Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][CH:21]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH:24]([CH3:26])[CH3:25])[CH3:22]>C(#N)C>[CH3:26][CH:24]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH:21]([CH3:20])[CH3:22])[CH3:25]
Reactant: CC(C)N(CC1CCCCN1CCN)C(C)C
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CC(C)N(CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21)C(C)C
Yield: 34 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[[bis(methylethyl)amino]methyl]-piperidin-l-yl]ethanamine in a yield of 34% of theory. Colourless crystals, m.p. 181°-182° C. (acetonitrile using activated charcoal).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2([CH2:29][NH:30][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)c3ccc4ccccc4n3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 37.6 %

Procedure:
Quinoline-2-carboxylic acid (0.502 g, 2.90 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (0.678 g, 2.90 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (894 μL, 6.38 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.54 g, 4.06 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.426 g, 1.09 mmol, 37.7%). ESI-MS m/z calc. 390.2, found 391.2 (M+1)+. Retention time of 3.94 minutes. 1H NMR (400 MHz, CD3CN) δ 1.69-2.15 (m, 8H), 3.62 (d, J=30.1 Hz, 2H), 3.77 (s, 3H), 3.90 (s, 3H), 6.91-7.03 (m, 3H), 7.69 (t, J=8.1 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.99 (t, J=8.8 Hz, 2H), 8.08 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.44 (d, J=8.5 Hz, 1H)
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.[C:10]([CH2:13][N:14]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][N:20]([CH2:26][C:27]([OH:29])=[O:28])[CH2:19][CH2:18][N:17]([CH2:30][C:31]([OH:33])=[O:32])[CH2:16][CH2:15]1)([OH:12])=[O:11].[OH-].[K+]>O1CCOCC1.O>[OH:4][CH:2]([CH2:1][O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][N:23]1[CH2:24][CH2:25][N:14]([CH2:13][C:10]([OH:12])=[O:11])[CH2:15][CH2:16][N:17]([CH2:30][C:31]([OH:33])=[O:32])[CH2:18][CH2:19][N:20]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:22]1
Reactant: CC(C)(C)OCC1CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OCC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
11.27 g (86.58 mmol) of glycidyl-tert-butyl ether and 10 g (28.86 mmol) of 1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6 N potassium hydroxide solution. It is stirred for 24 hours at 70° C. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl-methyl ether. The aqueous solution is adjusted to pH 1 with 5 N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent =gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.38 g (71% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:22]1([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:6]#[N:7])=[C:8]([O:28][CH2:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:9]=1
Reactant: N#Cc1c(F)cc(Br)cc1F
Reactant: OCC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(Br)cc1OCC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a stirred solution of the above benzonitrile intermediate (7.5 g, 34.4 mmol) in dry THF (50 mL) at 0° C. was added a mixture of sodium bis(trimethylsilyl)amide (1.0 M, 34 mL, 34 mmol) and cyclopentanemethanol (3.4 g, 34 mmol) in THF (100 mL). The reaction was allowed to warm up to room temperature and stirred overnight. Water (50 mL) was added to the reaction and the product was extracted by CH2Cl2 (2×50 mL). The solvent was washed with brine and dried over Na2SO4. The solvent was removed to give 4-bromo-2-cyclopentylmethoxy-6-fluorobenzonitrile (4.5 g, 43.9%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[C:14](=[O:29])[CH2:15][CH:16]([CH:23]2[CH2:28][CH2:27][CH2:26][S:25][CH2:24]2)[CH2:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])(=O)[CH3:11]>C(O)C>[C:20]([O:19][C:18]1[CH2:17][CH:16]([CH:23]2[CH2:28][CH2:27][CH2:26][S:25][CH2:24]2)[CH2:15][C:14](=[O:29])[C:13]=1[C:10](=[N:9][O:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])(=[O:22])[CH3:21]
Reactant: NOCc1ccc(Cl)s1
Reactant: CC(=O)OC1=C(C(C)=O)C(=O)CC(C2CCCSC2)C1
Solvent: CCO
Product: CC(=O)OC1=C(C(C)=NOCc2ccc(Cl)s2)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.34 g (2.0 mmol) of (5-chlorothien-2-yl)methoxyamine is added to a stirred solution of 0.59 g (2.0 mmol) of 2-acetyl-3-acetyloxy-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohex-2-en-1-one in 10 ml of absolute ethanol. After stirring overnight at room temperature, the reaction mixture is concentrated under reduced pressure. The resulting residue is diluted with 25 ml of dichloromethane and washed twice with 10 ml of saturated sodium chloride solution. The washed extract is then dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The product can then be purified by column chromatography employing tetrahydrofuran-hexane (1:2 by volume) as eluent to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[CH2:11][C:12]([NH:14][C:15]1[C:16]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[N:17][C:18]([CH3:27])=[CH:19][C:20]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:31][C:30]([F:33])([F:32])[CH2:29][O:28][C:16]1[C:15]([NH:14][C:12](=[O:13])[CH2:11][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[C:20]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[C:18]([CH3:27])[N:17]=1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
1-(2-Hydroxyethyl)piperazine (1.95 g, 15.0 mmol) and 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (5.00 g, 12.5 mmol) were dissolved in acetonitrile (30 mL). Potassium carbonate (2.25 g, 16.3 mmol) was added to the solution, followed by stirring for 5 hours at room temperature. The reaction mixture was dilluted with water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was purified through silica gel column chromatography (eluent: ammonia-saturated methanol/chloroform=1/20), to thereby yield 5.40 g of N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide as colorless crystals (yield 91%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[F:14][C:15]1[CH:22]=[C:21]([I:23])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C(OCC)(=O)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([I:23])=[CH:22][C:15]=2[F:14])=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: NCc1ccc(I)cc1F
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(I)cc1F)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A mixture of 4-bromo-2-nitrobenzoic acid (3.0 g) and N,N'-carbonyldiimidazole (2.37 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 4 hours. To this mixture was added a solution of 2-fluoro-4-iodobenzylamine (3.37 g) in tetrahydrofuran (10 ml), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed successively with water, aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed in vacuo and the crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-bromo-N-(2-fluoro-4-iodobenzyl)-2-nitrobenzamide (4.88 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[CH2:12](Br)[C:13]#[CH:14].O>O1CCCC1>[CH2:14]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7])[C:13]#[CH:12]
Reactant: C#CCBr
Reactant: COC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1cccc1C(=O)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3.302 g of methyl 1H-pyrrole-2-carboxylate were dissolved in 40 ml of tetrahydrofuran and then, at 0° C., 1.422 g of sodium hydride in suspension at 50% in vaseline oil were added. The mixture stirred for 1 hour at 20° C. and a solution of 2 ml of propargyl bromide in 10 ml of tetrahydrofuran was introduced dropwise. The mixture was stirred for 1 hour at 50° C. and after having added 5 ml of propargyl bromide, the reaction mixture was poured into water. The mixture was extracted with methylene chloride and the extracts were concentrated to dryness by distilling under reduced pressure. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (9-1) to obtain 2.993 g of methyl 1-(2-propynyl)-1H-pyrrol-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[C:14]=1[NH2:25].[C:26](OCC)(=[O:30])[C:27]([CH3:29])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:19]([C@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CCOC(=O)C(C)=O
Reactant: COC[C@@H](C)Nc1ncnc(-c2ccc(OC(F)(F)F)cc2Cl)c1N
Solvent: CCO
Product: COC[C@@H](C)n1c(=O)c(C)nc2c(-c3ccc(OC(F)(F)F)cc3Cl)ncnc21
Reaction time: 18 h

