Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].[SH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].FC(F)(F)C(O)=O>C(Cl)Cl>[C:34]([CH2:33][CH2:32][S:31][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C:4]([OH:6])=[O:5])([O:36][CH3:37])=[O:35]
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Reactant: COC(=O)CCS
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCSC(CC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of t-butyl 3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propanoate (4.0 gm, 9.7 mmole) in methylene chloride (40 ml) was stirred under an inert atmosphere at -10° C. To this cold solution was added methyl 3-mercaptopropionate (6.2 ml, 56 mmole) in one portion followed by dropwise addition of trifluoroacetic acid (80 ml). The reaction mixture was then stirred for 5 hours at 0° C. Solvent and excess trifluoroacetic acid were removed on a rotary evaporator. The residue was redissolved in methylene chloride and washed twice with water and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography on silica gel eluting with hexane-ethyl acetate-formic acid (85/15/0.5) gave the title compound. Anal.: Calcd. for C27H36O4S: C, 71.17; H, 7.74. Found: C, 70.46; H, 7.72. 250 MHz NMR (CDCl3) δ1.28-1.68 (12 H,m) 2.48 (2 H,t) 2.56-2.72 (6 H,m) 2.93 (2 H,d) 3.66 (3 H,s) 4.60 (1 H,t) 7.18-7.39 (9 H,m).
Reaction SMILES: C1(C(=O)CCC2C=CC(C(F)(F)F)=CC=2)C=CC=CC=1.[C:21]1(/[C:27](/[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1(/[C:27](/[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:38][CH:37]=2)=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: O=C(CCc1ccc(C(F)(F)F)cc1)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 1-phenyl-3-[4-(trifluoromethyl)phenyl]-propan-1-one, (Z)-ethyl 3-phenyl-5-[4-(trifluoromethyl)phenyl]pent-2-enoate and (E)-ethyl 3-phenyl-5-[4-(trifluoromethyl)phenyl]pent-2-enoate were obtained as colourless oils.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=[C:5]2[CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cn2ccc(CC)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1ccn2cc(C(=O)O)nc2c1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of ethyl 7-ethylimidazo[1,2-a]pyridine-2-carboxylate (1.1 g) in ethanol (6 ml) and water (6 ml) was added sodium hydroxide (806 mg) at ambient temperature, and the mixture was stirred for 1 hour. The reaction mixture was adjusted to pH 3.0 with conc. hydrochloric acid. After evaporation of ehtanol, the residual crystal was collected, washed with cold water and dried to give 7-ethylimidazo[1,2-a]pyridine-2-carboxylic acid (0.77 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18](OC)=[O:19])=[CH:9]1>O1CCCC1>[OH:19][CH2:18][CH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH3:7])[CH:9]=1
Reactant: COC(=O)Cc1cn(C)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cc(CCO)c2ccccc21
Temperature: 0 °C
Yield: 878 %

