Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:24][CH3:25])[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[C:5](=[C:6]([CH:21]([CH3:23])[CH3:22])[CH:7]=[C:8]([C:15]#[C:16][Si](C)(C)C)[CH:9]=2)[O:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:24]([C:3]1([CH2:1][CH3:2])[CH2:12][C:11]([CH3:14])([CH3:13])[C:10]2[C:5](=[C:6]([CH:21]([CH3:23])[CH3:22])[CH:7]=[C:8]([C:15]#[CH:16])[CH:9]=2)[O:4]1)[CH3:25]
Reactant: CCC1(CC)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C(C)C)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C(C)C)c2c(c1)C(C)(C)CC(CC)(CC)O2
Temperature: 80 °C
Yield: 96.5 %

Procedure:
A solution of 2,2-diethyl-8-isopropyl-6-trimethylsilanylethynyl-4,4-dimethyl chroman (Intermediate 28, 0.73 g, 2.04 mmol) in methanol (40 mL) was treated with potassium carbonate (0.15 g, 1.08 mmol) and the resulting reaction mixture was heated at 80° C. for 3 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown oil (0.56 g, 96%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (166 mg, 0.310 mmol) in CH2Cl2 (3 mL) was added TFA (0.358 mL, 4.65 mmol). Upon completion of addition, the reaction mixture was stirred at rt for 3 hrs. After this time, the reaction mixture was diluted with CH2Cl2 (10 mL) and washed with aq NaOH (1 N, 5 mL) and brine (5 mL) and then dried (Na2SO4). The resulting mixture was filtered and concentrated under reduced pressure to afford Compound 1E as a light yellow solid (124 mg, 0.285 mmol, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.17 (2H, s), 7.59-7.68 (2H, m), 7.42 (1H, dd, J=8.5, 1.9 Hz), 6.11-6.21 (1H, m), 5.39-5.55 (1H, m), 4.23 (2H, ddd, J=13.3, 6.8, 3.9 Hz), 3.62-3.77 (2H, m), 3.56 (2H, q, J=2.6 Hz), 3.14 (2H, t, J=5.7 Hz), 2.46-2.55 (2H, m), 2.41 (2H, t, J=7.6 Hz), 2.13-2.24 (2H, m), 1.88-2.00 (2H, m), 1.52-1.61 (3H, m), 0.95 (3H, t, J=7.5 Hz).
Reaction SMILES: [C:1]([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12](CC)[N:13]=2)[N:10]=1)([CH3:4])(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([O:41]C(=O)C(F)(F)F)[C@@H:37]2[CH2:48][O:49]C(=O)C(F)(F)F)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C2CC2)N=NN=1>CO>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]2[CH2:48][OH:49])[C:30]2[C:31](=[N:33][N:34]([CH2:8][C:9]3[N:10]([CH:5]4[CH2:1][CH2:4]4)[N:13]=[N:12][N:11]=3)[N:35]=2)[N:32]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)[C@@H]2COC(=O)C(F)(F)F)c2nn[nH]c2n1
Agent: ClCc1nnnn1C1CC1
Solvent: CO
Product: CC(C)(C)c1nc(N2CC[C@H](O)[C@@H]2CO)c2nn(Cc3nnnn3C3CC3)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from Trifluoro-acetic acid (2S,3S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-2-(2,2,2-trifluoro-acetoxymethyl)-pyrrolidin-3-yl ester and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole. After completion of the substitution reaction methanol was added and the mixture was stirred for 1 h at room temperature and subsequently subjected to purification with preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions the title compound was isolated as light-yellow solid. MS (m/e): 415.4 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CCOCC>[CH2:9]([OH:8])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Reaction time: 1 h
Yield: 93 %

Procedure:
To a magnetically stirred solution of 0.5 ml (0.5 mmol) of LiAlH4 in Et2O, 100 mg (0.314 mmol) of arachidonic acid methyl ester in 2 mL of Et2O was added dropwise at 0° C. The reaction mixture was stirred for 1 h and then quenched by addition of 1 mL of EtOAC. 2 mL of saturated NH4Cl solution was added and the organic layer was separated, dried with MgSO4, filtered and evaporated. Chromatography on silica gel (eluents: CH2Cl2/petroleum ether up to 70% CH2Cl2), evaporation, followed by membrane filtration of a CH2Cl2 solution of the product gave 99.3 mg (0.292 mmol, 93% yield) of arachidonyl alcohol as a colorless oil: TLC (CHCl3) Rf 0.28; 1H NMR (200 MHZ, CDCl3) δ 5.37 (m, 8 H), 3.61 (t, 2 H, J=6 Hz), 2.79 (m, 6H), 2.08 (m, 4 H), 1.66–1.17 (m, 8H), 0.92 (t, 3H, J=7 Hz); Anal. C, H.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1N
Product: COc1ccc(S(=O)(=O)Nc2ccccc2OC)cc1
Yield: 90.1 %

