Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[NH:30]1[C:35](=[O:36])[CH2:34][O:33][CH2:32][C:31]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:30]1[C:35](=[O:36])[CH2:34][O:33][CH2:32][C:31]1=[O:37]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Reactant: O=C1COCC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCN2C(=O)COCC2=O)cc1Cl
Reaction time: 18 h

Procedure:
To a solution of Compound 158 (47 mg, 0.1 mmol), morpholine-3,5-dione (16 mg, 0.14 mmol) and triphenylphosphine (37 mg, 0.14 mmol) in THF (5 ml) was added diethyl azodicarboxylate solution (40% in toluene, 0.1 ml, 0.23 mmol) at RT. The reaction solution was stirred at the same temperature for 18 h and concentrated in vacuo. The residue was purified by chromatography (petroleum ether/ethyl acetate 1:1) to furnish the title compound, which was impure. The product was further purified by preparative TLC (petroleum ether/ethyl acetate 1:1) to give the pure title compound as yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-6-methoxy-3-nitropyridine and 4-aminophenylethyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Cl:17][C:18]1[CH:19]=[C:20]([OH:27])[CH:21]=[N:22][C:23]=1[CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:20]2[CH:21]=[N:22][C:23]([CH:24]3[CH2:26][CH2:25]3)=[C:18]([Cl:17])[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 35.7 g, 143.86 mmol) in DMSO (97.6 mL) was added 5-chloro-6-cyclopropylpyridin-3-ol (Preparation 69, 24.4 g, 143.86 mmol) and stirred at room temperature until a solution obtained. Potassium carbonate (49.7 g, 359.65 mmol) was added portion wise maintaining the internal temperature at 15-25° C. with a cold water jacket. The reaction mixture was stirred at room temperature for 12 hours, cold water charged and the resulting slurry stirred for 90 minutes. The mixture was filtered, washed with water and dried to give the title compound as a pale yellow solid (54.0 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:33][CH2:34][CH3:35]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:33][CH2:34][CH3:35])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a stirred solution of 1.0 g (0.0033 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) and 10 mL of dimethylformamide was added 3.23 g (0.0099 mole) cesium carbonate followed by 0.8 mL (0.0099 mole) of 1-iodopropane. The mixture was stirred at room temperature for 18 hours, then water was added. After 15 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium metabisulfite solution and then brine. The aqueous layers were reextracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexanes-dichloromethane to give 1.0 g of 2-Chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144) as white crystals.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[CH:14]([NH:17][S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH2:16])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:34](Br)[CH:35]=[CH2:36]>CN(C=O)C>[CH2:36]([N:17]([CH:14]([C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[S:4][CH:1]1[CH2:3][CH2:2]1)[CH:15]=[CH2:16])[S@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH:35]=[CH2:34]
Reactant: C=CC(N[S@@](=O)C(C)(C)C)c1cc([N+](=O)[O-])ccc1SC1CC1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCN(C(C=C)c1cc([N+](=O)[O-])ccc1SC1CC1)[S@@](=O)C(C)(C)C
