Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([NH:4][C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C(=O)NC2CC2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(C(=O)NC2CC2)on1
Yield: 23.3 %

Procedure:
Ethyl 5-(cyclopropylcarbamoyl)isoxazole-3-carboxylate (1.267 mmol, 0.284 g) was dissolved in ethanol (10 ml). The mixture was cooled in an ice bath and NaOH 2 M solution (2.53 mmol, 1.267 ml) was added. The resulting mixture was stirred in cold until the reaction was complete. Ethanol was evaporated and water was added. The pH of the mixture was adjusted to 4 with HCl. The precipitate was removed by filtration. The filtrate was evaporated and purified by trituration from 1/9 MeOH/DCM. 0.058 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 0.57-0.66 (m, 2H), 0.67-0.75 (m, 2H), 2.77-2.88 (m, 1H), 6.97 (s, 1H), 8.85 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.Cl.[N:13](OCCCC)=[O:14]>C(O)C>[N:13](=[CH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1)[OH:14]
Reactant: CCCCON=O
Reactant: Cc1cnnc2ccccc12
Agent: Cl
Solvent: CCO
Product: ON=Cc1cnnc2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 1.44 g of 27A in 3 ml of absolute ethanol was added drop-by-drop over 3 minutes to 3.4 ml of stirred absolute ethanol containing 0.9 g of anhydrous hydrogen chloride, at 0° C. The resulting mixture was stirred for 30 minutes, then a solution of 1.03 g of butyl nitrite in 2 ml of absolute ethanol was added drop-by-drop over 3 minutes at 0° C. The mixture was stirred for 30 minutes at 0° C., for 4 hours at room temperature, then stored in a refrigerator overnight. A precipitated solid was collected, washed with a small amount of water, mixed with a saturated potassium bicarbonate solution, and filtered. Recrystallization from water gave 4-(hydroximinomethyl)cinnoline (27B), as a solid, m.p.: 223° C. (with decomposition).
Reaction SMILES: O[CH:2]([CH3:5])[CH2:3][NH2:4].[Cl-].ClC(C)C[NH3+].[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[S:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[NH:4][CH2:3][CH:2]([CH3:5])[S:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(O)CN
Agent: CC(Cl)C[NH3+]
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NCC(C)S1

Procedure:
2-Hydroxypropylamine was converted to 2-chloropropylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-chloropropylammonium chloride according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-5-methyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-3-(2-methylprop-2-en-1-yl)-5-methyl-1,3-thiazolidine HBr salt.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])[CH3:2].Br[CH2:18][CH2:19][OH:20].C(N(CC)CC)C>C(O)C>[CH2:1]([N:3]([CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])[CH2:18][CH2:19][OH:20])[CH3:2]
Reactant: CCNCCN1C(=O)c2ccccc2C1=O
Reactant: OCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN(CCO)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a solution of compound 2 (15.00 g, 68.7 mmol) in anhydrous ethanol (300 mL) were successively added, under argon, 2-bromoethanol (14.8 mL, 0.21 mol) and triethylamine (29.0 mL, 0.21 mol). The mixture was stirred under reflux for 60 h. After cooling to room temperature, the solvent was evaporated under vacuum and the residue was chromatographed (SiO2, AcOEt/EtOH, 99/1, v/v) to give compound 3 (13.00 g, 49.6 mmol) as a white solid. Yield 72%; Rf (SiO2, AcOEt/EtOH, 99/1, v/v) 0.49; mp 56-58° C.; IR (KBr) ν 1018, 1387, 1405, 1702, 2825, 2959, 3400-3600 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.93 (t, 3H, J=7.1 Hz), 2.58 (q, 2H, J=7.1 Hz), 2.68 (t, 2H, J=5.3 Hz), 2.76 (t, 2H, J=6.2 Hz), 3.11 (se, 1H), 3.53 (t, 2H, J=5.3 Hz), 3.77 (t, 2H, J=6.2 Hz), 7.71 (m, 2H), 7.82 (m, 2H); MS m/z 262 (M+, 1), 231 (11), 174 (21), 130 (8), 102 (100), 76 (10), 58 (29).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]#[N:12])([CH3:3])[CH3:2].Cl.[C:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>ClC1C=CC=CC=1.NC1C2C(=CC=CC=2)C=CC=1>[C:14]1([NH:24][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[NH:12])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2ccccc12
