Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:16]4=[N:23][NH:24][C:25](=[O:26])[C:15]4=[N:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.[F:45][C:46]1[C:51]([CH3:52])=[C:50](I)[CH:49]=[CH:48][N:47]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.[Cu]I>[F:45][C:46]1[C:51]([CH3:52])=[C:50]([N:24]2[C:25](=[O:26])[C:15]3=[N:14][N:13]([CH2:12][C:9]4[CH:10]=[CH:11][C:6]([N:1]5[CH:5]=[CH:4][CH:3]=[N:2]5)=[CH:7][CH:8]=4)[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:16]3=[N:23]2)[CH:49]=[CH:48][N:47]=1
Reactant: Cc1c(I)ccnc1F
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)nc1-2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1c(-n2nc3c4ccccc4n(Cc4ccc(-n5cccn5)cc4)nc-3c2=O)ccnc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-{[4-(1H-Pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (25 mg, 0.073 mmol), copper(I)iodide (14 mg, 0.073 mmol, 1 equiv), tribasic potassium phosphate (93 mg, 0.44 mmol, 6.0 equiv), (±)-trans-N,N′-bismethyl-1,2-cyclohexanediamine (31 mg, 3.0 equiv) and 2-fluoro-4-iodo-3-picoline (52 mg, 0.22 mmol, 3.0 equiv) were combined in degassed N,N-dimethylformamide (3 mL) and the mixture was placed into an oil bath preheated to 110° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (25 mL, aqueous saturated) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.32 (1H, d, J=8.1 Hz), 8.15 (1H, d, J=5.3 Hz), 7.91 (1H, d, J=2.5 Hz), 7.72 (2H, d, J=8.5 Hz), 7.72 (1H, m), 7.67-7.59 (3H, m), 7.46 (1H, m), 7.43 (2H, d, J=8.3 Hz), 6.47 (1H, m), 5.89 (2H, s), 2.37 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 452.1623 [(M+H)+; calculated for C25H19FN7O: 452.1630].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([C:19]4([CH3:26])[NH:24][C:23](=S)[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH4+:27].[OH-].C(OO)(C)(C)C>CO>[NH2:27][C:23]1[CH2:22][O:21][CH2:20][C:19]([C:15]2[CH:14]=[C:13]([NH:12][C:6]3[C:5]4[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[CH:18]=[CH:17][CH:16]=2)([CH3:26])[N:24]=1
Reactant: Cn1nc(Nc2cccc(C3(C)COCC(=S)N3)c2)c2ccc(Br)cc21
Reactant: [NH4+]
Agent: CC(C)(C)OO
Agent: [OH-]
Solvent: CO
Product: Cn1nc(Nc2cccc(C3(C)COCC(N)=N3)c2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5-[3-(6-bromo-1-methyl-1H-indazol-3-ylamino)-phenyl]-5-methyl-morpholine-3-thione (21 mg, 0.049 mmol) in MeOH (1.5 ml) were added NH4OH (0.303 ml of a 25% aq. soln., 273 mg, 1.947 mmol) and tBuOOH (0.101 ml of a 70% aq. soln., 94 mg, 0.730 mmol) and the reaction mixture was allowed to stir at rt for 20 h, quenched with sat. aq. NaHCO3 soln. and diluted with EtOAc. The layers were separated and the aq. layer was twice reextracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to leave the crude title compound that was purified by RP-HPLC (Waters SunFire C18 column, 5 μM, 19×150 mm, gradient 10 to 90% ACN+0.1% TFA).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[C:29]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30]1.Cl>C1COCC1>[C:16]([C@@H:15]([NH:19][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CCCC(=O)O)C(=O)O
Temperature: 5 °C
Reaction time: 3 h

Procedure:
S-trans, trans-Farnesyl-L-cysteine (500 mg, 1.54 mmol) was dissolved in mixture of THF (6 mL) and first portion of K2CO3 (3 mmol) and the resulting solution was cooled to 5° C. with vigorous stirring. To this stirred solution glutaric anhydride (263 mg, 2.30 mmol) was added slowly while maintaining the pH at 9.0-9.5 with another portion of K2CO3 (3 mmol). The mixture was stirred at RT for 3 h, TLC showed completion of the reaction. The pH of the reaction mixture then adjusted to 2.0 by the addition of 2 N hydrochloric acid. The acidic solution was extracted with ethyl acetate (10 mL×3). The combined organic extract was washed with water, brine and dried over Na2SO4, the solvent was removed on rotary evaporator to afford crude Compound E, which was further purified by preparative HPLC (459 mg, 68%) to yield Compound E. 1H-NMR (500 MHz, CD3OD): δ 1.60 (s, 6H), 1.70 (s, 3H), 1.72 (s, 3H), 2.02-1.95 (m, 4H), 2.15-2.05(m, 4H), 2.32 (t, 2H), 2.40 (t, 2H), 2.75 (m, 2H), 3.05 (dd, 1H), 3.15 (dd, 1H), 3.30 (d, 2H), 4.60 (dd, 1H), 5.14 (t, 2H), 5.25 (t, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.1, 17.7, 18.4, 22.2, 26.3, 27.4, 27.7, 35.7, 40.6, 53.3, 121.5, 125.2, 125.4, 131.8, 136.1, 140.1, 173.7, 175.3, 177.6; ES-MS: mass calcd for Chemical Formula: C23H37NO5S 439.6. Found (M+Na) m/z 462.3.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>O>[F:1][C:2]1[C:7]([N:19]2[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]2)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Solvent: O
Product: CC(C)N1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C