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To 85B (2.46 g, 6.95 mmol) in DMF (20 mL) at −20° C. was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 12.2 mL, 12.2 mmol) dropwise. The mixture was stirred at −20° C. for 20 min followed by addition of allyl bromide (3.0 mL, 34.8 mmol). After 1.0 h stirring at −20° C., the reaction was quenched with sat. NH4Cl and warmed to rt. It was extracted with EtOAc (3×50 mL), the organic layer was washed with brine and dried over Na2SO4. After removal of solvent, the crude was purified by silica gel column chromatography using gradient EtOAc in hexanes to give 85C (2.2 g, 80% yield). HPLC and 1H NMR indicated 85C is a mixture of two diastereoisomers in a ratio of 5:1. Major isomer: 1H NMR (400 MHz, CDCl3) δ ppm 0.67-0.76 (m, 2H) 1.15-1.20 (m, 2H) 1.25 (s, 9H) 2.12-2.20 (m, 1H) 3.02 (dd, J=17.14, 6.59 Hz, 1H) 4.05 (dd, J=17.14, 4.83 Hz, 1H) 5.06-5.26 (m, 5H) 6.00 (ddd, J=17.03, 10.22, 7.03 Hz, 1H) 7.70 (t, J=8.13 Hz, 1H) 8.10 (dd, J=8.79, 2.64 Hz, 1H) 8.49 (d, J=2.64 Hz, 1H), LC-MS 395 (M+H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(C[CH:15]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)(O)=O.[C:36](O)(=[O:38])C.O>ClCCl>[OH:38][CH2:36][CH:22]1[C:27]2[C:26]3[CH:25]=[CH:31][CH:30]=[CH:29][C:28]=3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[C:35]2[C:23]1=[CH:24][CH:32]=[CH:33][CH:34]=2
Reactant: CC(=O)O
Reactant: O=C(O)CC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: OCC1c2ccccc2-c2c1c1ccccc1c1ccccc21
Reaction time: 3 h
Yield: 10 %

Procedure:
Diisobutylaluminum hydride (4.6 ml, 4.62 mmol; 1M in CH2Cl2) was added at -65° C. to a solution of 13-carboxymethyl-dibenzo(a,c)fluorene (0.5 g, 1.54 mmol) in dichloromethane (10 ml). The reaction mixture was stirred for 3 h and the temperature maintained between -50° C. and -40° C. A white precipitate was obtained. The reaction mixture was treated with a mixture of acetic acid and water (1:1; 30 ml) and extracted with dichloromethane (3×60 ml). The organic layer was washed with saturated bicarbonate (50 ml), water (30 ml) and dried over MgSO4. The solvent was removed in vacuo to afford a crude solid. This crude solid was purified by flash chromatography using chloroform as the eluent. Compound (21) was obtained as a white solid which was washed with petrol (0.217 g, 48%); m.p. 167°-168° C.; (Found: C, 89.0; H, 5.39; C22H16O requires: C, 89.2; H, 5.41%); t.l.c. Rf (D) 0.26; Rf (E) 0.64; νmax (CH2Cl2) 3610 (free OH), 3490 (H bonded OH), 3060 (CH stretching), 2940, 2890 (CH stretching, alkyl), 1610, 1600, 1580 (aromatic rings) cm-1 ; λmax 366 (888), 338 (12728), 322 (14504), 266 (27232), 246 (31968) nm; δH (CDCl3, 200 MHz), 8.88-8.68 (3H, m, aromatic), 8.38 (1H, d, 3J=7.9 Hz, aromatic), 8.14-8.08 (1H, m, aromatic), 7.81-7.33 (7H, m, aromatic), 4.45 (2H, m, HaCH2 and Hc), 3.85 (1H, m, Hb, CH2), 1.64 (1H, S, OH), δC (CDCl3, 50 MHz), 146.7, 142.5, 139.4, 134.9, 130.9, 130.1, 128.7 (quaternary aromatic C's), 127.5, 126.8, 126.1, 125.9, 125.8, 124.7, 124.2, 124.1, 123.8, 123.4, 122.9 (aromatic CH's), 65.7 (CH), 50.0 (CH); m/z (EI) 296, 265.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]=[O:16])[O:5][CH2:6][CH2:7][CH2:8][C:9]([O-:11])=O.[Li+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[N+:47]([C:50]1[CH:55]=[C:54]([N+:56]([O-:58])=[O:57])[CH:53]=[CH:52][C:51]=1[NH:59][CH2:60][CH2:61][NH2:62])([O-:49])=[O:48]>CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]=[O:16])[O:5][CH2:6][CH2:7][CH2:8][C:9]([NH:62][CH2:61][CH2:60][NH:59][C:51]1[CH:52]=[CH:53][C:54]([N+:56]([O-:58])=[O:57])=[CH:55][C:50]=1[N+:47]([O-:49])=[O:48])=[O:11]
Reactant: Nc1cc(OCCCC(=O)[O-])ccc1C=O
