Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C:22]4[N:23]([CH:26]=[CH:27][CH:28]=4)[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2>ClCCl>[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C:22]4[N:23]([C:26](=[O:9])[CH2:27][CH:28]=4)[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1C[C@H]2CCCC[C@]23c2cccn2CCN13
Solvent: ClCCl
Product: O=C1CC=C2N1CCN1C(=O)C[C@H]3CCCC[C@]231
Reaction time: 4 h

Procedure:
A solution of 3.04 g (15 mmol) of m-chloroperbenzoic acid in 30 ml of dichloromethane is added dropwise over a period of 45 minutes, at -15° with stirring, to a solution of 2.3 g (10 mmol) of (9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole in 30 ml of dichloromethane. The reaction mixture is then stirred for 4 hours at -15°, then diluted with 100 ml of dichloromethane and washed in succession, ice-cold, with sodium hydrogen sulfite solution (5%) and sodium hydrogen carbonate solution (5%). The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation in vacuo. In this manner a crude product is obtained, which is chromatographed on 120 g of silica gel (0.040-0.063 mm) using trichloromethane as eluant. The desired (9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole is obtained from the appropriate fractions in the form of a foam, which is crystallised from dichloromethane/diethyl ether and then melts at 105° to 125°. Also obtained is the (9aR*,9bR*, 13aR*) isomer of 2,7-dioxo-1,4,5,7,9a,10,11,12,13,13a-decahydro-2H-pryrrolo[2',1':3,4]pyrazino[2,1-i]indole in the form of an oil, which is crystallised from dichloromethane/diethyl ether and then melts at 159° to 162°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2.[I-].[N:24]1([C:34](N2C=C[N+](C)=C2)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][C:34]([N:24]1[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]1)=[O:35])[CH:9]=2
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(2,6-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=494 (M+1), Rt: 5.79 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:26][CH3:27]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3)c2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)Nc2cccc(CCc3ccccc3)c2)ccc1O

Procedure:
4-Hydroxy-3-methoxy-N-[3-(2-phenylethynyl)phenyl]phenylacetamide (the compound of Example 36) (250 mg) is dissolved in ethyl acetate (10 ml), and thereto is added 10% palladium on carbon (25 mg), and the mixture is subjected to catalytic hydrogenation at 25° C. The catalyst is removed by filtration, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (200 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:11]([C:14]#[N:15])[C:12]#[N:13])[CH3:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:11]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:14]#[N:15])[C:12]#[N:13])[CH3:10])=[CH:7][CH:8]=1
Reactant: CC(c1ccc(C(F)(F)F)cc1)C(C#N)C#N
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccc(C(F)(F)F)cc1)C(C#N)(C#N)CCC(F)(F)F
Yield: 39 %