Reactant: CC(C)c1ccccc1NC#N
Agent: Cl
Solvent: Clc1ccccc1
Product: CC(C)c1ccccc1NC(=N)Nc1cccc2ccccc12
Yield: 44 %

Procedure:
A solution of o-isopropylphenylcyanamide (1.13 g, 7.05 mmol), 1-naphthylamine hydrochloride (1.1 g, 7.04 mmol) and 1-aminonaphthalene (14.38 mg, 0.1 mmol) in chlorobenzene (20 ml) was heated to 150° C. for 4 hours and at room temperature for 10 hours. It was concentrated and the residue was partitioned between dichloromethane and 10% NaOH solution. The organic layer was concentrated and the resulting solid was recrystallized from EtOH - H2O (10:1) to give N-(1-naphthyl)-N'-(o-isopropylphenyl)guanidine (940 mg, 44%) as white crystals. mp 175°-177° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C[Si](Cl)(C)C.[CH3:22][CH:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][C:25](Cl)=[O:26].N>N1C=CC=CC=1>[CH3:22][CH:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][C:25]([NH:14][C:13]1[CH:15]=[CH:16][N:9]([C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)[C:10](=[O:11])[N:12]=1)=[O:26]
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Product: CC(CC(=O)Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)CC(C)(C)C
Yield: 127.9 %

Procedure:
Suspending 2′-Deoxycytidine (2.3 g, 10.0 mmol) in dry pyridine, followed by concentration under reduced pressure was repeated 3 times to perform dehydrative azeotropic distillation, the concentrate was suspended again in dry pyridine (60 ml), and trimethylsilyl chloride (6.4 ml, 50 mmol) was added dropwise over 5 min. To the reaction mixture was added 3,5,5-trimethyl-1-hexanoyl chloride (9.5 ml, 50.0 mmol) over 5 min. After completion of the reaction, under ice-cooling, aqueous ammonia (25 ml) was added and the mixture was reacted for 20 min. The reaction mixture was concentrated under reduced pressure. Water (150 ml) was added to the concentrate, and the mixture was extracted 3 times with ethyl acetate (100 ml). The organic layer was concentrated and the obtained oil was purified by silica gel column chromatography to give the title compound (4.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:48][CH3:49])=[N:4][C:5]([CH2:46][CH3:47])=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[N:23]=[N:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=2)=[CH:12][CH:11]=1.[CH3:50]C(C)([O-])C.[K+].O1CCOCCOCCOCCOCCOCC1.IC>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:48][CH3:49])=[N:4][C:5]([CH2:46][CH3:47])=[CH:6][C:7]=1[N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[N:23]=[N:24][N:25]([C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=2)=[CH:14][CH:15]=1)[CH3:50]
Reactant: CC(C)(C)[O-]
Reactant: CCc1cc(NCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(Cl)c(CC)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cc(N(C)Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(Cl)c(CC)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
3-Chloro-2,6-diethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methylamino]pyridine (335 mg) was added to a mixture of potassium t-butoxide (75 mg) and 1,4,7,10,13,16-hexaoxacyclooctadecane (10 mg) in THF (10 ml) and the mixture was stirred for 15 minutes. Iodomethane (0.04 ml) was added and the solution heated at reflux for 6 hours. The mixture was cooled to ambient temperature and solvent was removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:1 v/v) to give 3-chloro-2,6-diethyl-4-[N-(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl-N-methylamino]-pyridine (A) (220 mg) as a foam; NMR (CDCl3): 1.28(double t, 6H), 2.60(s, 3H), 2.72(q, 2H), 2.96(q, 2H), 4.24(s, 2H), 6.59(s, 1H), 6.89(m, 6H), 7.13(m, 3H), 7.30(complex m, 14H), 7.95(m, 1H).
