Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[NH2:24][CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2′-Aminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.058 g, 0.17 mmol) in THF (0.59 mL) and MeOH (0.47 mL) was treated with 1N aqueous NaOH (0.17 mL, 0.17 mmol) and stirred overnight at room temperature. Analytical LCMS indicated that starting material was still present, so the reaction was stirred at 50° C. for 4.5 hours. Analytical LCMS showed that no change had occurred, so additional IN aqueous NaOH (0.20 mL, 0.20 mmol) was added, and the reaction was stirred at 50° C. overnight. The mixture was cooled to room temperature and acidified with 1N aqueous HCl. The aqueous layer was extracted with CH2Cl2, and then diluted with brine and extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[C:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]1=[O:24])[O:10][CH2:9]2.[H][H]>[Pd].CO>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[C:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]1=[O:24])[O:10][CH2:9]2
Reactant: [H][H]
Reactant: CN(C)CC#Cc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Yield: 23 %

Procedure:
A mixture of 3-[5-(3-dimethylamino-prop-1-ynyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (300 mg, 0.91 mmol) and 10% palladium on carbon (60 mg) in MeOH (20 ml) was shaken under 43 psi of hydrogen for 4 hours. The catalyst was removed by filtration through celite and rinsed with MeOH. The combined filtrates were evaporated to give a crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of MeOH in CHCl3, to give 3-[5-(3-dimethylamino-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (70 mg, 23%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([C@H:8]1CCC[N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C@H:2]1[CH2:1][CH2:6][CH2:8][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH2:4]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
n-Butyl lithium (1.6 M in hexanes) (27 mL, 43 mmol) was added to ice-cold hexamethyldisilazane (9.2 mL, 44 mmol) under a nitrogen atmosphere. The solution was stirred for 10 min and was then added to a suspension of methyl(triphenylphosphonium)bromide (15.5 g, 43 mmol) in 100 mL of THF at ambient temperature. After stirring for 1 h, the mixture was cooled to −78° C. and a solution of tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (7.9 g, 40 mmol) in 50 mL of THF was added. The cold bath was removed and the mixture stirred overnight at ambient temperature. The reaction mixture was then quenched with saturated NH4Cl, the phases were separated, and the organic phase was washed with saturated NH4Cl, brine, dried over Na2SO4, filtered, and concentrated to give an orange oil. The oil was purified on a Biotage 40M column eluting with heptane to give tert-butyl (2R)-2-vinylpyrrolidine-1-carboxylate (5.0 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[CH:9]=2)[N:3]=1.[CH:18]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1)=O.C(O)(=O)C.Cl>CO>[Cl:16][C:14]1[CH:15]=[C:8]([NH:7][C:4]2[N:3]=[C:2]([NH:1][CH2:18][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:22][CH:21]=3)[NH:6][N:5]=2)[CH:9]=[C:10]([Cl:17])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(Cl)cc(Nc2n[nH]c(N)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(CNc2nc(Nc3cc(Cl)c(C#N)c(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
To a solution of 4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-benzonitrile (60 mg, 223 μmol) in MeOH (3.5 ml) was added tert-butyl 4-formylbenzoate (55.2 mg, 268 μmol) followed by acetic acid (21.0 mg, 20 μl, 349 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (32.2 mg, 349 μmol) was added and the stirring was continued for 4 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and let stand. The resulting suspension was filtered to collect the solid. Purification by super fluid chromatography and trituration from acetonitrile afforded a white solid as desired product (54.5 mg, 53% yield). MS +m/z: 459 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.O.[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>O1CCOCC1>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([O:17][CH:24]([F:26])[F:25])[C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: FC(F)Cl
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1cc(-n2nc3c(c2Cl)CCCC3)c(Cl)cc1Cl
Reaction time: 0.25 h

