Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:27][OH:28]>CC1CCCO1>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:28][C:27]2[CH:18]=[CH:17][N:12]=[CH:13][CH:14]=2)=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: CO
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CBr)cc2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(COc3ccncc3)cc2)c(C)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
To a solution of an alcohol (1.276 mg, 0.075 mmol, see Table 4 for specific alcohol used for each reaction) and 4-(bromomethyl)-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (0.031 g, 0.075 mmol) in 2-Methyltetrahydrofuran (2-MeTHF) (1 mL) stirred under nitrogen at room temperature was added solid sodium hydride (1.800 mg, 0.075 mmol) (tip of spatula). The reaction mixture was stirred at 20° C. for 3 hrs. The reaction was carefully quenched with water (5 drops per reaction). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. The sample was dissolved in 1:1 MeOH:DMSO 1 mL and purified by mass directed autoprep on an Xbridge column using acetonitrile:water with an ammonium carbonate modifier. The solvent was dried under a stream of nitrogen in the Radley's blowdown apparatus to give the required product (3.89 mg, 10% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[N+:10]([O-])=O)#[N:2].[H][H].C(OCC)(=[O:17])C>O.[Pt]=O>[Br:9][C:6]1[CH:5]=[C:4]([NH2:10])[C:3](=[CH:8][CH:7]=1)[C:1]([NH2:2])=[O:17]
Reactant: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: [H][H]
Reactant: CCOC(C)=O
Agent: O=[Pt]
Solvent: O
Product: NC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 41.5 h
Yield: 65 %

Procedure:
To a solution of 2,5-dibromonitrobenzene (80 g, 285 mmol) in DMF (500 mL) was added copper cyanide (I) (38 g, 427 mmol) and the mixture was stirred at 100° C. for 1.5 hrs. The reaction mixture was allowed to reach room temperature and toluene (750 mL)-water (1250 mL) was added. Then, Celite (50 g) was added, and after thorough stirring, insoluble material was filtered off. The filtrate was partitioned and the organic layer was washed successively with water (500 mL), 1% aqueous ammonia (250 mL×2), water (250 mL) and saturated brine (500 mL), and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure to give a yellow solid (61.4 g) containing 2-cyano-5-bromonitrobenzene as a main component. This was dissolved in ethyl acetate (270 mL) and platinum oxide monohydrate (330 mg, 1.35 mmol) was added. The inside of the reaction container was displaced with hydrogen and the mixture was stirred under a hydrogen atmosphere for 41.5 hrs. Insoluble material was filtered off and the residue was washed with ethyl acetate (200 mL) and then with ethanol (100 mL). The filtrate was evaporated under reduced pressure, and after drying, suspended in ether (250 mL). The suspension was stirred with heating under reflux. The mixture was allowed to cool to room temperature and the insoluble material was collected by filtration to give 4-bromoanthranilic amide (40 g, 186 mmol, 65%).
Reaction SMILES: C[Al](C)C.COC(=O)C(O[Si](C(C)(C)C)(C)C)C1C=CC=CC=1.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:31]1([CH:37]2[CH:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH:40][C:39]([CH:48]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[OH:49])=[N:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:31]1([C@H:37]2[C@@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH:40][C:39]([CH:48]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[OH:49])=[N:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OC(C1=NC(c2ccccc2)C(c2ccccc2)N1)c1ccccc1
Agent: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: C[Al](C)C
Solvent: O=C(O)C(F)(F)F
Product: OC(C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1)c1ccccc1

Procedure:
Employing the general trimethylaluminum coupling procedure and using (tert-butyl-dimethyl-silanyloxy)-phenyl-acetic acid methyl ester prepared in accordance with the procedures set out in Step 1 above and meso-1,2-diphenylethylene-diamine there is made: (4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl-methanol trifluoroacetate. 1H NMR (DMSO) δ 10.95 (bs, 2 H), 7.70-7.67 (m, 2 H), 7.57-7.46 (m, 3 H), 7.2-7.0 (m, 7 H), 6.9-6.8 (m, 4 H), 5.88 (s, 1 H), 5.77 (s, 2 H); LC/MS: 2.39 min, m/z 329 (M++1)
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3]CC.[C:7]([CH2:12][CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:9][CH2:10][CH3:11])=[O:8].[CH2:33](Cl)Cl>>[CH3:33]/[C:12](=[CH:13]\[CH2:1][CH2:2][CH3:3])/[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: ClCCl
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC=O
Product: CCC/C=C(\C)C(=O)OCC
Temperature: 25 °C
Yield: 85 %

