Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][NH2:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(N(CC)CC)C.[CH:22]([S:25](Cl)(=[O:27])=[O:26])([CH3:24])[CH3:23]>C(Cl)Cl.C(OC(=O)C)C.CCCCCC>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C@@H:7]([CH3:10])[CH2:8][NH:9][S:25]([CH:22]([CH3:24])[CH3:23])(=[O:27])=[O:26])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C[C@@H](CN)Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)S(=O)(=O)NC[C@H](C)Oc1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To a reaction mixture of (2S)-2-(4-bromophenoxy)propylamine (19.0 g, 71.275 mmoles) and methylene chloride (200.0 ml) at room temperature was added 2N NaOH (150.0 ml) all at once with vigorous stirring for 45 minutes. The organic layer was separated, dried anhydrous magnesium sulfate, filtered, and the filtrate concentrated to an oil (16.22 g). To a solution of this oil in methylene chloride (225.0 ml) at room temperature was then added triethylamine (23.6 ml, 169.23 mmol) and N,N-dimethylaminopyridine (0.43 g) with stirring. The solution was cooled to −20° C. with dry ice/acetone bath, and a solution of isopropylsulfonyl chloride (9.5 ml, 84.62 mmol) dissolved in methylene chloride (25 ml) was added over a period of 30 minutes while maintaining the temperature at −20° C. The reaction was then stirred to room temperature overnight. The reaction was monitored with TLC (1:1 ethylacetate/hexane) until the reaction was complete. The reaction was quenched with 3N HCl solution (100.0 ml), the organic layer separated then dried with anhydrous magnesium sulfate. Subsequent filtration and concentration at reduced pressure afforded the final title compound (23.7 g, 100%) as an oil; 1H nmr (CDCl3) δ 1.25-1.26 (d, 3H, J=6.35 Hz), 1.33-1.35 (d, 6H, J=6.83 Hz), 3.14-3.19 (m, 1H), 3.22-3.26 (m, 1H), 3.34-3.36 (m, 1H), 4.43-4.46 (m, 1H), 4.74-4.76 (m, NH), 6.77-6.79 (d, 2H, J=9.03 Hz), 7.35-7.37 (d, 2H, J=9.03 Hz); 13C nmr (CDCl3) δ 16.91, 48.59, 53.94, 74.13, 113.84, 118.09, 132.72, 156.51).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:27]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1.CCOC(C)=O>[Br:27][C:9]1[N:8]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)[C:7]2[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=2[N:10]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(Cl)nc(Cl)c32)CC1
Temperature: 35 °C
Reaction time: 0.75 h

Procedure:
4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (1 g, 3.35 mmol) was dissolved in THF (10 mL). Disodium hydrogen phosphate (1.43 g, 10.1 mmol) was added, and the reaction was warmed to 35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (1.15 g, 4.02 mmol) was added in 1 portion, and the reaction was continued with stirring at 35° C. After 45 minutes, the reaction was diluted with EtOAc (100 mL) and washed with aqueous NaHSO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column with 0 to 50% EtOAc/hexanes provided 2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21]([OH:26])(=[O:25])[C:22]([CH3:24])=[CH2:23].[Na].S([O-])([O-])(=O)=O.C1OC1.C(O)(=O)C(C)=C>>[CH:13]([CH2:24][C:22](=[CH2:23])[C:21]([OH:26])=[O:25])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=Cc1ccccc1
Reactant: C=C(C)C(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1CO1
Product: C=C(CC=Cc1ccccc1)C(=O)O
Reaction time: 5 h

