Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16]CCC#N)=[O:15])=[C:12]([CH3:21])[NH:11][C:10]([CH2:22][O:23][CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:9]2[C:32]([O-])=[O:33])[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.Cl.[C:47]1([CH:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:54][CH2:55][NH2:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:32](=[O:33])[NH:56][CH2:55][CH2:54][CH:53]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:10]([CH2:22][O:23][CH2:24][CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[NH:11][C:12]([CH3:21])=[C:13]2[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)[O-])=C(COCCC2CCCCC2)N1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCC2CCCCC2)N1

Procedure:
0.25 g (0.51 mmol) of 5-(2-cyanoethyl) 4-(3-chlorophenyl)-2-(2-cyclohexylethoxymethyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate, 0.12 g (0.63 mmol) of WSC hydrochloride and 0.13 g (0.62 mmol) of 3,3-diphenylpropylamine were stirred together in 5 ml of dichloromethane at room temperature for 16 hours. 0.1 N hydrochloric acid was added to the reaction mixture. After the extraction with dichloromethane, the organic layer was concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4][O:3]1.[OH-].[Na+]>Cl>[OH:3][CH2:4][CH:5]([CH2:6][OH:7])[CH2:8][CH2:9][N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12]
Reactant: CC1(C)OCC(CCn2ccc(=O)[nH]c2=O)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccn(CCC(CO)CO)c(=O)[nH]1
Yield: 35.2 %

Procedure:
A solution of 17 (7.75 gm, 30.5 mmol) in 1M HCl (25 ml) was stirred at 25° C. for 30 min. The solution was neutralized by addition of 10% aq. NaOH. The resulting solution was filtered and evaporated under vacuo. The solid residue obtained was chromatographed on a silica gel column using dichloromethane-methanol (88:12, v/v) as eluent to yield 18 (2.3 gm, 35.2%), which was used in the next reaction step.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:8](OC)=[O:9])(=[O:4])=[O:3].[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>C1COCC1.CCO>[Cl:15][C:14]1[CH:13]=[CH:12][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[S:2]([NH2:1])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: NS(=O)(=O)c1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of methyl 3-(aminosulfonyl)-4-chlorobenzoate (950 mg, 3.8 mmol) in THF/EtOH (40 mL, 1:1), CaCl2 (843 mg, 7.6 mmol) and NaBH4 (575 mg, 15.2 mmol) were added in one portion respectively. The reaction mixture was stirred at room temperature for 6 hours, then quenched with water. 1 M aqueous citric acid (10 mL) was added to the mixture and extracted with EtOAc (3×100 mL). The extracts were combined, washed with brine, and dried (Na2SO4). The solvent was evaporated to afford the product (696 mg, 83%) as a white solid. MS (ES+) m/z 244 [M+Na]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[C:13]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)[CH:14]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 481 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.30-6.50 (m, 8H), 4.80-2.70 (m, 5H), 1.90-0.65 (m, 8H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)#[N:26]>CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][N:6]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:12])[F:13]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C#N)cc1