Procedure:
Valeraldehyde (2.5 g, 29.02 mmol) and (carbethoxyethylidene)triphenyl phosphorane (12.54 g, 34.83 mmol) in methylene chloride was refluxed for 7 hours. After cooling to room temperature, the solvent was evaporated. The residue was purified through flash chromatography on silica gel (EtOAc:Hexanes=2:98) to give 4.2 g as colorless oil in 85% yield. 1HNMR (CD3Cl): δ 0.920 (t, J=7.4 Hz, 3H), 1.30 (m, 7H), 1.81 (s, 3H), 2.19 (t, J=7.4 Hz, 2H), 4.18 (q, J=7.4 Hz, 2H), 6.75 (t, J=7.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].CO.[CH:7]([CH:9]=O)=O>O>[CH3:1][N:2]([CH3:4])[N:3]=[CH:7][CH:9]=[N:3][N:2]([CH3:4])[CH3:1]
Reactant: CN(C)N
Reactant: O=CC=O
Solvent: CO
Solvent: O
Product: CN(C)N=CC=NN(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,1-Dimethylhydrazine (3.20 ml, 41.9 mmol) was added to a mixture of MeOH (14 ml) and a 40 wt % glyoxal solution (2.40 ml, 20.9 mmol) in water at 0° C. The resulting mixture was stirred for 24 h at room temperature. The mixture was then dried over Na2SO4, filtered, and concentrated under vacuum to afford glyoxal bis(N,N-dimethylhydrazone) (abbreviated as bis-hydrazone A) as an orange-brown oil (2.78 g, 94% yield). The 1H NMR data (CDCl3, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.13 (singlet, 2 H), 2.89 (singlet, 12 H). The 13C NMR data (CDCl3, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 134.9, 43.1. From the 1H NMR and 13C NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[O:15][C:14](=S)[NH:13][C:12]1=[O:17].C([OH:20])C.OO>C(Cl)(Cl)Cl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[O:15][C:14](=[O:20])[NH:13][C:12]1=[O:17]
Reactant: CCO
Reactant: O=C1NC(=S)OC1c1ccc2ccccc2c1
Agent: OO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C(c2ccc3ccccc3c2)O1

Procedure:
5-(2-Naphthyl)oxazolidin-4-one-2-thione (2.0 g., 8.2 mmoles) was partially dissolved in 25 ml. of aqueous ethanol at 50° C. Hydrogen peroxide (30%, 7 ml. was added) and the mixture refluxed for 4 hours. The reaction mixture was cooled, diluted with chloroform and water and the organic layer separated. The organic layer was extracted with saturated sodium bicarbonate. The bicarbonate layer was carefully acidified with dilute hydrochloric acid and the precipitated product recoved by filtration. Recrystallization from toluene gave purified 5-(2-naphthyl)oxazolidine-2,4-dione [0.2 g., m.p. 187°-188° C., pnmr/CDCl3 /delta: 6.54 (s, 1H), 7.3-8.1 (m, 7H)].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:16])OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]>C1(C)C=CC=CC=1>[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[NH:16]
Reactant: CCOC(=N)NC(=O)OCc1ccccc1
Reactant: NCCCCCCCCN
Solvent: Cc1ccccc1
Product: N=C(NCCCCCCCCN)NC(=O)OCc1ccccc1
Temperature: 6 °C
Reaction time: 1 h

