Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.C(N(CC)CC)C.[C:30]([Cl:33])(=[O:32])[CH3:31]>CN(C=O)C>[ClH:33].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:30](=[O:32])[CH3:31])[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 are dissolved in 5 ml DMF, 71.4 mg (705 μmol) triethylamine and 20.3 mg (259 μmol) acetyl chloride are added, while cooling with ice, and the mixture is stirred overnight at RT. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[C:5]2[CH2:15][S:16][CH2:17][C:4]1=2)[CH3:2].N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[C:5]2=[CH:15][S:16][CH:17]=[C:4]12)[CH3:2]
Reactant: CCN1C2=C(CSC2)C(=O)Nc2ccccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: CCN1c2ccccc2NC(=O)c2cscc21

Procedure:
To a suspension of 0.246 g. of 4-ethyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one in 2 ml. of dry pyridine is added in portions a total of 0.133 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid is collected and recrystallized from methanol-water to give off-white crystals, m.p. 201°-202°C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20]N.Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24].C[N:31]1CCOCC1>C(Cl)Cl>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH:4]([NH2:31])[C:3]1([CH3:20])[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN1CCOCC1
Reactant: CN1c2ccccc2C(c2ccccc2F)=NCC1CN
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CC(C)COC(=O)C1(C)C(N)N=C(c2ccccc2F)c2ccccc2N1C
Temperature: 25 °C
Yield: 68.2 %

Procedure:
According to the method of Example 1, 1-methyl-2-aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (250 mg, 0.88 mmole) and isobutyl chloroformate (114 μl, 0.88 mmole) were combined with 4 ml of dry methylene chloride, and 97 μl of N-methyl-morpholine (0.88 mmole) at -5° C. was added to the mixture. The resulting reaction mixture was allowed to warm to room temperature over 2 hours, and after dilution and washing, rotoevaporation of the dried extracts of the reaction afforded 230 mg of an oil which was purified by silica gel chromatography (ethyl acetate-hexane elution, 7:3 v/v) to give the analytical sample (120 mg) which was 98% pure by HPLC.
Reaction SMILES: [C:1]([C:3]1[C:9]([O:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[C:8]([O:15][CH3:16])[C:7]([O:17][CH3:18])=[CH:6][C:4]=1[NH2:5])#[N:2].[C:19]([N:22]1[CH2:31][CH2:30][C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23]1)(=O)[CH3:20]>>[NH3:2].[CH:11]1([O:10][C:9]2[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:4]([N:5]=[C:19]([N:22]3[CH2:31][CH2:30][C:29]4[N:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:23]3)[CH3:20])[C:3]=2[C:1]#[N:2])[CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N1CCc2ncccc2C1
Reactant: COc1cc(N)c(C#N)c(OC2CCC2)c1OC
Product: COc1cc(N=C(C)N2CCc3ncccc3C2)c(C#N)c(OC2CCC2)c1OC
Product: N
Yield: 48 %

Procedure:
The subtitle compound was prepared from 2-cyano-3-cyclobutyloxy-4,5-dimethoxyaniline and 6-acetyl-5,6,7,8-tetrahydro-1,6-naphthyridine following the procedure described in Example 10(g), allowing the reaction to reflux for 3 hours. The crude product was purified on silica gel eluting with ethyl acetate:methanol:0.880 aqueous ammonia solution (95:5:1, v/v) to give the subtitle compound as a gum (382 mg, 48%). Rf 0.53 (dichloromethane: methanol:0.880 aqueous ammonia 90:10:1, v/v). MS m/z 407 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:25][C:20]5(OCC[O:21]5)[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:25][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-n2ncc3cc4c(cc32)CCCC2(C4)OCCO2)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(-n2ncc3cc4c(cc32)CCCC(=O)C4)ccn1
Reaction time: 24 h
Yield: 98.9 %

