Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([NH:15]C(=O)OC(C)(C)C)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:25]1[C:26]([C:31]#[N:32])=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH:14]1[C:9]2=[C:25]3[C:26](=[C:31]([NH2:32])[N:15]=[C:10]2[N:11]=[CH:12][CH:13]=1)[N:27]=[CH:28][CH:29]=[CH:30]3
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: Nc1nc2ncccc2c2cccnc12
Temperature: 25 °C

Procedure:
A solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate (1.0 eq.) and 3-bromopicolinonitrile (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give pyrido[3,2-f][1,7]naphthyridin-6-amine as a white solid. 1H NMR (dmso-d6): δ 9.14 (dd, 1H), 8.98 (dd, 1H), 8.90 (dd, 1H), 7.93 (dd, 1H), 7.60 (bs, 2H), 7.30 (dd, 1H). LRMS [M+H]=197.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:14]([Li])([CH3:17])(C)[CH3:15].[CH2:19]([Si:22](Cl)(C)[CH3:23])C=C>C1COCC1>[CH2:15]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[C:4]([SiH:22]([CH3:23])[CH3:19])[CH:3]=1)[CH:14]=[CH2:17]
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Reactant: [Li]C(C)(C)C
Reactant: C=CC[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C=CCc1ccc(C2(C)OCCO2)c([SiH](C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-methyl-1,3-dioxolane (22, 22.0 g, 90 mmol) in dried THF (600 mL) at −78° C. was added t-butyllithium (53.0 mL, 1.7 M solution in pentane, 90 mmol) over a period of 15 min. After 30 min of further stirring at −78° C., allylchlorodimethylsilane (12.2 g, 90 mmol) in THF (40 mL) was added dropwise over a period of 20 min. The reaction mixture was stirred for 1 h and warmed to room temperature. THF was removed under reduced pressure, and the residue was extracted with H2/ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated to give a colorless oil (19.8 g, 91%); 1H NMR (300 MHz, CDCl3) δ 0.30 (s, 6 H), 1.68 (s, 3 H), 1.77 (d, J=8.01 Hz, 2 H), 3.80 (m, 2 H), 4.06 (m, 2 H), 4.86 (m, 1 H), 4.90 (m, 1 H), 5.80 (ddt, J=16.89, 10.23, 8.07 Hz, 1 H), 7.47-7.52 (4 H)); 13C NMR (75 MHz, CDCl3) −3.3 (2C), 23.7, 27.6, 64.5 (2C), 108.8, 113.5, 124.6 (2C), 133.6 (2C), 134.6, 138.2, 144.1.
Reaction SMILES: [CH2:1]([CH:3]([CH2:26][CH3:27])[CH:4]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:26]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:27]
Reactant: CCC(CC)C(Nc1ccc(C(=O)OC)cc1)c1sc2ccccc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1sc2ccccc2c1C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a mixture of methyl 4-{[2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}benzoate (580 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (529 mg, 95%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:9](Cl)(Cl)=[O:10].[C:13]1([C@H:19]([OH:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C@H:19]([O:21][C:9](=[O:10])[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccccc1Br
Reactant: C[C@@H](O)c1ccccc1
Product: C[C@@H](OC(=O)Nc1ccccc1Br)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 2-bromo-phenylamine, phosgene, and (R)-1-phenyl-ethanol.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>C(OCC)C.C(#N)C>[I:46][CH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:6][O:5][Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)[Si](OCCc1cccc(CO)c1)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)[Si](OCCc1cccc(CI)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 15 (0.500 g, 1.63 mmol), triphenylphosphine (1.280 g, 4.89 mmol), imidazole (0.360 g, 5.22 mmol) and iodine (1.320 g, 5.22 mmol) in diethyl ether (20 mL) and acetonitrile (6.0 mL) was stirred at 0° C. for 2 h. The reaction mixture was diluted with ether, and the resulting mixture was washed with water and a 20 wt % solution of thiosulfate in water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography using ethyl acetate-hexanes 1:9 as eluent to provide the desired compound as colorless oil. Yield: 64%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:9]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][C:10]=3[S:30]([CH3:33])(=[O:32])=[O:31])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 32.3 %

Procedure:
Using pyrrolidin-2-one (119 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (664 mg) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 1, the title compound (206 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)CCc1ccccc1
Yield: 48.8 %

