 acid (1N, 50 mL) at 0° C. The mixture was stirred at room temperature for 4 hr. Then the mixture was neutralized with potassium carbonate. The mixture was extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude title compound (2.5 g, yield 98%). LC-MS (ESI) m/z: 386 (M+1)+.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:26]#[C:25][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[CH:3][N:4]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Reactant: C#Cc1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nn23)s1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 11) (457 mg, 1 mmol) and 5-ethynyl-thiophene-2-sulfonic acid amide (example D.3) (243 mg, 1.3 mmol) according to general procedure II. Obtained as a light yellow solid (210 mg, 41%). MS (ISP) 517.1 [(M+H)+]; mp 261–263° C.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:17]([N:19]2[CH:23]([CH:24]([CH3:26])[CH3:25])[CH2:22][O:21][C:20]2=[O:27])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:7][CH:8]([C:17]([N:19]2[CH:23]([CH:24]([CH3:25])[CH3:26])[CH2:22][O:21][C:20]2=[O:27])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C1COC(=O)N1C(=O)C(CC(=O)OC(C)(C)C)CC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1COC(=O)N1C(=O)C(CC(=O)O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A solution of tert-butyl 3-cyclohexylmethyl-4-(4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutyrate (2.90 g, 7.6 mmol) in methylene chloride (10 mL) was treated with trifluoroacetic acid (4.83 g, 42.5 mmol) and the mixture was stirred at ambient temperature for 3 hours. The solvent and excess acid were removed by evaporation at reduced pressure. The residue was dissolved in ether/hexane and product was crystallized out to provide 3-cyclohexylmethyl-4-(4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutyric acid (2 g, 81%). MS (M+1): 326.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[NH2:25])C1C=CC=CC=1.C([O-])(=O)C.[NH4+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(N)CC1

Procedure:
A solution of N-(tert-butoxycarbonyl)-hexahydro-1H-azepin-4-one (0.5 g, 2.34 mmoles), O-benzylhydroxylamine hydrochloride (0.41 g, 2.57 mmoles) and ammonium acetate (0.45 g, 5.86 mmoles) in methanol (10 mL) was refluxed for 1.2 hours. The solvent was evaporated in vacuo and the crude oxime was purified by flash column chromatography (hexanes:ethyl acetate 100:0 to 50:50). The product was taken in 4N NH3 in methanol (10 mL) and added 10% by weight Pd/C (100 mg) and stirred over H2 at balloon pressure for twelve hours. The reaction was filtered through a pad of celite and filtrate evaporated in vacuo to provide the title compound.
Reaction SMILES: [C:1]1([C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>O1CCCC1>[C:1]1([C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([N:14]2[CH2:21][CH2:20][CH2:19][C@H:15]2[C:16]([OH:18])=[O:17])=[O:13])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)/C=C/CC(=O)c1cccs1
Solvent: C1CCOC1
Product: O=C(C/C=C/C(=O)N1CCC[C@H]1C(=O)O)c1cccs1
Reaction time: 2 h

Procedure:
To a mixture of 0.01 mole of 4-(2-thenoyl)crotonic acid in 50 ml. of tetrahydrofuran is added 0.011 mole of N,N'-carbonyldiimidazole. After stirring for 2 hours, L-proline (0.01 mole) is added and the mixture is stirred for 24 hours at room temperature and refluxed for one hour to give 1-[4-(2-thenoyl)crotonyl]-L-proline.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16](/[CH:18]=[N:19]/[OH:20])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:22]=[C:23]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C1COCC1.C(OCC)(=O)C.Cl>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([C:18]2[CH2:22][C:23]([CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[O:20][N:19]=2)[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=C(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O/N=C/c1cc(OCc2ccccc2)ccc1Br
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Reaction time: 2 h
Yield: 82.1 %

Procedure:
An aqueous sodium hypochlorite solution (5%, 16.42 g) was added dropwise to a solution of (E)-1-(5-(benzyloxy)-2-bromophenyl)-N-hydroxymethanimine (3.07 g) and di-tert-butyl 2-methylenesuccinate (2.43 g) in THF (30 mL) at 0 C, and the obtained mixture was stirred at 0 C for 2 hours. The reaction mixture was diluted with ethyl acetate, and 1 M hydrochloric acid was added thereto. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (4.50 g).
Reaction SMILES: [C:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[C:4]1[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)#[N:2].C1C=CC=CC=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33]>O1CCCC1>[C:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[C:4]1[C:12]1[CH:18]=[CH:17][C:15]([N:16]=[C:32]=[S:33])=[CH:14][CH:13]=1)#[N:2]
Reactant: S=C(Cl)Cl
Reactant: N#Cn1cc2ccccc2c1-c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: N#Cn1cc2ccccc2c1-c1ccc(N=C=S)cc1
Yield: 38.4 %

Procedure:
84 mg (0.36 mmol) of 4-(2′-cyanoisoindolyl)aniline was suspended in 40 mL of a mixture of benzene and tetrahydrofuran (1:1, v/v) and refluxed for 1 hour in the presence of 65 mg (0.64 mmol) of triethylamine and 40 mg (0.35 mmol) of thiophosgene. The reaction mixture was concentrated under a vacuum, and then the residue was recrystallized with acetonitrile to obtain 37 mg of the titled 4-(2′-cyanoisoindolyl)phenylisothiocyanate expressed by the following formula in the form of a colorless needle crystal.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg, 1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (490 mg, 70%).