Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])=[O:10])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:15][CH2:14][CH2:13][N:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH3:12])(=[O:4])=[O:3]
Reactant: CCOC(=O)N(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C)CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
1.65 g of methanesulfonyl chloride was added dropwise, with stirring, to a solution of 1.66 g of 2-(N-ethoxycarbonyl-N-methylamino)ethanol and 1.65 g of triethylamine in 20 ml of methylene chloride, whilst ice-cooling, and the solution was then stirred at the same temperature for 30 minutes. At the end of this time, the mixture was poured into ice-water and extracted with methylene chloride. The extracts were combined and washed with water, after which they were dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave a residue which was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 2.62 g (yield 81%) of the title compound as an oil.
Reaction SMILES: C([O:5][C:6](=[O:13])[C@H:7]([CH2:9][CH2:10][CH2:11][CH3:12])[NH2:8])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C(OCC)C>[NH2:8][C@H:7]([C:6]([OH:13])=[O:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
25.8 mg of the isomer having a high Rf value of L-N-[(2R or S)-5-ethylsulfonyl-2-(1-naphthylmethyl)pentanoyl]norleucine tert-butyl ester was dissolved in 0.2 ml of dichloromethane. Then, 0.1 ml of TFA was added thereto, and the mixture was stirred at room temperature for 4 hours. Then, the reaction solution was concentrated under reduced pressure. The residue thereby obtained was diluted with diethyl ether and concentrated under reduced pressure. This operation was repeated to obtain 22.9 mg of L-N-[(2R or S)-5-ethylsulfonyl-2-(1-naphthylmethyl)pentanoyl]norleucine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22].[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(F)c(F)c(-c2c(F)c(F)c(CBr)c(F)c2F)c(F)c1F
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixed solution of a mixture comprising the 4-methylperfluorobiphenyl mentioned above, an N-bromo succinic imide (NBS) (26.7 g, 150 mmol), AIBN (0.99 g, 6 mmol) and a carbon tetrachloride (100 mL) was subjected to heating under reflux for 1 week. During this process, the progress of the reaction was confirmed by TLC, and NBS and AIBN were added on a timely basis. Ultimately, 285 mmol NBS and 15 mmol AIBN were added to the solution. After the reaction was completed, the solution was cooled to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=100:1), and the 4-(bromomethyl)perfluorobiphenyl (7.36 g, 18 mmol, total yield from methyl lithium 60%) was isolated.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]=1[C:14]1[CH:18]=[CH:17][O:16][N:15]=1.C(N1CCC(Cl)=C(C2C[CH:37]([O:39][CH2:40]C)ON=2)C1)(=O)C1C=CC=CC=1>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]=1[C:14]1[CH:18]=[C:17]([CH2:37][O:39][CH3:40])[O:16][N:15]=1
Reactant: ClC1=C(c2ccon2)CNCC1
Reactant: CCOC1CC(C2=C(Cl)CCN(C(=O)c3ccccc3)C2)=NO1
Agent: O=C(O)C(=O)O
Product: COCc1cc(C2=C(Cl)CCNC2)no1

Procedure:
4-Chloro-3-(3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalate starting from 1-benzoyl-4-chloro-3-(5-ethoxy-4,5-dihydro-3-isoxazolyl)-1,2,5,6-tetrahydropyridine. M.p. 195°-196° C.
Reaction SMILES: [Na].C[O-].[Na+:4].[CH2:5]([O:7][N:8]=[C:9]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])[CH3:6]>CO>[CH2:5]([O:7][N:8]=[C:9]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C:10]([O-:12])=[O:11])[CH3:6].[Na+:4]
Reactant: CCON=C(C(=O)O)c1ccco1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCON=C(C(=O)[O-])c1ccco1

Procedure:
To 50 ml. of methanol was added 250 mg. (0.0109 mole) of metallic sodium and stirred until all the sodium had dissolved. This sodium methoxide solution was treated with 2.0 g. (0.0109 mole) of α-ethoxyimino-α-(2-furyl)acetic acid dissolved in 10 ml. of methanol and stirred at room temperature for one hour. The methanol was removed at 40° C. (15 mm.) and the product was dried in vacuo over P2O5 at 25° C. to yield 2.22 g. white solid, m.p. decomp. >240° C. The IR and NMR were consistent for the structure. ##STR12##
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]([F:23])[CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Si:1]([O:18][CH2:19][CH:20]([F:23])[CH:21]=[O:22])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCC(F)CO)(c1ccccc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(F)C=O)(c1ccccc1)c1ccccc1
Reaction time: 0.67 h

