Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:23]=O)[N:14]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].Cl.[O:36]1[CH2:41][CH2:40][CH:39]([CH:42]2[CH2:45][NH:44][CH2:43]2)[CH2:38][CH2:37]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:23][N:44]4[CH2:45][CH:42]([CH:39]5[CH2:40][CH2:41][O:36][CH2:37][CH2:38]5)[CH2:43]4)[N:14]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C3CCCCO3)c2n1
Reactant: C1CC(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 126.4 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 2-(2-ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-9H-purine-8-carbaldehyde (0.22 g, 0.48 mmol), 3-(tetrahydropyran-4-yl)azetidine hydrochloride (0.093 g, 0.53 mmol) in DCE (5 mL), trimethoxymethane (0.518 mL, 4.8 mmol) and acetic acid (0.03 mL, 0.48 mmol). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (0.152 g, 0.72 mmol) was added and the reaction mixture was stirred for a further 72 h at room temperature. The suspension was partitioned between DCM and water; the organic layer was separated and washed with brine, dried with sodium sulphate and concentrated to give 2-(2-Ethylbenzoimidazol-1-yl)-6-morpholin-4-yl-9-(tetrahydropyran-2-yl)-8-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]-9H-purine as an orange oil (0.356 g, 99%). LCMS (Method A): RT=2.97 min, [M+H]+ 587.4
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.N>>[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)cc1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 4-chlorobenzoic acid (Aldrich) according to method A; yield 29 mg, 0.07 mmol (33%): 1H NMR (300 MHz, methanol-d4) δ 2.06-2.30 (m, 5H), 2.45 (s, 2H), 3.48 (d, J=12 Hz, 2 H), 3.55 (s, 2H), 3.80 (d, J=12 Hz, 2H), 4.25 (s, 1H), 7.49 (d, J=9 Hz, 2H), 7.86 (d, J=9 Hz, 2H); MS (DCI/NH3) m/z 291 (M+H)+; Anal. C16H19Cl2N2O.HCl.0.45HCl: C, H, N.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[NH:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].Br[CH:31]([CH3:37])[C:32]([O:34]CC)=[O:33].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:16][CH:31]([C:32]([OH:34])=[O:33])[CH3:37])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1)[C:2]#[C:3][CH3:4]
Reactant: CCOC(=O)C(C)Br
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(C)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(OC(C)C(=O)O)n(C)c(=O)c21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
8 mg of t-butyl 4-[7-(2-butynyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate and 10 mg of ethyl 2-bromopropionate were dissolved in 0.2 ml of N,N-dimethylformamide, and 10 mg of potassium carbonate was added thereto. The mixture was stirred at 50° C. overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and 1N hydrochloric acid. The organic layer was concentrated to give t-butyl 4-[7-(2-butynyl)-2-(1-carboxyethoxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. This compound was dissolved in 0.4 ml of ethanol, and 0.1 ml of a 5N aqueous sodium hydroxide solution was added thereto. The mixture was stirred at room temperature for 3 hours. 1N-hydrochloric acid was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was dissolved in trifluoroacetic acid. The mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.37 mg of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])(C(C)(C)C)(C)C.C(O)(=O)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:11]([CH2:10][CH2:9][OH:8])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(c1cc2c(s1)-c1ccccc1OCC2)N(CCO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of N-(2-(tert-butyldimethylsilyloxy)ethyl)-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.030 g, 0.058 mmol) in acetic acid (0.0033 mL, 0.058 mmol) and tetrahydrofuran (0.3 mL, 4 mmol) was added 1 M of tetrabutylammonium fluoride hydrate in tetrahydrofuran (0.058 mL). The reaction was stirred at room temperature w/TLC and LC/MS monitor. Deprotection was complete after overnight stirring. The reaction mixture was concentrated in vacuo, taken into ethylacetate and washed with water/saline and concentrated to a glassy residue, which was purified by MPLC, eluting with ethylacetate/hexanes, gradient 0-50% B to give 22.4 mg of 106 (yield 40%). MS: (ESI+) 401
Reaction SMILES: [N:1]1([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=N)OC>C(O)(=O)C>[N:1]1([CH:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Reactant: COC(=N)c1ccccn1
Solvent: CC(=O)O
Product: c1ccc(C(c2ccc3[nH]c(-c4ccccn4)nc3c2)n2ccnc2)cc1
Yield: 40 %

Procedure:
To a stirred and cooled solution of 5.3 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine in 50 parts of acetic acid were added 3.3 parts of methyl 2-pyridinecarboximidate while still cooling. The whole was stirred for 8 hours at room temperature and then allowed to stand over weekend. The reaction mixture was evaporated. The residue was taken up in water and treated with activated charcoal. The whole was filtered and the filtrate was made alkaline with ammonium hydroxide. The product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo for 24 hours at 50° C., yielding 2.8 parts (40%) of 5-[(1H-imidazol-1-yl)phenylmethyl]-2-(2-pyridinyl)-1H-benzimidazole; mp. 123.3° C. (compound 201).
