Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=1)[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][OH:22])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41](=[O:45])[CH:42]=[N+]=[N-])[CH3:39].C(O)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Si:1]([O:8][C@H:9]([CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=1)[CH2:10][O:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][O:22][CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:45])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cc1ccc(C[C@@H]2CCCN2C[C@H](CO[C@H](C)c2ccccc2CCO)O[Si](C)(C)C(C)(C)C)cc1F
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)COCCc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
2-{2-[(1R)-1-({(2R)-2-{[Tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}ethanol (545 mg, 1.03 mmol), which had been obtained in Example 180 (180d), was dissolved in methylene chloride (5 mL), added with rhodium diacetate dimer (46 mg, 0.10 mmol) and ethyldiazoacetate (267 μL, 2.58 mmol) at 0° C., and stirred for 1.5 hours. Ethanol was added to the reaction solution to terminate the reaction. The solvent was distilled off under reduced pressure. The residue was purified by basic silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (565 mg, yield 89%).
Reaction SMILES: CC(OC(C)=O)=O.OS(O)(=O)=O.[I:13]I.[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>O=[Mn]=O.C(Cl)Cl.CC(O)=O>[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:22]([I:13])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: II
Agent: O=[Mn]=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)c1cc(I)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 232.1 %

Procedure:
AcOH (1.2 L) and Ac2O (0.63 L) were added to a 5 L flask. H2SO4 (1.6 L) was then added to the same flask while cooling with ice to prevent the temperature from exceeding 40° C. Next, I2 (70 g), activated MnO2 (70 g) and 2,3,4-trifluorobenzoic acid (120 g, 0.68 mol) were added in solid form while stirring at room temperature. While stirring the resulting dark purple suspension at 50° C., I2 (70 g) and activated MnO2 (70 g) were added after 2 to 3 hours, and I2 (33 g) and activated MnO2 (37 g) were further added after 4 to 6 hours. After 24 hours, the reaction mixture was added to ice water (2 L). The purple organic layer obtained by extraction three times with CH2Cl2 (1.6 L, 1.0 L, 1.0 L) was washed twice with 0.2N Na2S2O3 aqueous solution (2.0 L, 1.0 L), resulting in alteration of the organic layer color to pale yellow. The organic layer was washed four times with 1.0 L of water to remove the AcOH, yielding a non-cloudy transparent organic layer. After removing water in the organic layer with Na2SO4 (1.3 kg), the solvent was removed by distillation to yield 192 g of 2,3,4-trifluoro-5-iodobenzoic acid (0.64 mol, 94%, purity: 99 LC area % (UV peak area % in LC)) as white powders. If necessary, rinsing may be performed with a mixed solvent of ethanol and hexane (EtOAc: hexane=1:9 (v/v)).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[CH:7][CH:6]=[CH:5][N:4]3[N:8]=2)=[CH:13][CH:14]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc3c(N4CCN(C)CC4)cccn3n2)cc1
Temperature: 100 °C

