Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@H:19]2[CH2:23][C@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:36])([F:35])[F:37])(=[O:26])=[O:25])[CH2:21][C@@H:20]2[O:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:18])[CH2:14][CH2:15]1)#[N:12]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC4CCCC4)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2,4-difluorophenylboronic acid and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-cyclopentyloxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 195) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 562.3 (M+H)+.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:36][CH:35]=2)[C:21]=1[Cl:47])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:47][C:21]1[C:22]([N:27]([CH3:46])[C:28](=[O:45])[CH2:29][NH:30][C:31](=[O:44])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40](=[O:43])[NH:41][CH3:42])=[CH:36][CH:35]=2)=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][OH:18]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cc1
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a suspension of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)-cinnamoylglycyl]amino]benzene (17.6 g) in tetrahydrofuran (138 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (38.4 ml) at ambient temperature. The reaction mixture was stirred for 1 hour. The mixture was concentrated and diluted with dichloromethane. The organic layer was washed with 1H hydrochloric acid, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo to give 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]-benzene (8.14 g).
Reaction SMILES: CI.[C:3](=O)(O)[O-].[Na+].[O:8]=[C:9]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[NH:12][CH2:11][CH:10]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CO>[O:8]=[C:9]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]([CH3:3])[CH2:11][CH:10]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CN1CC(NC(=O)OC(C)(C)C)C(=O)Nc2ccccc21
Yield: 66.9 %

Procedure:
Methyl iodide (1.4 ml) and sodium bicarbonate (630 mg) were added to a solution of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (832 mg) in methanol (20 ml), the mixture was refluxed for 2 days. The reaction mixture was concentrated under reduced pressure, Water (30 ml) was added to the residue and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodiun sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby obtain 585 mg of the title compound (Yield: 66.9%) as brown amorphous.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[N:16]3[N:17]=[N:18][N:19]=[C:15]3[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:13]([CH3:30])=[C:12]2[C:31]([O:33]CC)=[O:32])=[CH:7][CH:6]=1)#[N:4].Cl>C(O)C.C1COCC1.O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[N:16]3[N:17]=[N:18][N:19]=[C:15]3[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[C:13]([CH3:30])=[C:12]2[C:31]([OH:33])=[O:32])=[CH:9][CH:10]=1)#[N:4]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nnnn2[C@@H]1c1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2)n2nnnc2N1c1cccc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
The reaction was carried out under argon. Solid lithium hydroxide (15.8 mg, 660 μmol, 3 eq.) was added to a solution of ethyl (7R)-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (100 mg, 220 μmol) in an ethanol/THF/water mixture (4:1:0.6, 5.6 ml). The solution was heated at 55° C. for 1.5 h. At 0° C., the mixture was then acidified with 1 N hydrochloric acid (0.66 ml) and then directly purified by preparative HPLC (Kromasil C18 column; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless amorphous solid (67 mg, 71% of theory).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:58][N:59]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:61]([CH2:68]O)=[N:60]1>O1CCCC1>[CH3:1][C:2]1[N:3]([CH2:68][C:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:59]([CH3:58])[N:60]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: Cn1nc(CO)c2ccccc21
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCc1nc(C)n(Cc2nn(C)c3ccccc23)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.47 g), tributylphosphine (1.81 mL), (1-methyl-1H-indazol-3-yl)methanol (0.51 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated. The residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 47%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17]>C(Cl)Cl>[CH3:2][C:1]([C:14]1[CH:13]=[CH:12][C:11]([O:16][CH3:17])=[C:10]([F:9])[CH:15]=1)=[O:3]
Reactant: COc1ccccc1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)cc1F
Temperature: 0 °C
Yield: 88.1 %

