Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:6]1([NH:5][C:3](=[O:4])[CH2:2][N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
N-Chloroacetylaniline (0.5 g, 2.95 mmol), 1-(2-pyridinyl)piperazine (0.72 g, 4.42 mmol), and N,N-diisopropylethylamine (1.03 mL, 5.9 mmol) were combined in toluene and heated at reflux overnight. The mixture was allowed to cool to room temperature, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 60% ethyl acetate:hexanes) to provide 400 mg (46% yield) of the title compound as a hygroscopic white solid. 1H NMR (300 MHz, CDCl3) δ 2.60 (m, 4H), 3.18 (s, 2H), 3.55 (m, 4H), 6.65 (dd, 1H, J=12, 6 Hz), 6.85 (d, 1H, J=9 Hz), 7.05 (t, 1H, J=6 Hz), 7.3 (t, 2H, J=9 Hz), 7.51 (ddd, 1H, J=9, 7.5, 3 Hz) 7.68 (d, 2H, J=9 Hz) 8.1 (dd, 1H, J=6, 3 Hz) 9.75 (br s, 1H); MS (DCI/NH3) m/e 297 (M+H)+; Anal. calcd for C17H20N4O: C, 68.89; H, 6.80; N, 18.90. Found: C, 68.97; H, 6.87; N, 19.01.
Reaction SMILES: [Mg].CI.[CH2:4]([O:11][C:12]1[CH:21]=[CH:20]C(C(OC)=O)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+].C[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:27]([C:26]([OH:25])([CH3:29])[CH3:28])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(C)(C)C
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Under argon 6.63 g of magnesium (273 mmol) was suspended in 15 mL of tert-butyl methyl ether. A solution of 38.68 g of methyl iodide (273 mmol) in 145 mL of tert-butyl methyl ether was added during 45 minutes under stirring while maintaining the temperature at 40° C. Then stirring was continued at 40° C. for 1.5 hours and then the mixture was cooled to room temperature. A solution of 30.0 g of methyl 4-benzyloxybenzoate (124 mmol) in 120 mL of tetrahydrofuran was then added during 1 hour. The temperature was kept at 20° C. After complete addition, the reaction mixture was heated to 42° C. and stirred 3 hours at this temperature. After cooling to room temperature, the reaction mixture was poured into a mixture of 300 mL of 10% aqueous ammonium chloride and 100 g of ice and extracted with ethyl acetate. The organic phases were washed with water and saturated aqueous sodium bicarbonate, combined, dried and evaporated to give the crude product as an oil which partially crystallised. The product was dissolved at 25° C. in diethyl ether. When crystals started to separate the solution was cooled to 18° C. After 30 minutes hexane was added. The suspension was then stirred for 1 hour at 5° C. The crystalline 2-(4-benzyloxy-phenyl)-propan-2-ol was collected on a filter and washed with hexane.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCCC1O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCC2C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.8 %

Procedure:
A three-necked flask (500 cc) equipped with a mechanical stirrer was charged with 2-methylcyclopentyl alcohol (21.19, 0.210 mol) and p-toluenesulfonyl chloride (48.3 g, 0.252 mol), followed by the addition of pyridine (170 ml) under ice cooling to form a solution. The solution was stirred for 10 h as it was warmed gradually to room temperature. After completion of the reaction, the reaction mixture was poured into ice water and stirred thoroughly. Following extraction with ether (200 mL×3), the organic layers were washed with 2N HCl, water and saturated brine and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give 2-methylcyclopentyl p-toluenesulfonate as a colorless clear oil (49.7 9; yield=92.8%). 1H-NMR(CDCl3,TMS,ppm): δ0.85(3H,d,J=7.5Hz), 1.41-2.10(TH,m), 2.43(3H,s), 4.42 and 4.80(total 1H, each m), 7.33(2H,d,J=9.0Hz), 7.80(2H,d,J=9.0Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2].C(N(CC)CC)C.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[F:37])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([F:37])=[C:28]([F:27])[CH:29]=1)=[O:5])[CH3:2]
Reactant: CCCCNc1nc2n(c1C(=O)OCC)CCCC2
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(C(=O)c1ccc(F)c(F)c1)c1nc2n(c1C(=O)OCC)CCCC2
Temperature: 0 °C

Procedure:
Compound F (3.2 g, 12.1 mmol) and triethylamine (2.54 mL, 18.1 mmol, 1.5 eq.) were dissolved in DCM (70 mL) and the solution was cooled to 0° C. 3,4-difluorobenzoylchloride (1.66 mL, 13.3 mmol, 1.1 eq.) was added dropwise. After 90 minutes the reaction mixture was diluted with DCM (130 mL) and washed with 0.5 M KHSO4 in water (200 mL), saturated aqueous NaHCO3 solution (200 mL) and saturated aqueous NaCl solution (200 mL). The combined organic phases were dried over sodium sulphate and the solvent was removed under vacuum and the untreated product 2-[butyl-(3,4-difluoro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester was used directly in the next stage.
Reaction SMILES: O.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=O)[C:8]2[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:7]=2[O:6]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[OH2:6].[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:28])[C:8]2[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:7]=2[O:6]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=S
Reaction time: 1 h

