Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Brc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3ccc(Br)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 47.5 %

Procedure:
290 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 200 mg of 5-bromoisoindoline, 290 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 220 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([Cl:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:15])[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:7]=1
Reactant: CCOC(=O)Cc1c(Cl)nc(Cl)nc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1c(Cl)nc(Cl)nc1NCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(2,4,6-trichloropyrimidin-5-yl)acetate (from Intermediate A1, 200 mg, 0.74 mmol) in N,N′-dimethylformamide (5 mL) was added (4-methoxyphenyl)methanamine (112 mg, 0.82 mmol) and N,N′-diisopropylethylamine (115 mg, 0.89 mmol). The resulting mixture was stirred at 60° C. for 1 hour, quenched by water and then extracted with ethyl acetate. The organic phases were combined, washed by diluted hydrochloric acid (1 N), water and brine, dried over anhydrous sodium sulfate, evaporated and purified by silica gel chromatography to afford the product ethyl 2-(2,4-dichloro-6-(4-methoxybenzylamino)pyrimidin-5-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.26-7.28 (m, 2H), 6.88-6.90 (dd, 2H, J=2.0 Hz, 6.4 Hz), 6.15 (s, 1H), 4.60-4.62 (d, 2H, J=5.2 Hz), 4.11-4.16 (q, 2H, J=7.2 Hz), 3.81 (s, 3H), 3.60 (s, 2H), 1.21-1.26 (t, 3H, J=6.4 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 1.98 g (5 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 1.16 g (6.25 mmol) of tert-butyl 1-piperazinecarboxylate, and 1.29 g (10 mmol) of DIPEA in 100 mL of THF was stirred at room temperature for 1 hr, and the solution was concentrated under vacuum. The residue was diluted with water (100 mL) containing 1 mL of acetic acid. The resulting precipitate was collected, washed with water, and dried to give 2.71 g (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: mp (MeOH) 221-223° C.; 1H NMR (CDCl3) δ 7.88 (dd, J=8.4, 0.6 Hz, 1H), 7.47 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 3.87 (m, 8H), 3.78 (m, 4H), 3.53 (m, 4H), 1.50 (s, 9H); Anal. Calcd. for C25H32F2N8O4: C, 54.9; H, 5.9; N, 20.5. Found: C, 54.9; H, 5.9; N, 20.5%.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15]O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C(Cl)Cl.C1C=CC=CC=1>[Cl:19][CH2:15][C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: O=S(Cl)Cl
Reactant: OCc1c2ccccc2cc2ccccc12
Solvent: ClCCl
Solvent: c1ccccc1
Product: ClCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 10 h
Yield: 94.1 %

Procedure:
To a suspension of 9-anthracenemethanol (50 g, 0.24 mole) in methylene chloride (50 ml), a solution of thionyl chloride (32.3 g, 0.27 mole) in benzene (300 ml) was added, and reacted with stirring for 10 hours under reflux. The reaction mixture was poured into ice-water (500 ml). An organic layer separated was washed with H2O (100 ml×3), dried over anhydrous MgSO4 and evaporated to give 51.2 g of 9-chloromethylanthracene as residual crude orange yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc([N+](=O)[O-])ccc2Cl)n1
Temperature: 150 °C
Yield: 67.6 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-5-nitrobenzoyl chloride (0.086 g, 0.390 mmol) and triethylamine (0.5 mL, 6.81 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.051 g (68% yield) of pure product: MS (ES) m/z 489 (M+).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:29][CH:30]([O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)[CH2:31][CH2:32][CH3:33]>CCCCCC.O1CCCC1>[CH3:7][O:8][CH:9]=[CH:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH:30]([CH3:29])[CH2:31][CH2:32][CH3:33])=[CH:36][CH:37]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(C)Oc1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC(C)Oc1ccc(C=COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing butyllithium dissolved in hexane was added to a solution containing 120 g of methoxymethyltriphenylphosphonium bromide dissolved in tetrahydrofuran (THF), in an atmosphere of argon, and the mixture was stirred for one hour at room temperature. A solution of the compound (30) dissolved in THF was added thereto and stirring was continued for two hours. The reaction solution was washed with water, was dried over magnesium sulfate, and was then concentrated. The residue was purified by column chromatography to obtain 1-(2-methoxyethenyl)-4-(1-methylbutyloxy)benzene (31).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[C@@H:6]([NH:15][C:16]([C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:20][C:19]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])=[O:17])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CO>[OH:4][CH2:5][C@@H:6]([NH:15][C:16]([C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:20][C:19]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])=[O:17])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)[C@H](CCN1CCCCC1)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H](CO)CCN3CCCCC3)cc21
Temperature: 50 °C
Yield: 43.3 %