Procedure:
To a solution of 700 ml of dried methylene chloride and 157 g of acetyl chloride was added dropwise 267 g of anhydrous aluminum chloride over 30 minutes with stirring while holding temperature at 15°-25° C., which were further stirred at room temperature for about 2 hours. Separately, a solution of 206 g of o-fluoroanisole and 170 ml of dried methylene chloride was cooled on an ice water bath, to which was added dropwise the previously prepared solution of acetyl chloride and aluminum chloride in methylene chloride over about 2.5 hours. The resulting mixture was further stirred on the ice water bath for 1 hour and at room temperature for 1 hour. The resulting reaction mixture was poured into 1.4 l of ice water and separated into two layers. The extraction with 400 ml of methylene chloride on aqueous layer was repeated two times, and thereafter the organic layers were gathered, washed with water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and dried to obtain a light brown crystal. This crystal was recrystallized with ethanol to obtain 242 g (yield: 88%) of a white crystal having a melting point of 89.5°-90.0° C.
Reaction SMILES: CNN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][CH2:16][C:17]([O:19][C@:20]([C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=1[F:56])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[C@H:21]([S:23][C@@H:24]1[CH2:29][O:28][C@@H:27](/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][C:35]=2[F:42])[O:26][CH2:25]1)[CH3:22])=[O:18]>ClCCl>[NH2:6][CH2:15][CH2:16][C:17]([O:19][C@:20]([C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=1[F:56])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[C@H:21]([S:23][C@@H:24]1[CH2:29][O:28][C@@H:27](/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][C:35]=2[F:42])[O:26][CH2:25]1)[CH3:22])=[O:18]
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)CCN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1F
Agent: CNN
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)CCN)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 52 %

Procedure:
222.7 mg (4.38 mmol) of methylhydrazine were added to a solution of 100 mg (0.13 mmol) of [(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadien-1-yl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propyl] 3-(1,3-dioxo-1,3-dihydro-2-isoindolyl)propionate [prepared described in Step 13(i) above] in 2 ml of dichloromethane in an ice bath. The resulting mixture was stirred at ambient temperature for 20 hours. At the end of this time, the reaction mixture was concentrated and then evaporated to dryness in vacuo. Dichloromethane was added to the resulting residue and the dichloromethane was then evaporated under reduced pressure The resulting residue was then dissolved in dichloromethane, the solution was allowed to stand at ambient temperature for 12 hours and then concentrated. The residue thus obtained was purified by chromatography on a silica gel (15 g) column using a 9:1 mixture of ethyl acetate and methanol to give 41.5 mg (yield 50%) of the title compound as a pale yellow non-crystalline solid.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:10]([Cl:11])[C:4]=2[N:3]=1.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.O>[Cl:11][C:10]1[C:4]2[NH:3][C:2]([N:21]3[CH2:20][CH2:19][NH:18][C@H:17]([CH3:16])[CH2:22]3)=[N:6][C:5]=2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1
Temperature: 120 °C

Procedure:
A mixture of 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole (0.51 g, 2 mmol, Example 5b), (R)-(−)-2-methylpiperazine (0.25 g. 2.5 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.9 mmol) in NMP (5 mL) was heated at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH in dichloromethane to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 319 (M+1).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[C:11]([N:13]([CH3:27])[C:14](=[O:26])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Cl-].[Na+]>CN(C=O)C>[Br:9][C:10]1[C:11]([N:13]([CH3:27])[C:14](=[O:26])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[N:18]([CH3:1])[CH:17]=1)=[O:12]
Reactant: Cc1ccc2[nH]cc(C3=C(Br)C(=O)N(C)C3=O)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc2c(c1)c(C1=C(Br)C(=O)N(C)C1=O)cn2C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
Potassium carbonate (130 mg, 0.94 mmol) and methyl iodide (0.06 mL, 0.94 mmol) were added under ice cooling to 2-bromo-3-(5-methyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.31 mmol) dissolved in DMF (5 mL), and the whole was stirred for 1.5 hours. The reaction mixture was warmed to room temperature, added with saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:2) to obtain 2-bromo-3-(1,5-dimethyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 95.8%) as red solids.
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:22](=[O:24])[CH3:23])[CH2:14][C@H:13]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]1=[O:34])C1C=CC=CC=1>CO.[Pd]>[O:34]=[C:12]1[N:11]([CH2:10][C:9]([OH:35])=[O:8])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:22](=[O:24])[CH3:23])[CH2:14][CH:13]1[NH:25][C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CC(NC(=O)c2ccccc2)C(=O)N(CC(=O)O)c2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of (3S)-2-oxo-3-(benzoylamino)-5-acetyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid benzyl ester (602d; 510 mg, 1.08 mmol) and 5% Pd/C (250 mg) in MeOH (10 ml) stirred under H2 (1 atm) for 0.5 h. The reaction was filtered and concentrated in vacuo 410 mg of 603d as a white solid.
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4])[NH2:2].C(O)C.[S:21]=[C:22]=S.[OH-].[K+]>C(OCC)C.O>[S:21]=[C:22]1[O:4][C:3]([C@@H:5]2[CH2:9][CH2:8][CH2:7][C@@H:6]2[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[N:1][NH:2]1
Reactant: S=C=S
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1c1n[nH]c(=S)o1
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl [(1S,2R)-2-(hydrazinocarbonyl)cyclopentyl]carbamate (370 mg) and ethanol (5.6 ml) was ice-cooled, and dithioxomethane (230 μl) and potassium hydroxide (120 mg) were added thereto in this order, followed by stirring at the same temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour, warmed, and heated for 6 hours under reflux. The reaction mixture was left to be cooled, and water (50 ml) and diethyl ether (50 ml) were added thereto, followed by liquid separation. The aqueous layer was ice-cooled, and 1 M hydrochloric acid was added thereto to adjust the pH to about 4, followed by extraction with ethyl acetate (50 ml). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was washed with diisopropyl ether (5 ml) to obtain tert-butyl [(1S,2R)-2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)cyclopentyl]carbamate (308 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[Al].[H][H].[CH2:13]([S:15]SCC)[CH3:14].Cl>>[CH2:13]([S:15][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[OH:9])[CH3:14]
Reactant: [H][H]
Reactant: CCc1cccc(O)c1
Reactant: CCSSCC
Agent: Cl
Agent: [Al]
Product: CCSc1ccc(CC)cc1O
Reaction time: 7 h

Procedure:
To freshly distilled 3-ethylphenol (100 grams, 0.82 moles), was added aluminum turnings (1.62 grams, 0.06 moles) and the mixture was heated at 175° to 195° C. until hydrogen evolution had ceased. Ethyldisulfide (63 grams, 0.515 moles) was then added in one portion at 150° C. This mixture was then heated at 175° to 180° C. for 18 hours and then for about 7 hours at 196° C. The resulting mixture was hydrolyzed with 3 N HCl, extracted with diethylether, washed with water and dried over magnesium sulfate. Distillation of the mixture followed by a redistillation through a packed column gave, after removal of by-products and starting materials, 8.15 grams of 2-ethylthio-5-ethylphenol as verified by 1H and 13C NMR.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.Br[C:31]1[N:32]=[C:33]([CH2:46][CH3:47])[C:34]([NH:39][C@H:40]2[CH2:44][O:43][CH2:42][C@H:41]2[OH:45])=[N:35][C:36]=1[CH2:37][CH3:38].[Cl:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=1B(O)O>>[Cl:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[CH:51][C:50]=1[C:31]1[N:32]=[C:33]([CH2:46][CH3:47])[C:34]([NH:39][C@H:40]2[CH2:44][O:43][CH2:42][C@H:41]2[OH:45])=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: CCc1nc(N[C@H]2COC[C@H]2O)c(CC)nc1Br
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting cis-(+/−)-4-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol and 2-chloro-4-methoxyphenylboronic acid and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 3420, 2969, 2935, 2873, 1604, 1568, 1482, 1439, 1397, 1393, 1287, 1229, 1204, 1181, 1044 cm−1; OAMS supporting ions at: ESI+ 378.1; MS (EI) m/z 377 (M+); HRMS (FAB) calcd for C19H24CLN3O3+H1 378.1584, found 378.1566. Anal. Calcd for C19H24ClN3O3: C, 60.39; H, 6.40; N, 11.12. Found: C, 59.97; H, 6.46; N, 10.99.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(O)[CH2:8][CH2:9][CH2:10][CH2:11]OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[BrH:25]>O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH2:9][CH2:10][CH2:11][Br:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br
Reactant: COCCCCC(O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: BrCCCC=C(c1ccccc1)c1ccccc1

Procedure:
A mixture of the pentanol prepared as above (8.88 g., 0.0328 mole) in 132 ml. of glacial acetic acid and 66 ml. of distilled hydrobromic acid was stirred at ambient temperature for two hours and then refluxed for 90 minutes. The reaction mixture was cooled, diluted with water and extracted with ether. The ether extract was washed with 5% sodium carbonate solution, water, dried and concentrated to obtain an oil which is chromatographed on silica to yield 5,5-diphenyl-4-pentenyl bromide.
Reaction SMILES: COC(=O)[C@H](CC1C=C(I)C(OC2C=C(I)C(O)=C(I)C=2)=C(I)C=1)N[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]2=[O:19])[CH:8]=1.C1(=O)N(C2C=C(C=CC=2)C(O)=O)C(=O)C=C1.S(Cl)([Cl:59])=O>>[C:17]1(=[O:18])[N:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([Cl:59])=[O:20])[C:14](=[O:19])[CH:15]=[CH:16]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)c1cccc(N2C(=O)C=CC2=O)c1
Agent: O=C(O)c1cccc(N2C(=O)C=CC2=O)c1
Product: O=C(Cl)c1cccc(N2C(=O)C=CC2=O)c1