Procedure:
To 3-{[tert-butyl(diphenyl)silyl]oxy}-2-fluoropropan-1-ol (0.900 g, 2.707 mmol) in dichloromethane (13.5 mL) was added Dess-Martin Periodinane (1.72 g, 4.06 mmol). The reaction was stirred for 40 minutes and then quenched with Na2S2O3 (2.0 M aqueous solution) and saturated sodium bicarbonate. The reaction was partitioned into dichloromethane and water and the organic solution dried over sodium sulfate. The organic solution was filtered and concentration to afford the title compound as a clear oil. 1H NMR (500 MHz, CDCl3) δ 1.05 (s, 9H), 4.02-4.12 (m, 2H), 4.75-5.07 (m, 1H), 7.35-7.44 (m, 6H), 7.64-7.69 (m, 4H), 9.85-9.86 (m, 1H) ppm.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([F:33])[CH:27]=1)[NH:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[N:17][C:16]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:15][C:14]=2[CH2:13]1)=[O:11])(=O)=O.[CH3:34][NH2:35]>C1COCC1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:8]([NH:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[N:17][C:16]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:15][C:14]=3[CH2:13]2)=[O:11])[CH2:7][CH2:6][NH:35][CH3:34])=[CH:27][C:28]=1[F:33]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)NC(CCOS(C)(=O)=O)c1ccc(Cl)c(F)c1)CC2
Reactant: CN
Solvent: C1CCOC1
Product: CNCCC(NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)c(F)c1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 310 (0.059 g, 0.12 mmol) and THF (3 mL) was added methylamine (0.092 g, 1.2 mmol, 40% aqueous solution) and the reaction was stirred at 45° C. for 1 h. The solution was concentrated, poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:30) to afford 3 mg (5.8%) of I-78: MS m/z (APCI-pos) M+1=435.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>C1COCC1.CC#N>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccnn1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccnn1)Oc1ccccc1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a suspension of pyridazin-3-amine (5 g, 50 mmol) in THF (50 mL) and CH3CN (70 mL) was added pyridine (5.10 mL, 63.1 mmol) followed by phenyl chloroformate (6.95 mL, 55.2 mmol) slowly. The reaction was stirred overnight. The reaction was filtered to remove the precipitate. The filtrate was concentrated and then taken up in CH2Cl2 which was washed with water. The organic layer was dried using SPE phase separators and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH/CH2Cl2). An undesired side product eluted first followed by the title compound which was concentrated to give a white solid (7.5 g, 70% yield). MS (APCI 10 V) AP+1 216.12; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20-7.24 (m, 2H) 7.25-7.28 (m, 1H) 7.39-7.44 (m, 2H) 7.64-7.69 (m, 1H) 8.05 (dd, 1H) 8.94 (dd, 1H) 11.34 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([CH3:10])[C:8]#[N:9].N>O>[CH3:10][C:7]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)([CH3:6])[C:8]([NH2:9])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C#N)N1CCOCC1
Agent: N
Solvent: O
Product: CC(C)(C(N)=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
272 ml of concentrated sulfuric acid are slowly added, with stirring, to 57.9 g of 2-methyl-2-morpholino-propionitrile (exothermic reaction). After the addition of 43 ml of water, the mixture is stirred for 2 hours at 100°-110° C. The reaction mixture is cooled to 50° C. and added dropwise at 0° C. to a solution of 846 ml of 20% ammonia in 242 ml of water. The mixture is then extracted repeatedly with dichloromethane. The organic phases are washed with saturated sodium chloride solution and with sodium sulfate. The crude title compound is obtained from the concentrated filtrate: 1H NMR (CDCl3), δ(ppm)=7.08 (1H, bs), 5.38 (1H, bs), 3.72 (4H, m), 2.53 (4H, m), 1.22 (6H, s)
Reaction SMILES: [C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]CC.C(O)(=O)CCCCCCCCCCCCCCCCCCC>>[C:1]([OH:26])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)O