Procedure:
To a suspension of LiAlH4 (2.0 g, 0.052 mol) in 50 mL of dry tetrahydrofuran was added dropwise a solution of methyl 1-methylindole-3-acetate (5.25 g, 0.026 mol) in 70 mL of dry tetrahyqrofuran at -10° C. under Ar. The mixture was refluxed for 1 h and then it was cooled at 0° C. and quenched by the sequential addition of 2 mL of H2O, 2 mL of 15% aqueous NaOH and finally 6 mL of H2O. The resulting slurry was filtered and the filter cake was washed with additional tetrahydrofuran. Evaporation of the filtrate gave the product (40 g, 89%) as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH2:11])=[N:7][CH:6]=1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH:11][C:23](=[O:24])[CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:26][CH3:27])=[N:7][CH:6]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: Cn1c(Cc2ccccc2Cl)cnc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)n1C)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Chloro-benzyl)-1-methyl-1H-imidazol-2-ylamine (44 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (13 mg, 0.035 mmol, 18%). ESI-MS m/z calc. 367.2, found 368.1 (M+1)+ Retention time 2.42 minutes.
Reaction SMILES: C([N:8]1[CH2:23][CH2:22][CH2:21][C:9]21[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10]2)C1C=CC=CC=1>CO.[Pd]>[CH2:13]1[C:9]2([CH2:21][CH2:22][CH2:23][NH:8]2)[CH2:10][CH2:11][N:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCCN2)C1
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of t-butyl 6-benzyl-2,6-diazaspiro[4.4]nonane-2-carboxylate (1.70 g, 5.37 mmol) in methanol (30 mL) was mixed with 10% palladium on carbon (50 mg). The mixture was shaken under a hydrogen atmosphere (50 psi) in a Parr hydrogenation apparatus for 8 h and filtered through Celite. The filtrate was concentrated by rotary evaporation and high vacuum treatment, leaving 1.26 g of viscous, light brown oil (>100%), which was of sufficient purity to be used in the subsequent reaction.
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1)[CH3:2].O.O.[Sn](Cl)Cl>C(O)(=O)C>[CH2:1]([N:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)[CH3:2]
Reactant: CCN(c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: CCN(c1ccccc1)c1cccc(N)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
N-Ethyl-3-nitro-N-phenylaniline (400 mg, 1.65 mmol) was dissolved in acetic acid (5 ml) at 40° C. followed by slow addition of tin (II) chloride dihydrate (1.50 g, 6.60 mmol). The reaction mixture was stirred at 40° C. for 2 hours and then for a further 2 hours at 75° C. The mixture was concentrated in vacuo and the obtained residue was diluted with ether (10 ml). Aqueous sodium hydroxide solution (2 ml) was added dropwise to the cooled (0° C.) solution. A solid formed was separated by filtration and was rinsed twice with hot ethyl acetate (25 ml). The filtrate was concentrated to approximately 30 ml and washed with 1 N sodium hydroxide, brine, dried over sodium sulfate and concentrated in vacuo to give N-ethyl-N-phenylbenzene-1,3-diamine as a yellow oil (117 mg, 1.04 mmol, 63% yield). 1H NMR (400 MHz, CDCl3): 6.87-7.28 (m, 7H), 6.28-6.83 (m, 2H), 3.74 (q, 2H), 3.59 (s, 2H), 1.20 (t, 3H); MS (EI) for C14H16N2: 212 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH2:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:22]=[C:23]1[NH:28][CH2:27][CH:26]([C:29](O)=[O:30])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH:21][C:29]([CH:26]3[CH2:25][CH2:24][C:23](=[O:22])[NH:28][CH2:27]3)=[O:30])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(C(=O)O)CN1
Reactant: CCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cccc(-c2cc(NC(=O)C3CCC(=O)NC3)nn2-c2ccccc2)c1
Yield: 61.5 %

Procedure:
To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (56 mg) in tetrahydrofuran (1.5 ml) were sequentially added an optically active compound of 6-oxopiperidine-3-carboxylic acid (43 mg) synthesized in Preparation 7 (derived from the low-polarity component of 5-((R)-4-benzyl-2-oxoxazolidine-3-carbonyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one), HOBt.H2O (46 mg) and WSC.HCl (58 mg), and the mixture was stirred at room temperature overnight. To this reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (50 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.C([N:30]=[C:31]=[S:32])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[NH:2]([C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1)[C:31]([NH2:30])=[S:32]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=S)Nc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C

Procedure:
A solution of 10 g (48 mmol) 3-Amino-benzenesulfonamide hydrochloride in 100 ml THF and 8.2 ml (48 mmol) N,N-Diisopropylethylamine was treated with 6.45 ml (48 mmol) benzoyl isothiocyanate and allowed to stir at room temperature. After evaporation to dryness the residue was suspended in diethyl ether. The precipitate was filtered off, dried and suspended in 130 ml methanol and 100 ml THF. K2CO3 (130 mmol) in 45 ml water was added and the mixture was stirred for 60 h at room temperature. The mixture was evaporated to drynes and the residue was treated with water and extracted with ethyl acetate. The combined organic layers were dried with MgSO4 filtered and evaporated to dryness. After suspending the residue in diethyl ether, filtration and drying 8.4 g (76%) of the title compound was obtained as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:19][S:20]([C:23]2([CH2:26][CH:27]=[O:28])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].[OH:29]P([O-])(O)=O.[K+].CC(=CC)C.Cl([O-])=O.[Na+].Cl>C(O)(C)(C)C.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:19][S:20]([C:23]2([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][CH2:25]2)(=[O:22])=[O:21])=[CH:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: O=P([O-])(O)O
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)cn(C)c1=O
Agent: CC=C(C)C
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC(=O)O)CC2)cn(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dark brown solution of N-(4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(2-oxoethyl)cyclopropane-1-sulfonamide, potassium phosphate monobasic (27 mg, 0.20 mmol), and 2-methyl-2-butene (0.45 mL, 0.90 mmol) in tert-butanol (4 mL) and H2O (1 mL) at 0° C. is added sodium chlorite (55 mg, 0.60 mmol). After stirring at 0° C. for 30 min, the reaction is warmed to room temperature and stirred for 16 h. To the reaction is added aqueous HCl solution (5 mL, 1N) and saturated aqueous NaS2O3 solution (5 mL). The mixture is extracted with CH2Cl2 (20 mL), dried over MgSO4, concentrated, and may be purified by silica gel chromatography (CH2Cl2: CH3OH=90:10).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][CH:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=O>C(O)C.C(O)(=O)C>[CH3:16][C:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC1C(=O)CCC1=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC1=C(Nc2ccc(C3=NNC(=O)CC3C)cc2)CCC1=O
Yield: 43.1 %