Procedure:
Further, 30 parts of a 1% aqueous solution of ammonium persulfate were added thereto, and the mixture was aged for 5 hours at 75° C. Thus, an aqueous dispersion (i.e., a particulate resin dispersion (A2)) of a vinyl resin (i.e., a copolymer of styrene/methacrylic acid/sodium salt of sulfate of ethylene oxide adduct of methacrylic acid) was prepared.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:14]=2)[C:9]1=[O:27])([CH3:7])[CH3:6])C.[OH-].[Li+]>O.O1CCOCC1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:27])[N:8]([C:5]([CH3:6])([CH3:7])[C:4]([OH:28])=[O:3])[CH2:17][CH2:16]3)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(C)(C)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of the 2-[6-(4-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-2-methyl-propionic acid ethyl ester (220 mg, 0.571 mmol) and lithium hydroxide (274 mg, 11.41 mmol) in water and dioxane (1:1 v:v, 5 mL) was stirred at 50° C. overnight. The dioxane was evaporated and the mixture acidified to pH 3-4 with 0.1 N HCl. After extraction with ethyl acetate, drying of the organic layer with magnesium sulfate, filtration and evaporation a white solid was obtained (196 g, 96%). MS: m/e 356.1 (M−H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[S:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:32]2[S:31][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:33]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2cc3ccccc3s2)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 1-benzothiophen-2-yl-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 555.4 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15]COC)[C:12]([CH:19]([CH3:21])[CH3:20])=[CH:11][C:10]=1[C:22]1[N:23]([C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)[C:24]([OH:27])=[N:25][N:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:40]>CO>[ClH:40].[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:19]([CH3:21])[CH3:20])=[CH:11][C:10]=1[C:22]1[N:23]([C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)[C:24]([OH:27])=[N:25][N:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cc(OCc2ccccc2)c(-c2nnc(O)n2-c2ccc(N3CCOCC3)nc2)cc1C(C)C
Agent: Cl
Solvent: CO
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc(N3CCOCC3)nc2)c(OCc2ccccc2)cc1O
Yield: 74 %

Procedure:
To the solution of compound (4) (2.10 g, 3.95 mmol) in MeOH (100 ml), HCl (2 ml, 2N) was added, and then the resultant mixture was heated at 65° C. for 5 h, then cooled. The white precipitate thus obtained was filtered, washed with ether (2×20 ml) gave 1.53 g (74%) of 5-(2-(benzyloxy)-4-hydroxy-5-isopropylphenyl)-4-(6-morpholinopyridin-3-yl)-4H-1,2,4-triazol-3-ol hydrochloride (5).
Reaction SMILES: [C:1]([C:6]1[CH:20]=[C:19]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:7]=1[O:8][CH:9]([CH2:15][CH3:16])[C:10]([O:12]CC)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:20]=[C:19]([C:21]([CH2:24][CH3:25])([CH3:22])[CH3:23])[CH:18]=[CH:17][C:7]=1[O:8][CH:9]([CH2:15][CH3:16])[C:10]([OH:12])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(CC)Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)O
Reaction time: 6 h
Yield: 122.3 %

Procedure:
The above ethyl 2-(2,4-di-t-amylphenoxy)butyrate (317.9 g) and 27% aqueous sodium hydroxide (401.4 g) were placed in a 3-liter flask. The mixture was kept at 98° C. for 6 hours, and the hydrolysis reaction was completed. After completion of the reaction, the mixture was adjusted to pH 2 or lower by the addition of 40% aqueous sulfuric acid (349.9 g) and water (250 g), and toluene (317.9 g) was added thereto, followed by extraction. The water layer was separated with a separatory funnel, and the toluene layer was washed with water (317.9 g). Then, the toluene layer was concentrated by distillation under ordinary pressure for the removal of toluene, which afforded a concentrated solution (357.6 g) of the carboxylic acid compound in toluene. The analysis revealed that the concentrated solution contained the desired carboxylic acid compound in a yield of 99% on the basis of the raw material ester compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][O:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CNN>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][O:11][NH2:12])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: CNN
Solvent: CO
Solvent: ClCCl
Product: CN(CCON)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
To an ice-cold solution of tert-butyl[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl]methylcarbamate (4.3 g, 13=mmol) in CH2Cl2/MeOH (8:2, 90 mL) was added methylhydrazine (3.2 mL, 60 mmol) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 1.5 h, the reaction mixture was concentrated under reduced pressure. To the residue was added CH2Cl2 (35 mL) and the resulting white solid was collected by vacuum filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 50:50 hexanes/EtOAc to 35:65 hexanes/EtOAc) to afford tert-butyl[2-(aminooxy)ethyl]methylcarbamate (2.3 g, 90%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.46 (9H, s), 1.82-1.98 (1H, m), 2.88 (3H, br s), 3.44-3.46 (2H, m), 3.74 (2H, t, J=5.3 Hz), 5.44-5.77 (2H, m).
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2C1CCC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (142.5 mg, 0.4536 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (150.2 mg, 0.4533 mmol), Na2CO3 (120 mg, 1.13 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2 (13-37)→2% MeOH in CH2Cl2 (38-61)], yielding the title compound as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.88-2.00 (m, 2H), 2.44-2.56 (m, 2H), 2.56-2.65 (m, 2H), 5.27 (brs, 2H), 5.35 (quint, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.46-7.51 (m, 1H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=15.03 (−), 31.11 (2C, +), 48.26 (+), 101.15 (Cquart), 115.99 (Cquart), 118.99 (+), 120.86 (+), 125.97 (Cquart), 127.42 (+), 127.55 (2C, +), 128.26 (+), 128.48 (+), 128.87 (2C, +), 129.52 (+), 136.49 (Cquart), 136.55 (+), 139.43 (Cquart), 148.52 (Cquart), 150.79 (Cquart), 151.97 (+), 156.97 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (17) [MH+], 338.2 (22) [MH+−cyclobutene]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Fc1ccncc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccncc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=0.93 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: C(OC1C(=O)C=CN(CCO)C=1)C1C=CC=CC=1.C([O:26][C:27]1[C:32](=[O:33])[CH:31]=[CH:30][N:29]([CH2:34][CH2:35][OH:36])[C:28]=1[CH:37]([C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[O:38]C1CCCCO1)C1C=CC=CC=1>C(O)C.Cl>[F:51][C:48]1[CH:47]=[CH:46][C:45]([CH:37]([OH:38])[C:28]2[N:29]([CH2:34][CH2:35][OH:36])[CH:30]=[CH:31][C:32](=[O:33])[C:27]=2[OH:26])=[CH:50][CH:49]=1
Reactant: O=c1ccn(CCO)c(C(OC2CCCCO2)c2ccc(F)cc2)c1OCc1ccccc1
Agent: Cl
Agent: O=c1ccn(CCO)cc1OCc1ccccc1
Solvent: CCO
Product: O=c1ccn(CCO)c(C(O)c2ccc(F)cc2)c1O