Procedure:
To an oven dried tube was added (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol), 1-methyl-piperazine (21.0 L, 0.189), palladium acetate (7.0 mg, 0.031 mmol), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (15.0 mg, 0.0315 mmol, X-Phos), potassium phosphate (83.0 mg, 0.391 mmol) and 1,4-dioxane (3 mL) and kept under an atmosphere of nitrogen. The tube was evacuated and backflushed with nitrogen three times. The tube was sealed and heated at 100° C. for 18 hours. The mixture was cooled to room temperature and diluted with dichloromethane (10 mL). The suspension was filtered and the filtrate was evaporated. The residue was purified via chromatography using amine modified silica gel column (4.7 g) and 5%→100% ethyl acetate:hexane solvent gradient. The title compound was isolated as a tan foam (0.025 g, 47%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.04 (dd, J=6.5, 1.0 Hz, 1H), 7.51-7.46 (m, 2H), 6.93-6.88 (m, 2H), 6.74 (dd, J=7.8, 1.0 Hz, 1H), 6.58 (s, 1H), 3.80 (s, 3H), 3.55-3.45 (m, 4H), 2.71-2.65 (m, 4H), 2.39 (s, 3H). MS=339 (MH)+.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][NH:12]C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:20].CCOC(C)=O>>[ClH:20].[C:1]([N:5]1[CH2:6][CH2:7][CH:8]([NH:11][NH2:12])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CCC(NN)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 2-(1-tert-butylpiperidin-4-yl)hydrazinecarboxylate (350 mg, 1.29 mmol) in sat. HCl/EtOAc solution (20 mL) was stirred at room temperature overnight. The solvent was removed under reduce pressure to afford 1-tert-butyl-4-hydrazinylpiperidine hydrochloride (268 mg, 100% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 172.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:74]([NH2:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1.C(O)(C(F)(F)F)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:74]([NH:81][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2)[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(NCc3ccccc3)cccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A vial was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D, 0.100 g, 0.192 mmol), Pd2(dba)3 (0.018 g, 0.019 mmol), Xantphos (0.022 g, 0.038 mmol), and toluene (1.922 ml). Benzylamine (0.042 ml, 0.384 mmol) was added and the reaction was stirred for one hour at 100° C. The reaction was filtered through a plug of diatomaceous earth, which was then washed with ethyl acetate. The filtrate was concentrated, dissolved in 1 mL of DCM, and TFA (0.1 ml, 1.298 mmol) was added. The reaction was concentrated and purified via HPLC (50-95% MeCN:H2O with 0.1% TFA modifier) to afford 5-(benzylamino)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.48 (s, 1H), 8.42 (d, J=9.1 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 7.70 (dd, J=2.0, 9.0 Hz, 1H), 7.39 (d, J=7.6 Hz, 2H), 7.34-7.27 (m, 4H), 7.24-7.17 (m, 1H), 6.51 (dd, J=2.2, 6.6 Hz, 1H), 4.50 (s, 2H). m/z (ESI) 397.3 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)(=[O:4])=[O:3].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)n1ncc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CS(=O)(=O)n1ncc2cc(N)ccc21
Yield: 48.5 %

Procedure:
To a solution of 1-(methylsulfonyl)-5-nitro-1H-indazole (1.00 g, 4.15 mmol) in ethanol (20 ml) were added 10% Pd-C (100 mg) and then ammonium formate (1.57 g, 24.9 mmol), and the resulting mixture was heated under reflux for 1 hour. The solid was removed by filtration using Celite, and the solvent was distilled off under reduced pressure. Ethyl acetate/water was added to the residue, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 1-(methylsulfonyl)-1H-indazol-5-amine (425 mg, 49%) was obtained.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:17][C:18](=[O:28])[CH2:19][CH:20]1[NH:23][C:22](=[O:24])[CH:21]1[CH:25](O)[CH3:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>ClCCl>[CH2:10]([O:17][C:18](=[O:28])[CH2:19][CH:20]1[NH:23][C:22](=[O:24])[CH:21]1[CH:25]([F:7])[CH3:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(O)C1C(=O)NC1CC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(F)C1C(=O)NC1CC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
To a -78° cooled solution of 1.5 ml of diethylaminosulphurtrifluoride in 4 ml of dry dichloromethane is added a solution of 2.52 g of (3SR,4RS)-3-[1(SR)-hydroxyethyl]-2-oxoazetidine-4-yl-acetic acid benzyl ester (prepared analogously to D. G. Melillo et.al., Tetrahedron Letters 21, 2783 [1980]) in 4 ml of abs. dichloromethane. The mixture is stirred for 5 minutes at -78° and mixed with excess cold saturated NaHCO3. After addition of further dichloromethane the phases are separated, the organic phase dried over magnesium sulphate and evaporated to dryness. Chromatography of the residue over silica gel (cyclohexane/ethylacetate=2/1) yields the title compound m.p. 40°-43°.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
To 2,3,5-trichloropyridine (25 g) were added 1-BOC-piperazine (28.13 g), potassium carbonate (37.86 g), N,N-dimethylformamide (25 mL) and toluene (50 mL), and the mixture was stirred at 100° C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (39.13 g). To 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.35 g) were added palladium (II) acetate (0.46 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.71 g), potassium fluoride (9.556 g), methylboronic acid (5 g) and tetrahydrofuran (202 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g). To 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g) were added 4N hydrogen chloride/ethyl acetate (18.2 mL) and chloroform (45.5 mL), and the mixture was stirred at room temperature. After completion of the reaction, to the reaction mixture were added water and potassium carbonate, and the mixture was extracted with ethyl acetate. The solvent was evaporated to give the title compound (3.3 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:9]=1[O:10][CH2:11][C:12]#[N:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:48])C(=O)C1>C1COCC1>[Br:48][CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:9]=1[O:10][CH2:11][C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(COc2cccc(CO)c2)c1OCC#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(COc2cccc(CBr)c2)c1OCC#N

