Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO.C(OCC)(=O)C.[Zn]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C(C)(C)C)c(N)c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
5.52 g (84.4 mmol) of zinc powder were added to a suspension of 1.06 g (4.21 mmol) of methyl 2-(4-t-butyl-3-nitrophenyl)acetate [prepared as described in step (i) above] in 30 ml of methanol, and subsequently acetic acid was added to the mixture in four 0.8 ml portions over a period of 1 hour. The reaction mixture was stirred for 2 hours, after which it was diluted with ethyl acetate. It was then filtered using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was again dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of ammonium chloride, with a saturated aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 870 mg (yield 94%) of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1)[CH:2]([CH3:4])[CH3:3].[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][C:32]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]3[NH:8][C:9](=[O:17])[C:10]4[CH2:16][O:15][CH2:14][CH2:13][C:11]=4[N:12]=3)=[O:33])[CH2:29][CH2:30]2)=[O:24])=[CH:35][CH:36]=1
Reactant: CC(C)CNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: CC(C)CN(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following the general procedure of Example 4, the title compound was prepared (36.4 mg) from 2-((isobutylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C26H33FN4O4 484.6. found 485.6 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.98 (dd, J=8.84, 5.31 Hz, 2H) 7.20 (t, J=8.59 Hz, 2H) 4.48-4.67 (m, 4H) 4.21 (br. s., 2H) 3.89-4.01 (m, 2H) 3.82 (br. s., 3H) 3.23 (br. s., 4H) 2.62-2.83 (m, 2H) 2.19 (br. s., 3H) 2.13 (s, 1H) 2.07 (d, J=6.57 Hz, 1H) 0.98 (d, J=6.57 Hz, 4H) 0.88 (d, J=5.56 Hz, 2H).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:25][CH2:26][CH2:27][CH2:28][S:29](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:31])=[O:30]>>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([NH:21][CH2:20][CH:19]([CH2:22][O:23][CH3:24])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCOCC(CN)COC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCCl)COC

Procedure:
3-Hexadecyloxy-2-methoxymethylpropylamine IVk1 is allowed to react and worked up by the same procedure as described in (4). m.p. 44°-46.5° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: C1COCC1.[Br:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:12](=[O:36])[C:13]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@H:29]5[CH2:33][O:32]C(C)(C)[O:30]5)=[CH:23][C:14]=4[C:15]([CH3:22])([CH3:21])[C:16]=3[N:17]2[CH3:20])=[CH:9][CH:8]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)C.CO>[Br:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:12](=[O:36])[C:13]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@H:29]([OH:30])[CH2:33][OH:32])=[CH:23][C:14]=4[C:15]([CH3:21])([CH3:22])[C:16]=3[N:17]2[CH3:20])=[CH:9][CH:8]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@H]3COC(C)(C)O3)cc1C2(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@H](O)CO)cc1C2(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Under nitrogen atmosphere, to the THF (0.15 mL)-MeOH (0.1 mL) solution of 3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-5,6,6-trimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound T24-1, 15.5 mg, 0.0320 mmol), 0.5 M aqueous solution of sulfuric acid (128 μL, 0.0640 mmol) was added at room temperature. The reaction mixture was stirred at ambient temperature of 55° C. for 2 hr, cooled to room temperature, and then added with diethyl ether and subsequently with sodium hydrogen carbonate (11 mg). The mixture was extracted twice with diethyl ether/ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (white solid, 11.9 mg, 84%).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][O:19]C2CCCCO2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[CH2:26]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:14]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](OCCCOC3CCCCO3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: OCCCO[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
trans-N,N-Dibenzyl-4-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]cyclohexanamine (170 ml) was dissolved in methanol (1 mL), and a 4 M solution (972 μL) of hydrogen chloride in 1,4-dioxane was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-{[trans-4-(dibenzylamino)cyclohexyl]oxy}propan-1-ol (110 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17].O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cc([N+](=O)[O-])c(F)cc1F
Reaction time: 0.25 h