Procedure:
Using the method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.2 g, 0.78 mmol) was reacted with hydrocinnamoyl chloride (0.11 mL, 0.74 mmol) to provide 0.14 g of N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenylpropanamide as a white solid, m.p. 148-150° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:12])[C:3]=1[C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([CH3:12])[C:3]=1[C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([OH:27])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)[C@H](NC(=O)c1c(Cl)c2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1c(Cl)c2cc(F)ccc2n1C)C(=O)NC(CC(=O)O)C(=O)CF
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.3 %

Procedure:
A solution of N-[(3-chloro-5-fluoro-1-methylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid, t-butyl ester (682 mg) in anisole (1 mL) and methylene chloride (10 mL) was treated with TFA (5 mL), and the resultant reaction mixture was stirred for 45 minutes under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated and chased with methylene chloride, then triturated with ether to afford the title product as a white powder (500 mg). MS (EI) for C20H22ClF2N3O5: MH+=458/460; (M−H)−=456/458.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:6][CH:7]=1.[F:21][C:22]1([F:36])[CH2:24][C@@H:23]1[CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[F:21][C:22]1([F:36])[CH2:24][C@@H:23]1[CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:20][C:3]2[C:2]([NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([O:26][CH2:25][C@H:23]4[CH2:24][C:22]4([F:36])[F:21])=[CH:28][CH:29]=3)=[CH:7][N:6]=[C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[CH3:11])[CH:4]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: C[C@@H](COc1cc(O)c(N)cn1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(OC[C@H]2CC2(F)F)cc1
Product: C[C@@H](COc1cc(OC(=O)c2ccc(OC[C@H]3CC3(F)F)cc2)c(NC(=O)c2ccc(OC[C@H]3CC3(F)F)cc2)cn1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((5-amino-4-hydroxypyridin-2-yl)oxy)propan-2-yl)carbamate and 4-(((1R)-2,2-difluorocyclopropyl)methoxy)benzoic acid, and in the same manner as in Step D of Example 83, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].O.[O:32]1CCC[CH2:33]1>>[F:12][C:9]([F:10])([F:11])[C:8]([N:7]([CH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH2:6][CH2:5][O:4][C:3]1[C:2]2[NH:1][C:33](=[O:32])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:13]
Reactant: C1CCOC1
Reactant: Nc1cccc(OCCN(CCCc2c[nH]c3ccccc23)C(=O)C(F)(F)F)c1N
Solvent: O
Product: O=C(N(CCCc1c[nH]c2ccccc12)CCOc1cccc2[nH]c(=O)[nH]c12)C(F)(F)F
Temperature: 23 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
A mixture of N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-[3-(1H-indol-3-yl)-propyl]-acetamide (0.5 g, 1.19 mmol) and diimidazole carbonyl (0.39 g, 2.38 mmol) in anhydrous tetrahyrofuran (50 ml) was stirred at 23° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2×250 ml). The organic layer was washed with water (2×250 ml) and brine (200 ml) and dried over anhydrous magnesium sulfate. The resulting product was concentrated to give the crude product. Purification by chromatography (60% ethyl acetate-hexanes) followed by crystallization from ethyl acetate-hexanes afforded 0.44 g (82.9%) of product as yellowish colored solid: mp 180-181° C.; MS EI m/e 446 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.Cl>CCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][OH:9]
Reactant: CN1CCCCC1CO
Agent: Cl
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CCO
Product: CN1CCCC[C@@H]1CO
Yield: 15.6 %