Procedure:
To a solution of [2-(3-hydroxymethyl-phenoxymethyl)-6-methyl-phenoxy]-acetonitrile (230 mg, 0.81 mmol, example 75) in THF (3 mL) is added Ph3P (233 mg, 0.89 mmol) and stirred until homogeneous. Cooled solution to 0° C. then added portionwise NBS (151 mg, 0.85 mmol) and let stir 45 min. Concentrated reaction mixture under reduced pressure. The residue is purified by flash chromatography (silica, 40% CH2Cl2 in hexanes) to give the title compound as a white crystalline solid. MS (EI) 345, 347 (M)+, Br pattern.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:30][C:10]1([CH3:31])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)N2CCCC2)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
A mixture of 3,3-dimethyl-2-{3-[(pyrrolidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (842 mg, 2 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyrrolidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 44%) as a white solid: LC/MS m/e calcd for C23H27N3O3 (M+H)+: 394.49, observed: 394.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:8][C:7]=12)#[CH:2].Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][N:6]3[N:5]=[CH:4][C:3]([C:1]#[C:2][C:23]4[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=4)=[C:7]3[N:8]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1cnn2ccc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3ccc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.33) (144 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (153 mg, 68%). MS (ISP) 449.3 [(M+H)+]; mp 224-226° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].Cl>CN(C=O)C>[CH2:43]([O:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
2-Hydroxy-9-fluorenone (196 mg, 2.04 mmol) was dissolved in DMF (8 ml), potassium carbonate (423 mg, 3.06 mmol), and docosyl bromide (96%, 785 mg, 1.93 mmol) were added. The mixture was heated to 80° C. and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and 1N hydrochloric acid (4 ml) was added dropwise thereto in a water bath to quench the reaction. The mixture was extracted with chloroform (23 ml), and washed once with 1N hydrochloric acid (7.5 ml) and 4 times with pure water (7.5 ml). The solvent of the organic layer was evaporated, and the residue was precipitated with methanol (10 ml) to give 2-docosyloxy-9-fluorenone (934 mg, 1.85 mmol, 96%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:42])[CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH:35]([C:39]([NH2:41])=[O:40])[CH2:34]1)(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:42])[CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH:35]([C:39]([NH2:41])=[O:40])[CH2:34]1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccccc1NC(=O)CN1CCNC(C(N)=O)C1
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1NC(=O)CN1CCN(CCCC=C(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Temperature: 80 °C
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A mixture of 1.86 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis-[4-fluorobenzene], 1.50 parts of N-(2-acetylphenyl)-3-(aminocarbonyl)-1-piperazineacetamide, 0.80 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred for 20 hours at 80° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 2.07 parts (73.9%) of N-(2-acetylphenyl)-3-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)-4-pentenyl]-1-piperazineacetamide; mp. 110.7° C. (compound 18).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[S:8][C:9]([NH2:18])=[C:10]([CH2:12][C:13](OCC)=[O:14])[CH:11]=1)[CH3:2].C[Al](C)C>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[S:8][C:9]2[NH:18][C:13](=[O:14])[CH2:12][C:10]=2[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(CC(=O)OCC)c(N)s1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cc2c(s1)NC(=O)C2
Reaction time: 1 h
Yield: 27.8 %