Reaction SMILES: [C:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[NH2:15])([O:3][CH3:4])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20]2.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=N)C>O1CCCC1.C(OCC)(=O)C>[C:1]([C@@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C@@H:6]1[NH:15][C:26]([C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([Cl:16])=[CH:25][CH:24]=2)=[O:27])([O:3][CH3:4])=[O:2].[C:1]([C@@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C@H:6]1[NH:15][C:26]([C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([Cl:16])=[CH:25][CH:24]=2)=[O:28])([O:3][CH3:4])=[O:2]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C1c2ccccc2CCC1N
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1c2ccccc2CC[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Product: COC(=O)[C@@H]1c2ccccc2CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 16 h

Procedure:
To a stirring suspension of 1-carbomethoxy-2-amino-1,2,3,4-tetrahydronaphthalene (cis-trans mixture, 10:1, 150 mg), 5-chloroindole-2-carboxylic acid (143 mg) and 1-hydroxy-7-azabenzotriazole (119 mg) in tetrahydrofuran (20 mL) at room temperature under argon, was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (167 mg). After 16 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed sequentially with 1.0 M aqueous hydrochloric acid solution (20 mL), 1.0 M aqueous sodium hydroxide solution (20 mL) and brine (20 mL), dried over anhydrous magnesium sulfate and evaporated under vacuum to obtain crude product (243 mg) as an oil. The crude product was purified by reverse phase preparative HPLC to obtain cis 1-carbomethoxy-2-(5-chloroindole-2-carbonylamino)-1,2,3,4-tetrahydronaphthalene (167 mg) and trans 1-carbomethoxy-2-(5-chloroindole-2-carbonylamino)-1,2,3,4-tetrahydronaphthalene (14 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.I[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.Cl>O1CCCC1.CN1CCCN(C)C1=O>[CH:32]1([CH2:31][CH:26]([C:23]2[CH:22]=[CH:21][C:20]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:25][CH:24]=2)[C:27]([OH:29])=[O:28])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: ICC1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
A solution of diisopropylamine (2.52 mL, 19.3 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated with a 2.5M solution of n-butyllithium in hexanes (7.7 mL, 19.3 mmol). The reaction mixture was stirred at −78° C. for 15 min and then slowly treated with a solution of 4-phenoxyphenylacetic acid (2.00 g, 8.8 mmol) in tetrahydrofuran (12 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL) via cannulation. The resulting bright yellow solution was allowed to stir for 1 h at −78° C. After this time, the reaction mixture was treated with a solution of iodomethylcyclopentane (2.02 g, 9.6 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) via cannulation. The resulting reaction mixture was stirred for 1 h at −78° C. and then allowed to warm to 25° C. where it was stirred for 14 h. The reaction was then acidified to pH=2 by the dropwise addition of a 1N aqueous hydrochloric acid solution and then extracted with ethyl acetate (3×25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) afforded 3-cyclopentyl-2-(4-phenoxy-phenyl)propionic acid (2.49 g, 91%) as a white foam: EI-HRMS m/e calcd for C20H22O3 (M+) 310.1568, found 310.1568.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17][CH3:18])=[O:16])[C:7](=[CH:12][C:13]=1[OH:14])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].N1C[CH2:22][CH2:21][CH2:20]1>CC(C)=O>[CH3:20][C:21]1([CH3:22])[CH2:2][C:1](=[O:3])[C:4]2[CH:5]=[C:6]([C:15]([O:17][CH3:18])=[O:16])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][C:13]=2[O:14]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(O)c(C(C)=O)cc1C(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1cc2c(cc1C(=O)OC)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 100 ml of acetone was dissolved 4.2 g of dimethyl 4-acetyl-5-hydroxyphthalate synthesized in accordance with the process of Bulletin of the Chemical Society of Japan, Vol. 57, p. 3221 (1984). To the solution were added 1.0 ml of pyrrolidine and a small amount of Molecular Sieve (3A), followed by stirring at room temperature for 3 days. Any insoluble material was removed by filtration, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.6 g (86.3%) of a yellow oily substance.