Reactant: NCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(OCCCC(=O)NCCNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium 4-(3-amino-4-formylphenoxy)butanoate (50 mg), HBTU (80 mg) and DMF (2 mL) were combined in a 20 mL glass vial and stirred at ambient temperature. After 30 minutes, N1-(2,4-dinitrophenyl)ethane-1,2-diamine (Oakwood, 45 mg) was added in one portion and the reaction was stirred at ambient temperature overnight. The reaction mixture was diluted with EtOAc, washed successively with dilute aq. citric acid, water, sat. aq.NaHCO3, water, and sat. aq.NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure, affording the title compound as a yellow solid. Rf: 0.18 (SiO2, EtOAc). MS (ESI+): m/z 432.20 (MH+). H-NMR (400 MHz, DMSO-d6): 1.914 (2H, quint, J=7.0 Hz), 2.224 (2H, t, J=7.0 Hz), 3.349 (2H, q, J=6.0 Hz), 3.538 (2H, q, J=6.0 Hz), 3.928 (2H, t, J=6.4 Hz), 6.165 (1H, s), 6.176 (1H, dd, J=2.4, 10.0 Hz), 7.133 (1H, br.s), 7.268 (1H, d, J=10.0 Hz), 7.371 (1H, d, J=8.4 Hz), 8.167 (1H, t, J=5.8 Hz), 8.250 (1H, dd, J=2.8, 8.8 Hz), 8.835 (1H, d, J=2.8 Hz), 8.913 (1H, t, J=5.6 Hz), 9.599 (1H, s). C-NMR (100 MHz, DMSO-d6): 24.489, 31.436, 37.331, 42.745, 66.782, 98.040, 104.339, 112.751, 115.130, 123.472, 123.564, 129.725, 134.731, 137.484, 148.305, 152.824, 163.873, 172.251, 191.400.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].[CH2:13](I)[C:14]([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1c([N+](=O)[O-])ccc(OCC(C)(C)C)c1Cl
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Reaction of 2-chloro-3-methyl-4-nitrophenol (2.26 g) with neopentyl iodide (4.78 g) in 1-methyl 2-pyrrolidinone (30 ml) in the presence of potassium carbonate (3.34 g) was conducted at 140° C. overnight. The crude product was partitioned between 2M HCl and ethyl acetate, and the organic phase was washed with water, dried (MgSO4) and evaporated to dryness. The residue was chromatographed (SiO2 ; hexane/ether) to give 2-chloro-3-neopentyloxy-6-nitrotoluene as a yellow solid (2.44 g).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1Br.[C:11]([O:16][CH2:17][C:18]([CH2:20][O:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:19])(=[O:15])[CH:12]([CH3:14])[CH3:13].S(=O)(=O)(O)O>C1COCC1>[C:11]([O:16][CH2:17][C:18]([C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[F:2])([OH:19])[CH2:20][O:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])(=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)C(=O)OCC(=O)COC(=O)C(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)C(=O)OCC(O)(COC(=O)C(C)C)c1ccc(F)cc1F
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Under an atmosphere of argon, 5 ml of THF was slowly added to 925 mg of magnesium turnings, and then thereto was added dropwise 7 g of 2,4-difluorobromobenzene dissolved in 30 ml of THF with keeping the temperature at 20° C. After the reaction mixture was stirred for 1 hour with keeping the temperature at 20° C., 7.9 g of 1,3-diisobutyryloxyacetone dissolved in 10 ml of THF was added dropwise thereto with keeping the temperature at 0° C. After the dropping, the reaction mixture was stirred for 4 hours and then the reaction was stopped by adding 35 ml of 1N sulfuric acid. The obtained liquid was extracted twice with 35 ml of ethyl acetate. The organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride, in turn. The solvent was removed under reduced pressure. Thus obtained concentrate was distilled under reduced pressure to give 10 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][O:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[C:21]([O:20][CH3:19])=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 74.9 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 2-methoxypyridine-3-boronic acid (142 mg, 0.94 mmol) were reacted. After purification the title compound (118 mg, 76% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.04(d, J=4.9 Hz, 1H), 8.43 (m, 1H), 8.24 (d, J=5.0 Hz, 1H), 7.77 (m, 2H), 7.71 (a d, J=7.2 Hz, 1H), 7.71 (a dd, J=5.1, 7.2 Hz, 1H), 3.73 (s, 3H), 2.95 (m, 1H), 0.67 (m, 4H). MS APCI, m/z=336.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-])=O)=[CH:7][CH:8]=2)[CH2:3]1.[CH3:15][C:16](OC(C)=O)=[O:17]>CCO.[Pd]>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH:12][C:16](=[O:17])[CH3:15])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)CN(C)CC2
