Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16]3)=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:1]([C:8]1[O:9][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([O:23][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:17]=[CH:16]3)=[CH:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2cc(-c3cnc(Cc4ccccc4)o3)ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc(-c3cnc(Cc4ccccc4)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
A mixture of 6-(2-benzyl-1,3-oxazol-5-yl)-2-naphthol (500 mg, 1.66 mmol), prepared in step 3 of Example 11, methyl bromoacetate (160 μL, 1.69 mmol) and cesium carbonate (1.08 g, 3.32 mmol) in 45 mL of acetone was stirred under nitrogen at room temperature for 16 h (overnight). The acetone was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to produce 628 mg of a white solid. Purification of the solid on a Biotage KP-SIL 60 Å 25+M 40 g column using methylene chloride-ethyl acetate as the eluent gave methyl {[6-(2-benzyl-1,3-oxazol-5-yl)-2-naphthyl]oxy} acetate (454 mg, 73%) as a white solid, mp 140-142° C. Elemental Analysis for C23H19NO4 Calc'd: C, 73.98; H, 5.13; N, 3.75. Found: C, 73.49; H, 4.96; N, 3.45.
Reaction SMILES: [Cl:1][C:2](=[CH:7][CH:8](Cl)[CH:9]([CH3:11])[CH3:10])[C:3]([F:6])([F:5])[F:4].[Cl-].[Li+].O>CN(C)C=O>[Cl:1][C:2](=[CH:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:3]([F:4])([F:5])[F:6]
Reactant: CC(C)C(Cl)C=C(Cl)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CC=C(Cl)C(F)(F)F
Temperature: 160 °C
Yield: 76 %

Procedure:
2,4-Dichloro-5-methyl-1,1,1-trifluorohex-2-ene (22.1 g) in dimethylformamide (100 ml) containing lithium chloride (5.0 g) is heated under a nitrogen atmosphere in an oil bath at 160° C. for 1.5 hours. The cooled mixture is added to water (1.5 l), extracted with dichloromethane and the extracts dried over anhydrous sodium sulphate and distilled to afford 2-chloro-5-methyl-1,1,1-trifluorohexa-2,4-diene (76%). The identity of the product was proved by comparison to 'Hnmr and infra-red spectra with those of authentic material.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:15]=2[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].ClCCl.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH3:24][O:23][CH2:22][O:21][C:19]1[CH:18]=[CH:17][C:16]2[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:45]([C:42]3[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=3)(=[O:47])=[O:46])[C:12]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)([CH3:25])[CH2:13][O:14][C:15]=2[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
(3RS,4RS)-4-(9-Hydroxynonyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (90 mg, 0.19 mmol) was dissolved in pyridine (2 ml) and dichloromethane (0.5 ml) and then cooled to 0° C. p-Toluenesulfonylchloride (0.12 g, 0.63 mmol) was added dropwise thereto, and the mixture was stirred for 3 hours at room temperature, quenched with water and then extracted with ethyl acetate. The extracted organic substance was washed with 2N hydrochloric acid, dried over magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 105 mg (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]([CH:4]([C:9]1[C:14]2[N:15]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=4[Cl:30])[C:16]3=[N:17][C:13]=2[C:12]([Cl:31])=[CH:11][CH:10]=1)[C:5]([F:8])([F:7])[F:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Cl:31][C:12]1[C:13]2[N:17]=[C:16]3[N:18]([C:22]4[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=4[Cl:30])[CH2:19][CH2:20][CH2:21][N:15]3[C:14]=2[C:9]([CH:4]([NH2:1])[C:5]([F:6])([F:7])[F:8])=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Temperature: 60 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A mixture of 6-(1-azido-2,2,2-trifluoroethyl)-9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (286 mg, 0.560 mmol), triphenylphosphine (220 mg, 0.839 mmol) and water (0.560 mL) in tetrahydrofuran (5.6 mL) was stirred at 60° C. for 1 day. After the mixture was diluted with ethyl acetate, the resultant mixture was extracted with 1N hydrochloric acid. The extract was washed with diethyl ether and neutralized with aqueous saturated sodium hydrogen carbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless solid (257 mg, 0.532 mmol, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:5]=[CH:4][N:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:23][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1ccnc(Cl)c1)Oc1ccccc1
Reactant: NC1CCCC1
Solvent: CC(C)=O
Product: O=C(Nc1ccnc(Cl)c1)NC1CCCC1
Yield: 85.8 %