Procedure:
Ethyl-4-[(ethoxycarbonyl)methyl]-5-amino-2-thiopheneacrylate (150 mg, 0.53 mmol) was dissolved in dichloromethane (20 ml), treated at room temperature with trimethyaluminium (2M in heptane, 1 ml, 2 mmol) and stirred for 1 hour. The reaction was quenched with water, diluted with ethyl acetate, washed with saturated brine solution and dried over magnesium sulfate. The organic phase was evaporated to dryness and the residue chromatographed on silica gel using hexane/ethyl acetate (2:1) as eluent to give 35 mg of 3-(5-oxo-5,6-dihydro-4H-thieno[2,3-b]pyrrol-2-yl)-acrylic acid ethyl ester as a tan colored solid.
Reaction SMILES: [Br:1][C:2](=[O:7])[CH:3](Cl)[CH2:4][CH3:5].[NH:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:9]1=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[Br:1][C:2](=[O:7])[CH:3]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:8][C:9](=[O:10])[CH2:11][CH2:12]2)[CH2:4][CH3:5]
Reactant: CCC(Cl)C(=O)Br
Reactant: O=C1CCc2ccccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC(C(=O)Br)c1ccc2c(c1)CCC(=O)N2

Procedure:
A solution of α-bromobutanoyl chloride (78.9 g) in methylene chloride (50 ml) is added to a stirred mixture of 3,4-dihydrocarbostyril (31.3 g) and aluminum chloride (59.6 g) in methylene chloride (300 ml). The reaction mixture is stirred at reflux for about 3.5 hours, cooled, poured into a mixture of ice and water, resulting in the formation of a white precipitate which is filtered, washed with water, dried, and recrystallized from isopropanol, affording the desired product.
Reaction SMILES: [Br:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH2:3].[CH:10]([Br:13])(Br)[Br:11].[Br-].[Br-].C([N+](C)(C)CC[N+](CC1C=CC=CC=1)(C)C)C1C=CC=CC=1.[OH-].[K+]>C(Cl)Cl.O>[Br:11][C:10]1([Br:13])[CH2:3][C:2]1([Br:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: BrC(Br)Br
Reactant: C=C(Br)CCCCCC
Agent: C[N+](C)(CC[N+](C)(C)Cc1ccccc1)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCC1(Br)CC1(Br)Br
Reaction time: 120 h
Yield: 50.9 %

Procedure:
To 5.42 g (0.0284 mol) of 2-bromo-oct-1-ene in 7.42 ml (0.0851 mol) of bromoform and 48.8 ml of methylene chloride, were added 1.30 g ( 0.00284 mol) of N,N′-dibenzyl-N,N,N′,N′-tetramethylethylenediammonium dibromide and 12.1 ml (0.142 mol) of 45% aqueous potassium hydroxide. The mixture was left at room temperature for 5 days. There was then added hexanes and water. This mixture was gravity filtered through qualitative fluted filter paper. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 5.25 g (51.0% of theoretical) of 1,1,2-tribromo-2-hexyl-cyclopropane as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[N:11][N:10]=[C:9]1[Br:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH2:1]([N:8]1[C:12]([O:16][CH3:15])=[N:11][N:10]=[C:9]1[Br:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Brc1nnc(Br)n1Cc1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1nnc(Br)n1Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4-benzyl-3,5-dibromo-4H-1,2,4-triazole (compound 91.2, 3.71 g, 11.7 mmol) in MeOH 15 mL) was added NaOMe (1.26 g, 23.4 mmol) and the mixture was refluxed for 18 hours. The mixture was cooled somewhat and additional NaOMe was added (1.26 g, 23.4 mmol). The mixture was refluxed for an additional 5 hours, then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with water (30 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to yield 3.13 g (theoretical) of the title compound as a clear oil. m/z (ES+) 269 (M+H)+.