Procedure:
A mixture of N-benzyloxycarbonyl-O-methyl-isourea (II-OMe) (0.42 g, 2.0 mmol) and 1,8-diaminooctane (Ie) (0.72 g, 12 mmol) in toluene (3.5 mL) was stirred at 40° C. for 24 h and at 6° C. for 1 h. The crystals were collected by filtration. The white crystalline product was washed with toluene (3×1 mL) and dried (vacuum, 30°-35° C., 2 h). The yield of N-(8-aminooctyl)-N'-benzyloxycarbonyl guanidine (IIIe) was 0.32 g (50% in theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([CH:19]([CH:26]2[CH2:28][CH2:27]2)[NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:16]=[N:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:26]1([CH:19]([C:15]2[CH:16]=[N:17][CH:18]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH:14]=2)[NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH2:28][CH2:27]1
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccccc2OC)c1)C1CC1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
A mixture of 3-methoxyphenylboronic acid (48 mg, 0.31 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (100 mg, 0.31 mmol), PdCl2(PPh3)2 (18 mg, 0.02 mmol) and Na2CO3 (2 M in water, 0.39 mL, 0.78 mmol) in DMF (2 mL) was heated at 100° C. for 2 h. After concentration, the resulting residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (38 mg, 35%); ESI-MS m/z: 347 [M+1]+. 1H-NMR (MeOD, 400 MHz) δ 8.75 (1H, bs), 8.61 (1H, bs), 8.17 (1H, bs), 7.46 (1H, t, J=8.0 Hz), 7.27 (1H, dd, J=8.0, 2.4 Hz), 7.24 (1H, t, J=2.4 Hz), 7.05 (1H, dd, J=8.0, 2.4 Hz), 3.94 (1H, d, J=9.2 Hz), 3.91 (3H, s), 3.03-2.89 (2H, m), 1.35-1.29 (1H, m), 1.29 (3H, t, J=7.2 Hz), 0.81-0.75 (1H, m), 0.676-0.60 (2H, m), 0.53-0.48 (1H, m)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:20]=[CH:19][C:18]=1[C:32]1[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=1
Reactant: CS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 1-bromo-2-(methylsulfonyl)-4-(trifluoromethyl)benzene and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H13F4N3O2S, 411.07; m/z found, 412.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.61-8.51 (d, J=1.4, 2H), 8.44 (s, 1H), 8.11-8.05 (d, J=7.5, 1H), 7.72-7.66 (d, J=8.0, 1H), 7.66-7.59 (m, 1H), 7.45-7.35 (m, 2H), 2.89 (s, 3H).
Reaction SMILES: ClC1C=CC(NN)=CC=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[C:13]([F:19])[CH:12]=1.ClC1C=CC(N2[C:31](=[O:32])[C:30]3[CH2:33][CH2:34][CH2:35][C:29]=3N2)=CC=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:31](=[O:32])[C:30]3[CH2:33][CH2:34][CH2:35][C:29]=3[NH:18]2)=[C:13]([F:19])[CH:12]=1
Reactant: NNc1ccc(Cl)cc1F
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCC2
Agent: NNc1ccc(Cl)cc1
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCC2

Procedure:
By substituting 4-chlorophenylhydrazine in the former procedure for 4-chloro-2-fluorophenylhydrazine, 2-(4-chlorophenyl)-1,4,5,6-tetrahydrocyclopentapyrazol-3(2H)-one was prepared, m.p. 193.5°-195°.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]([CH:6](O)/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C(/C1C(=O)CC([OH:25])C=1C)=C/CCC>O>[CH:7](/[CH:6]1[C:2]([OH:13])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:25])=[CH:8]/[CH2:9][CH2:10][CH3:11]
Reactant: CCC/C=C\C1=C(C)C(O)CC1=O
Reactant: CCC/C=C\C(O)c1ccc(C)o1
Solvent: O
Product: CCC/C=C\C1C(=O)C=CC1(C)O
Temperature: 100 °C

Procedure:
In the same flask as used in Example 1, there were charged 5-methyl-α-(2-cis-pentenyl)furfuryl alcohol (I-2) (18 g) and water (720 g), and the mixture was stirred at 100° C. under a pH of 4.7-4.9. The reaction mixture was then treated in the same manner as in Example 1 to give a mixture (14.2 g) of 2-(2-cis-pentenyl)-3-hydroxy-3-methyl-4-cyclopentenone (II-2) and 2-(2-cis-pentenyl)-4-hydroxy-3-methyl-2-cyclopentenone (III-2). Yield, 79%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])=[CH:18][CH:17]=1)[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:6])[CH3:2].[CH:38]1([N:44]=[C:45]=[O:46])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C1COCC1>[CH2:1]([O:3][C:4](=[O:37])[C:5]([N:7]([CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:45]([NH:44][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:46])[CH2:13][CH2:14]1)[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])=[CH:20][CH:21]=1)=[O:6])[CH3:2]
Reactant: O=C=NC1CCCCC1
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCNCC2)C(=O)C(=O)OCC)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCN(C(=O)NC3CCCCC3)CC2)C(=O)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The resin-bound ethyl[{4-[(dodecylamino)carbonyl]benzyl}(piperidin-4-ylmethyl)amino]-(oxo)acetate (described in step h, 0.0426 mmol) was swelled in THF (0.5 mL) for 15 min at rt. Cyclohexyl isocyanate (18 mg, 0.143 mmol) dissolved in THF (0.9 mL) and TEA (29 mg, 0.282 mmol) was added and the reaction mixture was shaken 14 h at rt. The resin was washed successively with THF (1×0.15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the title compound which was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6](NC(=O)C)=[CH:7][CH:8]=2)[NH:3]1.NC1C=C2C(=CC=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][C:20](=[O:25])[CH3:19])[CH:8]=2)[NH:3]1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2