Temperature: 20 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A solution of isoquinoline 252 (2.5 g, 13.0 mmol) in EtOH (200 mL) was stirred with Pd/C (5%, 200 mg) under H2 (35 psi) for 4 h. The solution was filtered through Celite, washed with EtOH (50 mL) and the solvent was evaporated. The residue was dissolved in dioxane (50 mL), Ac2O (2.7 mL, 28.6 mmol) was added and the solution stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4×125 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 5% MeOH/DCM, to give acetamide 253 (2.1 g, 77%) as a brown solid: mp 157-159° C.; 1H NMR δ 7.29 (br s, 1H, H-8), 7.27 (br s, 1H, H-6), 7.22 (br s, 1H, NH), 7.12 (br d, J=8.1 Hz, 1H, H-5), 4.18 (d, J=16.2 Hz, 1H, H-1), 3.82 (d, J=16.1 Hz, 1H, H-1), 3.11-3.25 (m, 2H, H-3), 2.91-3.00 (m, 2H, H-4), 2.61 (s, 3H, NCH3), 2.16 (s, 3H, COCH3); 13C NMR δ 168.3, 136.6, 131.0, 129.2, 126.6, 119.2, 118.1, 61.5, 56.6, 47.3, 24.5, 24.0; MS (APCI) m/z 205 (MH+, 100%). Anal. calcd for C12H16N2O.½CH3OH.½H2O: C, 65.5; H, 8.4; N, 12.2. Found: C, 65.8; H, 8.8; N, 12.6%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: C#CCCc1nc2c(Cl)cccc2o1
Reactant: Brc1ccccn1
Product: Clc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 11.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (15 mg, 97 μmol) and 2-(but-3-ynyl)-4-chlorobenzo[d]oxazole (20 mg, 97 μmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 3 mg (11 μmol, 11%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[N:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH2:14][S:13][C:4]2[N:3]=[C:2]([NH:26][CH2:25][CH2:23][OH:24])[C:11]3[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=3[N:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: NCCO
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Product: O=c1cnc2c(NCCO)nc(SCc3cccc(Cl)c3F)nc2[nH]1

Procedure:
The titled compound (51 mg) was prepared by the method of Example 6, step (f) using the product from Example 6, step (e) (75 mg) and ethanolamine (25 μl).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13](Br)=[CH:14][C:15]1[CH:16]=[C:17]([C:20]2([CH3:37])[CH2:24][O:23][C:22]3[CH:25]=[C:26]4[C:31](=[CH:32][C:21]2=3)[C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28][C:27]4([CH3:36])[CH3:35])[S:18][CH:19]=1.Cl[C:40]([O:42][CH3:43])=[O:41].[Cl-].[NH4+]>C1COCC1>[CH3:37][C:20]1([C:17]2[S:18][CH:19]=[C:15]([C:14]#[C:13][C:40]([O:42][CH3:43])=[O:41])[CH:16]=2)[CH2:24][O:23][C:22]2[CH:25]=[C:26]3[C:31](=[CH:32][C:21]1=2)[C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28][C:27]3([CH3:36])[CH3:35]
Reactant: CC1(C)CCC(C)(C)c2cc3c(cc21)OCC3(C)c1cc(C=C(Br)Br)cs1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C#Cc1csc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.5 M solution of butyllithium in hexane (0.82 ml, 2.45 mmol) was added to a solution of 3-[4-(2,2-dibromovinyl)thiophen-2-yl]-3,5,5,8,8-pentamethyl-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan (478 mg, 0.94 mmol) in THF (5 ml) at -78° C. The stirring was continued for 1 h at -78° C. and then methyl chloroformate (80 μl) was added. The mixture was stirred at room temperature for 1 h, treated with a saturated ammonium chloride solution and extracted with ethyl ether. After washing with water, the organic phase was dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum. The desired compound was purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([OH:8])[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]([F:10])([F:11])[F:12])[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([OH:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)cc(F)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