Procedure:
Sodium borohydride (0.012 g, 0.31 mmol) was added portion-wise to a heated (50° C.) solution of (S)-2-{[5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-piperidin-1-yl-butyric acid methyl ester (0.022 g, 0.042 mmol) in MeOH. The reaction mixture was stirred at 50° C. until HPLC analysis showed consumption of the starting material. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and 1N HCl. The organics were extracted with 1N HCl until the organic layer contained no product by HPLC analysis. The aqueous solution was basified to pH 14 with NaOH and then extracted with dichloromethane several times. The combined organics were dried over MgSO4 and concentrated under reduced pressure to afford 9.1 mg of oil (44% yield). MS (APCI+) m/z 501 (M+1) detected.
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[N:16]=[C:15]([F:17])[CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:22]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[CH2:23].CCN(C(C)C)C(C)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>[CH2:18]([N:6]1[C:5]2[N:20]=[CH:21][C:2]([CH2:23][CH2:22][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:3][C:4]=2[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[CH:14][C:15]([F:17])=[N:16][C:7]1=2)[CH3:19]
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(F)nc21
Reactant: C=Cc1ccc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1c2ncc(CCc3ccc4ccccc4c3)cc2C(=O)N(C)c2ccc(F)nc21

Procedure:
8-Bromo-2-fluoro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (35 mg, 0.10 mmol) was coupled with 2-vinylnaphthalene in the presence of bis(triphenylphosphine)palladium(II) chloride and (i-Pr)2NEt as described in example 1h. The product was hydrogenated as described in example 3b. Purification by flash chromatography (elution with ethyl acetate-hexanes) and recrystallization (diethyl ether-hexanes) afforded 20 mg of the title compound as white crystals, m.p. 112°-114° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:7][CH2:6][N:5]([S:8](Cl)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[C@H:13]1([NH:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:33])[CH:29]=3)[N:24]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[C@H:13]1([NH:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH:33][S:8]([N:5]4[CH2:6][CH2:7][S:2](=[O:12])(=[O:1])[CH2:3][CH2:4]4)(=[O:10])=[O:9])[CH:29]=3)[N:24]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: O=S1(=O)CCN(S(=O)(=O)Cl)CC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=S1(=O)CCN(S(=O)(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from 1,1-dioxo-thiomorpholine-4-sulfonyl chloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=473.7 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].N1C=CC=CC=1>[Cu]Cl.ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20])=[O:4]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl[Cu]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COC(=O)c1cccc(ON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 46 %

Procedure:
3-Methoxycarbonylphenylboronic acid was subjected to similar coupling procedures with NHP as outlined above (method 1). A 100 mL round bottom flask was charged with N-hydroxyphthalimide (2.19 g, 13.4 mmol), copper (I) chloride (1.34 g, 13.5 mmol), freshly activated 4 Å molecular sieves (˜5 g), and 3-methoxycarbonylphenylboronic acid (4.79 g, 26.6 mmol). 1,2-Dichloroethane (60 mL) was added followed by pyridine (1.20 mL, 14.8 mmol), and the reaction suspension was stirred in an air atmosphere at room temperature. After 4 days, the mixture was adsorbed onto silica gel and concentrated to a powder. Flash chromatographic purification over silica (33-50% gradient EtOAc in hexanes) afforded 13 as a white solid (1.85 g, 46%). 1H-NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 7.38-7.41 (ddd, J=1.0, 2.5, 8.3 Hz, 1H), 7.44 (t, J=8.3 Hz, 1H), 7.78 (dd, J=1.0, 2.5 Hz, 1H), 7.82-7.86 (m, 3H), 7.92-7.96 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 52.5, 115.0, 119.3, 124.3, 125.9, 129.0, 130.0, 132.1, 135.2, 159.0, 163.0, 166.2; ESI-MS 298 m/z [MH]+, C16H12NO5 requires 298.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH3:15])[C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][C:20]([NH2:22])=[NH:21].C([O-])([O-])=O.[Cs+].[Cs+].O>CC1OCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[C:10]([CH:11]([CH3:13])[CH3:12])[N:22]=[C:20]([NH:19][CH3:18])[N:21]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)C(C)C(=O)c1ccc(F)cc1
Reactant: CNC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC1CCCO1
Solvent: O
Product: CNc1nc(-c2ccc(F)cc2)c(C)c(C(C)C)n1
Temperature: 40 °C
Reaction time: 10 h