Procedure:
4,5-Difluoro-2-nitrophenylamine (1.0 equivalent) and N-isopropyl piperazine were heated at 100° C. for 3 hours. The solution was then cooled to room temperature and diluted with water. The resulting precipitate was filtered and dried under vacuum to provide title compound product. LC/MS (m/z) 283.2 (MH+), Rt 1.56 minutes.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>[OH-].[Na+].CC(C)=O>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)[C@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=C(C)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
D-Proline, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath; the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of methacryloyl chloride (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-11° C. during the addition of the methacryloyl chloride. After stirring (3 h, room temperature), the mixture was evaporated in vacuo at a temperature at 35-45° C. to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes afforded 16.2 g (68%) of the desired compound as colorless crystals: mp 102-103° C. (lit. [214] mp 102.5-103.5° C.); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH2), 4.48-4.44 for the first rotamer, 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral center), 3.57-3.38 (m, 2H, CH2), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 13C NMR (75 MHz, DMSO-d6) δ for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C═O), 1647 (CO, COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm−1; [α]D26+80.8° (c=1, MeOH); Anal. Calcd. for C9H13NO3: C, 59.00; H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][NH:9][C:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[O:12][N:11]=2)=[CH:6][CH:5]=1.N1C=CN=C1.II>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:30][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]2[CH:14]=[C:13]([CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]4)[O:12][N:11]=2)=[CH:28][CH:29]=1
Reactant: O=C1CCc2cc(OCC3CC(NCc4ccc(OC(F)F)cc4)=NO3)ccc2N1
Agent: II
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1ccc2cc(OCc3cc(NCc4ccc(OC(F)F)cc4)no3)ccc2[nH]1
Temperature: 110 °C
Yield: 19.4 %

Procedure:
Into a sealed tube was placed a solution of 6-((3-((4-(difluoromethoxy)benzyl)amino)-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (0.12 g, 0.287 mmol), imidazole (0.117 g, 1.725 mmol), and iodine (0.219 g, 0.862 mmol) in toluene (5 mL). The tube was sealed and heated at 110° C. for 24 h. The reaction mixture was diluted with ethyl acetate, washed with 10% Na2S2O4 and brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative HPLC on an Xbridge phenyl column (150×19×5μ) using a 10 mM NH4OAc/ACN gradient (0-100%) to give 6-((3-(4-(difluoromethoxy)benzylamino)isoxazol-5-yl)methoxy)quinolin-2(1H)-one as a white solid (0.023 g, 23%). 1HNMR: 400 MHz, DMSO-d6: δ 4.24 (d, J=6.00 Hz, 2H), 5.11 (s, 2H), 6.06 (s, 1H), 6.51 (d, J=9.20 Hz, 1H), 6.73 (t, J=6.00 Hz, 1H), 7.01-7.39 (m, 8H), 7.83 (d, J=9.60 Hz, 1H), 11.66 (s, 1H). LCMS: RT 1.558 min; LCMS (ES-API), m/z 412.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10]([O:21][CH2:22][CH3:23])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:55][C:56]1[CH:57]=[C:58]([CH:60]=[CH:61][C:62]=1[CH3:63])[NH2:59]>CN(C=O)C.C(OCC)(=O)C>[CH3:55][C:56]1[CH:57]=[C:58]([NH:59][C:18]([C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]3[O:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)=[O:19])[CH:60]=[CH:61][C:62]=1[CH3:63]
Reactant: Cc1ccc(N)cc1C
Reactant: CCOn1c(-c2c(Cl)cccc2Cl)cc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOn1c(-c2c(Cl)cccc2Cl)cc2ccc(C(=O)Nc3ccc(C)c(C)c3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-1-ethoxy-1H-indole-6-carboxylic acid (230 mg, 660 μmol) in DMF (5 mL) was added HATU (375 mg, 990 μmol), triethylamine (137 μL, 99 mg, 980 μmol) and 3,4-dimethylaniline (80 mg, 660 μmol). After stirring the mixture for 72 h at ambient temperature, the solution was poured into ethyl acetate and extracted with water once and brine five times. The organic layer was dried, filtered, and solvent removed under reduced pressure. The residual material was chromatographed with a 10-60% gradient of heptane/ethyl acetate to afford 2-(2,6-dichlorophenyl)-1-ethoxy-1H-indole-6-carboxylic acid (3,4-dimethylphenyl)-amide. 1H NMR (DMSO-d6, 400 MHz): δ 10.16 (s, 1H), 8.19 (s, 1H), 7.71 (m, 4H), 7.58 (m, 3H), 7.12 (d, J=8.2 Hz, 1H), 6.60 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.12 (t, J=7.1 Hz, 3H). MS (m/z) 453.0 (M+1); Retention time=1.72 min (Method 10). Anal. Calcd.: C, 66.23; H, 4.89; N, 6.18. Found: C, 66.34; H, 4.97; N, 6.06.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[BH3-]C#N.[Na+].O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH2:14][NH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CSc1ccc2cnnc(-c3ccc(NC(C)=O)cc3)c2c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc2c(c1)C(c1ccc(NC(C)=O)cc1)=NNC2
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a solution of the phthalazine 7 (130 mg, 0.42 mmol) in acetic acid (7 mL) was added NaBH3CN in portions. After stirring for 15 min, water was added. The aqueous phase was neutralized by NaHCO3, and then extracted with DCM. The combined organic phase was dried over Na2SO4. Removal of the solvent afforded the product (97 mg, 74%) which can be used directly for next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]C)=O.[H-].[Na+].[CH3:12][C:13]([CH3:15])=[O:14].Cl>C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:12][C:13](=[O:14])[CH3:15])=[O:8]
Reactant: COC(=O)c1ccco1
Reactant: CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)CC(=O)c1ccco1
Yield: 99.6 %