Procedure:
To a solution of 2,4-difluorobenzaldehyde (2.27 g) in methylene chloride (6 mL) was added concentrated sulfuric acid (6 mL) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added fuming nitric acid (1 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate. To the mixture was added water, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution twice, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=7/3) to give 2,4-difluoro-5-nitrobenzaldehyde (2.63 g). The obtained 2,4-difluoro-5-nitrobenzaldehyde (1 g) was dissolved in tetrahydrofuran (15 mL). To the solution was added sodium borohydride (0.3 g), and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane −n-hexane/ethyl acetate=1/1) to give the title compound (0.76 g)
Reaction SMILES: [CH2:1]([O:48][CH:49]1[C@H:53]2[C@H:54](O[Si](C(C)(C)C)(C)C)[N:55](C(OCC(Cl)(Cl)Cl)=O)[C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH:51]=[C:50]1[C:82]1[CH:87]=[CH:86][C:85]([O:88][CH3:89])=[CH:84][CH:83]=1)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]1[C@H:11]2[C@H:12](O[Si](C(C)(C)C)(C)C)[N:13](C(OCC(Cl)(Cl)Cl)=O)[C:14]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=3[C:16](=[O:17])[N:10]2[CH:9]=[C:8]1[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1.C1COCC1>C(Cl)(Cl)Cl.CO>[CH2:1]([O:48][CH:49]1[C@@H:53]2[CH:54]=[N:55][C:56]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:57]=3[C:58](=[O:59])[N:52]2[CH:51]=[C:50]1[C:82]1[CH:83]=[CH:84][C:85]([O:88][CH3:89])=[CH:86][CH:87]=1)[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]1[C@@H:11]2[CH:12]=[N:13][C:14]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=3[C:16](=[O:17])[N:10]2[CH:9]=[C:8]1[C:40]1[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)ccc4N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]3C2OCCCCCOC2C(c3ccc(OC)cc3)=CN3C(=O)c4cc(OC)ccc4N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]23)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)ccc4N=C[C@H]3C2OCCCCCOC2C(c3ccc(OC)cc3)=CN3C(=O)c4cc(OC)ccc4N=C[C@@H]23)cc1
Yield: 54.7 %

Procedure:
10% Cd/Pb couple (192 mg, 1.55 mmol) was added to a rapidly stirring mixture of 45 (107 mg, 77.3 μmol), THF (2.5 mL) and 1N NH4OAc (2.5 mL). The reaction mixture was allowed to stir for 3 hours at which point TLC (95:5 v/v CHCl3/MeOH) showed the formation of desired PBD accompanied by side-products. The solids were collected by filtration and rinsed with H2O and DCM. The aqueous layer was extracted with DCM (3×10 mL) and the organic extracts were combined, washed with brine (50 mL) and dried (MgSO4). Filtration and evaporation of solvent afforded the crude product which was purified by flash column chromatography (gradient elution: CHCl3 to 99:1 v/v CHCl3/MeOH) to afford the imine 46 as a yellow glass (32.5 mg, 55%): 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 2H, J=3.9 Hz), 7.53 (s, 2H), 7.39 (s, 2H), 7.34 (d, 4H, J=8.8 Hz), 6.90 (d, 4H, J=8.8 Hz), 6.82 (s, 2H), 4.43-4.38 (m, 2H), 4.18-4.05 (m, 4H), 3.95 (s, 6H), 3.83 (s, 6H), 3.58 (ddd, 2H, J=16.2, 11.5, 1.9 Hz), 3.38 (ddd, 2H, J=16.3, 5.1, 1.6 Hz), 2.01-1.94 (m, 4H), 1.73-1.66 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.6, 161.3, 159.2, 151.3, 148.1, 140.3, 126.2, 126.0 (×2), 123.2, 122.0, 119.1, 114.3, 111.9, 110.9, 68.8, 56.2, 55.4, 53.9, 35.6, 28.7, 22.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH3:20][C:21](=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:22]=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH3:22])=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15]1
Reactant: CC(C=O)=Cc1ccccc1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Product: CC(=Cc1ccccc1)CN1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Yield: 25.8 %

Procedure:
According to Procedure A above, 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one and 2-methyl-3-phenyl-propenal (0.031 g, 0.216 mmol) were allowed to react to give the title compound (0.008 g, 25.8%, mono-TFA salt) as a off-white solid. 1H NMR (400 MHz, DMSO) δ ppm 8.35 (d, J=3, 1H), 7.66 (dd, J=3, 9, 1H), 7.32-7.47 (m, 6H), 6.76 (br s, 1H), 5.46 (s, 1H), 3.94-3.99 (m, 1H), 3.86 (d, J=3, 9, 1H), 3.53-3.60 (m, 2H), 3.05-3.20 (m, 2H), 2.18-2.28 (m, 2H), 2.05-2.15 (m, 1H), 2.01 (s, 3H), 1.82-1.91 (m, 2H); MS (ESI+Q1MS) m/z 409 [M]+
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)C(OC)=O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cccc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Methyl 2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (3.8 g, 14.0 mmol) [prepared as in Example 7, Step (a)] was dissolved in a 1:1 mixture of MeOH-THF (100 ml) and cooled in an ice bath under argon. A solution of 0.4 M lithium hydroxide (69 ml) was added and the reaction mixture was stirred at room temperature. After 2 h, the reaction mixture was poured into 1 M HCl/ice and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The solid residue was redissolved in DMF (40 ml) and heated at reflux. After 20 min the reaction mixture was poured into ice/water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness. Purification on a Florisil® column (hexane-ethyl acetate,9:1) gave 4-(1-methylpyrrol-2-yl-methyl)nitrobenzene (2.53 g, 82%) as a solid. ##STR40##
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10]CC)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1>N1C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:8](=[O:10])[C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:21]2=[S:22])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ncccc1N
Reactant: Fc1ccc(N=C=S)cc1
Solvent: c1ccncc1
Product: O=c1c2ncccc2[nH]c(=S)n1-c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 21 h