Procedure:
A mixture of 1-(4-fluorophenyl)-2,4-dimethylpentane-1,3-dione (MDK, 1.00 g, 4.5 mmol), N-methyl guanidine hydrochloride salt (0.49 g, 4.5 mmol) and Cs2CO3 (2.61 g, 8.0 mmol) in MeTHF (10 mL) was stirred at 40° C. for 10 h. The resulting suspension was cooled down to room temperature. Water (10 mL) and MeTHF (10 mL) were added. Layers were separated and the water layer was back-extracted with MeTHF (10 mL). The combined MeTHF fractions were washed with brine (20 mL) and dried over magnesium sulphate. Then, approximately 90% of the solvent was evaporated under reduced pressure and methanol (5 mL) was added to the resulting oily residue. White crystalline precipitate was collected by filtration, washed with ice-cold methanol (5 mL) and dried to afford the pyrimidine derivative CMDK (1.1 g, 92%) as pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH:12](Br)[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2].C(#N)C.[N+]1([O-:27])C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[O:27])[C:13]([O:15][CH3:16])=[O:14])[N:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1nc(C(Br)C(=O)OC)ns1
Reactant: [O-][n+]1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Nc1nc(C(=O)C(=O)OC)ns1
Yield: 93.6 %

Procedure:
Into a 1 L round bottom flask equipped with mechanical stirring and reflux condenser was charged methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)-bromoacetate (50.0 g, 0.154 mol, 1.0 eq.) followed by acetonitrile (500 mL). To the clear light yellow solution was charged pyridine N-oxide (37.0 g, 0.385 mol, 2.5 eq) and the reaction mixture was heated to reflux and maintained there for three hours until reaction completion was determined by proton NMR analysis. The solution was cooled and the acetonitrile was removed by rotary evaporation to give a thin yellow oil. The oil was dissolved in dichloromethane (500 mL) and the organic was washed once with brine (1×200 mL). The brine solution was extracted several times with dichloromethane (5×100 mL) and the organic layers were combined and dried with sodium sulfate, filtered and the solvent evaporated to give a clear slightly yellow oil which solidified upon standing at room temperature. The solid was dried under high vacuum to give 37.36 grams of the title compound. 1H NMR (CDCl3) δ 1.40 (t, 3H); 4.06 (s, 3H); 4.46 (q, 2H).
Reaction SMILES: [C:1]([C@@:6]12[N:13]([CH3:14])[C@@H:10]([CH2:11][CH2:12]1)[C@H:9]([N:15]=[N+]=[N-])[CH2:8][CH2:7]2)([O:3][CH2:4][CH3:5])=[O:2].[H][H]>[Pd].C(O)C>[C:1]([C@@:6]12[N:13]([CH3:14])[C@@H:10]([CH2:11][CH2:12]1)[C@H:9]([NH2:15])[CH2:8][CH2:7]2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CCOC(=O)[C@]12CC[C@@H](N=[N+]=[N-])[C@H](CC1)N2C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@]12CC[C@@H](N)[C@H](CC1)N2C
Yield: 112.2 %

Procedure:
A mixture of 4.5 g of the 1-carbethoxy-4β-azidotropane, 300 mL of ethanol and 1 g of 10% palladium on carbon was shaken under 1 atm of hydrogen (balloon) for 18 h. The mixture was filtered and concentrated under reduced pressure. Drying under vacuum gave 4.5 g of 1-carbethoxy-4β-aminotropane as a gum: 1H NMR (400 MHz, CDCl3) 4.3 (br m, 2H), 4.18 (q, 2H), 3.15 (m, 1H), 1.95 (m, 2H), 1.82 (m, 2H), 1.7 (m, 2H), 1.4 (m, 2H), 1.30 (t, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1)(=[O:17])[CH3:16]
Reactant: CC1CN(Cc2ccccc2)CC1N
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NC1CN(Cc2ccccc2)CC1C