Procedure:
Using 0.48 g of 2-(1-(4-(trifluoromethyl)phenyl)ethyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.34 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.26 g of 2-(1-(4-(trifluoromethyl)phenyl)ethyl-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (57)).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:5]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]([N:16]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:17](=[O:20])[O:18][CH3:19])[CH:5]=[C:6]([N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)Nc1cc(NC(=O)OC(C)(C)C)cc(Br)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)cc(Br)c1Cl
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
A stirred solution of tert-butyl methyl (5-bromo-4-chloro-1,3-phenylene)dicarbamate (710 mg, 1.870 mmol) in DMF (10 mL) was treated with NaHMDS (3.93 mL, 3.93 mmol) at 0° C. dropwise. The reaction mixture was stirred for 15 min, and 1-(chloromethyl)-4-methoxybenzene (0.533 mL, 3.93 mmol) was added. The reaction was stirred for 45 min, then heated at 75° C. for 1.5 h. The reaction was quenched with half saturated NH4Cl solution and extracted with EtOAc 3×. The organic layers were combined, dried over Mg2SO4, filtered and concentrated. The crude material was purified by flash column chromatography, eluting with 0%-40% EtOAc/Hex. The desired fractions were concentrated to yield tert-butyl methyl (5-bromo-4-chloro-1,3-phenylene)bis(4-methoxybenzylcarbamate) (953.4 mg).
Reaction SMILES: C([Li])CCC.CC(C)=O.C(=O)=O.Br[C:14]1[CH:32]=[CH:31][C:17]([N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.C(O[B:37]1[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1)(C)C>C1COCC1>[C:19]1([N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[CH:31]=[CH:32][C:14]([B:37]3[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]3)=[CH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccccc3)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
Following the general procedure of arylboronic ester synthesis as reported in Ranger et al., Chem. Commun. 1597-1598 (1997), incorporated herein by reference, n-butyllithium was added dropwise via syringe to a −78° C. (acetone-dry ice cooling bath) solution of 4-bromo-N,N-diphenylaniline (24 g, 0.074 mole) in 175 ml dry THF. Stirring was continued at −78° C. for an hour and then at −50° C. for an hour. The mixture was cooled to −78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.22 g, 0.0925 mole) added via syringe in one portion. The temperature was maintained at −78° C. for three hours. The cooling bath was removed and the reaction left to warm to room temperature while standing for 12 hours. The reaction mixture was poured into saturated ammonium acetate and extracted with ether. The ether layer was dried over magnesium sulfate and concentrated to give a viscous oil. Purification by column chromatography (silica gel eluting with hexane:toluene mixtures of increasing gradient from 100% hexane to 40% hexane) gave N,N-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as an oil (19.9 g, 72.8% yield), which slowly crystallized to a solid on standing.
Reaction SMILES: C([O:8][C:9](=O)[NH:10][C:11]1[S:15][C:14]2[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:13]=2[CH:12]=1)C1C=CC=CC=1.[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1>O1CCOCC1>[CH3:21][O:20][C:19]1[C:13]2[CH:12]=[C:11]([NH:10][C:9]([N:29]3[CH2:34][CH2:33][S:32][CH2:31][CH2:30]3)=[O:8])[S:15][C:14]=2[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Reactant: C1CSCCN1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCSCC3)cc12
Yield: 47.7 %

Procedure:
A stirred solution of (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester (200 mg, 0.513 mmol) in dioxane (5 ml) was heated with thiomorpholine (10 eq., 5.13 mmol) for 68 h at reflux under argon. After cooling the reaction the solvents were evaporated and the residue was chromatographed over silica gel eluting with heptane/EtOAc (1:2). The product fractions were then combined, evaporated and dried under vacuum at 60° C. to afford the pure title product (94 mg, 47% yield) as a light brown solid MS m/e=383.2 (M−H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([S:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=NS(=O)(=O)c1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and benzenesulfonyl chloride, there is obtained ethyl N-(phenylsulfonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 145.5°-149.5° C.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:3]=[C:2]1[NH:4][C:5](=[O:6])[CH:7]=[CH:8][N:1]1[C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:21]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=C=NCCCCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(NCCCCc1ccccc1)n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
Uracil (0.10 g, 0.89 mmol) was dissolved in dry pyridine (4.4 mL). DMAP (0.12 g, 0.96 mmol) was added and the reaction mixture was stirred under nitrogen atmosphere at room temperature for 30 min. 4-Phenyl butyl isocyanate (0.27 mL, 1.60 mmol, 1.8 equiv) was then added and the resulting mixture was stirred for 12 hrs. The solvent was evaporated under reduced pressure and the crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc from 50:50 to 30:70) to afford the title compound (0.10 g, 59%) as white powder. 1H NMR (400 MHz, CDCl3): δ 1.59-1.82 (m, 4H), 2.66 (t, J=7.2 Hz, 2H), 3.29-3.60 (m, 2H), 5.89 (d, J=8.5 Hz, 1H), 7.11-7.22 (m, 3H), 723-734 (m, 2H), 8.41 (d, J=8, 5 Hz, 1H), 8.66 (s, 1H), 9.06 (t, J=5.7 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 28.69, 28.92, 35.56, 41.23, 77.16, 104.01, 126.06, 128.53, 139.08, 141.95, 149.84, 151.51, 162.30 MS (ESI) m/z: 310 [M-N]−.
Reaction SMILES: ClC1C=CC(C2C([C:12]3C=C[C:19]4[C:14](=[CH:15][CH:16]=[C:17](C(O)=O)[CH:18]=4)[N:13]=3)=CC(OC)=CC=2)=CC=1.C[N:30](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:30]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:13][CH:12]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(C(=O)O)ccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 525c (0.38 g, 0.97 mmol) was reacted with HBTU (0.444 g, 1.2 mmol) in anhydrous DMF (5 mL) in the presence of DIEA (0.41 mL, 2.35 mmol) for 30 min. The mixture was then transferred to a suspension of amine-resin in DMF (5 mL). The reaction mixture was shaken at room temperature overnight. The solution was drained and the resin was washed with DMF (5 mL×5), MeOH (5 mL×5), and CH2Cl2 (5 mL×5). The resin was dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1Br.C(N(CC)CC)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[CH:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:30]#[C:29][C:26]1[CH:25]=[CH:24][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccncc1Br
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccncc1C#Cc1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromo-isonicotinic acid methyl ester (648 mg, 3.00 mmol) in DMF (6 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (210 mg, 0.30 mmol), copper(I) iodide (17.1 mg, 0.090 mmol), triethylamine (1.25 ml, 9.00 mmol) and 1-tert-butyl-4-ethynyl-benzene (570 mg, 3.60 mmol). The resulting dark brown solution is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 3 hours. The reaction mixture is allowed to cool to room temperature and reduced in volume under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-tert-butyl-phenylethynyl)-isonicotinic acid methyl ester as brown oil; HPLC/MS 2.28 min (A), [M+H] 294.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:14]1([C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([CH:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)=[CH:21][CH:22]=3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Product: CC(C)N1CCC(c2noc(-c3ccc(C4CCCCC4)cc3)n2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and 4-cyclohexylbenzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(OCC)OCC
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Product: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Temperature: 90 °C
Yield: 94.9 %

Procedure:
A mixture of 4-fluoro-3-phenoxybenzyl bromide (28.1 g, 100 mmol) and triethyl phosphite (18.27 g, 110 mmol) is heated at 90° C. for 30 minutes while allowing some low boiling materials to distill off. The resultant mixture is heated at 140° C. for 3.5 hours and distilled at 120° C./2 mmHg to give the title product as a syrup (32.1 g, 95% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=C.[O:13]=[O+][O-]>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:13]
Reactant: C=Cc1ccc([N+](=O)[O-])cc1C
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1C=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
2Bromo-5-nitrotoluene (1.0 g, 4.54 mmol) and vinyltributyl tin (1.59 g, 4.99 mmol) were dissolved in toluene (25 mL) under argon. Palladium dibenzylidene acetone (4.15 g, 0.455 mmol) and triphenylphosphine (488 mg, 1.86 mmol) was added and the reaction refluxed overnight. The solvent was evaporated and the residue dissolved in 200 mL of methylene chloride and washed with 10% ammonium hydroxide, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography heptane-methylene chlolride 1:1) to yield 726 mg of 2-methyl-4-nitrostyrene. 2-methyl-4-nitrostyrene (700 mg, 4.5 mmol) was dissolved in methylene chloride (20 mL) and cooled to −78° C., and treated with ozone until a blue color remained, after 5 minutes the excess ozone was removed by passing a stream of oxygen through the solution. Dimethyl sulfide (1 mL) was added and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography to yield 580 mg of the 2-methyl-4-nitrobenzaldehyde. 2-Methyl-4-nitrobenzaldehyde (570 mg, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) were suspended in methanol. Tosylmethylisocyanide (674 mg, 3.45 mmol) was added and the reaction mixture refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 710 mg (94%) of 5-(4-nitro-2-methylphenyl)oxazole. 5-(4-Nitro-2-methylphenyl)oxazole was dissolved in methanol (100 mL) and 10% palladium on carbon 200 mg was wetted with water and added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and 560 mg of 5-(4-amino-2-methylphenyl)oxazole was isolated in 92% purity by HPLC method A. Mass spectrum M+H+=175.1, 1H 400 MHz NMR (CDCl3): δ7.88 (s, 1H), 7.45 (m, 1H), 7.08 (s, 1H), 6.60 m(m, 2H), 2.38 (s, 3H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:5]1=2)=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][C@H:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[C:19]([C:23]([F:26])([F:24])[F:25])[C:20]([CH3:22])=[CH:21][C:5]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N
Yield: 97 %

Procedure:
Shake a mixture of (S)-tert-butyl 5-azido-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (1.44 g, 3.89 mmol) and 5% palladium on charcoal (0.15 g, 50% wet) in methanol (50 mL) under 20 psi of hydrogen in a Parr bottle at room temperature for 12 h. Filter the mixture through Celite® and remove the solvents under reduced pressure to provide the title compound as a colorless oil (1.30 g, >99%), which is used in the next step without further purification. APCI MS m/z 344 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[CH2:21]=[C:22]1O[C:24](=[O:25])[CH2:23]1.C1(C=CC(O)=CC=1)O>ClC(Cl)C>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:21])[NH:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Agent: Oc1ccc(O)cc1
Solvent: CC(Cl)Cl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A solution of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (3.0 g, 10.6 mmol), diketene (1.2 ml, 15.9 mmol), hydroquinone (50 mg, 0.45 mmol) and dichloroethane (100 ml) was heated at reflux for 36 hours. After cooling to room temperature, the solution was washed with water, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate-toluene followed by 50% ethyl acetate-toluene) to provide (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (1.45 g, 39% yield) followed by (R)-3-(5-acetoxyhexyl)-1,5-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (1.26 g, 34% yield). 1H NMR (300 MHz, CDCl3) δ 1.17 (d, 3H), 1.28-1.67 (m, 6H), 1.99 (s, 3H), 2.67 (s, 3H), 3.59 (s, 3H), 3.95 (t, 2H), 4.85 (sextet, 1H), 6.23 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.65, 21.16, 22.58, 22.74, 27.31, 29.87, 35.25, 41.34, 70.88,100.16, 109.56, 150.05, 150.49, 156.07,160.41, 164.03,171.07.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCN(c1ccc(O)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.13 h
Yield: 90.6 %

Procedure:
4-[(4-hydroxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (In, 1.18 g, 3.26 mmol) was dissolved in DMF (7 mL), treated with NaH (0.26 g, 6.52 mmol, 60% dispersion in mineral oil), and stirred for 8 minutes. 4-Fluorobenzyl methanesulfonate (Ie, 0.93 g, 4.56 mmol) was added and the reaction was stirred for 5 minutes, then diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate solution and with brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 4:1 hexane/EtOAc to give 1.39 g (91%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.O[N:29]1[C:33]2C=C[CH:36]=[CH:37][C:32]=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(N)CCC>C1COCC1>[CH2:33]([NH:29][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([C:18]#[C:17][Se:16][C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:14])([CH3:15])[C:5]=3[CH:4]=2)=[N:20][CH:21]=1)[CH2:32][CH2:37][CH3:36]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(C#C[Se]c2cc3c(cc2C)C(C)(C)CCC3(C)C)nc1

Procedure:
In a manner similar to that of Example 10, 300 mg (0.72 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinic acid are reacted with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 63.5 mg (0.87 mmol) of butylamine in 20 ml of THF. After purification on a column of silica (ethyl acetate 20/heptane 80), 60 mg (17%) of a yellow solid are obtained. m.p.=172° C.