Procedure:
To a stirred solution of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746] (254 mg, 1.0 mmol) and triethylamine (0.17 ml, 1.2 mmol) in EtOAc (15 ml) was added a solution of 4-cyanobenzene sulphonyl chloride (220 mg, 1.1 mmol) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature for 2 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (280 mg, 0.56 mmol). Mp: 186-187° C.; NMR: 0.95 (d, 3H), 1.25 (d, 3H), 1.75 (s, 3H), 3.25 (dd, 1H), 3.35 (d, 1H), 3.5 (dd, 1H), 4.2 (m, 3H), 4.75 (s, 1H), 7.8 (d, 2H), 7.9 (d, 2H); m/z 418.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH:21]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:18])([CH3:15])([CH3:14])[CH3:13].O1CCCC1.C(N(CC)CC)C>O>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:21]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)CC1NCCCC1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1C(NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Benzyloxycarbonyl chloride (2.55 mL) was added dropwise to the compound 12 (3.40 g), tetrahydrofuran (50 mL) and triethylamine (4.15 mL) with stirring at 0° C. The reaction solution was stirred at 0° C. for 20 minutes, added water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to obtain the title compound (4.81 g) having the following physical properties.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:20]#[N:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][NH:30][OH:31].Cl>CCO>[OH:31][N:30]([C:20](=[NH:21])[CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:29]
Reactant: N#CC1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: CNO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(O)C(=N)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1-Benzyloxycarbonyl-2-cyanoindoline was added to a solution of triethylamine (2 eq.) and MeNHOH.HCl (2 eq.) in EtOH. After stirring overnight the reaction mixture was evaporated, dissolved in EtOAc, washed with water, dried over Na2SO4 and evaporated to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([NH:11][NH2:12])[N:5]=1)[CH3:2].[C:13](=S)=[S:14].[O-]CC.[Na+].Cl>C(O)C.O>[CH2:1]([O:3][C:4]1[N:5]2[C:13](=[S:14])[NH:12][N:11]=[C:6]2[CH:7]=[C:8]([F:10])[N:9]=1)[CH3:2]
Reactant: CCOc1nc(F)cc(NN)n1
Reactant: S=C=S
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nc(F)cc2n[nH]c(=S)n12
Temperature: 0 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A 1.74 g (10 mmol) sample of 2-ethoxy-4-fluoro-6-hydrazinopyrimidine was dissolved in 20 mL of absolute ethanol and 2.84 g (37 mmol) of carbon disulfide and 3.20 g (10 mmol) of 21 percent by weight sodium ethoxide were added. The mixture was heated at reflux with stirring for 3 hours and then was cooled by adding 20 mL of ice water. The mixture was then acidified to a pH of about 2 by adding 2 mL of 6.25N hydrochloric acid diluted to 8 mL with water. The yellow precipitate that formed was recovered by filtration, washed with water, and dried to obtain 0.85 g (40 percent of theory) of 5-ethoxy-7-fluoro-1,2,4-triazolo[4,3-c]pyrimidine-3(2H)-thione. The proton and carbon NMR spectra of this material were consistent with its assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22].[C:30]1(S(Cl)(=O)=O)C=CC=C[CH:31]=1>>[CH2:30]([O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:22])=[O:23])[CH:4]=2)=[CH:17][CH:16]=1)[CH3:31]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3ccccc3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3ccccc3)c2)cc1

Procedure:
4-[4-Chloro-3-(benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=429.2 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using benzenesulfonyl chloride and yielded 4-[4-chloro-3-(benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:11]=[C:10]2[N:29]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:30]=[C:31]([CH2:32][CH:33]([OH:36])CO)[C:9]=12.O1CCCC1.CO>O>[Cl:7][C:8]1[N:13]=[C:12]([N:14]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[N:11]=[C:10]2[N:29]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[N:30]=[C:31]([CH2:32][CH2:33][OH:36])[C:9]=12
Reactant: COc1ccc(Cn2nc(CC(O)CO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(CCO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Sodium periodate (19 g) was added to a mixture composed of the above di-tert-butyl {4-chloro-3-(2,3-dihydroxypropyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (10 g), tetrahydrofuran (100 ml), methanol (100 ml) and water (100 ml) under cooling in an ice bath, and the mixture was stirred at room temperature for one hour. The reaction mixture was separated with water (600 mL) and ethyl acetate (400 mL). The organic layer was washed with brine, and then dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Methanol (200 mL) was added to the resulting residue. Sodium borohydride (1000 mg) was added under cooling in an ice bath, and the mixture was stirred for one hour. Water (400 ml) was added to the reaction mixture, followed by extraction with ethyl acetate (300 ml) twice. Then, the organic layers were washed with brine. The organic layers were dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain the title compound (8.5 g, 90%) as an oil.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)(=[O:3])[CH3:2].Cl>[Pd].C(O)C>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)NC1CCNC1
Yield: 89 %