Procedure:
A 200 mL round-bottom flask equipped with air cooled reflux condenser outfitted with a nitrogen inlet adapter was charged with 1-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (82, R1=2-methylpyridin-4-yl) (3.26 g, 9.72 mmol) and PTSA (2.31 g, 12.2 mmol) in acetone (49 mL). The mixture was heated to reflux. After 24 h, the reaction was diluted with additional acetone (50 mL) and water (2.5 mL) was added. After 1 h the reaction was cooled before adding sat. aq. NaHCO3 (30 mL). The mixture was then concentrated under reduced pressure. EtOAc (70 mL) was added, and after separating the layers, the aqueous phase was extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine (75 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(2-methylpyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (6, R1=2-methylpyridin-4-yl) (2.8 g, 99%); LC/MS, method 3, Rt=1.71 min, MS m/z 292 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.65-8.60 (m, 1H), 8.20-8.16 (m, 1H), 7.71 (s, 1H), 7.69-7.65 (m, 1H), 7.63-7.59 (m, 2H), 3.85 (s, 2H), 3.21-3.11 (m, 2H), 2.71 (s, 3H), 2.62-2.54 (m, 2H), 2.14-1.94 (m, 2H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[C:6]([C@@H:9]1[CH2:14][C:13](=[O:15])[C:12]([CH3:16])=[CH:11][CH2:10]1)(=O)[CH3:7].O1CCC[CH2:18]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.CCCCCC>[CH3:16][C:12]1[C:13](=[O:15])[CH2:14][C@@H:9](/[C:6](/[CH3:18])=[CH:7]\[CH2:1][CH2:2][CH3:3])[CH2:10][CH:11]=1
Reactant: CC(=O)[C@H]1CC=C(C)C(=O)C1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: CCC/C=C(/C)[C@H]1CC=C(C)C(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
44 g of n-butyltriphenylphosphonium bromide are suspended in 500 ml of dry tetrahydrofuran under argon and cooled to -50°. 69 ml of 1.33N n-butyllithium in hexane are added thereto. The orange coloured suspension is warmed to room temperature and then again cooled to -50°. 14 g of (5S)-5-acetyl-2-methyl-2-cyclohexen-1-one dissolved in 20 ml of dry tetrahydrofuran are added dropwise thereto over a period of 20 minutes. The cooling bath is then removed and the suspension is left to warm to room temperature. After stirring for 2 hours the reaction mixture is filtered through siliceous earth. The filtrate is evaporated, the dark residue is dissolved in 500 ml of ethyl acetate and washed twice with 200 ml of water each time. The organic phase is dried over sodium sulphate and evaporated. The thus-obtained oil is purified by column chromatography on silica gel with hexane/ethyl acetate (95:5) as the elution agent. There is obtained (5S)-2-methyl-5-[(Z)-1-methyl-1-pentenyl]-2-cyclohexen-1-one which still contains about 15% of the corresponding (E)-isomer.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[CH2:8]([N:11]([CH:17]([CH3:20])[CH:18]=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH2:10].O>CO.C1(C)C=CC=CC=1>[CH3:2][N:3]1[O:4][CH2:10][CH:9]2[CH:18]1[CH:17]([CH3:20])[N:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]2
Reactant: CNO
Reactant: C=CCN(C(=O)OCC)C(C)C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CON(C)C2C1C

Procedure:
A methanolic methylhydroxylamine solution is prepared from 16.4 g (0.2 mol) of N-methylhydroxylamine hydrochloride in 33 ml of absolute methanol and 36 g (0.2 mol) of 30% strength sodium methylate solution, and the solution formed is diluted with 130 ml of toluene and added dropwise to 354 g (0.17 mol) of N-allyl-N-(1-oxoprop-2-yl)-urethane in 250 ml of toluene, which is heated under reflux using a water separator. The mixture is heated under reflux overnight, the product is extracted with dilute hydrochloric acid and the hydrochloric acid solution is rendered alkaline with K2CO3 and extracted with CHCl3. The extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Br:18][C:19]1[CH:20]=[C:21]([C:25](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:26])[NH:22][C:23]=1[CH3:24]>CC(N(C)C)=O>[Br:18][C:19]1[CH:20]=[C:21]([C:25]([NH:17][CH:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:26])[NH:22][C:23]=1[CH3:24]
Reactant: NC1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Nitropyridin-2-yl)piperidin-4-amine hydrochloride salt (Intermediate 39) (41 mg, 1.35 mmol) and TEA (37 μl, 1.35 mmol) were added to pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17): (50 mg, 1.35 mmol) in anhydrous DMA (1 ml). The mixture was stirred at room temperature overnight. The crude mixture was filtered and purified by semi-preparative HPLC using CH3CN/H2O (0.1% TFA) to yield the title compound as a yellow solid (26 mg).
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([O:6][CH3:7])[O:4][CH3:5].[F:14][C:15]([F:22])([F:21])[S:16]([O:19]C)(=[O:18])=[O:17]>C(OCC)(=O)C>[F:14][C:15]([F:22])([F:21])[S:16]([O-:19])(=[O:18])=[O:17].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N+:11]([CH3:15])([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CO[Si](CCCN(C)C)(OC)OC
Solvent: CCOC(C)=O
Product: CO[Si](CCC[N+](C)(C)C)(OC)OC
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
5.0 g of trimethoxysilylpropyldimethylamine and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 5.9 g of methyl trifluoromethanesulfonate was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, trimethoxysilylpropyldimethyl amine and methyl trifluoromethanesulfonate as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylpropyltrimethylammonium trifluoromethanesulfonate.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[BH4-].[Na+]>C(O)C>[OH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1([CH3:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C)CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C)CCCCC1O