Procedure:
According to procedure for the synthesis of N-(2-oxoindolin-6-yl)acetamide, except substituting 5-aminoindolin-2-one (50 mg, 0.34 mmol), the title compound was prepared as a beige solid (46 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.31 (d, J=7.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 3.52 (s, 2H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[C:5]2[CH:8]=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.[N+:15]([O-])([O-:17])=[O:16].[NH4+]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2c(c1C)OC(C)(C)C2=O
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])cc2c(c1C)OC(C)(C)C2=O
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 2,2,6,7-tetramethyl-1-benzofuran-3 (2H)-one obtained in Reference Example 41 (5.20 g, 27.3 mmol) in anhydrous trifluoroacetic acid (50 mL) and chloroform (5 mL) was added ammonium nitrate (2.10 g, 32.8 mmol) at 0° C., and the mixture was stirred at the same temperature for 2 hours, and then concentrated under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate. The extract was washed with water and a saturated sodium hydrogen carbonate solution, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain 5.40 g (yield 84%) of the title compound. Melting point: 131-132° C. (ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:5]([CH3:20])=[C:6]([CH:18]=[CH2:19])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N+]1([O-])CCOCC1.C(#N)C.[OH2:41].[OH2:42].CC(C)=O>[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:5]([CH3:20])=[C:6]([CH:18]([OH:42])[CH2:19][OH:41])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O
Reactant: C=Cc1c(OCc2ccc(F)cc2F)c(Br)c(=O)n(-c2c(F)cccc2F)c1C
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CC(C)=O
Product: Cc1c(C(O)CO)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reaction time: 1 h

Procedure:
To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin-2(1H)-one (0.970 g, 2.07 mmol) in water/acetone 1:3 (8.7 mL) was added, sequentially, osmium tetroxide (0.110 g, 0.433 mmol) and N-methyl morpholine oxide (1.32 g, 11.2 mmol). The resulting solution was stirred for one hour until complete consumption of starting material by LCMS analysis, and the reaction was concentrated in vacuo. The resulting dark residue was subjected to SiO2 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid. 1H NMR (400 MHz, CDCl3) δ 7.59 (app q, J=8.2 Hz, 1H), 7.45 (ddd, J=14.7, 8.5, 6.8 Hz, 1H), 7.08 (app t, J=8.5 Hz, 2H), 6.94 (app t, J=8.2 Hz, 1H), 6.88 (app t, J=8.5 Hz, 1H), 5.31 (AB-q, J=10.6 Hz, Δ=38.3 Hz, 2H), 5.07 (dd, J=9.1, 3.8 Hz, 1H), 3.83 (t, J=10.8 Hz, 1H), 3.60 (dd, J=11.4, 3.9 Hz, 1H), 2.94 (br s, 1H), 2.16 (s, 3H); LC/MS C-18 column, tr=2.26 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 502 (M+H). ES-HRMS m/z 502.0276 (M+H calcd for C21H17BrF4NO4 requires 502.0272).
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[N:29][C:30]([O:33]C)=[CH:31][CH:32]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C>O1CCOCC1.Cl>[F:35][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:32]=[CH:31][C:30](=[O:33])[NH:29][CH:28]=5)[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1cc2ccccc2c(-c2ccc(=O)[nH]c2)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 90 °C