Procedure:
Mixed with 120 kg of isopropyl alcohol was 100 kg of behenic acid (trade name Edenor C22-85R), manufacture by Henkel Co., dissolved at 50° C. and filtered employing a 10 μm filter. Thereafter, the temperature was lowered to 30° C., and recrystallization was performed. The cooling rate during recrystallization was controlled to be 3° C./hour. The resulting crystals were subjected to centrifugal filtration, were washed with 100 kg of isopropyl alcohol, and subsequently dried. The resulting crystals then underwent esterification. Subsequently, GC-FID was performed, resulting in a silver behenate proportion of 99 percent and a lignoceric acid proportion of 0.5 percent, and an arachidic acid proportion of 0.5 percent as other products.
Reaction SMILES: [C:1]([C@H:4]([C@@H:14]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]([NH:17][N:18]1[C:22](=[O:23])[CH2:21][N:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:19]1=[O:29])=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(O)=[O:2].[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.C(OCC)(=O)C.Cl.C(N=C=NCCCN(C)C)C>[CH2:34]([O:41][NH:42][C:1]([C@H:4]([C@@H:14]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]([NH:17][N:18]1[C:22](=[O:23])[CH2:21][N:20]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:19]1=[O:29])=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:2])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(CCN(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(CCN(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
A solution of 0.151 g of 2(R)-[1(S)-(carboxy)-4-phenylbutyl]-N-[3-[2-(dimethylamino)ethyl]-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide and 0.157 g of O-benzylhydroxylamine in 0.25 ml of dimethylformamide was treated with 0.054 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give a residue which was purified by flash column chromatography on silica gel, using methanol/dichloromethane (5:95) for the elution, to give 0.061 g of 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-N-[3-[2-(dimethylamino)ethyl]-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide in the form of a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[CH3:14]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:12][CH2:13][CH2:2][CH:3]([CH3:14])[CH3:4])=[CH:4][C:3]=1[CH3:14]
Reactant: CON(C)C(=O)c1ccc(Br)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CCCC(C)C)ccc1Br
Temperature: 0 °C
Yield: 159.7 %

Procedure:
4-Bromo-N-methoxy-3,N-dimethyl-benzamide (5.94 g, 23.05 mmol) was suspended in anhydrous tetrahydrofuran (200 mL), and cooled to 0° C. with stirring under nitrogen. 1-magnesium bromo-4-methyl-pentane (23 mL, 1.5M in tetrahydrofuran, 34.8 mmol) was slowly added to the reaction over 1 h. The reaction was allowed to warm slowly to room temperature and monitored by TLC. Upon complete consumption of starting material, the reaction was carefully neutralized with 1N hydrochloric acid, extracted with diethyl ether, washed, dried, and concentrated. The 1-(4-Bromo-3-methyl-phenyl)-5-methyl-hexan-1-one (5.2 g, 18.4 mmol) 80% yield, was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16]CC)=[O:15])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>C(O)C>[CH3:24][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)Cc1cccc(OCc2c(OC)cccc2OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(OC)c1COc1cccc(CC(=O)O)c1
Reaction time: 3 h

Procedure:
To a stirred solution Ethyl 2-(3-(2,6-Dimethoxybenzyloxy)phenyl)acetate (Step A, 6 g, 18.2 mmol) in absolute ethanol (100 ml) was added 1N NaOH (40 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and acidified by 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH:12]=[CH:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([N:32]2[CH2:37][CH2:36][C@:35]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:34][C:33]2=[O:49])[CH3:31])=[CH:26][CH:25]=1>>[OH:48][C:45]([CH3:46])([CH3:47])[CH2:44][C@@:35]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C:33](=[O:49])[N:32]([C@H:30]([C:27]2[CH:26]=[CH:25][C:24]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]4=[O:21])[N:14]=3)=[CH:29][CH:28]=2)[CH3:31])[CH2:37][CH2:36]1
Reactant: CC1(C)OB(c2cccc(N3CCCCC3=O)n2)OC1(C)C
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(N3CCCCC3=O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 1-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperidin-2-one (purchased from CombiPhos Catalysts Inc., Princeton, N.J., USA) and (S)-3-[(S)-1-(4-bromophenyl)ethyl]-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-1,3-oxazinan-2-one following a procedure analogous to that described in Example 35. LC (method 5): tR=1.62 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30]C)=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:11]=[N:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][NH:16][C:17]3=[O:22])[CH:7]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]2[C:7]=1[CH:11]([NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=1[CH2:15][NH:16][C:17]3=[O:22])[C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:9][C:8]2([CH3:29])[CH3:28]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2c1CNC2=O)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c2CNC3=O)c2c(F)ccc(O)c21
Temperature: 25 °C
Yield: 7.9 %