Procedure:
Following the known procedure of patent EP 0 429 984 A2 (reference example 8). The resolution was identical to the above given procedure except that 4 rounds of crystallization were performed instead of the two as sited above. To a mixture of (±)-1-methyl-2-piperidinemethanol (77 g, 596 mmol) in EtOH (615 mL) was added dibenzoyl-D-tartaric acid (205 g, 573 mmol). The resulting mixture was slowly heated until a solution was obtained at which time the solution was slowly cooled with gentle stirring. After 12 h the crystals were isolated and dried to afford 131.6 g. This process was repeated: (2) EtOH (533 mL) provided 92.5 g. (3) EtOH (225 mL) provided 68 g (4) EtOH (200 mL) provided 49 g. The resulting salt was treated with 3M HCl (200 mL) which was heated to induce it to dissolve. The still warm solution was poured into a separatory funnel and extracted with ethyl acetate. The remaining aqueous layer was adjusted to pH 10 with K2CO3. The solution was extracted with CH2Cl2, dried (MgSO4) and concentrated to give 12 g of the alcohol. This alcohol (12 g, 92.8 mmol) was suspended in CH2Cl2 (200 mL) and SOCl2 added. After stirring for 12 h, the solvent was removed to provide a crude HCl salt. This salt was dissolved in EtOH (100 mL) and treated with NH2NH2 (89 mL, 1.86 mol) and heated to reflux for 12 h. NaOH (74 g) in H2O (30 mL) was added and stirred for 1 h. Half the solvent was removed and the residue extracted with ether to give a crude oil. After distillation under reduced pressure (50-60° C.) the pure hydrazine product (4.87 g) was obtained. This hydrazine (1.6 g, 11.2 mmol) was dissolved in THF (10 mL) and triphenylmethylisocyanate (3.19 g, 11.2 mmol) was added slowly. The solution was then stirred overnight and filtered to provide 650 mg of the desired product in good purity. 1H NMR (DMSO-d6): δ 1.10 (m, 2H), 1.30-1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71 (d, 1H), 3.25 (q, 1H), 3.55 (q, 1H), 4.80 (s, 2H), 7.12-7.32 (m, 15H), 8.02 (s, 1H). ESI-MS m/z 429.2 (100, M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:16])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([CH3:27])=[CH2:26]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:16])=[C:13]([O:15][CH2:26][C:25]([CH3:27])=[CH2:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CBr
Reactant: Oc1cc(OCc2ccccc2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 5-(benzyloxy)-2-bromophenol (Simas, A. B. C., et al, Synthesis, (1999):1017-21) (8.15 g, 29.3 m mol) in DMF (150 mL) was added potassium carbonate (4.46 g, 32.2 mmol) slowly at 0° C. The mixture was stirred at ambient temperature for half an hour, followed by the addition of 3-bromo-2-methylpropene (3.35 mL, 32.2 mmol) during half an hour at 0° C. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonium chloride (50 mL). The aqueous mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/20) to give the title compound (10.0 g, 94%): 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (m, 5H), 6.53 (d, 1H), 6.45 (dd, 1H), 5.15-4.94 (m, 4H), 4.43 (s, 2H), 1.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.1, 155.6, 140.1, 136.5, 133.1, 128.6, 128.1, 127.5, 112.9, 107.2, 103.3, 102.0, 72.4, 70.3, 19.3.
Reaction SMILES: C([N:8]1[CH:30]=[N:29][C:28]2[N:13]([C@@H:14]3[O:27][C@H:17]([CH2:18][O:19]CC4C=CC=CC=4)[CH2:16][CH2:15]3)[CH:12]=[N:11][C:10]=2[C:9]1=[O:31])C1C=CC=CC=1.[OH-].[Na+].[H][H]>[OH-].[Pd+2].[OH-].[C].CN(C)C=O>[C@@H:14]1([N:13]2[C:28]3[N:29]=[CH:30][N:8]=[C:9]([OH:31])[C:10]=3[N:11]=[CH:12]2)[O:27][C@H:17]([CH2:18][OH:19])[CH2:16][CH2:15]1
Reactant: O=c1c2ncn([C@H]3CC[C@@H](COCc4ccccc4)O3)c2ncn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a N,N-dimethylformamide solution (1 mL) of N1,5′-O-dibenzyl-2′,3′-dideoxyinosine (52 mg, 0.125 mmol), an aqueous solution of sodium hydroxide (0.3 mL) at a concentration of 1 mol/L was added, and the mixture was stirred at room temperature for 2 hours. To the obtained solution, 20% palladium hydroxide-carbon (10 mg) was added, and the mixture was stirred at room temperature for 2 hours in an atmosphere of hydrogen (1 atm) and thereafter stirred at 80° C. for 16 hours and at 100° C. for 6 hours. The palladium catalyst was removed from the obtained reaction mixture by filtration, and the resultant filtrate was concentrated under reduced pressure. After purification by chromatography (using 10 g of silica gel and a mixed solvent of dichloromethane and methanol (4:1) as an eluting solution), 21 mg of the intended product was obtained in a yield of 70% as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:24]1[S:25][C:26]([CH2:35][CH2:36][C:37]([O:39]C)=[O:38])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:28]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])=[CH:6][CH:5]=1.[OH-].[Na+].O1CCCC1.[ClH:48]>O.CO>[ClH:48].[CH3:1][N:2]([C:24]1[S:25][C:26]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:28]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])=[CH:6][CH:5]=1
Reactant: COC(=O)CCc1sc(N(C)Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CN(C)c2nc(-c3ccccc3)c(CCC(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A mixture of methyl 3-[2-[N-methyl-N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]amino]-4-phenyl-5-thiazolyl]propionate (570 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and methanol (5 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in diethyl ether (40 ml) and 10% hydrochloric acid-methanol (0.5 ml) was added. The precipitated solid was collected by filtration and recrystallized from methanol-diethyl ether to give 3-[2-[N-methyl-N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]amino]-4-phenyl-5-thiazolyl]propionic acid hydrochloride (270 mg, yield 46%) as colorless crystals. melting point: 106–108° C.
Reaction SMILES: [CH2:1]([C:10]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:23][O:24][C:25]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[C:26]=1[NH2:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:10]1([C:20]([NH:27][C:26]2[C:28]([O:34][CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:25]=2[O:24][CH3:23])=[O:21])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCC1(C(=O)Cl)CCc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC1(C(=O)Nc2c(OC)cc(OC)cc2OC)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared according to the procedure described in Example 65, except that 422 mg 2-n-nonyl-1,2,3,4-tetrahydro-2-naphthoyl chloride, 247 mg (1.3 mmole) 2,4,6-trimethoxyaniline, and 165 mg (1.3 mmole) 4-dimethylaminopyridine in 12 ml methylene chloride were stirred at room temperature for 20 hours. There was obtained 421 mg product (68% yield). IR(CHCl3) 1670 cm-1. 1H NMR: δ0.87 (t, 3H); 1.25 (c, 12H); 1.5 (c, 3H); 1.85 (c, 2H); 2.21 (c, 1H); 2.8 (C, 2H); 3.0 (c, 1H); 3.3 (d, 1H); 3.66 (s, 6H); 3.75 (s, 3H); 6.06 (s, 2H); 6.56 (s, 1H); 7.1 (s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1.FC1C=C(F)C=CC=1CN1C2=CN=C(C(OCC)=O)C=C2C(COCC)=C1.C(OCC1C2C(=CN=C([C:71]([NH:73][OH:74])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.Cl.CNO>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:73]([OH:74])[CH3:71])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH3:20])=[CH:6]1
Reactant: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)OCC)cc12
Agent: CNO
Agent: Cl
Product: CCOCc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)N(C)O)cc12