Procedure:
(R)-6-(2-Chloro-4-trifluoromethoxy-phenyl)-N4-(2-methoxy-1-methyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.53 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.59 ml, 5.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.0 mg of (R)-4-(2-chloro-4-trifluoromethoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 1067a). 1H NMR (300 MHz, CDCl3) δ ppm 9.02 (s, 1 H), 7.49 (d, J=8.42 Hz, 1 H), 7.39 (d, J=1.10 Hz, 1 H), 7.26 (dd, J=8.42, 1.10 Hz, 1 H), 5.95 (s, 1 H), 4.36 (t, J=9.52 Hz, 1 H), 3.68 (dd, J=10.07, 5.31 Hz, 1 H), 3.30 (s, 3 H), 2.48 (s, 3 H), 1.58 (d, J=6.96 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21])=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:30][O:29][C:22](=[O:28])[CH2:23][C:24]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[O:20][CH3:21])=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:27]
Reactant: COC(=O)CCC(C)=O
Reactant: COc1cc(C)ccc1C(=O)c1c(N)sc2c1CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1OC)CCCC3
Yield: 79.8 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-methoxy-4-methylphenyl)methanone (0.602 g; 2 mmol), methyl levulinate (0.282 mL; 2.2 mmol), chlorotrimethylsilane (1.02 mL; 8 mmol) in DMF (8 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.631 g (80%) of the title compound as a yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:32]=[CH:31][C:12]([O:13][C:14]3[N:22](COCC[Si](C)(C)C)[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:35]1[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[N:37]([CH2:44][CH3:45])[N:36]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:44]([N:37]1[C:38]2[C:39](=[N:40][CH:41]=[CH:42][CH:43]=2)[C:35]([C:9]2[CH:10]=[CH:11][C:12]([O:13][C:14]3[NH:22][C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]=3)=[CH:31][CH:32]=2)=[N:36]1)[CH3:45]
Reactant: CC1(C)OB(c2ccc(Oc3nc4cccnc4n3COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CCn1nc(Br)c2ncccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Yield: 118 %

Procedure:
A mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine (100 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (140 mg), Pd(PPh3)4 (7 mg), Na2CO3 (79 mg), DME (5 mL), and water (1 mL) was refluxed overnight under Ar atmosphere. The mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH3:20][N:21]([CH3:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:25]3[CH2:26][CH2:27][CH:22]([N:21]([CH3:28])[CH3:20])[CH2:23][CH2:24]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 24.4 %

Procedure:
The title compound of Example 2 (1.0 g, 3.40 mmol) was reacted with N,N-dimethyl-4-piperidinamine (0.48 g, 3.74 mmol) by the method of Example 4. Following chromatographic separation, 0.32 g of the title product was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[C:10]=3Br)=[CH:7][C:6]=1[F:24])(=[O:3])[CH3:2].N#N.C([Sn](CCCC)(CCCC)[C:32]([O:34][CH2:35][CH3:36])=[CH2:33])CCC>C1(C)C=CC=CC=1.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>[C:1]([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[C:10]=3[C:32]([O:34][CH2:35][CH3:36])=[CH2:33])=[CH:7][C:6]=1[F:24])(=[O:3])[CH3:2]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)cc1C2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: Cc1ccccc1
Product: C=C(OCC)C1=C2c3cc(F)c(NC(C)=O)cc3CC2(CCCC)CCC1=O
Temperature: 100 °C
Yield: 49 %

Procedure:
A partial solution of 7-(acetylamino)-4-bromo-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (495 mg, 1.26 mmol) in anhydrous toluene (6.3 mL) was purged with N2, treated with dichlorobis(triphenylphosphine)palladium(II) (177 mg, 0.25 mmol), purged with N2, and treated with tributyl(1-ethoxyvinyl)tin (0.600 mL, 1.9 mmol). The resulting mixture was stirred under a N2 atmosphere and heated in an oil bath at 100° C. for two hours. After cooling to room temperature, the mixture was filtered through a pad of silica gel, washing the product off with EtOAc. The filtrate and washings were evaporated under vacuum to an oil. The crude product was purified by flash chromatography on a Biotage 40S KP-Sil column, eluting with 4:1 hexanes-EtOAc (1 L) followed by 2:1 hexanes-EtOAc (1 L). The product containing fractions were concentrated under vacuum to afford 7-(acetylamino)-9a-butyl-4-(1-ethoxyvinyl)-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (238 mg, 49%) as a yellow foam.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][CH3:15])[NH:10][C:9]=2[C:8](=O)[NH:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].O>N1C=CC=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][CH3:15])[NH:10][C:9]=2[C:8](=[S:19])[NH:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)[nH]c(=O)c2[nH]c(CC)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: CCCCn1c(=O)[nH]c(=S)c2[nH]c(CC)nc21
Temperature: 25 °C

Procedure:
11.8 g (50 mM.) of 3-butyl-8-ethyl-xanthine (mp 304°-9° C., and 18.2 g (82 nM.) of phosphorus pentasulfide were refluxed in 170 ml of pyridine for 2 hrs. The solution was cooled to ambient temperature and treated slowly with 110 ml. of water (exothermic). The suspension was concentrated to 100 ml. in vacuo at 60° C., further diluted with 140 ml. of water, and concentrated again to about 120 ml. The crude product was collected and washed with ice water. The dried material (11.1 g.) was dissolved in about 100 ml. of chloroform, and the solution filtered through 55 g. of silicagel. The chloroform was evaporated and the residue crystallized from acetone-ether: 7.2 g. (57.5%) of 3-butyl-8-ethyl-6-thioxanthine, mp. 206°-7° C. From the mother liquor, a second crop of 2.1 g. (16.3%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.O.NN>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(Cl)ccc1N
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of Compound 35A (1 g) in methanol (30 mL) was added Raney-Ni (0.05 g) and the resulting mixture was cooled at 0-5° C.; 98% hydrazine hydrate (1.5 mL) was dropped in at the same temperature and the suspension stirred at room temperature for 2 h. The catalyst was filtered off and the solvents evaporated in vacuo. The crude was dissolved in dichloromethane (100 mL) and washed with water (60 mL); the organic layer was dried over sodium sulphate and evaporated to dryness affording 0.78 g (90%) of the title product as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[C:15]([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(-c2cccnc2F)cs1
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.5 %

Procedure:
A suspension of 4-bromothiophene-2-carbaldehyde (10.0 g), 2-fluoro-3-pyridineboronic acid (9.1 g), tetrakis(triphenylphosphine)palladium (0) (3.1 g) and sodium carbonate (13.7 g) in 1,2-dimethoxyethane (100 mL) and water (50 mL) was stirred at 80° C. for 20 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a pale-yellow solid (yield 5.8 g, yield 53%).