Procedure:
To a suspension of 17.4 g (0.043 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diposphetane-2,4-disulfide in ~300 ml of toluene was added 20 g (0.078 mole) of 2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrate [1:1]. The mixture was heated to reflux for 3 hr and 4.0 g (0.01 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and heating was continued for 1 hr. After cooling, toluene was decanted off and washed with 3×100 ml 1N sodium hydroxide and 100 ml water. The organic layer was then extracted with 2×100 ml of 2N hydrochloric acid. The aqueous layer was made basic to litmus with conc. sodium hydroxide causing the product to precipitate out. Of the 25 g of crude collected, 2 g were recrystallized from diisopropyl ether to give pale yellow crystals, m.p. 80°-86° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[NH:21]1[CH2:29][CH2:28][CH2:27][CH:23]([C:24]([OH:26])=[O:25])[CH2:22]1.C([O-])([O-])=O.[K+].[K+].Cl>O.CN1CCCC1=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([N:21]2[CH2:29][CH2:28][CH2:27][CH:23]([C:24]([OH:26])=[O:25])[CH2:22]2)[CH:3]=1
Reactant: O=C(O)C1CCCNC1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(N2CCCC(C(=O)O)C2)n1
Temperature: 140 °C
Reaction time: 5 h
Yield: 47.4 %

Procedure:
In a tube is combined (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [200 mg, 0.6 mmol, Intermediate (44)], nipecotic acid (194 mg, 1.5 mmol), K2CO3 (249 mg, 1.8 mmol) and 1-methyl-2-pyrrolidinone (2.5 mL). The tube is sealed and heated to 140° C. and stirred for 5 hours. The mixture is allowed to cool to ambient temperature, stand for 12 hours, diluted with water (20 mL) and acidified using 3M HCl. A precipitate forms and is collected by filtration and dried under high vacuum to afford 1-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-piperidine-3-carboxylic acid [121 mg, 47%, Example 73] as a solid. LCMS RT=2.15 minutes, MS: 425 (M+H). IC50=0.8 nM
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[NH:4][CH:5]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:4]2[CH:5]=[N:1][N:2]=[C:3]2[C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=1
Reactant: c1cc(-c2nnc[nH]2)ccn1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cnnc2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.3 %

Procedure:
A mixture of 4-(4H-1,2,4-triazol-3-yl)pyridine (0.56 g, 3.8 mmol), PMBCl (0.66 g, 4.2 mmol), and K2CO3 (2.12 g, 15.3 mmol) in DMF (10 mL) was stirred for 4 h at room temperature. The reaction mixture was then diluted with water and extracted with DCM. The combined organic layers were washed with water three times, dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to give 4-(4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)pyridine (0.60 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[C:22]([C:23](Cl)([N:25]=[CH:26][N:27]=2)[NH2:24])=[N:21][CH2:20]1)(=[O:3])[CH3:2].N[C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>C(O)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH:24][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](N2CN=C3C2=NC=NC3(N)Cl)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1cccc(O)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Nc4cccc(O)c4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 24.8 %