Procedure:
1-(2,4-Difluorobenzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(2,4-difluorobenzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6). δ: 8.96 (s, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.08-7.40 (m, 2H), 7.07 (m, 1H), 5.62 (s, 2H), 4.63 (s, 2H), 3.48 (q, 2H, J=7.0 Hz), 1.11 (t, 3H, J=7.0 Hz). LCMS (API-ES, M+H+): 347.0. (b) 1-(2,4-Difluorobenzyl)-3-ethoxymethyl-N-hydroxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-3-ethoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid and N-methyl hydroxylamine hydrochloride in a manner similar to step (c) of example 1. 1H NMR (CD3OD) δ: 8.81 (s, 1H), 8.27 (s, 1H), 7.71 (s, 1H), 7.29 -7.30 (m, 1H), 6.98 -7.30 (m, 2H), 5.58 (s, 2H), 4.72 (s, 2H), 3.59 (q, 2H, J=7.0 Hz), 3.43 (s, 3H), 1.20 (t, 3H, J=7.0 Hz). LCMS (APCI, M+H+): 376.1. HRMS calcd for C19H20F2N3O3 (M+H) 376.1473, found 376.1454. Anal. (C19H19F2N3O3×0.2H2O) C, H, N. HPLC: 100% purity.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].O[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: OCC1CCCNC1
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OCC3CCCNC3)c2c1C

Procedure:
A solution of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (1 g), 3-(hydroxymethyl)piperidine (661 μl), triphenylphosphine (1.55 g) and azodicarboxylic acid diethyl ester (930 μl) in THF (20 ml) was stirred overnight at room temperature. A white precipitate separated out. The precipitate was filtered out and the filtrate was evaporated to dryness. The residue was separated by silica gel column chromatography developed by dichloromethane-methanol to give 3-methyl-4-(piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester (1.1 g) as a colorless oil. FAB-MS: m/z 318 (MH+); 1H-NMR (CDCl3): δ 1.42-2.02 (4H, m), 1.43 (3H, t, J=7 Hz), 2.43 (1H, m), 2.74 (2H, m), 2.75 (3H, s), 3.34 (1H, br d, J=12 Hz), 3.49 (1H, br d, J=12 Hz), 3.96 (1H, dd, J1=9 Hz, J2=6 Hz), 4.02 (1H, dd, J1=9 Hz, J2=5 Hz), 4.43 (2H, q, J=7 Hz), 6.59 (1H, d, J=8 Hz), 7.13 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz).