Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11][CH3:12])=[O:10]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[CH2:5][CH:6]1[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13][CH2:14][NH:15]1
Reactant: COC(=O)c1ccnc(Cc2cc(F)cc(F)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2cc(F)cc(F)c2)C1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
Methyl 2-(3,5-difluorobenzyl)isonicotinate (7.417 g, 28.18 mmol) was dissolved in acetic acid (72 mL) and platinum(IV) oxide (0.320 g, 1.41 mmol) was added. The mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 5 h. The reaction mixture was filtered through celite and the catalyst was washed with MeOH. The eluate was concentrated and DCM and 1 M K2CO3 were added. The phases were separated and the organic phase was washed with brine before it was dried and concentrated to yield methyl 2-(3,5-difluorobenzyl)piperidine-4-carboxylate (7.08 g, 93%). MS m/z 270 (M+H)+
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl.[OH-].[Na+].C(C(C)=O)C(C)C>O1CCCC1.C(OCC)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[N:12]([CH3:18])[C:13](=[O:17])[C:14]([CH3:16])=[CH:15][C:10]=1[C:8]([NH:7][O:6][CH2:5][CH2:4][OH:3])=[O:9]
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)CC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-vinyloxy-ethoxy)-amide (500 mg, 915 μmol) and hydrogen chloride (1 mL) in tetrahydrofuran (5 mL) was stirred overnight. Sodium hydroxide (1M, 2.00 mL) was then added, and after a further 10 minutes methyl isobutyl ketone (3 mL) and ethyl acetate (3 mL) were added to the mixture. The layers were separated and the organic solution was washed with 50% brine (4 mL), then evaporated (approximately half the material was lost by spillage). The residue was taken up in methyl isobutyl ketone (3 mL) and ethyl acetate (1 mL) and the mixture was heated to reflux. Upon cooling to 50° C. the mixture went cloudy and isohexane (5 mL) was added. This caused solid to crystallize and the mixture was cooled to 20° C., followed by a further addition of isohexane (5 mL). The solid was then filtered, washed with isohexane (1 mL) and dried in a vacuum oven at 40° C., to provide the title compound, 140 mg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17]([N:18]=[C:19]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]=24)=[CH:16][CH:15]=[N:14]3)=[CH:8][CH:7]=1.[CH3:26][CH:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17]([N:18]=[C:19]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]=24)=[CH:16][CH:15]=[N:14]3)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCCN1CCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A mixture of 10-[4-(3-chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (50 mg, 0.2 mmol), 2-methyl-pyrrolidine (71 mg, 1.0 mmol) and K2CO3 (45 mg, 0.3 mmol) in DMF (1 mL) was stirred at 80° C. overnight. The reaction was cooled, diluted with EtOAc (3 mL) and washed with H2O, brine, dried over MgSO4, and concentrated. The residue was purified by preparative LCMS to give 10-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (33 mg, 66% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]([OH:42])[C:23]2[N:27](COCC[Si](C)(C)C)[C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.CC1C(C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2.B(F)(F)F.CCOCC>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[CH3:1][C:2]1[C:3]([CH:22]([OH:42])[C:23]2[NH:27][C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (90 mg, 0.150 mmol) in CH2Cl2 (1.5 mL), BF3.OEt2 (0.095 mL, 0.749 mmol) was added at 0° C. After stirring for 5 min., the mixture was warmed to room temperature. After stirring for 1 h, the reaction mixture was diluted with 2M aq. Na2CO3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound, without need of further purification. MS (ESI+) m/z 471 (M+H).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1>[C:28]1([N:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: Nc1ccccc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
A 0.66 weight % toluene solution 100 μl of tri-t-butylphosphine was added to a toluene 100 ml solution of 4-bromo-4′-(N,N-diphenylamino)biphenyl 4.00 g, aniline 1.11 g, tris(benzylideneacetone)-dipalladium (0) 183 mg and t-butoxysodium 1.35 g, and the mixture was stirred at room temperature for 5 hours. After finishing the reaction, the mixture was filtered through celite, and the filtrate was extracted with toluene. This was concentrated under reduced pressure, and the resulting crude product was subjected to column refining to obtain 3.20 g of pale yellow powder of N,N,N′-triphenylbenzidine.
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20](O)=[O:21])[CH2:10][N:9]4[CH3:23])=[CH:5]1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN(C)C=O>[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:20]([C@@H:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][C:6]4[C:19]5[C:18](=[CH:17][CH:16]=[CH:15][C:14]3=5)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=4)[N:9]([CH3:23])[CH2:10]2)=[O:21])[CH2:39][CH2:38]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)O)CN(C)[C@@H]1C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)N[C@H]3CC[C@H](N)CC3)CN(C)[C@@H]1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.07 g of (8β)-1-isopropyl-6-methylergoline-8-carboxylic acid in 300 ml of dimethylformamide were added 5.5 g of 1,1'-carbonyldiimidazole. After stirring at room temperature for 3 hours, this solution was added to a solution of 36.9 g of trans-1,4-diaminocyclohexane in 600 ml of dimethylformamide; the addition was made dropwise over a period of 3.5 hours. After the addition was complete, the reaction mixture was allowed to stir at room temperature overnight. The solution was poured into 4 liters of ice and the aqueous solution extracted 8 times with 500 ml each of methylene chloride. The combined organic extracts were washed three times with water, one time with a saturated sodium chloride solution, dried over sodium sulfate, and then concentrated in vacuo to provide 12.5 g of title compound as a yellow solid. A portion of this free base material was treated with p-toluenesulfonic acid in ethyl acetate/ethanol to provide the ditosylate salt, m.p. 236°-239° C. NMR, MS.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:19]([N:20]([CH3:29])[C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:7].[F:30][C:31]([F:40])([F:39])[C:32](I)([F:37])[C:33]([F:36])([F:35])[F:34]>CN(C)C=O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[F:3][C:4]1[C:19]([N:20]([CH3:29])[C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:32]([F:37])([C:33]([F:36])([F:35])[F:34])[C:31]([F:40])([F:39])[F:30])=[CH:11][C:10]=1[CH3:15])=[O:7]
Reactant: Cc1ccccc1NC(=O)c1cccc(N(C)C(=O)c2ccccc2)c1F
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1cccc(N(C)C(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
0.55 g (14 mmol) of powdery sodium hydroxide and 0.64 g (2.3 mmol) of iron(II) sulfate heptahydrate were stirred in an ice bath, until the color of the mixture changed to black. Immediately after the discoloration, 3 g of N,N-dimethylformamide were added thereto, and then, a solution obtained by dissolving 0.60 g (1.7 mmol) of 2-fluoro-3-(N-methylbenzamido)-N-(2-methyl-phenyl)benzamide and 0.68 (2.3 mmol) of heptafluoroisopropyl iodide in 3 g of N,N-dimethylformamide was added thereto, followed by stirring at room temperature for 3 hours. The obtained reaction liquid was filtered through cerite and the residue was washed with 50 mL of ethyl acetate. Then, 40 g of water were added to the resulting reaction liquid, and after performing extraction, the organic layer was dried over magnesium sulfate. Then, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. Thereafter, the condensed residue was purified by silica gel chromatography, to obtain 0.26 g (yield 30%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CN1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:46]([O:53][NH2:54])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C>[CH2:46]([O:53][NH:54][C:21](=[O:23])[CH2:20][N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCCCCCCCN(CC(=O)O)S(=O)(=O)c1ccc(C)cc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCCCCCCCN(CC(=O)NOCc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.6 %