Procedure:
2-[4-Fluorophenyl)-hydroxy-methyl]-3-benzyloxy-1-(2-hydroxy-ethyl)-1H-pyridin-4-one: 13.7 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[(4-fluorophenyl)-(tetrahydropyran-2-yloxy)-methyl]-1H-pyridin-4-one are boiled under reflux for 3 hours in 150 ml of ethanol and 50 ml of 2N HCl. For working-up, the ethanol is removed using a rotary evaporator. The residue is diluted with 50 ml of water and covered with 50 ml of ethyl acetate. Then, with stirring, 50 ml of 2N NaOH are added. The resulting product is filtered off and washed with water and ethyl acetate. After drying, 2-[(4-fluorophenyl)-hydroxy-methyl]-3-benzyloxy-1-(2-hydroxy-ethyl)-1H-pyridin-4-one remains, in the form of colourless crystals. M.p.: 187°-187.5° C.
Reaction SMILES: C([O:4][CH:5]1[CH:6]([CH3:59])[CH2:7][CH2:8][CH:9]([O:51][Si:52]([CH2:57][CH3:58])([CH2:55][CH3:56])[CH2:53][CH3:54])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:50])=[CH:20]/[CH:21]=[CH:22]/[C:23]([CH3:49])([O:41][Si:42]([CH2:47][CH3:48])([CH2:45][CH3:46])[CH2:43][CH3:44])[CH2:24][CH:25]2[O:40][CH:26]2[CH:27]([CH3:39])[CH:28]([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[OH:4][CH:5]1[CH:6]([CH3:59])[CH2:7][CH2:8][CH:9]([O:51][Si:52]([CH2:53][CH3:54])([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:50])=[CH:20]/[CH:21]=[CH:22]/[C:23]([CH3:49])([O:41][Si:42]([CH2:47][CH3:48])([CH2:43][CH3:44])[CH2:45][CH3:46])[CH2:24][CH:25]2[O:40][CH:26]2[CH:27]([CH3:39])[CH:28]([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12]
Reactant: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(OC(C)=O)C=CC1C)O[Si](CC)(CC)CC
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(O)/C=C/C1C)O[Si](CC)(CC)CC
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(OC(C)=O)/C=C/C1C)O[Si](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)C(O)C=CC1C)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (77 mg, 0.0875 mmol) was dissolved in methanol (2 mL). Potassium carbonate (36.5 mg, 0.262 mmol) and methanol (1 mL) were added to this methanolic solution, and the reaction mixture was stirred at room temperature for four hours. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9->1:6->1:4->1:3) to obtain the title compound (38.6 mg, 50%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:40]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41]1>C1COCC1.CN(C=O)C.C1COCC1.CCOC(C)=O>[CH:40]1([C:44]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:11][C:10]=3[F:32])[CH:5]=[CH:4][N:3]=2)=[O:45])[CH2:43][CH2:42][CH2:41]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)C1CCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CCC4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (100 mg, 0.231 mmol) in THF/DMF (15 mL/0.5 mL) was added Et3N (0.058 mL, 0.462 mmol). The suspension was cooled to 0° C., then a solution of cyclobutanecarbonyl chloride (30 mg, 0.254 mmol) in THF (5 mL) was added to the mixture drop wise over 1 hour. The reaction was stirred at rt for 2 hours, then diluted with EtOAc (20 mL). The mixture was washed with water (25 mL×3), followed by washing with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=100/20/1) to give the title compound as a white solid (51 mg, 44%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[C:26]1([C@@H:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@H]2c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)cc1)N1c2ccccc2-c2ccccc2[C@H]1c1ccccc1