Reaction SMILES: [NH2:1][O:2]C1CCCCO1.[C:9]1([S:15]([C:18]2[C:26]3[C:21](=[CH:22][C:23]([CH:27]=[CH:28][C:29]([OH:31])=O)=[CH:24][CH:25]=3)[NH:20][CH:19]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C.CO>[C:9]1([S:15]([C:18]2[C:26]3[C:21](=[CH:22][C:23]([CH:27]=[CH:28][C:29]([NH:1][OH:2])=[O:31])=[CH:24][CH:25]=3)[NH:20][CH:19]=2)(=[O:16])=[O:17])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)C=Cc1ccc2c(S(=O)(=O)c3ccccc3)c[nH]c2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccc2c(S(=O)(=O)c3ccccc3)c[nH]c2c1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
NH2OTHP (0.04 g, 0.37 mmol) was added to a solution of 24 (0.10 g, 0.31 mmol), PyBOP (0.17 g, 0.33 mmol), triethylamine (0.1 ml, 0.74 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 1 h before it was quenched with water, followed by extraction with EtOAc (15 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2:CH3OH=30:1:1% NH3(aq)) to give a white solid, which was treated with TFA (0.70 ml, 9.44 mmol) in the presence of CH3OH (15 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give a white residue, which was recrystallized by CH3OH to afford Compound 24 (0.08 g). 1H NMR (500 MHz, CD3OD): δ 6.45 (d, J=15.8 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.50-7.65 (m, 5H), 7.81 (d, J=8.4 Hz, 1H), 7.98-8.00 (m, 2H), 8.04 (s, 1H). MS (EI) m/z: 342. HRMS (EI) for C17H14N2O4S (M+): calcd, 342.0674. found, 342.0674.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[N+:16]([O-:18])=[O:17])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20]O.[OH-].[K+].O>CCO.CO>[NH2:20][C:10]1[C:9]2[C:14](=[CH:15][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:7][CH:8]=2)[C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: NO
Reactant: CC(C)(C)Oc1ccc2cccc([N+](=O)[O-])c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)Oc1ccc2c(N)ccc([N+](=O)[O-])c2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7-tert-butoxy-1-nitronaphthalene, as described above in Step D, (3.35 g, 13.7 mmol) and hydroxylamine hydrochloride (5.94 g, 85.5 mmol) in 95% EtOH (140 mL) at 60° C. was added KOH (11.9 g, 212 mmol) in MeOH (75 mL), dropwise over 30 min. The reaction mixture was stirred at 60° C. for 6 hours, then poured into H2O (200 mL) and extracted with CH2Cl2 (3×300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—20% to 40% EtOAc to yield the titled product.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])O.[Na+]>O.CC(C)=O>[CH3:16][O:15][C:13]([O:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:14]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)=NOC(=O)OC
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A solution of sodium salt of ethyl 2-hydroxyimino-2-cyanoacetate (41.0 g) in water (200 ml) is stirred under ice-cooling, and a solution of methyl chloroformate (23.6 g) in acetone (20 ml) is dropwise added thereto. The resulting mixture is adjusted to pH 6 to 7 with the addition of an aqueous solution of sodium hydrogencarbonate and stirred for 1 hour. The precipitates are collected by filtration, washed with water and dried to give ethyl 2-methoxycarbonyloxyimino-2-cyanoacetate (41.1 g) as crystals melting at 68° to 70°C which is identified with the compound obtained in Example 9 by IR absorption spectrum.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-(4-ethoxycarbonylphenyl) ethynyl]pyrrolidine (2.75 g, 8 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL), and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo and made basic with sat. NaHCO3 and extracted with CHCl3. The extract was washed with brine, dried over MgSO4, evaporated to give 1.95 g (q.y.) 2-[2-(4-ethoxycarbonylphenyl) ethynyl]pyrrolidine as a light yellow oil. 1H-NMR (CDCl3) δ 1.38 (3 H, t, J=6.8 Hz), 1.82–2.16 (4 H, m), 3.01–3.48 (2 H, m), 4.00–4.11 (1 H, m), 4.37 (2H, q, J=6.8 Hz), 4.54–4.77 (1 H, m), 7.44–7.46 (2 H, m), 7.95–7.97 (2 H, m).