Reaction SMILES: [I:1]I.[C:3]([O:6][CH:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)(=[O:5])[CH3:4]>C(O)(=O)C>[C:3]([O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH:19]([I:1])[CH2:20]1)[CH2:15][CH2:14]3)(=[O:5])[CH3:4]
Reactant: II
Reactant: CC(=O)OC1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C(I)C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
2.79 g (11 mmol) of iodine is added to 3.28 g (10 mmol) of 17-acetoxy-androst-4-en-3-one and 0.875 g (11 mmol) of CuO in 30 ml of glacial acetic acid with stirring at room temperature. The reaction solution is stirred under nitrogen atmosphere for 24 hours at 60° C. Under reduced pressure, acetic acid is distilled off, and the residue is taken up in 50 ml of water. The water phase is extracted 3 times with 50 ml of ethyl acetate each, the ethyl acetate phases are washed with sodium thiosulfate solution and dried on sodium sulfate. Concentration by evaporation of the solution yields 4.5 g of crude product. After recrystallization from ethyl acetate, 2.85 g of 17β-acetoxy-2-iodo-androst-4-en-3-one (65% of theory) of melting point 92° C. is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Clc1ncccn1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccc(Oc2ncccn2)c1
Yield: 70.9 %

Procedure:
EX-605A) A slurry of 3-hydroxybenzaldehyde (1.22 g, 10 mmol), 2-chloropyrimidine (1.14 g, 10 mmol) and K2CO3 (1.65 g, 12 mmol) in DMSO (20 mL) was heated to 100° C. for 1 h. The cooled mixture was poured into water and extracted with Et2O. The organic layer was washed with 2.5 N NaOH, 1 N HCl, saturated NaCO3 and brine, dried (MgSO4) and evaporated to yield 1.42 g (71%) of the desired 3-(2-pyrimidinyl-oxy)benzaldehyde product as a white solid which was used without further purification. 1H NMR (C6D6) δ7.12 (t, 1H), 7.54 (m, 1H), 7.66 (t, 1H), 7.78 (m, 1H), 7.83 (m, 1H), 8.64 (d, 2H), 10.05 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18]([O-:20])=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)[NH:29][C:25]=2[CH:24]=1>>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]2[NH:27][C:26]3[CH:39]=[CH:40][C:23]([NH:22][C:18]([C:16]4[CH:15]=[CH:14][C:12]5[NH:13][C:9]([C:6]6[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:8][CH:7]=6)=[N:10][C:11]=5[CH:17]=4)=[O:20])=[CH:24][C:25]=3[N:29]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)c1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Reactant: COc1cccc(Nc2nc3ccc(N)cc3[nH]2)c1
Product: COc1cccc(Nc2nc3cc(NC(=O)c4ccc5[nH]c(-c6ccc(N(C)C)cc6)nc5c4)ccc3[nH]2)c1

Procedure:
Compound 439 was prepared from 2-(4-dimethylaminophenyl)benzimidazole-5-carboxylate and 5-amino-2-(3-methoxyphenyl)aminobenzimidazole by standard conditions. [M+H]+ calcd for C30H27N7O2: 518.22; found: 518.03.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]2[N:7]([CH3:15])[CH:8]3[CH:13]([CH:5]2[CH2:4][CH2:3]1)[CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]3.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH3:15][N:7]1[CH:8]2[CH:13]([CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]2)[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH:6]12
Reactant: CN1C2C=CC(O)=CC2C2CCC(N)C21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2C=CC(O)=CC2C2CCC(NC(=O)OCc3ccccc3)C21
Reaction time: 2 h

Procedure:
To a solution of 3-amino-1,2,3,3a,4,8a-hexahydro-4-methylcyclopent[b]-indol-7-ol (10.7 grams) in methylene chloride (125 ml) was added triethylamine (5.6 grams) followed by the dropwise addition of benzyl chloroformate (10.0 grams) in methylene chloride (25 ml). The mixture as stirred for 2 hours, extracted with water, dried (Na2SO4) an concentrated. The product was purified by chromatography on silica gel, eluting with 2:1 hexane/acetone to provide 1,2,3,3a,4,8a-hexahydro-4-methyl-3-phenylmethyloxycarbonylaminocyclopent[b]indol-7-ol.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH3:15][CH:16]([N:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[C:32](O)=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:19]1)[CH3:17].[H-].[Na+].[OH2:36]>CN(C=O)C>[CH3:15][CH:16]([N:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[CH:32]=[CH:31][C:30]([O:36][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][N:28]=2)=[N:19]1)[CH3:17]
Reactant: CC(C)n1nc(-c2ncccc2O)c2ncccc21
Reactant: O
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2ccc(Oc3nc4cccnc4n3C)cn2)c2ncccc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (174 mg) and 6-[(1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]pyridin-3-ol (140 mg) in DMF (1.5 ml) was added NaH (60% in oil, 35.2 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) and silica gel column chromatography (AcOEt/hexane). The eluent was evaporated and the residue was purified by preparative HPLC (C18, eluent: H2O/CH3CN (10 mM NH4HCO3)). The eluent was evaporated to give the title compound (68.1 mg).