Procedure:
For the synthesis of the protected acid side-chain 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid, ethyl 2-oxocyclohexane carboxylate (8.5 g, 50 mmol) was dissolved in dry THF at ambient temperature under N2. Potassium tert-butoxide (75 mmol) was added slowly and the reaction was stirred for 5 minutes. Iodomethane (100 mmol) was then added and the reaction was stirred at ambient temperature for 1 hour. The reaction solvent was removed under reduced pressure and the residue was partitioned between water and hexane. The organic layer was dried over sodium sulfate and reduced under reduced pressure to give racemic ethyl 1-methyl-2-oxo-cyclohexanecarboxylate as a colourless oil (8.11 g 88%); δH (400 MHz, CDCl3) 4.25-4.12 (2H, m, OCH2CH3), 2.55-2.40 (3H, m, CH2CO and one other cyclohexane peak), 2.05-1.95 (1H, m, cyclohexane), 1.77-1.57 (3H, m, cyclohexane), 1.50-1.40 (1H, m, cyclohexane), 1.28 (3H, s, CCH3) and 1.25 (1H, t, J 7, CH2CH3). Ethyl 1-methyl-2-oxo-cyclohexanecarboxylate (5.52 g, 30 mmol) was dissolved in ethanol (100 ml) at ambient temperature and sodium borohydride (1.14 g, 30 mmol) was added slowly. After 1 hour the reaction solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic extracts were dried over sodium sulphate and reduced to give ethyl 2-hydroxy-1-methylcyclohexanecarboxylate as a mixture of diastereoisomers (5.37 g 96%). This material was then protected and the ester hydrolysed as follows: Ethyl 2-hydroxy-1-methylcylclohexanecarboxylate (16.7 mmol) was dissolved in dichloromethane along with 3,4-dihydro-2H-pyran (17 mmol) and para-toluene-sulphonic acid (5 mg), and the reaction was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure to give a residue to which was added ethanol (40 ml), water (10 ml) and potassium hydroxide (20 mmol). The mixture was heated at reflux overnight and allowed to cool. The reaction solvent was removed under reduced pressure and the residue was partioned between water and diethyl ether. The aqueous layer was acidified to pH 2 and then extracted with diethyl ether. This ether layer was dried over sodium sulphate and reduced in vacuo to give crude 1-methyl-2-(tetrahydropyran-2′-yloxy)-cyclohexane carboxylic acid (2.52 g) as a mixture of diastereoisomers. This material was used in the synthesis of (S)-3-(2′-hydroxy-1′-methylcyclohexanecarbonyl)amino-caprolactam above
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18]([Cl:20])=[O:19].N1C=CC=CC=1>C(OCC)(=O)C>[ClH:20].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:18]([O:1][CH2:2][CH2:3][NH:4][CH3:5])=[O:19]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)c1cc(OC)c(OC)c(OC)c1
Product: Cl
Temperature: 60 °C
Reaction time: 14 h
Yield: 58.6 %