Procedure:
A mixture of 0.51 g of 4,5-dihydro-6-(4-aminophenyl)-5-methyl-3(2H) pyridazinone and 0.28 g of 2-methyl-cyclopentane-1,3-dione in 5 ml of ethanol and 5 ml of acetic acid was refluxed over night. After cooling, the solution was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=20:1) and recrystallized from methanol to give 0.32 g of the title compound. m.p. 285°-286° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12.C([O-])(=[O:14])C.[Na+]>C(O)(=O)C>[CH3:11][C:9]1[NH:8][C:4]2[N:5]=[CH:6][CH:7]=[C:2]([OH:14])[C:3]=2[CH:10]=1
Reactant: Cc1cc2c(Cl)ccnc2[nH]1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2c(O)ccnc2[nH]1
Yield: 84.4 %

Procedure:
A mixure of 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (120 mg, 0.72 mmol) and sodium acetate (150 mg, 1.83 mmol) in acetic acid (1.5 mL) was microwaved at 200° C. for 40 minutes. The mixture was purified by preparative HPLC and the appropriate fractions were concentrated in vacuo and lyophilized to afford the title compound (90 mg, 47%). 1H NMR (CD3OD) δ 8.09 (d, 1H, J=5.5 Hz), 6.80 (d, 1H, J=5.5 Hz), 6.49 (s, 1H), 2.46 (s, 3H); MS(ESI+) m/z 149 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1cccc(F)n1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Product: Cc1cccc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=299.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-fluoro-6-methylpyridine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][C@H:24]2[CH3:29])[N:9]=1.[Br:30]C(Br)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Br:30][C:13]1[N:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:15]2[C:11]([N:12]=1)=[C:10]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][C@H:24]1[CH3:29])[N:9]=[C:8]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C@H:2]1[CH3:1])[N:16]=2
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2ncn(C3CCCCO3)c2n1
Reactant: ClC(Cl)(Cl)C(Cl)(Br)Br
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Diisopropylamine (290 μl, 2.04 mmol) was dissolved in 4 mL of THF at −60° C., when butyllithium in hexane was added (1.27 mL, 2.04 mmol) to form LDA. 2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9-(tetrahydro-pyran-2-yl)-9H-purine (585 mg, 1.45 mmol) was dissolved in 8 mL of THF and added to the reaction mixture at −78° C. within 10 minutes. The reaction was stirred for 1 hour at −78° C. Dibromotetrachloroethane (947 mg, 2.91 mmol) in 4 mL of THF was added within 10 minutes. The reaction was stirred for 2 hours at −78° C. The reaction was quenched by addition of saturated aqueous NH4Cl and warmed to room temperature. The mixture was diluted with 80 mL of EtOAc and 50 mL of brine. The organic layers were separated, dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by column chromatography (30 g SiO2, heptane/TBME in a ratio 7/3) to give the product as a foam (546 mg, 78%).
Reaction SMILES: [Cl-].[Cl-].[Ca+2].O.FC1C=CC(N)=C(N)C=1.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-])=O>CCO.CCOCC.[Zn]>[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]
Reactant: CNc1ccccc1[N+](=O)[O-]
Agent: Nc1ccc(F)cc1N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CNc1ccccc1N