Procedure:
A stirred solution of 3.5 grams (0.0141 mole) of phenyl N-(2-chloro-4-pyridinyl)carbamate and 1.7 ml (0.0172 mole) of cyclopentylamine in 60 ml of acetone was heated under reflux for three hours. The reaction mixture was cooled and concentrated under reduced pressure to a residual oil. The oil was dissolved in 20 ml of methylene chloride and passed through a column of silica gel. Elution was accomplished with 5% and 10% acetone-methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to yield 2.9 grams of N-(2-chloro-4-pyridinyl)-N'-cyclopentylurea; m.p. 119°-121° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(N)cn1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)c2ccc(OCc3c(-c4ccc(Cl)cc4)noc3CO)nc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and 1-methyl-1H-pyrazol-4-ylamine (26.9 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) to afford the title compound (101 mg, 83%) as a white solid. MS: m/e=440.2 [M+H]+.
Reaction SMILES: [N:1]#[N:2].C[CH:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([NH:13][C:14](=[O:16])[CH3:15])[CH:11]=2)[CH2:6][CH:5]1[NH:18][C:19](=[O:21])[CH3:20].[N+:22]([O-:25])(O)=[O:23].F[C:27](F)(F)C(O)=O>>[N:1]#[N:2].[CH3:27][CH:6]1[C:7]2[C:12](=[C:11]([N+:22]([O-:25])=[O:23])[C:10]([NH:13][C:14](=[O:16])[CH3:15])=[C:9]([Br:17])[CH:8]=2)[CH2:4][CH:5]1[NH:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Nc1cc2c(cc1Br)CC(NC(C)=O)C2C
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C(F)(F)F
Agent: N#N
Product: CC(=O)Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(NC(C)=O)C2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N2 -methyl-2,6-diacetamido-5-bromoindane (21.8 g, 67 mmol) in trifluoroacetic acid (200 mL) was cooled in an ice bath and treated with fuming nitric acid (25 mL). After stirring for 1 h, the mixture was warmed to room temperature and stirred for an additional 3 h. The solvent was removed and the residue taken up in water. The mixture was triturated in diethyl ether to give a precipitate, which was collected by filtration and dried to give the product (22.5 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=2[O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22](OC)=[O:23])[CH:20]=3)[CH:15]=[CH:14]2)[CH2:3][CH2:2]1.[OH-:30].[Na+].[NH2:32]O.O>CO>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=2[O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH:32][OH:30])=[O:23])[CH:20]=3)[CH:15]=[CH:14]2)[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2ccn(CCOc3ccccc3CN3CCOCC3)c2c1
Reactant: NO
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NO)c1ccc2ccn(CCOc3ccccc3CN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
To a solution of methyl 1-(2-(2-(morpholinomethyl)phenoxy)ethyl)-1H-indole-6-carboxylate (0.3 g, 0.83 mmol) in methanol (25 mL) was added a premixed (5 min) solution of NaOH (0.24 g, 6 mmol) and NH2OH (50% wt/wt in H2O, 1 mL) and H2O (2 mL). After stirring 5 hr at room temperature, the solution was concentrated and then diluted with H2O (30 mL) and the pH was adjusted to ˜9 with 1N HCl. The mixture was then extracted with ethyl acetate (100 mL) and concentrated to ˜3 mL and allowed to sit at room temperature for 16 hr. The resulting solid was isolated by filtration to provide 96 mg (29%) of 1-(2-(2-(morpholinomethyl)phenoxy)ethyl)-N-hydroxy-1H-indole-6-carboxamide as a tan solid. 1H NMR (300 MHz, DMSO) δ 11.11 (s, 1H), 8.90 (s, 1H), 8.03 (s, 1H), 7.62-7.55 (m, 2H), 7.44 (d, 1H, J=8.2 Hz), 7.19 (m, 2H), 6.90 (m, 2H), 6.50 (d, 1H, J=3.0 Hz), 4.63 (t, 2H, J=5.2 Hz), 4.30 (t, 2H, J=5.2 Hz), 3.43 (m, 4H), 3.18 (s, 2H), 2.12 (m, 4H). EM (calc.): 395.18; MS (M+H): 396.04.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[CH3:38][C@H:39]1[CH2:41][O:40]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:40][C@@H:39]([CH3:41])[CH2:38][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Reactant: C[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OC[C@H](C)O