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Synthetic Example 1 and ethyl acetate (10 mL) were added 3,4,5-trimethoxybenzoyl chloride (2.54 g) and pyridine (0.97 mL). After stirring at 60° C. for 14 hrs, to the reaction solution were further added 3,4,5-trimethoxybenzoyl chloride (1.30 g), pyridine (0.97 mL) and ethyl acetate (10 mL), and stirred at 60° C. for 24 hrs. The reaction solution was filtered, and to the filtrate were added ethyl acetate (50 mL) and water (30 mL). After separating the layers, the ethyl acetate layer was washed sequentially with 1 N hydrochloric acid (30 mL), water (30 mL), aqueous solution of copper (II) sulfate (30 mL), water (30 mL) and saturated brine (30 mL), followed by drying over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elute with ethyl acetate:hexane=1:1). To the purified materials was added 4N hydrogen chloride-ethyl acetate solution (10 mL). After stirring at room temperature for 4 hrs, the solution was concentrated under reduced pressure. Toluene (10 mL) was added to the residue, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the solid was collected by filtration. After washing with ethyl acetate (15 mL), the solid was dried under reduced pressure to give title compound as white solid (1.79 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:6]=[C:5]2[S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:31]([CH2:42][OH:43])[CH2:30]1)(=[O:28])=[O:27].[CH:44]1([NH:47][C:48](=[O:66])[C:49]2[CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[C:52]([CH3:64])=[C:51]([F:65])[CH:50]=2)[CH2:46][CH2:45]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C:14]([CH3:24])([CH3:25])[CH2:13][N:7]1[CH:6]=[C:5]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C@@H:31]([CH2:42][OH:43])[CH2:30]2)(=[O:28])=[O:27])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:53]3[CH:54]=[C:49]([C:48](=[O:66])[NH:47][CH:44]4[CH2:45][CH2:46]4)[CH:50]=[C:51]([F:65])[C:52]=3[CH3:64])[CH:3]=2)[C:8]1=[O:12])([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:19])[CH3:18]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1cc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)[C@@H](CO)C2)c2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)[C@@H](CO)C3)c2c1
Temperature: 75 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
A solution of tert-butyl (2R)-4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfonyl}-2-(hydroxymethyl)piperazine-1-carboxylate (Example 49b, 0.58 g) in DMF (10 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.263 g), Pd-118 (0.016 g) and potassium carbonate (0.228 g). The resulting mixture was stirred at 75° C. for 6 h. The cooled reaction was concentrated under reduced pressure then purified (SiO2 chromatography, loaded in DCM, flushed with isohexane (100 mL), then DCM (200 mL), followed by a 10-100% gradient of ethyl acetate/isohexane) to afford the subtitle compound (0.537 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10]S)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([C:22](=[CH2:33])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[S:34]([O:38]OS([O-])(=O)=O)([O-])(=O)=[O:35].[K+].[K+]>>[CH2:26]([O:25][C:23]([CH:22]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:33][S:34]([CH2:10][C@@H:9]([C:12]([OH:14])=[O:13])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])(=[O:38])=[O:35])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CS)C(=O)O
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)O

Procedure:
In an analogous manner to that described in Example 1, paragraphs (d) and g), by adding Boc-L-cysteine to benzyl 2-benzylacrylate and subsequently oxidizing with potassium monopersulphate triple salt there was obtained 3-[[(RS)-2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-N-(tert-butoxycarbonyl)-L-alanine as a colourless oil, MS: 506 (M+H)+.
Reaction SMILES: [CH:1]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][C:1]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:26][CH:27]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OC(F)(F)F)cc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a solution of triethyl methanetricarboxylate (4.55 g) in DMF (40 mL) were added 4-(trifluoromethoxy)benzyl bromide (5.00 g), potassium iodide in catalytic amount and potassium carbonate (4.07 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate (200 mL) and water (100 mL) were added to extract the reaction mixture. The extract was washed sequentially with water and brine, and concentrated under reduced pressure to give the title compound (7.97 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:42]I>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=2)[C@H:10]([CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH3:42])[CH:32]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (1.15 g) in dimethylformamide (60 ml) was added 60% sodium hydride (0.1 g) under nitrogen atmosphere, and the mixture was stirred for 5 minutes. After addition of methyl iodide (0.13 ml), the reaction mixture was stirred for 40 minutes. The reaction was quenched with 0.5N hydrochloric acid (60 ml) and diluted with dichloromethane (80 ml). The organic layer was washed with water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of the solvent, the residue was purified on a silica gel column eluting with a mixture of toluene and ethyl acetate (10:1) to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(N-methyl-1H-indol-3-yl-methyl)piperazine (1.12 g) as a syrup.
Reaction SMILES: [CH2:1]([I:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH2:20]=[CH:21][CH2:22][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][CH3:39].[Cl-].C([Al+]CC)C.CO>C1(C)C=CC=CC=1>[I-:12].[CH2:1]([N+:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:20]=[CH:21][CH2:22][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][CH3:39]
Reactant: C=CCCCCCCCCCI
Reactant: CC[NH+](CC)CC
Agent: C=CCCCCCCCCCCCCCCCCCC
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CCCCCCCCCC[N+](CC)(CC)CC
Product: [I-]
Reaction time: 1.5 h
Yield: 146.4 %

Procedure:
Triethyl ammonium undecylenyl iodide (7.5 grams), eicosene (22.5 grams) and toluene (60 grams) were added to a glass screw cap jar under an argon atmosphere. Diethyl aluminum chloride (25 milliliters of a 1.8 molar solution in toluene) and 1.25 teaspoons of TiCl3 --AA (available from Alfa, about 5 grams) were added. After 1.5 hours, the reaction was treated with methanol until the mixture turned green. The mixture was added to methanol in a Waring blender to precipitate the polymer which was washed successively with water and then methanol. The solid polymer was isolated by filtration and dried in vacuo to afford 19 grams of a white powder. Solid state 13C NMR analysis was consistent with the attachment of 5 weight percent of quaternary ammonium groups. The DSC of this product showed two semicrystalline melting endotherms at 45° and 81° C. and a melting peak at 117° C. attributed to the quaternary ammonium iodide group.