Procedure:
3-Amino-1-benzyl-4-methylpyrrolidine (Japanese Laid-Open Patent Publication No. 22699/1980) was allowed to react with acetic anhydride to give 3-acetylamino-1-benzyl-4-methylpyrrolidine; IR 3300, 1650 cm-1. This compound was hydrogenated catalytically in the presence of 5% palladium-carbon to give 3-acetylamino-4-methylpyrrolidine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH2:15])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.I[CH2:17][CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH2:4][CH2:3][CH2:2][CH3:14])[CH2:10][CH2:9][CH2:8][CH3:7])=[CH:10][C:11]=3[C:12]2([CH2:13][CH2:5][CH2:6][CH3:11])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCI
Product: CCCCN(CCCC)c1ccc2c(c1)C(CCCC)(CCCC)c1cc(Br)ccc1-2

Procedure:
As shown in Scheme 2, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21). Then, (7-bromo-9,9-dibutyl-9H-fluoren-2-yl)-dibutylamine (21) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a). Finally, in acetonitrile, 5-(9,9-Dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (22a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-Cyano-3-[5-(9,9-dibutyl-7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (23a).
Reaction SMILES: Br.[CH2:2]([N:9]([CH2:21][C@H:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Br:32])[CH:28]=2)[O:23]1)[CH2:10][C@H:11]([OH:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>ClCCl>[Br:32][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[O:23][C@@H:22]([CH2:21][N:9]([CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:10][C@H:11]([O:20][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:31][CH2:30]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(Br)ccc2O1
Agent: Br
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(Br)ccc2O1
Reaction time: 15 h

Procedure:
The compound of Example 86 (5.0 g, 10.4 mmol) and imidazole (1.06 g, 15.6 mmol, 1.5 eq.) were dissolved in dichloromethane. tert-Butyldimethylsilylchloride (2.03 g, 13.5 mmol, 1,3 eq.) was added, and the mixture was stirred for 15 hours. Solids were removed by filtration, and the filtrate was concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel eluted with 90:10 hexanes/ethyl acetate. The title compound was obtained as a yellow oil (5.3 g, 85%): 1H NMR (300 MHz, CDCl3) δ7.30-7.26 (m, 5 H), 7.25-7.20 (m, 3 H), 7.09 (s, 1 H), 6.91 (t, 1 H), 6.80 (d, 2 H), 6.63 (d, 1 H), 4.07-4.00 (m, 2 H), 3.81 (s, 2 H), 3.73 (dd, 1 H), 2.88-2.77 (m, 2 H), 2.64-2.56 (m, 4 H), 1.96-1.90 (m, 1 H), 1.61-1.55 (m, 1 H), 0.85 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H); MS m/z 596.3 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[C:19](=[O:30])[CH2:18][S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[C:19](=[O:30])[CH2:18][S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C2SCC(=O)N2c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C2SCC(=O)N2c2ccc(N)cc2)cc(C(C)(C)C)c1O
Temperature: 70 °C
Yield: 69 %

Procedure:
1.3 g of 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone (3 mmol) and 3.4 g (15 mmol) of dihydrated tin chloride are dissolved in 25 ml of ethyl acetate. The reaction is maintained for 2 hours at 70° C. After the mixture has returned to ambient temperature, it is poured into a saturated solution of sodium hydrogen carbonate. The expected product is then extracted from the organic phase then it is washed 3 times with 10 ml of water. The 2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinone is purified on silica gel in an ethyl acetate/heptane mixture (1/1) and is obtained in the form of a beige oil with a yield of 69% (0.82 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[C:25]([CH3:38])[C:24]=1[OH:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.ClCCl>>[OH:39][C:24]1[C:25]([CH3:38])=[CH:26][C:27]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)=[CH:28][C:23]=1[CH3:22]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1O
Yield: 82.1 %

Procedure:
Nitrogen was bubbled through a mixture of tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate (5.80 g, 0.0175 mol), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.82 g, 0.0194 mol) and potassium carbonate (7.26 g, 0.0525 mol) in N,N-dimethylformamide (50.0 mL, 0.646 mol) for 10 min. To the reaction mixture was then added [1, F-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (0.8 g, 0.001 mol). The resultant mixture was heated at at 80 Celsius overnight. After quenched with water, the mixture was neutralized with 1N HCl, extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated to dry. The residue was applied on column, eluting with 0 to 50% EtOAc in hexane, to yield the desired product (4.36 g, 82.09%). MS (ESI): (M-Boc+2) 204.0.