Procedure:
A mixture of 12.5 g (0.057 mol) of the compound obtained in stage c) above, 1.3 g of 10% Pd/C, 80 ml of 95% ethanol and a drop of concentrated hydrochloric acid is hydrogenated at 40° C. When the theoretical quantity of hydrogen has been consumed, it is filtered and the filtrate is concentrated to obtain 6.5 g of the title compound in the form of an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
4-Chlorophenylacetic acid (1.7 g, 10 mmol) and oxalyl chloride (2 ml, 23 mmol) were stirred in 100 ml methylene chloride with two drops of dimethylformamide for two hours. The solvent and excess oxalyl chloride were removed under vacuum to give p-chlorophenylacetyl chloride. The 4-chlorophenylacetyl chloride and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.5 g, 8.2 mmol) were dissolved in methylene chloride. Triethylamine (3 ml) was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), 5% potassium carbonate (5% K2CO3) and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 15 ml acetonitrile. Triethylamine (3 ml) and acetone cyanohydrin (0.3 g) were added and the mixture stirred at room temperature for 4 hours. Afer dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and concentrated under vacuum yielding 1.0 g of an oil that solidified on standing (m.p. 57°-61° C). It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH:24]=[CH:25][CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[NH2:32][C@@H:33]([CH2:37][CH2:38][C:39]([NH:41][C@H:42]([C:45]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:46])[CH2:43][SH:44])=[O:40])[C:34]([OH:36])=[O:35]>C(Cl)Cl.CO>[NH2:32][C@@H:33]([CH2:37][CH2:38][C:39]([NH:41][C@@H:42]([CH2:43][S:44][CH2:30][CH2:29][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=3)[N:4]=2)[CH:22]=1)=[O:31])[C:45]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:46])=[O:40])[C:34]([OH:36])=[O:35]
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)CCSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O)c3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a suspension of N-(3-{5-fluoro-2-[4-(2-methoxy-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-acrylamide 3 (0.1 g, 0.236 mmol) and glutathione (0.1 g, 0.325 mmol) in DCM (10 mL) and CH3OH (10 mL) was added TEA (0.1 g, 0.988 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 16 h and then concentrated. The residue was washed with H2O and dried to afford the title compound, (S)-2-amino-5-((R)-1-(carboxymethylamino)-3-(3-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenylamino)-3-oxopropylthio)-1-oxopropan-2-ylamino)-5-oxopentanoic acid (0.17 g, 100%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[O:41][C:42]([CH3:54])=[C:43]([CH2:45][CH2:46][N:47]3[CH2:51][CH2:50][C@H:49]([CH2:52][F:53])[CH2:48]3)[N:44]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[F:53][CH2:52][C@H:49]1[CH2:50][CH2:51][N:47]([CH2:46][CH2:45][C:43]2[N:44]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=4)=[CH:35][CH:36]=3)[O:41][C:42]=2[CH3:54])[CH2:48]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CC[C@H](CF)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CC[C@H](CF)C1
Yield: 34.4 %