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: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C(OCc1ccccc1)C(O)CO
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: C1(OC([N:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=3[F:25])[CH2:14][C:13](=[O:26])[CH:12]=[C:11]2[C:27]([O:29][CH3:30])=[O:28])=O)C=CC=CC=1.C[O-].[Na+]>CO>[CH3:30][O:29][C:27]([C:11]1[NH:10][CH:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[CH2:14][C:13](=[O:26])[CH:12]=1)=[O:28]
Reactant: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1C(=O)Oc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-5,6-dihydro-4H-pyridine-1,2-dicarboxylic acid 2-methyl ester 1-phenyl ester (15; 7.213 g, 0.0166 mol) was slurried in MeOH (80 mL). The suspension was cooled in an ice bath, and solid sodium methoxide (NaOMe; 1.08 g, 0.02 mol) was added. After 1 h, the reaction was quenched with saturated aqueous NH4Cl solution (80 mL) and H2O (50 mL) and then cooled in ice. The precipitate was filtered, washed with H2O followed by cold MeOH and dried in air to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16; 4.93 g, 94%) as a white powder: mp 164.9-166.2° C.; 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, JF-H=1.8 Hz, JH-H=8.7 Hz, 1H, aromatic), 7.10 (dd, JF-H=6.9 Hz, JH-H=8.7 Hz, 1H, aromatic), 5.84 (d, J=0.9 Hz, 1H, H3), 5.68 (br s, 1H, NH), 5.10 (t, J=9.3 Hz, 1H, H6), 3.98 (d, JF-H=1.5 Hz, 3H, OMe), 3.91 (s, 3H, CO2Me), 2.71 (d, J=9 Hz, 2H, H5); 13C{1H} NMR (75.4 MHz, CDCl3) δ 193.0 (C4), 163.6 (CO2Me), 153.8 (d, JF-C=251 Hz, C2′), 147.9 (C2), 144.6 (d, JF-C=13 Hz, C3′), 128.6 (d, JF-C=3 Hz, C1′/C4′), 126.8 (d, JF-C=11 Hz, C1′/C4′), 125.5 (d, JF-C=3 Hz, C5′), 121.5 (d, JF-C=4 Hz, C6′), 102.0 (C3), 61.6 (d, JF-C=5 Hz, OMe), 53.4, 50.8, 42.0; HRMS-ESI (m/z): calcd for C14H13ClFNO4, 313.0512. found, 313.0511; Anal. Calcd for C14H13ClFNO4: C, 53.60; H, 4.18; N, 4.46. Found: C, 53.30; H, 4.14; N, 4.35.
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[NH2:27][OH:28].CC(O)C>O>[OH:28][N:27]=[C:23]([NH2:24])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7][CH2:6][OH:5])[CH2:14][CH2:13]2)=[CH:26][CH:25]=1
Reactant: NO
Reactant: N#Cc1ccc(OCCCN2CCC(CCCO)CC2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CC(C)O
Product: NC(=NO)c1ccc(OCCCN2CCC(CCCO)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a dimethylsulfoxide (200 mL) solution of 18.7 g of 4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzonitrile was added 8.92 mL of a 50% hydroxylamine aqueous solution at room temperature, which was then stirred at the same temperature for 5 hours and 30 minutes. Thereto was added 8.92 mL of a 50% hydroxylamine aqueous solution at room temperature, which was stirred at the same temperature for 15 hours and 50 minutes. To the reaction mixture were added 2-propanol and water, which was then stirred at room temperature for one hour. The precipitate was collected by filtration and washed with water to provide 17.5 g of N′-hydroxy-4-{3-[4-(3-hydroxypropyl)-1-piperidinyl]propoxy}benzamidine as white solid form.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH2:12].[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][N:17]=[C:18]=[S:19]>>[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][NH:17][C:18]([NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])=[S:19]
Reactant: CN(C)CCN=C=S
Reactant: Cc1ncoc1CCNCCN
Product: Cc1ncoc1CCNCCNC(=S)NCCN(C)C

Procedure:
By the procedure of Example 40(a)(ii), N-[2-(4-methyl-5-oxazolyl)ethyl]ethylenediamine [prepared by reacting ethylenediamine with 5-(2-chloroethyl)-4-methyloxazole] is reacted with 2-dimethylaminoethyl isothiocyanate to give the titel compound.