Procedure:
[Octyl-(toluene-4-sulfonyl)amino]-acetic acid (4.0 g, 0.012 mol) was taken up in DMF (150 ml) and treated at room temperature with NMM (1.55 ml, 0.014 mol) followed by EDC (2.92 g, 0.015 mol). The reaction mixture was allowed to stir for 15 minutes at room temperature before the addition of HOBt (2.1 g, 0.016 mol). The reaction mixture was left to stir for a further 20 minutes before a mixture of O-benzylhydroxylamine hydrochloride (1.87 g, 0.012 mol) and NMM (2.6 ml, 0.024 mol) in DMF (50 ml) was added. The reaction mixture was allowed to stir at room temperature for a further 48 h. The DMF was removed under reduced pressure and the resulting crude oil was dissolved in ethyl acetate (200 ml). The solution was washed consecutively with 1 M HCI, 0.5M Na2CO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give an oil which was further purified by flash chromatography (silica gel, 20% ethyl acetate in hexane) to give the title compound as a white solid (1.91 g, 37%). 1H NMR: δ (CDCl3), 9.39 (1H, br s), 7.65 (2H, d, J=8.2 Hz), 7.45-7.20 (7H, m), 4.91 (2H, s), 3.67 (1H, br s), 3.07 (2H, dd, J=7.5, 7.9 Hz), 2.40 (3H, s), 1.50-1.33 (2H, m), 1.31-1.10 (10H, m) and 0.86 (3H, t, J=6.5 Hz).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][CH2:16][CH2:17][CH3:18].P(Cl)(Cl)Cl.[Br-:25].BrBr>C(O)C.O.C(Cl)(Cl)(Cl)Cl>[Br:25][CH: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][CH2:16][CH2:17][CH3:18])[C:1]([OH:20])=[O:19]
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: BrBr
Solvent: O
Solvent: CCO
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCCC(Br)C(=O)O
Temperature: 90 °C

Procedure:
Stearic acid (42.6 g) was heated in an oil bath to 90° C. until it melted. Phosphorus trichloride (0.6 ml) was added to the melt while bromide (8.5 ml) was added dropwise over 3 hours under stirring. Another portion (7.7 ml) of bromine was added dropwise over 2.5 hours, and thereafter the mixture was heated at 90° C. for 3.5 hours. The reaction mixture was cooled, followed by the addition of 200 ml of carbon tetrachloride and 100 ml of water. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under vacuum to give a yellow oily substance. The substance was dissolved in 60 ml of ethanol under heating, then the solution was cooled to produce a pale yellow solid product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12]>[Rh]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCC#Cc1ccccn1
Agent: [Rh]
Product: OCCCCCC1CCCCN1

Procedure:
5-(2-Pyridyl)-4-pentyn-1-ol, prepared as in Example 41, is reduced by hydrogenating using rhodium on carbon as catalyst to give 5-(2-piperidyl)-pentan-1-ol. Treating that intermediate with methyl iodide and sodium hydride gives the N-methyl compound. Brominating, reacting the bromo compound with t-butyl lithium and 5-trimethylsilyl-3-furaldehyde, then oxidizing by the procedure of Example 41 gives 4-[1-acetoxy-6-(N-methylpiperidyl)hexyl]-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>>[C:2]1([C:7]2=[CH:8][C:9]([O:11][C:6]2=[O:12])=[O:10])[CH2:1][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCC=C1
Reactant: O=C1C=CC(=O)O1
Product: O=C1C=C(C2=CC=CC2)C(=O)O1
Temperature: 205 °C

Procedure:
A solution of 0.3 ml. of t-butyl hydroperoxide-70 in 6.6 g. of cyclopentadiene was added in 4 portions over 10 min. to 9.8 g. of maleic anhydride at 205° C. After a subsequent 15 min. heating period at 205° C., the 1:2 cyclopentadiene-maleic anhydride copolymer was obtained in a yield of 4.5 g. (34%). When the additional heating period was increased from 15 min. to 80 min. at 205° C., the yield was increased to 5.0 g. (38%). The copolymer had a softening point of 280° C.
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[CH3:11][C:12]([O:15][C:16](=[O:27])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=O)([CH3:14])[CH3:13].[C:28]([O:34][CH3:35])(=[O:33])[CH2:29][C:30]([CH3:32])=[O:31]>C(O)(C)C>[CH3:11][C:12]([CH3:14])([O:15][C:16](=[O:27])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[C:29]([C:30](=[O:31])[CH3:32])[C:28]([O:34][CH3:35])=[O:33])[CH3:13]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)C=Cc1ccccc1C=O
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccccc1C=CC(=O)OC(C)(C)C)C(C)=O
Yield: 57.9 %

Procedure:
A solution of piperidine (0.11 g) and acetic acid (0.078 g) in iospropanol (1 ml) was added to a solution of 3-(2-formylphenyl)propenoic acid 1,1-dimethylethyl ester (5.2 g) and methyl acetoacetate (2.55 g) in isopropanol (15 ml). The mixture was stirred at 60° C. for 1h, then the solvent was evaporated and the residue taken up with ether (100 ml). The solution was washed with 1N HCl, water, with saturated bicarbonate solution, then water again and dried over Na2SO4. Evaporation of the solvent gave an oil which was purified by column chromatography (gradient Petrol/Ether, 7:3 -1:1) to give the title compound as a pale oil (4.2 g; mixture E/Z isomers).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([C:16]1[N:20]([CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:19]=[N:18][CH:17]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[ClH:53]>ClCCCl.C(#N)C>[ClH:53].[C:1]1([N:7]2[CH2:8][CH2:9][CH:10]([NH:13][CH2:14][C:16]3[N:20]([CH2:21][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH:19]=[N:18][CH:17]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: NC1CCN(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CNC2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Phenylpiperidin-4-ylamine (75 mg, 0.43 mmol) (from Example 123) and 4-(5-formylimidazol-1-ylmethyl)benzonitrile (99 mg, 0.47 mmol) were dissolved in 1,2-dichloroethane (2 mL) and acetic acid (49 μL, 0.86 mmol) was added. The mixture was stirred for 2 hrs at room temperature, then sodium triacetoxyborohydride (117 mg, 0.55 mmol) was added, then the reaction mixture was stirred at room temperature for 18 hrs. Sat. NaHCO3 (aq) (30 mL) was added, and the organic layer was extracted. The aqueous phase was extracted with dichloromethane (2×5 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane--5% methanol--0.5% NH4OH to give the product as a free base. This was lyophilized from HCl (aq)--acetonitrile to give the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:28]1[CH:37]=[N:36][C:35]2[NH:34][CH2:33][C:32]([CH3:39])([CH3:38])[O:31][C:30]=2[CH:29]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl.CO>[CH3:38][C:32]1([CH3:39])[O:31][C:30]2[CH:29]=[C:28](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]3[O:9][C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[C:12]=3[CH3:13])=[O:6])[CH:37]=[N:36][C:35]=2[NH:34][CH2:33]1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: CC1(C)CNc2ncc(Br)cc2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CCC#N
Solvent: ClCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OC(C)(C)CN3)oc2ccccc12
Yield: 56.1 %

Procedure:
A solution of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.190 g, 0.637 mmol) in propionitrile (3 mL) and DMF (0.6 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.23 mL, 1.33 mmol) and 7-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (0.154 g, 0.828 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.014 g, 0.063 mmol) and P(o-tol)3 (0.038 g, 0.12 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 2 h, then allowed to cool. The mixture was diluted with H2O (200 mL) and the solution was washed with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried (Na2SO4) and concentrated to give a dark green oil. Column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.14 g, 59%) as a light yellow solid and as a mixture of amide rotamers: 1H NMR (500 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.56-7.54 (m, 1H), 7.51-7.47 (m, 2H), 7.41-7.38 (m, 1H), 7.32 (br s, 1H), 7.29-6.93 (m, 3H), 4.95-4.76 (m, 2H), 3.19 (m, 2H), 3.14-2.90 (m, 3H), 2.25 (s, 3H), 1.26 (s, 6H); MS (ESI) m/e 392 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[C:8]([N:10]=NC2C=CC=CC=2)[CH:7]=[CH:6][C:5]=1[OH:18]>C(O)C.[Pd]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([OH:18])=[C:4]([O:3][C:2]([F:1])([F:19])[F:20])[CH:9]=1
Reactant: Oc1ccc(N=Nc2ccccc2)cc1OC(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(O)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48.9 %

Procedure:
25 g (0.09 mol) of 2-trifluoromethoxy-4-(phenyldiazenyl)phenol from Example 7 and 1 g of Pd/C (10%) were initially charged in 350 ml of ethanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 72 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate concentrated on a rotary evaporator, in the course of which the product already crystallizes out. The resulting solid was filtered off with suction, washed with a little cold ethanol and dried under high vacuum for 4 hours. 8.5 g (50%) of the desired compound were obtained as a light brown powder.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[C:12](=[O:27])[NH:13][C:14](=[O:26])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([C:11]2[C:12](=[O:27])[NH:13][C:14](=[O:26])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[C:17]=2[Cl:28])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc(C2=C(c3ccc(O)c4ccoc34)C(=O)NC2=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1c(Cl)c(C2=C(c3ccc(O)c4ccoc34)C(=O)NC2=O)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
Dissolve 3-(4-hydroxybenzofur-7-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (0.25 g, 0.70 mmol) in 50 mL chloroform under nitrogen. Add 0.093 g (0.70 mmol, 1 equiv) N-chloro succinimide and attach a reflux condenser. Heat to 50° C. and let go overnight. Let cool to room temperature, then extract with ethyl acetate versus water. Wash with brine, then dry over sodium sulfate. Filter and concentrate in vacuo. Purification by column chromatography (20% ethyl acetate: hexanes) yields 0.034 g (12%) product. High Res. Mass Spec (m/z): Calcd 393.0655 Found 393.0642.