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(6-methoxypyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (100 mg, 0.210 mmol) was dissolved in a mixture of 1.2 mL of 1,4-dioxane and 0.6 mL of 4M aqueous hydrochloric acid. The solution was heated at 90° C. for 2 hours. The crude reaction mixture was quenched with one equivalent of triethylamine and was then evaporated to dryness. The crude product was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate, and a portion of the material was purified on 12 g of silica gel utilizing a gradient of 0-10% methanol in dichloromethane to yield 1-(2,2-difluorobenzo-[d][1,3]dioxol-5-yl)-N-(1-(6-oxo-1,6-dihydropyridin-3-yl)isoquinolin-3-yl)cyclopropane-carboxamide as a white solid. ESI-MS m/z calc. 461.1. found 461.9 (M+1)+. Retention time 1.67 minutes.
Reaction SMILES: IN1C(=O)CCC1=O.[CH3:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15](=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18].[NH2:22][C:23]([NH2:25])=[S:24].C[CH2:27][O:28][C:29](C)=O>>[NH2:22][C:23]1[S:24][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:11]2[N:10]([CH2:9][CH2:27][O:28][CH3:29])[CH:14]=[CH:13][N:12]=2)[N:25]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)CC(=O)c1nccn1C
Reactant: NC(N)=S
Agent: O=C1CCC(=O)N1I
Product: COCCn1ccnc1-c1nc(N)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Iodosuccinimide (9.3 g, 41 mmol) was added to a mixture of 7.52 g (41 mmol) methyl 3-(1-methyl-1H-imidazol-2-yl)-3-oxopropanoate (Intermediate 10) and 7.5 g Amberlyst-15 resin in 400 ml EtOAc followed by stirring for 1 hour at room temperature. The resin was filtered off and rinsed with EtOAc. Solvent was removed from the filtrate and the residue was taken up in diethyl ether. Insoluble material was filtered off and rinsed with additional ether. Solvent was removed from the filtrate and the residue was dissolved in 200 ml MeOH before added 4.7 g (62 mmol) thiourea. The mixture was heated at reflux for 1 hour. Solvent was removed and the residue was taken up in aqueous Na2CO3. Insoluble material was collected by filtration and rinsed well with water. The solids were dried in vacuo affording 4.51 g of product: MS (ES) (M+H)+: 283 for C11H14N4O3S
Reaction SMILES: [CH2:1]([NH:5][CH:6]([P:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[OH:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C[CH2:23][O-:24].[Na+].C([OH:28])C>C(C(CCCC)C([O-])=O)C.C(C(CCCC)C([O-])=O)C.[Ni+2]>[CH2:1]([NH:5][CH:6]([P:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])[O-:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[CH2:9]([CH:10]([CH2:11][CH2:12][CH2:7][CH3:6])[C:23]([O-:24])=[O:28])[CH3:8]
Reactant: CCCCNC(c1ccccc1)P(=O)(O)c1ccccc1
Reactant: CC[O-]
Reactant: CCO
Agent: [Ni+2]
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Product: CCCCNC(c1ccccc1)P(=O)([O-])c1ccccc1

Procedure:
30.3 g (0.1 mol) of α-(n-butylamino)benzyl-phenylphosphinic acid ##STR19## are dissolved in 400 ml of absolute ethanol and neutralised with an approx. 1.5 molar ethanolic solution of 0.1 mol of sodium ethylate. 34.5 g (0.1 mol) of nickel(II) bis (2-ethylhexanoate) are additionally dissolved in this solution and the mixture is heated at reflux temperature for 30 minutes. The solvent is then evaporated and the residue is dried for 15 hours at 80° C. under a pressure of 11 mm Hg. These instructions give a light green product of the composition XLNi (X=α-(n-butylamino)benzyl-phenylphosphinate; L=2-ethylhexanoate), which contains 4.2% of phosphorus and 9.0% of nickel and is readily soluble in ethanol, chloroform, toluene and hexane at room temperature.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([CH3:19])=[CH2:18])[CH:8]=1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[OH:21][CH:20]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:17]([CH3:19])=[CH2:18])[CH:8]=1)[C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1
Reactant: C=C(C)c1cc(Br)c2ccccc2n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)c1cc(C(O)c2ccc(C(=O)OC)cc2)c2ccccc2n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A solution of n-BuLi (2.5 M, 7.5 mmol, 3 mL) was added to a solution of (56b) (1.55 g, 6.25 mmol) in 20 mL of anhydrous THF at −78° C. The resulting solution was cannulated to another flask charged with methyl 4-formylbenzoate (1.34 g, 8.1 mmol) in 20 mL of anhydrous THF at −78° C. The reaction mixture was stirred for 3 h at −78° C. before quenched with MeOH. The solution was then diluted with ethyl acetate and washed with H2O and brine, and dried over MgSO4. After filtration and concentration, the residue was purified on silica gel column to provide methyl 4-[hydroxy(2-isopropenyl-4-quinolinyl)methyl]benzoate (0.95 g, 46%). MS (AP+): 333 (M+1).