Procedure:
The title compound was prepared according to the procedure described in Example 15 by using N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (4.93 g, 9.93 mmol), (S)-2-methyloxirane (8.8 mL, 150 mmol) and K2CO3 (2.74 g, 19.8 mmol) in DMF/H2O (21 mL/4 mL). The title compound was purified by a silica gel column chromatography (DCM/MeOH=50/1 to 20/1) and was obtained as a pale solid (2.1 g, 38.3%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])(C)(C)C>Cl.O1CCOCC1>[Cl:25][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1
Reactant: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A solution of 6-chloro-4-(3-chloro-phenyl)-2-diethylamino-quinoline-3-carboxylic acid tert-butyl ester (60 mg, 0.13 mmol) in 3 ml of 4M HCl solution in dioxane was heated to reflux and stirred for 4 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was diluted with ethyl acetate (25 ml) and washed with brine (5 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to yield 6-chloro-4-(3-chloro-phenyl)-2-diethylamino-quinoline-3-carboxylic acid (45 mg, 86%) as a pale yellow solid. LC-MS (ESI): 389 (M+H)+.
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][NH:11][CH2:10][C@@H:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[NH:29][N:28]=[C:27]([CH:30]3[CH2:32][CH2:31]3)[CH:26]=2)[CH:21]=[C:20]([CH3:33])[N:19]=1.ClC1N=C(NC2NN=CC=2)C=C(C)N=1>>[CH:1]1([C@H:7]2[CH2:12][N:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[NH:29][N:28]=[C:27]([CH:30]5[CH2:32][CH2:31]5)[CH:26]=4)[CH:21]=[C:20]([CH3:33])[N:19]=3)[CH2:10][C@@H:9]([C:13]([O:15][CH3:16])=[O:14])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)[C@@H]1CNC[C@H](C2CCCCC2)C1
Reactant: Cc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Agent: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Product: COC(=O)[C@H]1C[C@@H](C2CCCCC2)CN(c2nc(C)cc(Nc3cc(C4CC4)n[nH]3)n2)C1

Procedure:
The title compound was prepared by the similar manner described in Example 1 using methyl cis-5-cyclohexylpiperidine-3-carboxylate instead of (S)-3-(tert-butoxycarbonylamino)piperidine, and 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methylpyrimidin-4-amine prepared in Referential Example 2 instead of 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(OC(C)(C)C)=O)=[C:18]([F:30])[CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.O1CCOCC1.[ClH:37]>CCOCC>[ClH:37].[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:30])[CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(N)c(F)c1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
A suspension of ethyl 4-amino-5-{4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (400 mg, 0.963 mmol) in 4N HCl in dioxane (9.63 mL, 38.5 mmol) was heated to 60° C. for 5 min, then cooled to rt and diluted with 40 mL ether. Filtration through a teflon membrane filter gave the title compound as a yellow solid (310 mg, 91.5% yield). 1H-NMR (DMSO-d6) 8.33 (s, 1H), 8.14 (s, 1H), 7.16 (d, J=12 Hz, 1H), 6.96 to 7.03 (m, 2H), 4.13 (q, J=8 Hz, 2H), 1.15 (t, J=8 Hz, 3H); MS [M+H]+=316.1; LCMS RT=2.39.
Reaction SMILES: C([O:5][C:6](=[O:48])[CH2:7][C:8]1([C:41]([O:43]C(C)(C)C)=[O:42])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([O:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=3)[CH:16]=[C:15]([CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[CH:14]=2)[CH2:9]1)(C)(C)C.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>>[F:52][C:51]([F:54])([F:53])[C:49]([OH:55])=[O:50].[NH:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]([O:19][C:17]2[CH:18]=[C:13]([C:10]3[CH2:9][C:8]([CH2:7][C:6]([OH:48])=[O:5])([C:41]([OH:43])=[O:42])[O:12][N:11]=3)[CH:14]=[C:15]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:16]=2)=[O:31])=[CH:22][CH:23]=1)[C:28]([NH2:30])=[NH:29]
Reactant: CC(C)(C)OC(=O)CCc1cc(OC(=O)c2ccc(NC(=N)N)cc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccc(C(=O)Oc2cc(CCC(=O)O)cc(C3=NOC(CC(=O)O)(C(=O)O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(3-(3-tert-butoxy-3-oxopropyl)-5-((4-carbamimidamidobenzoyl)oxy)phenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (104 mg) and TFA (2 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and then, the residue was washed with diethyl ether to obtain the title compound (70.0 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)C>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:7]3[CH:6]=[C:5]4[O:1][CH2:2][O:3][C:4]4=[CH:9][C:8]=3[CH2:10][CH2:11][O:12]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCCc1ccc2c(c1)OCO2
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C2OCCc3cc4c(cc32)OCO4)cc1
Yield: 81 %