Procedure:
To a solution of 6.4 g of 3-chloro-2-(2,4-dichloro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole II-1 in 12.5 ml of dioxane were added 12.5 ml of water and 6.4 g of 50% sodium hydroxide. The mixture was heated at 50°~60° C., mixed with excessive amount of chlorodifluoromethane, and heated at 50°~60° C. To the mixture was dropwise added 6.4 g of 50% sodium hydroxide respectively 2.5 hours later and 4 hours later within 15 minutes. The resulting mixture was allowed to react for 2.5 hours, cooled, neutralized, and extracted with ether. The extract was washed with saturated aqueous sodium chloride, dried and concentrated. The residue was purified by silica-gel chromatography to give 4.0 g of the titled compound I-1.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=O)[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:45][C@@H:46]([C:59]([NH:61][C@H:62]([C:70]([N:72]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:73])=[O:71])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:60])[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([CH:57]=[O:58])[CH:49]=1>CN(C=O)C>[NH:1]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C@H:2]([C:19]([NH:45][C@@H:46]([C:59]([NH:61][C@H:62]([C:70]([N:72]([CH2:74][C:75]1[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=1)[CH3:73])=[O:71])[CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)=[O:60])[CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([CH:57]=[O:58])[CH:49]=1)=[O:21])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)Cc1cn(C=O)c2ccccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc3cn(C=O)c4ccccc34)C(=O)N[C@@H](Cc3ccccc3)C(=O)N(C)Cc3ccccc3)c2)cc1

Procedure:
A solution of Boc-His(Tos)-OH (0.82 g) in DMF (10 ml) was cooled at -15° C. To the solution, NMM (0.22 ml) and isobutyl chloroformate (0.26 ml) were added successively and the mixture was stirred for ten minutes. On the other and, a solution of HCl.H-D-Trp(CHO)-Phe-NMeBzl in DMF (10 ml) was cooled at -15° C. and thereto was added NMM (0.22 ml). This solution was added to the above mentioned mixture and stirred for an hour at -15° C. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water and saturated sodium chloride solution, and dried over magnesium sulfate to give Boc-His(Tos)-D-Trp(CHO)-Phe-NMeBzl. After evaporation, the residue was dissolved in DMF (20 ml). To the solution, pyridinium chloride (2.18 g) was added under stirring at room temperature. After an hour, additional pyridinium chloride (0.5 g) was added and stirred for additional fifty minutes. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with water, 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water, saturated sodium chloride solution and dried over magnesium sulfate. After evaporation, the residue was subjected to column chromatography on silica gel (60 g) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were combined and evaporated. The residue was pulverized with a mixture of ethanol, diethyl ether and n-hexane. The powder was filtered, washed with n-hexane and dried to give Boc-His-D-Trp(CHO)-Phe-NMeBzl (1.04 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].B1(C=C)OB([CH:17]=[CH2:18])OB(C=C)O1.C1C=CN=CC=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([CH:17]=[CH2:18])[C:3]=1[CH:4]=[O:5]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: O=Cc1c(F)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1cccc(F)c1C=O
Temperature: 180 °C

Procedure:
To a vial charged with 2-chloro-6-fluorobenzaldehyde (158 mg, 1.0 mmol), 2,4,6-trivinylcyclotriboroxane pyridine complex (380 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (52 mg, 5 mol %) and potassium carbonate (280 mg, 2.0 mmol) was added a 3:1 mixture of 1,2-dimethoxyethane and water (2 mL). Upon completion of addition, the reaction was heated at 180° C. for 1 h under microwave conditions and then diluted with EtOAc (5 mL). The resulting mixture was washed with satd NaHCO3 (5 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide crude 2-fluoro-6-vinylbenzaldehyde. The crude 2-fluoro-6-vinylbenzaldehyde was dissolved in methanol (5 mL) and 10% palladium on carbon was added. The resulting reaction mixture was stirred under an atmosphere of H2 for 3 h and then filtered through celite. Once again, the volatiles were removed under reduced pressure to provide Intermediate 27 (approximately 300 mg) as a pale yellow oil, which was used without further purification.
Reaction SMILES: N1C=CC=CC=1.[S:7]([O:14]S(C(F)(F)F)(=O)=O)([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8].[C:22]([O:26][C:27]([C:29]1([CH2:38]O)[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([C:29]1([CH2:38][O:14][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)N1CCC(CO)(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(COS(=O)(=O)C(F)(F)F)(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
A mixture of 2.0 ml (250 mmol) of pyridine and of 20 ml of dichloromethane is cooled to −78° C. under nitrogen. Triflic anhydride (2.10 ml, 12.5 mmol) is added drop by drop. After 10 min, a solution of 1.29 g of the compound from step 2 (5.0 mmol) in 15 ml of CH2Cl2 is added drop by drop. The mixture is stirred for 2 hours at −78° C. The organic phase is washed with 1N HCl, H2O, sat. NaCl, dried over Na2SO4 and concentrated at reduced pressure to produce 1.68 g of the expected product (yield: 86%) used as it is for the next step.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[C@H:17]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH2:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:13]([O:15][CH:16]2[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:18][CH:19]=[CH:20][O:21]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(OC1OC=CN=C1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 159.3 %

Procedure:
A solution of (2R-cis)-2-[[1-[3.5-bis(trifluoromethyl)phenyl]-ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)mopholine (1082 g, 94% pure, 1.94 moles) in 1:1 ethyl acetate:ethanol (13 L) was mixed with 10% palladium-on-carbon (165 g). The resulting slurry was treated with hydrogen (40 psi, 20-25° C.) for 12 hours. The reaction was monitored by hydrogen uptake and HPLC. The vessel was vented, and the catalyst was removed by filtration. After washing the catalyst with 1:1 ethyl acetate:ethanol (6 L) followed by ethyl acetate (2 L), the combined organic phases containing crude product were vacuum concentrated. A second batch, starting with 1078 g of (2R-cis)-2-[[1-[3.5-bis(trifluoromethyl)phenyl]ethenyl]oxy]-3-(4-fluorophenyl)-4-(phenylmethyl)mopholine (1.93 moles) was prepared. The resulting crude product was vacuum concentrated and combined with the first batch. The combined batches of crude product were flushed with methyl-t-butyl ether (2×3 L) in order to remove residual ethyl acetate and ethanol, then were dissolved in methyl-t-butyl ether (3 L). The solution was assayed to contain 1348 g (3.09 moles, 80% yield) of the title compound (as the free base). Alternatively, 60 g of the vinyl ether, 650 mL of methyl t-butyl ether (MTBE), and 18 g of 5% Pd on alumina were stirred under 40 psi hydrogen pressure at 40° for 12 H. Assay yield was 87%, with a 91:9 ratio of diastereomers. At the end of the reaction age, the catalyst was removed by filtration through Solka-Floc, then the filtrate was concentrated to 140 mL.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(N(CC)CC)C>C(O)C>[C:16]1(=[O:25])[N:15]([CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[3-(bromo)propyl]phthalimide (5.90 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour and heated at reflux for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.79 g of the desired product (71.1%, colorless crystals).
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[Cl:9][C:10]1[C:15](Cl)=[N:14][CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[C:15]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: Clc1nccnc1Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: Clc1nccnc1Oc1ccccc1

Procedure:
A suspension of 0.1 mole of sodium phenoxide and 0.1 mole, 2,3-dichloropyrazine is refluxed 10-20 hours. The cooled mixture is extracted with diethyl ether, washed with cold 2 N sodium hydroxide solution, dried, and evaporated to give 2-chloro-3-phenoxypyrazine.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:21][CH3:22])[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[S-:23][C:24]#[N:25].[Na+]>>[C:17]([C:8]1[CH:7]=[C:6]([C:4]2[NH:25][C:24](=[S:23])[NH:2][C:3]=2[CH2:21][CH3:22])[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]=1[OH:16])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#C[S-]
Reactant: CCC(N)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Product: CCc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 45.2 %

Procedure:
By following the same procedure as in Example 8 using 13.1 g of 2-amino-1-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-butanone hydrochloride, 6.5 g of sodium thiocyanate, 3.4 ml of concentrated, and 100 ml of acetic acid and recrystallizing the reaction product from isopropanol, 6 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-thioxo-4-imidazoline was obtained.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4](Br)=[CH:3][C:2]=1[CH:10]=[O:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].N#N>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:4]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH:7]=[O:8])[CH:1]=[C:2]([CH:10]=[O:11])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cc(Br)cc(C=O)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(C=O)cc(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 73.7 %