Procedure:
To a solution of O2′,O3′,O5′-tri-acetyl-6-chloroadenosine (5.4 g) in absolute ethanol (30 mL) were added 3-aminophenol (4.28 g) and dry triethylamine (3.96 g), and the mixture was refluxed 8 h at 60° C. The solution was allowed to cool and was concentrated in vacuo and the residue was chromatographed (ethyl acetate:petroleumether=2:1) to give O2′,O3′,O5′-tri-acetyl-N6-(3-hydroxylphenyl)adenosine as a white solid (1.51 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O[C:7](=[O:19])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])C.[O-][Si]([O-])=O.[Mg+2]>C(O)C.C(Cl)Cl>[CH3:1][N:2]([CH3:3])[C:7](=[O:19])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: CNC
Reactant: CCOC(=O)CNc1ccncc1[N+](=O)[O-]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: ClCCl
Product: CN(C)C(=O)CNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Condensed dimethylamine (20 ml) was added in portions to a solution of crude N-(3-nitro-4-pyridinyl)glycine ethyl ester (4.0 g, 0.018 mole) in absolute ethanol (10 ml). The reaction was allowed to stir at ambient temperature over the weekend. The mixture was diluted with petroleum ether and the solid was collected by filtration. The solid 3-g was dissolved in tetrahydrofuran, filtered and diluted with isopropyl ether to produce a dark amorphous solid which was filtered off. The filtrate was further diluted with petroleum ether and placed in the freezer to produce a dark orange crystalline solid. The solid (2.5 g) was dissolved in methylene chloride, treated with Florisil.COPYRGT., and the filtrate was evaporated to a yellow solid, which was dried under high vacuum at 70° C. to give 1.8 g (45%), mp 142°-143° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[CH:23]=[CH:24][CH2:25]Br)#[N:19].CCOCC>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:25][CH:24]=[CH:23][C:22]3[CH:27]=[CH:28][CH:29]=[C:20]([C:18]#[N:19])[CH:21]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: N#Cc1cccc(C=CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cccc(C=CCN2CCc3nc(N)sc3CC2)c1
Yield: 48 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 3-cyano-cinnamyl bromide (melting point: 52°-55° C.) in anhydrous dimethylformamide for 2 hours at 20° C. Yield: 48% of theory, Melting point: 136°-140° C. (ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][NH2:13].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:13][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CN
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: Cl
Solvent: O
Product: CNc1cc(C(=O)O)cc(Cl)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (25 g, 130.2 mmol) in 52 mL water was added 60 mL of 40% methylamine in water. Reaction heated to reflux at 100° C. After 16 h, reaction was cooled to rt. Reaction was acidified with 1N HCl (200 mL) and extracted with EtOAc (300 mL×4). The combined organics were washed with brine (150 mL), dried over Mg2SO4, filtered, and concentrated in vacuo to give 24.2 g (100%) of 2-chloro-6-(methylamino)isonicotinic acid as a brown solid. LC/MS [M+H]+ 187.0.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[N:4][CH:3]=1.[NH3:18]>CO>[Br:1][C:2]1[C:7]([C:8]([NH2:18])=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[N:4][CH:3]=1
Reactant: N
Reactant: CCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Solvent: CO
Product: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of methyl 5-bromo-2-(3-ethylureido)isonicotinate (Intermediate 1, 56.22 g, 186.0 mmol) in 7N ammonia in methanol (1 L) was allowed to stir at room temperature in a sealed flask for 1½ d. The precipitate that formed was collected by filtration, rinsed with acetonitrile (500 mL), and then dried on the high vacuum pump overnight, yielding 50.8 g of a solid (95.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([Br:10])=[CH:8][N:7]=[C:6]([NH2:11])[CH:5]=1.C([O-])(O)=O.[Na+].Cl[CH2:19][CH:20]=O>CCO>[CH3:1][O:2][C:3]([C:4]1[C:9]([Br:10])=[CH:8][N:7]2[CH:19]=[CH:20][N:11]=[C:6]2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1cc(N)ncc1Br
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc2nccn2cc1Br
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A mixture of 2-amino-5-bromo-isonicotinic acid methyl ester (500 mg, 2.16 mmol), NaHCO3 (309 mg, 3.68 mmol) and chloracetaldehyde (1.16 mL, 9.8 mmol) in EtOH (15 mL) was vigorously stirred and refluxed for 14 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was suspended in AcOEt (100 mL). The organic fraction was washed with water (2×50 mL), then dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5-100% TBME) to yield the title compound (505 mg, 1.98 mmol, 91%). MS: 255 [M+1]+; HPLC: AtRet=0.58 TLC: RF 0.16 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH3:58])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=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>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][CH3:58])=[O:54])=[CH:48][CH:47]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
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: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, propyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:22][CH2:23][N:24]([C:2]3[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=3[N+:10]([O-:12])=[O:11])[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the 4-(4-fluoro-phenyl)-piperidine hydrochloride in N,N-dimethylformamide in the presence of N-ethyldiisopropylamine at room temperature to yield the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one as yellowish solid;
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:32]([C:34]1[C:35]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[N:36][CH:37]=[CH:38][N:39]=1)#[CH:33].C(N(CC)CC)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.[Cu]I.CN(C=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:35]1[C:34]([C:32]#[C:33][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:3]=2)=[N:39][CH:38]=[CH:37][N:36]=1)[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1nccnc1CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nccnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 51.1 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I43) (140 mg, 0.306 mmol), ethyl 2-(3-ethynylpyrazin-2-yl)acetate (I101) (64 mg, 0.34 mmol), bis(triphenylphosphine)palladium(II) chloride (11 mg, 5 mol %) and DMF (2 mL) were loaded into a microwave tube and degassed with a nitrogen for ten minutes. Copper(I) iodide (3 mg, 5 mol %) and triethylamine (0.192 mL, 1.38 mmol) were added under nitrogen and the resulting mixture heated under microwave irradiation (120° C./15 minutes). The cooled mixture was concentrated, and the residue evaporated onto silica gel. Chromatography (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I102) (95.5 mg, 52% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.47 (s, 1H), 8.87 (d, J=0.5 Hz, 1H), 8.76-8.71 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.15-3.99 (m, 6H), 2.80 (s, 2H), 2.70-2.63 (m, 1H), 1.80-1.70 (m, 2H), 1.55-1.44 (m, 2H), 1.42 (s, 9H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.73 min; m/z 633.1 [M+Na]+, 555.0 [M-tBu+2H]+, 511.1 [M-Boc+2H]+; m/z 609.1 [M−H]−.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:48]([C:51]#[N:52])[C:49]#[N:50])[O:34][C:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:38]([F:41])([F:40])[F:39])[C:36]=1[CH3:37])#[N:31]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:38]([F:41])([F:39])[F:40])[O:34][C:33](=[C:48]([C:51]#[N:52])[C:49]#[N:50])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
In 9 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 400 mg (1.02 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 360 mg (1.14 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 70° C. for 2 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography to give 441 mg of a black powder (yield: 62.8%; mp: 177-179° C.)