Procedure:
36.0 g (0.21 mmol) of 2-(1,3-benzodioxol-5-yl)-ethanol is reacted with an equivalent amount of 4-nitrobenzaldehyde analogously to C.A. 105, 1986, 226357, and 50.7 g (81%) of the title compound, melting point 149-150° C. (ethanol), is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[C:16]3[CH:17]=[C:18]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:19]=[CH:20][C:15]=3[O:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[C:16]3[CH:17]=[C:18]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:19]=[CH:20][C:15]=3[O:14][N:13]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2noc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Oc2noc3ccc(C4CCNCC4)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(3-{[(4-methylphenyl)sulfonyl]oxy}-1,2-benzisoxazol-5-yl)piperidine-1-carboxylate (285 mg, 0.603 mmol) was dissolved in anhydrous 4N HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated to afford 5-piperidin-4-yl-1,2-benzisoxazol-3-yl 4-methylbenzenesulfonate hydrochloride which did not require further purification.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[N:13]1([C:2]2[N:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CCO
Product: CCOC(=O)c1cccnc1N1CCNCC1

Procedure:
10.0 g of ethyl 2-chloronicotinate were reacted with 27.8 g of piperazine in 400 ml of ethanol analogously to Example 18a, 6.9 g (54%) of the product being obtained.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].Cl.[CH3:27][NH:28][O:29][CH3:30]>C(Cl)Cl>[CH3:30][O:29][N:28]([CH3:27])[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:14]=1[CH3:13]
Reactant: CNOC
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carbonyl diimidazole (9.8 g, 60.7 mmol) was added to a solution of 2-methyl-3-nitrobenzoic acid (10 g, 55 mmol) in CH2Cl2 (200 mL) at 0° C. and stirred for 30 min. The reaction mixture was warmed to room temperature, stirred for 2 h, and cooled to 0 C. N,O-dimethylhydroxylamine hydrochloride was added to the reaction mixture at 0 C, stirred for 30 min., and heated to 45 C for 1 h. The reaction mixture was cooled to room temperature, stirred for 12 h, and quenched with aqueous K2CO3 (10%, 200 mL). The reaction mixture was extracted with CH2Cl2 (3×200 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 6:4 hexanes:EtOAc) provided the title compound a white solid (2.6 g, 21%). MS: 225 (MH+); HPLC Rf: 3.96 min. (HPLC method 4); HPLC purity: 98%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.[CH2:33]([NH2:40])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(=O)(O)[O-].[Na+]>C(#N)C>[C:13]1([C:11]2[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:40][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1c(CCCCCCBr)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CCCCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCNCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Yield: 96.9 %

Procedure:
Part B. A solution of 6-bromo-1-(4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl)hexane (1.0 g, 0.00195 mol) and n-heptylamine (0.45 g, 0.00389 mol) in acetonitrile (25 mL) was heated to 60° for 8 hours. The reaction mixture was poured into 10% aqueous sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The combined organic extract was washed with water, brine, dried over magnesium sulfate and concentrated to give N-[6-(4,5-diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl) hexyl ]-N-heptylamine as a colorless viscous oil (1.04 g, 0.00189 mol). 1H NMR (CDCl3) δ 7.52-7.2 (m,10H), 5.11(s,2H), 4.7-4.2(bs,1H), 3.3(t,2H), 2.93-2.70(m,6H), 1.95-1.34(m,18H), 0.93(t,3H), 0.86(t,2H), 0.005(s,9H).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:19]2[C:10](=[NH+:11][CH:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)[CH:9]=[CH:8][CH:7]=1.[C:20]1([C:26]([CH3:31])=[CH:27][C:28](=O)[CH3:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:29][C:28]1[N+:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:19]=3[C:18]3[C:13]([C:12]=2[CH:31]=[C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: CC(=O)C=C(C)c1ccccc1
Reactant: c1ccc2c(c1)c[nH+]c1ccccc12
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: Cc1cc(-c2ccccc2)cc2c3ccccc3c3ccccc3[n+]12

Procedure:
Phenanthridinium perchlorate (2 g) and 4-phenylpent-3-ene-2-one (4 g) were heated together at 150° for 16 hours. The reaction mixture was cooled and diluted with methanol. The product was isolated by filtration and recrystallized from acetonitrile. Yield 1.5 g, m.p. 252°-3°.