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:7]([OH:9])=O>C(OCC)C>[Br:3][C:4]1[CH:5]=[C:6]([C:7](=[O:9])[CH3:1])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)c1cc(F)cc(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Methyllithium (1.3 M in diethyl ether, 35 mL) was added dropwise to 3-bromo-5-fluorobenzoic acid (5 g) in diethyl ether at −78° C. keeping the temperature below −60° C. The reaction was then left to warm to −10° C. and was stirred for 1 h before being carefully quenched with saturated ammonium chloride (100 mL) until pH=3. The product was extracted with diethyl ether (2×100 mL), dried over sodium sulfate and the solvent removed by evaporation to yield 1-(3-bromo-5-fluorophenyl)ethanone as an off-white solid (4.67 g, 94%). 1H NMR (CDCl3): 2.59 (3H, s, ArCOCH3), 7.44 (1H, dd, Ar), 7.59 (1H, dd, Ar), 7.87 (1H, s, Ar).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccccc1
Reactant: c1cn[nH]c1
Product: c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with bromobenzene (212 μL, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 270 mg (94% isolated yield) of the desired product as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[NH2:8].[OH:18][C:19]1[C:20]([CH3:35])=[C:21]2[C:26](=[C:27]([CH3:30])[C:28]=1[CH3:29])[O:25][C:24]([CH3:34])([C:31](O)=[O:32])[CH2:23][CH2:22]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[NH2:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[N:4]([CH3:16])[C:3](=[O:17])[C:2]=1[NH:1][C:31]([C:24]1([CH3:34])[CH2:23][CH2:22][C:21]2[C:26](=[C:27]([CH3:30])[C:28]([CH3:29])=[C:19]([OH:18])[C:20]=2[CH3:35])[O:25]1)=[O:32]
Reactant: Cn1c(=O)c(N)c(N)n(-c2ccccc2)c1=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)Nc1c(N)n(-c3ccccc3)c(=O)n(C)c1=O)O2
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 5,6-diamino-3-methyl-1-phenyl-2,4 (1H, 3H) -pyrimidinedione (3.02 g, 13 mmol), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (3.58 g, 14.3 mmol) and 4-(dimethylamino)pyridine (0.32 g, 2.6 mmol) was suspended in dichloromethane (60 mL). To the resultant suspension was added dropwise a solution of N, N'-dicyclohexylcarbodiimide (2.82 g, 13.7 mmol) indichloromethane (60 mL) at room temperature. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated and then subjected to silica-gel column chromatography, thereby giving the title compound (yield 57%). TOF-MS (Time-of-flight type mass spectrum): m/z 465 [M+H]+1H-NMR (CDC13):δ1.60(3H, s), 1.90-2.04(1H, m), 2.08(3H, s), 2.18(3H, s), 2.29(3H, s), 2.30-2.38(1H, m), 2.54-2.64(2H, m), 3.34(3H, s), 4.32(1H, s), 5.17(2H, bs), 7.27-7.36(2H, m), 7.53-7.60 (3H, m), 8.41 (1H, bs)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:28][CH:29]1[O:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH2:30]1)(=O)=O>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:28][CH:29]4[O:34][C:33]5[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=5[O:31][CH2:30]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)OCC1COc2ccccc2O1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (2.45 g, 17.7 mmol), 2-methanesulfonyloxymethyl-1,4-benzodioxan (3.35 g, 13.7 mmol) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichloromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%). Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan as off-white crystals, 2.22 g, m.p.=86-87° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH3:25])[C:20](=[O:26])[CH2:19][CH2:18]4)[CH:11]=[N:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:58](O)(=[O:61])[CH2:59][CH3:60].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:25][N:21]1[C:22]2[C:17](=[CH:16][C:15]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]4[C:9]=3[CH2:8][CH2:7][CH2:6][N:5]4[CH2:4][CH2:3][NH:2][C:58](=[O:61])[CH2:59][CH3:60])=[CH:24][CH:23]=2)[CH2:18][CH2:19][C:20]1=[O:26]