Procedure:
Preparation of m-maleimidobenzoyl thyroxine methyl ester (as described by Monji, N., Malkus, H, and Castro, A., Biochem. Biophys. Res. Commun., 1978, 85, 671-677). m-Maleimidobenzoic acid (225 mg, 1.06 mmol) was dissolved in 4 mL of thionyl chloride and refluxed for 30 minutes. Removal of excess thionyl chloride under reduced pressure afforded m-maleimidobenzoyl chloride as a pale yellow solid. The acid chloride (220 mg dissolved in 10 mL of tetrahydrofuran) was added dropwise to a stirred suspension of 400 mg (0.51 mmol) of thyroxine methyl ester and 400 mg of sodium carbonate. After the addition was complete, the mixture was refluxed for 30 minutes. Removal of the solvent under reduced pressure yielded a crude yellow product. The material was purified by silica gel chromatography with chloroform as the eluent. 1NMR (CDCl3) δ 3.85 (3 H,s), 3.92 (1 H,m), 5.77 (1 H,s), 6.90 (2 H,s), 7.12 (2 H,s), 7.57 (2 H,m), 7.70 (2 H,s), 7.80 (2 H,m). Anal. calcd. for C27H18I4N2O7 : C, 32.8; H, 1.82; N, 2.80. Found: C, 32.7; H, 2.09; N, 2.42.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[CH3:18])[CH2:6]1)=[O:4].[NH:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:13]1[C:12]([CH3:18])=[C:11]([N:7]2[C:8](=[O:10])[CH2:9][N:5]([C:3](=[O:4])[CH2:2][N:20]3[CH:21]=[C:22]4[C:23]([N:24]=[CH:25][CH:26]=[CH:27]4)=[N:19]3)[CH2:6]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O
Reactant: c1cnc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1N1CN(C(=O)Cn2cc3cccnc3n2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-Chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (230 mg, 0.8 mmol, 1 eq), 1H-Pyrazolo[3,4-b]pyridine (96 mg, 0.8 mmol, 1 eq), Cesium carbonate (653 mg, 2.0 mmol, 2.5 eq) in DMF (6 ml) was stirred at room temperature overnight. It was diluted with ethyl acetate, washed with water and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 370.1
Reaction SMILES: [OH:1][CH:2]([CH2:34][CH2:35]CCCCCCCCCCCCC)[CH:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]CCCC)[C:4]([O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH2:53]([O:1][CH:2]([CH2:34][CH2:35][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:3][CH2:2][CH2:34][CH3:35])[CH:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]([O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:5])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCC(C(=O)OCC(=O)c1ccccc1)C(O)CCCCCCCCCCCCCCC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(OCc1ccccc1)C(CCCCCCCCCCCCCC)C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
Then, phenacyl 3-hydroxy-2-n-octadecyl-octadecanoate (IV) (1.81 g, 2.94 millimole) was dissolved in dry methylene chloride (80 ml) under, argon atmosphere, and benzyl 2,2,2-trichloro-acetimidate (0.66 ml, 3.53 millimole) and trifluoromethane sulfonic acid (0.052 ml, 0.59 millimole) were successively added dropwise thereto with ice cooling. The reaction mixture was allowed to warm to room temperature, and to react for 17 hours, then methylene chloride was added to the reaction mixture, and the obtained solution was successively washed with saturated aqueous sodium bicarbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off from the solution. The residue was dissolved in a developing solvent (benzene:n-hexane=6:4), and fractionated through silicagel column (benzene:n-hexane=6:4), and the fast eluting fractions comprising impurities were discarded and then the later colorless fractions were pooled and the solvent was distilled off to give phenacyl 3-benzyloxy-2-n-tetradecyl-octadecanoate (V) (783.9 mg) in the form of colorless oil.