5-Fluoro-3-(trifluoromethyl)phenol (1.27 g) was dissolved in acetic acid (3 ml) and water (1.5 ml), and nitric acid (3.0 ml) was added thereto. The reaction mixture was stirred at 50° C. for 30 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with ether. The extract was washed with an aqueous saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (developing solution:ethyl acetate-hexane=1:3) to obtain the title compound as oil (0.33 g, 21%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:22]=1)[CH2:18]Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CN(C=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[C:17]([CH:16]=[C:15]([O:14][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:22]=1)[CH2:18][N:1]=[N+:2]=[N-:3])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCC)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Sodium azide (3.25 g, 50.0 mmol) and DMF (25 mL) were introduced into a 1 L RBF containing 3,5-dinonoxybenzylchloride (10.0 g, 25.0 mmol) and a stir bar. The reaction mixture was then capped with a septum and an out-vent needle. The mixture was heated until warm to touch, allowed to cool to room temperature, then heated again (repeated 4 times). The mixture was then transferred to a separatory funnel and diluted with 500 mL distilled water and washed with ether (4 times using 100 mL). The combined ether layers were washed with ammonium chloride (2 times with 50 mL), then dried with magnesium sulfate and gravity filtered into a 1 L RBF. The solvent was removed under reduced pressure and the trace solvent was removed with a high vacuum. The compound was purified by flash column chormatography (silica gel using 1 L pure hexanes, 1 L 5% ether and hexanes, 1 L 10% ether and hexanes). The product was present in all fractions, the solvent was removed by rotary evaporation and then the trace solvent was removed by a high vacuum. The resulting yellow oil was dissolved in 400 mL ethanol and placed in a freezer overnight. Extreme crystal growth was present in the morning. The mixture was then vacuum filtered and the crystals were collected and air dried while the filtrate was placed in the freezer. Analysis of the crystals indicates they are impurities. As a result, the solvent was removed from the filtrate using rotary evaporation and the trace solvent was then removed using high vacuum. There was a 5.3 g yield or a 51.4% yield of the derivative. The NMR characterization data for this derivative is as follows. 1H NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.1-1.55 (m, 28H, CH2(CH2)6), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.93 (t, J=6.6, 4H,), 4.24 (s, 2H,) 6.42 (q, J=2.2, 1H, ArH). 13C (75 MHz, CDCl3): 160.68, 137.45, 106.52, 101.10, 68.19, 55.01, 31.95, 31.02, 29.47, 29.34, 29.31, 26.12, 22.76, 14.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(Cl)ccc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
A solution of 6-methoxyquinoline N-oxide (5.0 g, 29 mmol) in CHCl3 (30 mL) was treated by slow addition of POCl3 (5.3 mL, 57 mmol) at 0° C. The mixture was heated at 80° C. for 14 hours. The mixture was cooled and poured onto ice. After stirring for 30 min., the aqueous layer was adjusted to pH 9 by Na2CO3 addition. The mixture was extracted with CH2Cl2. The organic layer was worked-up. HPLC (1:10 EtOAc/hexane) gave 2.5g (46%) of 2-chloro-6-methoxyquinoline as a white solid, (M+) 193(100).