Procedure:
Using o-anisidine (1.0 ml, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.26 g (90.1%) of the title compound in the form of colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[C:10]([CH3:17])[C:11]([CH2:15][CH3:16])=[CH:12][C:13]=1[O:14][CH2:27][CH:26]=[CH2:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=CCBr
Reactant: CCc1cc(O)c(C(=O)OC)c(C(=O)OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(CC)c(C)c(C(=O)OC)c1C(=O)OC
Temperature: 60 °C
Reaction time: 14 h
Yield: 83.1 %

Procedure:
4-Ethyl-6-hydroxy-3-methyl-phthalic acid dimethyl ester (1.01 g, 4.02 mmol) was dissolved in DMF (5 mL). Potassium carbonate (3.33 g, 24.14 mmol) was added, followed by allylbromide (2.92 g, 24.14 mmol). The suspension was heated at 60° C. After 14 hrs, the reaction was cooled to room temperature and filtered. The solvents were removed in vacuo and the crude material was purified by silica gel chromatography to provide 0.976 g (83%) of the desired product as a colorless oil. 1H NMR (300 MHz, CDCl3): δ=1.16 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 2.62 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.84 (s, 3H), 4.57 (m, 2H), 5.26 (dd, J=9.3, 1.5 Hz, 1H), 5.41 (dd, J=13.5, 1.5 Hz, 1H), 5.98 (m, 1H), 6.82 (s, 1H) ppm.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[Cl:17])[N:7]=[C:6]([N:18]2[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19]2)[N:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[ClH:16].[NH2:3][C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[Cl:17])[N:7]=[C:6]([N:18]2[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]2)[N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCC1CCN(c2nc(N)nc(-c3cc(Cl)ccc3Cl)n2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)NCC1CCN(c2nc(N)nc(-c3cc(Cl)ccc3Cl)n2)C1

Procedure:
In 40 ml of THF was dissolved 2.1 g of the free base obtained by neutralizing the compound of Example 62, followed by addition of 0.94 g of potassium carbonate and 0.78 g of methanesulfonyl chloride. The mixture was reacted at room temperature for 20 hours. The THF was removed by concentration and the residue was diluted with water and extracted with chloroform. The extract was washed with water and dried and the chloroform was distilled off. The residue was purified by silica gel column chromatography (elution with CHCl3 :MeOH=19:1) and the resulting oil, 2.3 g, was treated in the same manner as in Example 32 (Step 2) to provide the title compound. m.p. 220-230° C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC.CCCCCCC>[CH2:23]([C:24]1[CH:23]=[C:2]([C:1]([CH:8]2[C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)([CH3:4])[CH3:3])[CH2:26][CH:25]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCCC
Product: CCCCC1=CCC(C(C)(C)C2c3cc(C(C)(C)C)ccc3-c3ccc(C(C)(C)C)cc32)=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.4 %

Procedure:
To 2,7-di-tert-butylfluorene (27.8 g, 100 mmol) dissolved in Et2O (200 mL) was added n-BuLi (11 mL of 10 M in hexanes, 110 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. To the anion solution was added to 2-butyl-6,6-dimethylpentafulvene (F-2) (20 g, 123 mmol) at −78° C. in less than one minute. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and saturated NH4Cl aqueous solution. The mixture was extracted with Et2O. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave a viscous oil. The oil was dissolved in heptane and purified through silica gel column with 5-10% CH2Cl2 in heptane. A mixture of isomers for the desired product (33.8 g, 76.8% yield) was obtained as a viscous oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+].O>CC#N>[CH3:15][C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccccc1
Yield: 47.5 %

Procedure:
To a solution of phenol (2 g, 21.25 mmol) in CH3CN (50 mL) was added ethyl 2-bromo-2-methylpropanoate (5 g, 25.5 mmol) and Cs2CO3 (20 g, 63.75 mmol) at 25° C. The mixture was heated at reflux for 16 h then water (100 mL) added and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (2.1 g, 47.7%) as colorless oil which was used in next step without further purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.O.[NH2:29][NH2:30]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:29][N:30]=[C:19]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=C(Cc1cccnc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CCO
Solvent: O
Product: O=c1c2c(Cc3cccnc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 76 %