Procedure:
Prepare using the method of Example 103 with palladium (II) acetate (0.002 g, 0.01 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.010 g, 0.04 mmol), distilled water (1 mL), 4-(methanesulfonyl)benzeneboronic acid (0.10 g, 0.49 mmol), 2-(4-bromophenyl)-4-{2-[(3S)-3-(fluoromethyl)pyrrolidin-1-yl]ethyl}-5-methyl-1,3-oxazole (See Example 110) (0.17 g, 0.46 mmol) and potassium carbonate (0.19 g, 1.39 mmol). Additionally triturate the resulting solid with 2:1 diethyl ether:ethyl acetate to give the title compound as a yellow coloured solid (0.07 g): MS (m/e): 443(M+1).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH:14][C@H:15]([C:26]([O:28]C)=[O:27])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:13])[C:2]1=[O:3].[OH-].[Na+]>CO>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH:14][C@H:15]([C:26]([OH:28])=[O:27])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:13])[C:2]1=[O:3]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)c1cc2ccccc2oc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)c1cc2ccccc2oc1=O
Yield: 98.5 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 19 (2.0 g), 1 mol/L of an aqueous sodium hydroxide solution (7.7 mL), and methanol (80 mL), to give the captioned compound (1.9 g, 99%) as crystals.
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12>CN(C)C=O>[CH3:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH2:5][CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:17](=[O:25])[C:16]2=[CH:26][S:27][CH:28]=[C:15]12
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(CCN2CCCCC2)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.31 g. of 55% sodium hydride-mineral oil dispersion and 0.65 g. of N-(2-chloroethyl)piperidine hydrochloride in 25 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.40 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an oil which is purified by preparative thin layer chromatography (tlc) on silica gel with 10:1 benzene:methanol as eluent. The oil obtained is crystallized from hexane to give white crystals, m.p. 84°-88°C.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:15]([OH:17])=O.[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[NH:21][CH3:22]>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:17]
Reactant: O=C(O)c1cc2c(s1)-c1ccccc1OCC2
Reactant: CNc1ccc(F)cc1F
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(F)cc1F

Procedure:
Following General Procedure C, 156 is prepared from 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid and 2,4-difluoro-N-methylaniline. MS: (ESI+) 371.9
Reaction SMILES: [C:1]([O:18][CH2:19][CH:20]([O:31][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:21]([O:23]CC1C=CC=CC=1)=[O:22])(=[O:17])[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][CH3:16]>C(OCC)(=O)C>[C:32]([O:31][CH:20]([CH2:19][O:18][C:1](=[O:17])[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][CH3:16])[C:21]([OH:23])=[O:22])(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)C(=O)O

Procedure:
For example, idebenone dipalmitoyl glycerate may be prepared by a method comprising the steps of (a) subjecting benzyl acrylate to a dihydroxylation reaction to form benzyl 2,3-dihydroxypropanoate; (b) reacting the benzyl 2,3-dihydroxypropanoate with palmitoyl chloride to form 3-(benzyloxy)-3-oxopropane-1,2diyl dipalmitate; (c) reacting the 3-(benzyloxy)-3-oxopropane-1,2diyl dipalmitate with ethyl acetate to form 2,3-bis(palmitoyloxy)propanoic acid; and (d) reacting the 2,3-bis(palmitoyloxy)propanoic acid with idebenone to form idebenone dipalmitoyl glycerate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([NH:20][C@H:21]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=3[C:32]([O:34]C)=[O:33])[CH2:26][CH2:25]2)=[O:23])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([NH:20][C@H:21]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=3[C:32]([OH:34])=[O:33])[CH2:26][CH2:25]2)=[O:23])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2C(=O)O)CC1
Temperature: 60 °C
Yield: 61.8 %

Procedure:
To a 150 mL round-bottomed flask equipped with magnetic stirring was added methyl 2-{4-[(2R)-2-({(3S)-2-[(tert-butyl)oxycarbonyl](3-1,2,3,4-tetrahydroisoquinolyl)}carbonylamino)-3-(4-chlorophenyl)propanoyl]piperazinyl}benzoate (1.6 g, 2.4 mmol) in THF (30 mL). A soln of LiOH (Aldrich) (303 mg, 7.14 mmol) in H2O (ca. 10 mL) was added and the reaction was heated at 60° C. for 12 h. After cooling to RT, the mixture was concentrated in vacuo and diluted with EtOAc (100 mL). A 10% soln of citric acid (25 mL) was added, the organic layer was separated, and the aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with H2O, and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a white solid (960 mg). MS (ESI, pos. ion) m/z: 647 (M+H). Calc'd for C35H39ClN4O6: 646.26.