Procedure:
4.27 ml (5.04 g, 40 mmol) methyl 2-furoate was added to a suspension of NaH (made from 3.83 g commercial NaH slurry by removal of the mineral oil with pentane) in 30 ml anhydrous diethyl ether. To this was added, so as to maintain the temperature below 30° C., 5.87 ml (4.64 g, 80 mmol) acetone (dried over CaCl2). This mixture was heated under reflux for 2 h, cooled, and divided between diethyl ether and 3M HCl. The ether layer was washed with brine, dried (MgSO4), and concentrated to yield 6.06 g of a red oil (raw yield 99%) which was purified by vacuum distillation (b.p. 85°-90° C./1 torr).
Reaction SMILES: [O:1]=[C:2]1[N:10]2[C:11]([CH2:14][NH:15]C(=O)OCC3C=CC=CC=3)=[N:12][N:13]=[C:9]2[N:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2.[ClH:31]>CO.[Pd]>[ClH:31].[NH2:15][CH2:14][C:11]1[N:10]2[C:2](=[O:1])[C:3]3[NH:4][CH:5]=[N:6][C:7]=3[N:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]2=[N:13][N:12]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CNC(=O)OCc3ccccc3)nnc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CN)nnc12
Reaction time: 3 h
Yield: 92 %

Procedure:
To the solution of benzyl [(5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)methyl]carbamate (0.30 g, 0.73 mmol) in methanol (20 mL) and 1 mL of conc. HCl was added 110% Pd/C under N2. The mixture was shaken under 30 PSI H2 for 3 hours. The reaction mixture was filtered through celite and concentrated to yield the desired product (210 mg, 92%). LCMS calculated for C12H18N7O(M+H): 276.2; found: 276.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[C:11]([C:20]#[N:21])=[C:10]2/[CH:22]=[CH:23]/[C:24](O)=[O:25])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[O:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[C:11]([C:20]#[N:21])=[C:10]2/[CH:22]=[CH:23]/[C:24]([NH:47][CH:44]2[CH2:45][CH2:46][O:41][CH2:42][CH2:43]2)=[O:25])=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)NC3CCOCC3)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (250 mg, 0.570 mmol) in THF (2.5 ml) were added DMF (0.025 ml) and oxalylchloride (0.060 ml, 0.680 mmol), the mixture was stirred at room temperature for 1 hour and the solvent distilled off under reduced pressure. The residue was added under ice-cooling to a solution of tetrahydro-2H-pyran-4-ylamine hydrochloride (136 mg, 1.13 mmol), triethylamine (0.472 ml, 3.39 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective product as a solid material. The resultant material was recrystallized from hexane and ethyl acetate. Yield (amount) 200 mg, yield (rate) 66.7%
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12](O)=[O:13])[C:6]=2[O:5][CH2:4][C:3]1=[O:18].S(Cl)([Cl:21])=O>>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12]([Cl:21])=[O:13])[C:6]=2[O:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)COc2c(C(=O)O)cc([N+](=O)[O-])cc21
Reactant: O=S(Cl)Cl
Product: CN1C(=O)COc2c(C(=O)Cl)cc([N+](=O)[O-])cc21