Procedure:
The procedure of Example 1 was repeated using a suspension of 4-hydroxy-3-[1-oxo-2-(pyridin-3-yl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (16 mg, 0.045 mmol, prepared in Synthetic Example 3) in ethanol (5 ml), and hydrazine monohydrate (80%, 10 μl, 0.25 mmol, 5.5 eq.) to obtain 5-phenyl-3-(pyridin-3-yl)methyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (yield: 76%).
Reaction SMILES: [OH:1][CH:2](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6].C12CCCN=C1CCCCN2.Cl>C(Cl)Cl>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:2](=[O:1])/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6])=[CH:16][CH:15]=1
Reactant: COC(=O)C#CC(O)/C=C/c1ccc(OC)cc1
Agent: C1CCC2=NCCCC2NC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)/C=C/c1ccc(OC)cc1

Procedure:
A solution of 20 g (8.12 mmol) of methyl (E)-4-hydroxy-6-(4-methoxyphenyl)-5-hexen-2-ynoate and 62 mg (~5 mol %) of 2,8-diazabicyclo[5.4.0]undec-7-ene in 80 ml of methylene chloride was stirred at 0° under argon for 35 hours. Thereafter, 25 ml of 0.1N hydrochloric acid were added and the phases are separated. The aqueous phase was extracted twice with 25 ml of methylene chloride. The combined organic fractions were dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on 130 g of silica gel with petroleum ether/ether (1:1), and there were obtained first methyl (E,E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoate of melting point 103°-103.5° and then methyl (2Z,5E)-6-(4-methoxyphenyl)-4-oxo-2,5-hexadienoate of melting point 54°-55°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:15][C:16]([O:18]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.Cl.[CH2:29]([NH:31][CH2:32][CH2:33][C:34]1[N:35]=[CH:36][NH:37][CH:38]=1)[CH3:30].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>CN(C=O)C>[CH2:29]([N:31]([CH2:32][CH2:33][C:34]1[N:35]=[CH:36][NH:37][CH:38]=1)[C:16](=[O:18])[NH:15][C@@H:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:30]
Reactant: CCNCCc1c[nH]cn1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCc1c[nH]cn1)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 105.4 %

Procedure:
0.14 g (0.38 mmol) of methyl(S)-3-(4-methoxyphenyl)-2-(4-nitrophenoxycarbonyl-amino)propionate is diluted in 2 mL of DMF. The solution is heated to 80° C. and 0.16 g (0.76 mmol) of ethyl[2-(1H-imidazol-4-yl)ethyl]amine hydrochloride and 0.13 mL (1.3 mmol) of diisopropylethylamine are then added. After 5 minutes, the reaction medium is cooled to room temperature and stirred for 15 minutes. Toluene is added and the solvents are evaporated off. The crude product obtained is chromatographed on silica gel (eluent: 8/2 dichloromethane/methanol). 0.15 g of methyl(S)-2-{3-ethyl-3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)-propionate in the form of a colourless oil is obtained in a yield of 100%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[C:20]([O:22]CC)=O)=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:28][C:29]#[N:30].[K+]>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[O:25][C:29](=[O:28])[NH:30][C:20]2=[O:22])=[CH:11][C:10]=1[O:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[O-]
Reactant: CCOC(=O)C(O)CCCCc1ccc(OCc2ccccc2)c(OC)c1
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(CCCCC2OC(=O)NC2=O)ccc1OCc1ccccc1
Reaction time: 72 h
Yield: 74.3 %