Procedure:
420 mg (0.958 mmol) of the compound 4-{[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}-2,3-dihydroisoindol-1-one that is described in the paragraph above is mixed with 9.6 ml of a 1 M solution of boron tribromide in dichloromethane, and it is stirred for 1¾ hours at room temperature. The reaction mixture is mixed drop by drop with saturated sodium bicarbonate at −30° C., specifically up to pH 8. After dilution with ethyl acetate, the cold bath is removed and stirred vigorously for 15 minutes. After 2× extraction with ethyl acetate, the organic phases are washed with water and saturated sodium chloride solution. After the solvent is dried (sodium sulfate) and spun off, the residue is chromatographed on a Flashmaster (silica gel, NH2 phase) (mobile solvent dichloromethane/methanol). 67.7 mg (16.6%) of 4-{[8-fluoro-2-hydroxy-5-methoxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer A, F1); 12.9 mg (3.2%) of 4-{[8-fluoro-2,5 dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer A, F2), and 32.2 mg (7.9%) of 4-{[8-fluoro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2,3-dihydroisoindol-1-one (diastereomer B, F3) are isolated.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3S(C)(=O)=O)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-methanesulfonylbenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (97% yield). 1H NMR (400 MHz, CDCl3) δ 8.11, 8.03, 7.85, 7.74-7.62, 7.38, 4.32-3.33, 3.27, 1.73-1.62, 1.52-1.46, 0.94. MS (ES+) m/z 484.3 (M+1).
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[S:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[S:13])=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=S)c1ccc(C2CCCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC(=S)c1ccc(C2CCCCCC2)cc1
Reaction time: 8 h
Yield: 100.9 %

Procedure:
Add methyl 4-cycloheptylthio-benzoate (1.1 g, 4.16 mmol) and sodium hydroxide (500 mg, 12.5 mmol) to methanol (20 mL) and stir overnight. Add 2M aqueous HCl (20 mL) and extract the aqueous phase with dichloromethane. Wash the combined organic extracts with water (20 mL) and brine (20 mL). Dry the organic solution over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as a white solid (984 mg, 94%). MS (APCI) m/z: 251 (M+H)+.
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([OH:24])=[C:20]([CH:23]=1)[C:21]#[N:22]>CN(C=O)C.O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][CH:2]([F:6])[F:7])=[C:20]([CH:23]=1)[C:21]#[N:22]
Reactant: N#Cc1cc(Br)ccc1O
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Br)ccc1OC(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Sodium chloro(difluoro)acetate (9.62 g, 63.1 mmol) and cesium carbonate (12.3 g, 37.9 mmol) were added to a mixed solution of 5-bromo-2-hydroxybenzonitrile (5.00 g, 25.2 mmol) in DMF (50 mL) and water (5 mL), and the mixture was stirred at 100° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-98/2] to obtain the title compound (3.83 g, yield: 61%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[N:39]=[C:40]=[O:41]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:40]([NH:39][C:33]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=2[F:31])=[O:41])[CH:25]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)Nc3cc(C)ccc3F)c2)c1

Procedure:
A solution of methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate (85.6 mg, 0.2 mmol, 1 eq) and 2-fluoro-5-methylphenyl isocyanate (29 μL, 1.1 eq) in anhydrous DMF (2 mL) was stirred at room temperature overnight. The reaction was then diluted with EtOAc, washed sequentially with aq NH4Cl, saturated aq NaHCO3, brine, and lastly dried with sodium sulfate. The clear solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtOAc-Hex from 1:1 to neat EtOAc). The product containing fractions were concentrated to give the title compound as a white foam (86.2 mg).