Procedure:
To 99 g of 3,4-dihydro-4-methyl-6-nitro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid is added portionwise 285 ml of thionyl chloride at room temperature, and the system heated with reflux for about an hour. After the resultant solution is dried under reduced pressure, to the residue is distilled off under reduced pressure. To the residue is added 200 ml of benzene to make the crystals finely particulate. After collecting by filtration, the crystals are washed with benzene and dried to give 103 g of 3,4-dihydro-4-methyl-6-nitro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.[O:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[N:33]=[CH:32]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[F:26][C:24]([F:27])([F:25])[C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:15]([C:14]2[CH:13]=[C:12]([CH:30]=[CH:29][CH:28]=2)[O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36]([C:34]4[N:33]=[CH:32][O:31][CH:35]=4)=[O:37])[S:3][C:4]=3[CH:10]=2)=[O:16])=[CH:23][CH:22]=1
Reactant: O=C(O)c1cocn1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4ccc(C(F)(F)F)cc4)c3)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.3 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[4-(trifluoromethyl)phenyl]benzamide (215 mg, 0.50 mmol) produced in Example A25(v), 1,3-oxazole-4-carboxylic acid (113 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 1.00 mmol), 1-hydroxybenzotriazole (135 mg, 1.00 mmol) and N-ethyl-N-isopropylpropane-2-amine (260 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (90 mg, 34%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[C@@H:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH2:6]2.Br>C(O)(=O)C>[C:27]1([C@H:8]2[CH2:7][CH2:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11][C:10]=3[C@H:9]2[C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CC[C@H](c1ccccc1)[C@@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 100 °C

Procedure:
A mixture of cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine (12 g, 28 mmol), acetic acid (75 mL), and 48% HBr (75 mL) was heated at 100° C. for 15 h. The solution was cooled and the resulting white precipitate was collected by filtration. The hydrobromide salt (9.6 g, 69%) was dissolved in CHCl3 /MeOH and was stirred with satd NaHCOa (aq). The layers were separated and the aqueous layer was further extracted with CHCl3 /MeOH. The combined organic layers were dried (MgSO4), filtered, and concentrated to yield product as an off-white foam. 1H NMR (250 MHz, CDCl3): δ 7.04 (m, 3H), 6.74 (m, 2H), 6.63 (d, J =8.3 Hz, 2H), 6.50 (m, 3H), 6.28 (d, J =8.6 Hz, 2H), 4.14 (d, J=4.9 Hz, 1H), 3.94 (t, J=5.3 Hz, 2H), 3.24 (dd, J=12.5, 4.1 Hz, 1H), 2.95 (m, 4H), 4H), 2.14 (m, 1H), 1.88 (m, 4H), 1.68 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@H:14]2[CH2:19][CH2:18][CH2:17][O:16][CH2:15]2)[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[OH:10][CH2:11][C@@H:12]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][O:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCCOC2)COC1(C)C
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCCOC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
(S)-tert-Butyl-2,2-dimethyl-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)oxazolidine-3-carboxylate (9 g, 30.1 mmol) was dissolved in 80% aq CH3CO2H (90 ml). The solution was stirred at 50° C. during 1.5 hr and evaporated to dryness at reduced pressure. The residue was dissolved in Et2O (150 ml) and washed with saturated NaHCO3 (4×100 mL). The organic layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure to give tert-butyl (S)-1-hydroxy-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate (6.2 g, 79.5%) as an oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[I-].[Na+].C([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)(=O)C.Cl>C(#N)C.C(O)C>[ClH:1].[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C1CCc2cc(CCl)ccc2C1
Reactant: CC(=O)n1ccnc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(Cc3ncc[nH]3)ccc2C1

Procedure:
The crude ethyl 6-(chloromethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate obtained in Referential Example 5 was dissolved in 100 ml of anhydrous acetonitrile and then 3.22 g of sodium iodide and 3.94 g of 1-acetylimidazole were added thereto. The resulting mixture was heated under reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and 100 ml of methanol was added to the residue. The mixture was stirred and concentrated in vacuo. Water was added to the residue. The mixture was neutralized by adding sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of ethanol and chloroform (3:97 by volume) for elution to give an oily product. The product was suspended in ethanol, and an ethanolic solution of hydrogen chloride was added thereto. The mixure was concentrated to dryness in vacuo to give 4.8 g of ethyl 6-(1-imidazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate hydrochloride as colorless crystals with m.p. 170°-172° C.