Procedure:
N-Methyl-1,2-diaminobenzene was prepared using an adaptation of the method of Tsuji et al. (J. Org. Chem. 55: 580 (1990)). Zn powder (8.07 g, 0.123 mol), CaCl2 (807 mg), H2O (9.9 mL) and 30 mL EtOH were combined and brought to reflux as described for 4-fluoro-1,2-diaminobenzene (see Example 10), and to this mixture was added slowly dropwise a solution of N-methyl-2-nitroaniline (1.50 g, 9.86 mmol) in 15 mL EtOH. Analysis and workup were as described for 4-fluoro-1,2-diaminobenzene except that the reaction residue was dissolved in 50 ml Et2O. This Et2O solution was then extracted with 3×25 mL 1N HCl and the aqueous layers combined and basified with 5 g of 50% NaOH solution. This solution was then extracted with 3×25 mL Et2O. These Et2O layers were then combined, dried (MgSO4) and the solvent evaporated at reduced pressure to yield 911.1 mg (76.1%) of a dark brown oil. 1H NMR (CDCl3) δ 2.87 (s, 3H, CH3), 3.31 (br s, 3H, NH), 6.67 (m, 3H, ArH), 6.86 (m, 1H, ArH).
Reaction SMILES: [OH:1][CH:2]([CH2:13][OH:14])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:15](Cl)(=[O:31])[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][CH3:30]>>[C:15]([O:14][CH2:13][CH:2]([O:1][C:15](=[O:31])[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][CH3:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])(=[O:31])[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][CH3:30]
Reactant: O=C(OCc1ccccc1)C(O)CO
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)C(=O)OCc1ccccc1

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: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:18][C:19]1[N:23]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:22]=[N:21][CH:20]=1>CN(C=O)C>[CH:24]1([N:23]2[C:19]([CH2:18][S:8][C:6]3[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=3)=[CH:20][N:21]=[CH:22]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: ClCc1cncn1C1CCCCC1
Reactant: Cc1cc(O)nc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cncn2C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 32.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (1.1 g, 7.7 mmol) was dissolved in anhydrous DMF (40 mL), then potassium carbonate (3.19 g, 23.1 mmol) and 5-(chloromethyl)-1-cyclohexyl-1H-imidazole hydrochloride (8.5 mmol) in DMF (10 mL) were added. The mixture was stirred for 3.5 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM/MeOH to afford 2-{[(1-cyclohexyl-1H-imidazol-5-yl)methyl]sulfanyl)-6-methylpyrimidin-4-ol (770 mg, 44% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.17-1.30 (m, 2H), 1.62-1.67 (m, 4H), 1.77-1.81 (m, 2H), 1.92-1.95 (m, 2H), 2.23 (s, 3H). 3.92-3.96 (m, 1H), 4.51 (s, 2H), 6.03 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H).
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:30][CH3:31])=[N:21][N:22]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15])=[O:11])C1C=CC=CC=1.O.C(OCC)(=O)C>CO.[Pd]>[OH:8][NH:9][C:10]([CH2:12][NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:30][CH3:31])=[N:21][N:22]2[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)=[O:15])=[O:11]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)NCC(=O)NOCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCC(=O)NO)ccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 110.5 %

Procedure:
A mixture of 120 mg (0.285 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (benzyloxycarbamoyl-methyl)-amide and 0.08 g 10% Pd/C, 50% water wet, in 10 mL methanol and 10 mL ethyl acetate was placed on a Parr® hydrogenation apparatus and shaken under 30 psi H2 at room temperature for 40 minutes. The reaction mixture was filtered through Celite®, and the filtrate concentrated and dried to give 104 mg of a tan solid. Trituration with hexanes gave 69 mg (73%) of a tan crystalline powder: mp 105° C. (dec); HRMS calcd for C17H22N4O3+H: 331.1772. Found: 331.1769.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:8][C:7]1[C:2]([C:10]#[N:11])=[N:3][CH:4]=[CH:5][C:6]=1[CH3:9]
Reactant: CN(C)C=O
Reactant: Cc1ccnc(Br)c1F
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccnc(C#N)c1F
Temperature: 90 °C

Procedure:
To a mixture of 2-bromo-3-fluoro-4-methylpyridine (4.89 g, 25.7 mmol) and zinc cyanide (3.02 g, 25.7 mmol) in DMF (45 mL) was added palladium tetra(triphenylphosphine) (2.97 g, 2.57 mmol). The mixture was degassed and then heated to 90° C. for 18 hours. After this time, the mixture was diluted with water (500 mL) and EtOAc (500 mL), filtered and the resulting layers were separated. The aqueous layer was further extracted with EtOAc (2×500 mL). The combined extracts were washed with water (300 mL), dried over MgSO4, filtered and the solvent removed in vacuo. The resulting residue was chromatographed using RediSep column (330 g) and eluting with a gradient of 0-100% EtOAc/CH2Cl2. The pure fractions were combined and the solvent removed in vacuo to give title compound.