Procedure:
A solution of 5-bromoisophthaldehyde (40.0 g, 187.8 mmol), phenylboronic acid (22.9 g, 187.8) and potassium carbonate (64.8 g, 469.5 mmol) in DME/H2O (5:1, 600 mL) was purged with N2 for 5 min. Tetrakispalladium triphenylphosphine (1.1 g mg, 0.9 mmol) was added and the reaction mixture was heated to 90° C. and stirred for 16 h. The reaction mixture was cooled, filtered through a pad of Celite diatomaceous earth, and the solvent was evaporated under reduced pressure. Purification by column chromatography (10% EtOAc/hexanes) afforded the desired product (74%, 29.1 g) as a tan solid. 1H NMR (300 MHz, CDCl3) δ ppm 10.18 (s, 2H), 8.37 (d, J=1.2 Hz, 2H), 8.35 (t, J=1.5 Hz, 1H), 7.70-7.66 (m, 2H), 7.55-7.43 (m, 3H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31](Br)[C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1)[CH3:20]>CN(C)C=O.O>[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]([CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH:31]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=1)[CH3:20]
Reactant: Sc1ccccc1
Reactant: COC(=O)C(Br)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccccc1
Temperature: 25 °C

Procedure:
Thiophenol (0.92 mL) was added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in oil, 0.38 g) in dry N,N-dimethylformamide (60 mL). The mixture was allowed to warm to room temperature over 30 minutes prior to the addition of a solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-bromopropanoate (3.85 g) in N,N-dimethylformamide (40 mL) and the mixture was then heated at 80° C. for 72 hrs, cooled and diluted with water (1 L). The mixture was extracted with ethyl acetate (3×250 mL) and the combined organic solutions washed with water (3×1 L) and brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using a gradient of 1% methanol to 2% methanol in dichloromethane as eluent to afford the title compound, mp 78°-9° C. (dichloromethane-hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH4-].[Na+].O>C(O)C>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Reaction time: 1 h
Yield: 44.8 %

Procedure:
A stirred solution of d 6-amino-5-fluoro-1,3-dihydro-indol-2-one (2.26 g, 13.6 mmol) obtained from Example 6 in 40 ml of ethanol was added with 4-fluoro-benzaldehyde (1.5 ml, 13.6 mmol) at 0° C. in an ice-water bath. The resulting solution was stirred for 1 hour, added with sodium borohydride (1.08 g, 28.5 mmol) and heated to reflux overnight. The resulting mixture was added with water until a precipitate was formed. The solid was filtered and washed with water (50 ml×3). The crude was purified by silica gel column chromatography with dichloromethane and methanol (20:1) as eluents to give 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one (1.67 g, 45%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:26]([N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[O:27])[CH2:10]2)[O:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1>>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:26]([N:28]3[CH2:29][CH2:30][S:31](=[O:42])[CH2:32][CH2:33]3)=[O:27])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Yield: 44.1 %

Procedure:
129 mg (0.266 mmol) of the compound from Example 64 were reacted according to General Method 2 with 82.7 mg (0.240 mmol) of meta-chloroperbenzoic acid. Enantiomer separation of 132 mg of the racemate according to Method 8D gave 51.0 mg of the title compound from Example 65 (enantiomer 1) and 53.0 mg of the title compound from Example 66 (enantiomer 2).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][NH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C(N(CC)CC)C>ClCCCl>[CH3:15][N:16]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNc1nccs1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N(C)c2nccs2)cc1
Temperature: 100 °C
Yield: 79.2 %

Procedure:
To methyl 4-chlorosulfonylbenzoate (4 g, 17.05 mmol), N-methylthiazol-2-amine (1.95 g, 17.05 mmol), 1,2-dichloroethane (20 mL), and triethylamine (2.38 mL, 17.05 mmol) were added and the reaction was heated at 100° C. in a pressure vessel for 20.5 hours on a heat block. The solvent was evaporated under reduced pressure. The crude compound was dissolved in dichloromethane and filtered. The filtrate was purified by silica gel chromatography utilizing a gradient of 0-30% ethyl acetate in dichloromethane to yield methyl 4-[methyl(thiazol-2-yl)sulfamoyl]benzoate (4.22 g, 79.2%). 1H NMR (400 MHz, DMSO) δ 8.16 (d, J=8.5 Hz, 2H), 7.95 (d, J=8.5 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H), 3.89 (s, 3H), 3.39 (s, 3H). ESI-MS m/z calc. 312.0, found 313.3 (M+1)+; Retention time: 1.52 minutes (3 min run).