Procedure:
A mixture of ethyl 3-aminopyridine-2-carboxylate (2.0 g, 12.0 mmol) and 4-fluorophenylisothiocyanate (1.84 g, 12.0 mmol) in 7 mL of anhydrous pyridine is stirred at 45° C. for 21 h. After cooling, the pyridine is evaporated in vacuo, and ice water is added to the residue. The resulting mixture is slurried in EtOAc and filtered to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (1H, m), 7.79 (2H, m), 7.33 (4H, m).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]2[C:15]=1[C:16](=[O:25])[C:17](=[O:24])[NH:18]2.O>C(OCC)C.C1COCC1>[OH:25][C:16]1([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[C:15]2[C:19](=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=2[Cl:13])[NH:18][C:17]1=[O:24]
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)cc(Cl)c2C1(O)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
1.8 g of Grignard magnesium are placed in 19 ml of anhydrous ethyl ether in a round-bottomed flask equipped with a mechanical stirrer, and under a stream of nitrogen. A mixture of 8.9 ml of 4-bromotrifluoromethylbenzene in 46 ml of anhydrous ethyl ether is then added. The mixture is stirred for one hour, followed by addition of a solution of 5.7 g of 4,6-dichloro-1H-indole-2,3-dione in 100 ml of anhydrous THF. The mixture is stirred at room temperature for 4 hours 30 minutes. Water is added and the resulting mixture is extracted with ethyl acetate. The organic phase is separated out and dried over Na2SO4, filtered and evaporated under vacuum. The residue is taken up in ethyl acetate and washed with 1N sodium hydroxide solution. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. The solid is taken up in ethyl ether and filtered off. 4.7 g of expected product are obtained.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([O:23][Si](C)(C)C)(C#N)[CH2:6][C:7]([CH3:20])=[CH:8][CH2:9][CH2:10][C:11]([CH3:19])=[CH:12][CH2:13][CH2:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:3][CH:2]([C:4]1[C:5](=[O:23])[CH2:6][C:7]([CH3:20])=[CH:8][CH2:9][CH2:10][C:11]([CH3:19])=[CH:12][CH2:13][CH2:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:1]
Reactant: CC1=CC=C(C(C)C)C(C#N)(O[Si](C)(C)C)CC(C)=CCCC(C)=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1=CC=C(C(C)C)C(=O)CC(C)=CCCC(C)=CCC1
Reaction time: 48 h
Yield: 84.4 %

Procedure:
The above cyanohydrine trimethylsilyl ether compound, 2-(1-methylethyl)-5,9,13-trimethyl-1-trimethylsiloxy-2,4,8,12-cyclotetradecatetraen-1-carbonitrile (657 mg, 1.7 mmol) was dissolved in 10% aqueous tetrahydrofuran (10 ml). To the solution on an ice-water bath was added a solution of 1M tetra n-butylammonium fluoride in tetrahydrofuran (0.02 ml), and the mixture was stirred and then allowed to stand at room temperature for 2 days. Most of the tetrahydrofuran was removed in vacuo and the residue was dissolved in ethyl ether. The ether layer was dried over MgSO4, filtered, concentrated, and subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate=30:1) to obtain the ketone compound, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraen-1-one (411 mg, 85%).
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][CH3:16])=[O:14].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:19]([O:18][CH3:17])[CH:20]=[CH:21][C:22]=3[O:25][CH3:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH3:16])=[O:14]
Reactant: CNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(OC)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)cccc2c1N
Yield: 59.2 %