Procedure:
The title compound was prepared from (R)-5-[(4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine* (1.35 g, 3.16 mmol), cyclohexene (6.16 g, 75 mmol), and 1.0 M boron tribromide in dichloromethane (20 mL, 20 mmol) according to the procedure and in the same manner as described in Example 1, step b; and yielded, after chromatographic purification and crystallization from diethyl ether-hexane, 4-{[(R)-6-phenylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.691 g, 1.67 mmol, 53%) as a homogeneous, colorless, crystalline, single enantiomer*, m.p. 208-210° C.;
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[N:5]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[N:4]=1)#[N:2].C(C1C2C(=CN=CC=2)N(CC(O)=O)N=1)(=[O:30])N>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[N:5]([CH2:20][C:21]([OH:23])=[O:22])[N:4]=1)(=[O:30])[NH2:2]
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2cc(OCc3ncccn3)ccc21
Product: NC(=O)c1nn(CC(=O)O)c2ccc(OCc3ncccn3)cc12

Procedure:
The title compound was prepared from tert-butyl 2-(3-cyano-5-(pyrimidin-2-ylmethoxy)-1H-indazol-1-yl)acetate in a similar manner as described in step D of Scheme A6 for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid. MS (LC-MS): 328.2 [M+H]+, 326.3 [M−H]−, tR (HPLC conditions e): 2.77 min.
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C1C=CC=CC=1.[C-:21]#[N:22].[K+].O1CCOCC1>O>[C:21]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)#[N:22]
Reactant: [O-][n+]1cccc2ccccc21
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(Cl)c1ccccc1
Product: N#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.7 %

Procedure:
To a solution of quinoline N-oxide (2g, 13.8 mmol) was added benzoyl chloride (2.6 mL, 22.0 mmol), followed by water (20 mL). Then, a solution of potassium cyanide (3.6 g, 55.1 mmol) in water (80 mL) was added slowly over a period of 15 minutes with vigorous stirring. Dioxane (15 mL) was added to help the solubility. After the mixture was stirred at RT for 2.5 hours, it was extracted with equal volume of dichloromethane three times. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was then purified by flash chromatography with 30% of ethyl acetate in hexane. 2.1 g of product was obtained (yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:15]1(=[O:22])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]1.C(#N)C.CC(C)(O)C#N>C(OCC)(=O)C.Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([CH:16]1[C:17](=[O:21])[CH2:18][CH2:19][CH2:20][C:15]1=[O:22])=[O:5]
Reactant: O=C(Cl)c1ccc(OC(F)F)cc1Cl
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CCCC(=O)C1C(=O)c1ccc(OC(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.3 %

Procedure:
7.23 g of 2-chloro-4-difluoromethoxybenzoyl chloride and 2.80 g of 1,3-cyclohexanedione are introduced into 30 ml of acetonitrile, and 6.32 g of triethylamine is added dropwise in such a manner that the internal temperature does not exceed 40° C. The mixture is subsequently stirred for 15 minutes at room temperature, 1.95 g of acetone cyanohydrin are added, and stirring is continued for 3 hours at room temperature. The reaction mixture is diluted with 100 ml of ethyl acetate and 50 ml of 1N hydrochloric acid are added. After vigorous shaking, the phases are separated, and the organic phase is extracted twice with 50 ml portions of 5% strength potassium carbonate solution. The combined aqueous phases are acidified using concentrated hydrochloric acid and reextracted using dichloromethane (2 times 50 ml). The mixture is dried over magnesium sulfate, the solvent is stripped off, and 6.9 g (87% of theory) of 2-(2-chloro-4-difluoromethoxybenzoyl)-cyclohexane-1,3-dione are then obtained as pale yellow crystals of melting point 68°-72° C.