Procedure:
A mixture of ethyl 6-(4-benzyloxy-3-methoxyphenyl)-2-hydroxyhexanoate (15.22 g), potassium cyanate (KCNO) (13.26 g) and butanol (180 ml) was stirred for 72 hours under reflux. The reaction mixture was concentrated under reduced pressure. The residue was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), followed by distilling off the solvent. The residual oily product was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:1, v/v), was obtained 5-[4-(4-benzyloxy-3-methoxyphenyl)butyl]-2,4-oxazolidinedione (11.22 g, 74%), which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.92-93° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:5].Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:4]([CH3:5])[C:3]([OH:2])=[O:18])=[CH:7][CH:8]=3)[CH2:13][CH2:14]2)=[CH:21][CH:22]=1)[CH3:28]
Reactant: COC(=O)C(C)c1ccc(C2CCNCC2)cc1
Reactant: CCOc1ccc(Br)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: CCOc1ccc(N2CCC(c3ccc(C(C)C(=O)O)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
1.00 g (4.04 mmol) 2-(4-Piperidin-4-yl-phenyl)-propionic acid methyl ester (XI.3) are added to a mixture of 813 mg (4.04 mmol) 1-bromo-4-ethoxy-benzene, 1.60 g (97%, 16.2 mmol) sodium tert-butyrat, 483 mg (1.62 mmol) 2-(di-tert-butylphosphino)biphenyl and 370 mg (0.40 mmol) tris-(dibenzylidenaceton)-dipalladium(0) in 10 mL 1,4-dioxane. The mixture is stirred for 12 h at 70° C. After that time, the precipitate is filtered off and washed with ACN and diethyl ether. The residue is purified by HPLC (column: Waters XBridge 50; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]2)=[N:3][CH:4]=1
Reactant: OC1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(N2CCC(O)C2)nc1
Yield: 79.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with pyrrolidin-3-ol (330 mg, 3.5 mmol) followed by reduction to afford the desired product (440 mg, 52%) as a purple solid: ESI MS m/z 180 [C9H13N3O+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6](I)[CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.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>[Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[C:17]([O:18][CH3:19])[CH:16]=2)[CH:7]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Nc1ncc(I)cc1Br
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: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cnc(N)c(Br)c2)cc1OC
Yield: 94.9 %

Procedure:
3-Bromo-5-iodopyridin-2-amine (7.50 g), 3,4-dimethoxyphenylboronic acid (4.79 g), tetrakis(triphenylphosphine)palladium (1.45 g) and potassium carbonate (10.4 g) were suspended in dioxane (100 ml) and water (10 ml), and the suspension was heated at 80° C. for 9.5 hours. After leaving to cool, a saturated aqueous ammonium chloride solution was added, and the organic layer was extracted with ethyl acetate and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate] to give 7.36 g of the title compound as a solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1.Br[CH2:23]/[CH:24]=[CH:25]/[C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(#N)C.FC(F)(F)C(O)=O>[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH2:23]/[CH:24]=[CH:25]/[C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH2:17][C:16]3=[O:21])=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Reactant: Clc1ccc(/C=C/CBr)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1ncnc2cc(CN3CCN(C/C=C/c4ccc(Cl)s4)CC3=O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
To a solution of 1-(4-amino-quinazolin-7-ylmethyl)-piperazin-2-one bishydrochloride (100 mg, 0.31 mmol), EXAMPLE 72, in 3 mL of DMF is added 2-(3-bromo-(E)-propenyl)-5-chloro-thiophene (73 mg, 0.31 mmol), prepared as described in EXAMPLE 17., and K2CO3 (0.21 g, 1.54 mmol). The solution is stirred at room temperature for 16 hours. After this time, the solution is diluted with water/acetonitrile and neutralized with trifluoroacetic acid. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyopholized to give the title compound (80 mg, 0.12 mmol) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ9.76 (bs, 2H), 8.81 (s, 1H), 8.40 (d, 1H), 7.70 (s, 1H), 7.62 (dd, 1H), 7.10 (m, 2H), 6.90 (d, 1H), 6.05 (dt, 1H), 4.80 (s, 2H), 3.77 (m, 4H), 3.50 (m, 2H), 3.37 (m, 2H), ESI MS, [M+H]+=414,416 (Cl pattern). Anal. (C20H20ClN5OS.2.0TFA.1.1H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]#[N:12].Br[CH2:14][CH2:15]Br.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.COC(C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]1([C:11]#[N:12])[CH2:15][CH2:14]1
Reactant: BrCCBr
Reactant: Cc1cc(CC#N)c(Cl)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(C2(C#N)CC2)c(Cl)cc1Cl
Yield: 72.9 %

Procedure:
To a mixture of (2,4-dichloro-5-methylphenyl)acetonitrile (385 mg) and 1,2-dibromoethane (1.0 g) were added benzyltriethylammonium-chloride (44 mg) and a 50% solution of sodium hydroxide (0.8 ml) and the mixture was stirred overnight at room temperature. Ice-cold water and tert-butyl methyl ether were added to the reaction mixture and the organic layer was separated. The obtained organic layer was sequentially washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (carrier: Wakogel™ C-200; elution solvent:heptane:ethyl acetate 49:1→19:1) to obtain the title compound (317 mg). The property values of the obtained compound are as follows; 1H-NMR (CDCl3) δ (ppm): 1.32 (dd, J=7.6, 5.2 Hz, 2H), 1.72 (dd, J=7.6, 5.2 Hz, 2H), 2.34 (s, 3H), 7.20 (s, 1H), 7.43 (s, 1H).