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-methyl-cinnoline-3-carboxamide (20.0 g, 63.1 mmol) and 2,5-dimethoxyphenyl boronic acid (22.3 g, 122.4 mmol) according to Method B except that potassium carbonate was used as the base and tetrahydrofuran:ethanol:water (1:1:1) was used as the solvent system. The reaction mixture was filtered and the yellow solids were slurried in 10% methanol in chloroform and filtered. The combined filtrates were concentrated to a solid, slurried in hot ethyl acetate, and filtered. The combined solids were further purified on silica gel using 5% methanol in chloroform as the eluent. A final crystallization from refluxing ethyl acetate followed by drying under high vacuum at 45° C. afforded the title compound as a light yellow solid (12.65 g, 59%). 1H NMR (500.333 MHz, DMSO) δ 9.07 (d, J=4.6 Hz, 1H), 8.39 (d, J=8.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.03 (d, J=9.1 Hz, 1H), 6.97 (dd, J=8.9, 3.0 Hz, 1H), 6.87 (d, J=3.2 Hz, 1H), 3.73 (s, 3H), 3.55 (s, 3H), 2.86 (d, J=4.8 Hz, 3H). MS APCI, m/z=xx (M+H). HPLC 2.23 min. MP=279.1-279.8.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[C:37]([CH:38]4[CH2:40][CH2:39]4)=[CH:36][C:35]([CH:41]4[CH2:43][CH2:42]4)=[CH:34][N:33]=3)[CH2:28][CH2:27]2)=[O:25])=NC=1>>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:37]1[C:32]([C@@H:28]2[CH2:27][N:26]([CH:24]=[O:25])[CH2:31][CH2:30][N:29]2[C:32]2[C:37]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][C:35]([CH:41]3[CH2:42][CH2:43]3)=[CH:34][N:33]=2)=[N:33][CH:34]=[CH:35][CH:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: O=CN1CCN(c2ncc(C3CC3)cc2C2CC2)[C@H](c2ncccc2N2C(COCc3ccccc3)CCS2(=O)=O)C1
Yield: 132.8 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (287 mg) described in Preparation Example 1 and (5-bromopyridin-2-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (460 mg) described in Preparation Example 142 and by the reaction and treatment in the same manner as in Example 1, (S)-5-[(3-benzyloxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)pyridin-2-yl][4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (420 mg) was obtained. To a mixture of the obtained (S)-5-[(3-benzyloxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)pyridin-2-yl][4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (420 mg), palladium carbon (50 mg) and ammonium formate (500 mg) were added methanol (30 mL) and water (3 mL), and the mixture was stirred at 40° C. for 14 hr. Insoluble material was filtered off from the reaction mixture, and the filtrate was concentrated. To the obtained residue was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (46 mg).
Reaction SMILES: CS([O-])(=O)=O.[C:6]([CH2:8][C@H:9]([NH3+:12])[CH2:10][CH3:11])#[N:7].CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>ClCCl>[CH:26]([O:25][C:23](=[O:24])[NH:12][C@H:9]([CH2:10][CH3:11])[CH2:8][C:6]#[N:7])([CH3:28])[CH3:27]
Reactant: CC(C)OC(=O)Cl
Reactant: CC[C@@H]([NH3+])CC#N
Agent: CS(=O)(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](CC#N)NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of (R)-2-cyano-1-ethylethylammonium methanesulfonate (50 mmol; 9.72 g) and DIPEA (105 mmol; 13.6 g) in dichloromethane (100 mL) is added isopropyl chloroformate (52.5 mmol; 6.43 g) at 0° C. The solution is warmed to room temperature and stirred for 4 hours. The reaction mixture is quenched with brine and extracted with dichloromethane. The organic layer is washed with aqueous 0.1M HCl, saturated aqueous NaHCO3 solution and then brine, dried over MgSO4, filtered concentrated under reduced pressure to give ((R)-2-cyano-1-ethyl-ethyl)-carbamic acid isopropyl ester (8.75 g, 95%); ESI-MS m/z: 185 [M++1], Retention time 1.60 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[C:7]2[CH3:24].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39](=[O:42])[CH2:40]Br>O.C(O)(=O)C>[CH3:37][O:38][C:39](=[O:42])[CH2:40][O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:24])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2
Reactant: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8-chloro-5-hydroxy-3-(4-methanesulfonylbenzyl)-4-methyl-1H-quinolin-2-one (0.20 g), N,N-dimethylformamide (4.0 mL), potassium carbonate (0.091 g) and bromoacetic acid methyl ester (0.079 g) was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL) and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 1:1 by volume) to afford title compound as a white solid, 0.14 g.