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4CCN)ccc21
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)NCCN1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a solution of 6-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro-[1,7]naphthyridin-5-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 12, 0.037 g, 0.099 mmol) in dry DMF (1.5 mL) were added TBTU ((O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) 0.038 g, 0.119 mmol), Hünig's base (0.032 g, 0.248 mmol) and propionic acid (0.015 g, 0.198 mmol) and the reaction mixture was stirred at room temperature over night. Then, the reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (5 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 10% MeOH (1% NH4OH)-DCM gradient to give the title compound (0.023 g, 59%) as a yellow solid. MS: 393.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:35])=O)(C)(C)C.C(OC(N1C2C=C(C(OC)=O)C(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC=2N=C1C)=O)(C)(C)C>CO>[CH3:35][C:9]1[NH:10][C:11]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:13][C:12]=2[N:8]=1
Reactant: COC(=O)c1cc2nc(C)n(C(=O)OC(C)(C)C)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(=O)c1cc2c(cc1OC1CCN(C(=O)OC(C)(C)C)CC1)nc(C)n2C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)c1cc2[nH]c(C)nc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-tert-butoxycarbonyl-2-methyl-5-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole and 1-tert-butoxycarbonyl-2-methyl-6-methoxycarbonyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole (2.5 g) in methanol (200 mL) was bubbled in ammonia at 0° C. After stirring for 2 hours at ambient temperature the reaction mixture was concentrated. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate/CH2 Cl2 /methanol, gradient) to afford 2-methyl-5-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole. To this product (0.66 g) in DMF (20 mL) was added NaH (0.075 g) at ambient temperature. After stirring at ambient temperature for 30 minutes 7-bromomethyl-2-naphthonitrile (0.5 g) was added at 0° C. The reaction mixture was stirred at ambient temperature for 0.5 hours. The reaction was worked up between ethyl acetate and H2O. The organic layer was dried and concentrated to afford a mixture of 1-(4-cyanonaphth-1-yl)methyl-2-methyl-5-methoxycarbonyl-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole and 1-(4-cyanonaphth-1-yl)methyl-2-methyl-6-methoxycarbonyl-5-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)benzimidazole in a ratio of 2 to 1, respectively.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:11]=23)[N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1COCC1.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:1][C:2]1[C:6]([C:7]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[CH:17]=[CH:18][C:11]=23)[N:3]=1
Reactant: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C(=O)O
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C(=O)N1CCCCC1
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A solution of 3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carboxylic acid (0.040 g, 0.00011 mol) (1:1 of AcOH) and N,N-carbonyldiimidazole (0.035 g, 0.00021 mol) in THF (1 mL, 0.01 mol) was stirred for 1.2 h, after which time piperidine (32 mL, 0.00032 mol) was added. After another 2 h, another portion of piperidine (15 mL) was added and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water, and washed sequentially with sat. NaHCO3 and brine. The organic phase was dried and evaporated to give 49 mg of the crude product as an orange oil/glass. The crude product was chromatographed with 75-100% ethyl acetate/hexanes, sample in DCM. Collected 25 mg of the purified product as a colorless glass/oil (50% yield).