Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[C:13](N)=[CH:14][C:15]([F:18])=[C:16](Br)[C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.N1CCCCC1.[CH3:26][C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:30]#[C:29][C:27]([CH3:28])([OH:31])[CH3:26])[C:15]([F:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2cnc3c(Br)c(F)cc(N)c32)n1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)ncn2-c1ccnc(N)n1
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 26.7 %

Procedure:
To a pressure tube was added 3-(2-aminopyrimidin-4-yl)-7-bromo-6-fluoro-1,3benzodiazol-4-amine (66%, 250 mg, 0.54 mmol), piperidine (1.5 mL), tetrakis(triphenylphosphine)palladium (61.9 mg, 0.05 mmol), copper(I) iodide (10.2 mg, 0.05 mmol) and 2-methylbut-3-yn-2-ol (0.1 ml, 1.07 mmol). The reaction was stirred at 75° C. for 2.5 h before concentrating in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM: methanol gradient (98:3 to 90:10). Material obtained triturated with methanol to obtain the title compound as an off-white solid. (45 mg, 26.7% yield); 1H NMR (500 MHz, DMSO) delta 1.52 (6H, s), 5.53 (1H, s), 7.14 (1H, d, J=5.20 Hz), 7.18 (2H, br. s.), 7.67 (1H, d, J=9.62 Hz), 8.40 (1H, br. s.), 8.63 (1H, d, J=6.62 Hz), 9.16 (1H, s); LC-MS m/z+312.5 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[N:11]([CH2:12][CH2:13][CH2:14][N:15]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[CH2:16]2)[N:10]=1)C1C=CC=CC=1>CCOC(C)=O.CN(C=O)C.[OH-].[OH-].[Pd+2]>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:15]2[CH2:14][CH2:13][CH2:12][N:11]3[C:17](=[CH:18][C:9]([OH:8])=[N:10]3)[CH2:16]2)=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(F)cc1)N1CCCn2nc(OCc3ccccc3)cc2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)N1CCCn2nc(O)cc2C1
Yield: 92.7 %

Procedure:
A solution of (2-benzyloxy-7,8-dihydro-4H,6H-1,5,8a-triaza-azulen-5-yl)-(4-fluoro-phenyl)-methanone (0.902 g, 2.47 mmol) in a mixture of AcOEt/DMF (25/25 mL) was hydrogenated in a H-Cube reactor (1.5 ml/min, 70 mm, Pd(OH)2/C cartridge, full H2 mode, 80° C., 1 cycle). The solvents were evaporated in vacuo to yield (4-Fluoro-phenyl)-(2-hydroxy-7,8-dihydro-4H,6H-1,5,8a-triaza-azulen-5-yl)-methanone (0.63 g, 93% yield) as a colorless oil, that was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][NH2:16]>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:16][CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(4-hydroxyphenyl)cyclohexanone (3 g) in tetrahydrofuran (20 mL) and a solution of methylamine in tetrahydrofuran (7.9 mL, 2 M) is stirred overnight at room temperature, concentrated under reduced pressure, dissolved in a mixture of dichloromethane and methanol (30 mL, 1/1) and cooled at a temperature close to 0° C. Sodium borohydride (822 mg) is added portionwise and the mixture is stirred at room temperature for one hour. The precipitate is filtered and washed with diethyl oxide to give 1.1 g of trans-4-(4-hydroxyphenyl)-N-methylcyclohexanamine used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4](Cl)[N:3]=1.CC1C=CC=CC=1C.[NH:19]1[CH2:24][CH2:23][CH:22]=[CH:21][CH2:20]1.[OH-].[Na+]>O>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:19]2[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Reactant: C1=CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Temperature: 5 °C

Procedure:
155 G. of 2,4-diamino-6-chloropyrimidine-3-oxide are mixed under an argon atmosphere with 640 ml. of o-xylene and 260 ml. of 1,2,5,6-tetrahydropyridine and the mixture is stirred. The mixture is then heated to reflux for 30 minutes, the internal temperature rising from 115° C. to 123° C. The mixture is then cooled to 5° C., treated with 40 g. of sodium hydroxide in 400 ml. of water and stirred at 5° C. for 1 hour. The precipitate formed is filtered off, washed with 200 ml. of water and recrystallized from 3000 ml. of water, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide, having a melting point of 263°-265° C. (decomposition).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:21]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]#[N:33])[CH:25]=[N:24][CH:23]=[N:22]1>CN(C=O)C.CCOC(C)=O>[N:21]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]#[N:33])[CH:25]=[N:24][CH:23]=[N:22]1.[N:10]1[N:11]=[CH:12][N:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]#[N:9])[CH:14]=1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccccc1F
Agent: N#Cc1ccccc1-n1cncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cnnc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-fluorocyanobenzene (5.0 g, 41 mmol) in DMF (75 mL) was added 1,2,4-triazole (3.0 g, 43 mmol) and cesium carbonate (14 g, 43 mmol). The mixture was warmed to 50° C. and stirred under inert atmosphere for 18 h. The mixture was cooled to ambient temperature, diluted with an equal volume of EtOAc, filtered, and the filtrate solvents were removed under reduced pressure. The residue was partitioned between ether (50 mL) and water (100 mL). The undissolved solid was collected by suction filtration and dried under reduced pressure to give 4.6 g of a 10:1 mixture of 2-(1,2,4-triazol-1-yl)cyanobenzene (hplc retention time=2.29 min, 5% to 100% CH3CN in water containing 0.1% TFA, Zorbax C8, 4.6 mm ID×7.5 cm, 3.5 micron; TLC Rf=0.6, EtOAc) and 2-(1,2,4-triazol-4-yl)cyanobenzene (hplc retention time=1.91 min, 5% to 100% CH3CN in water containing 0.1% TFA, Zorbax C8, 4.6 mm ID×7.5 cm, 3.5 micron; TLC Rf=0.1, EtOAc). The mixture was separated by flash chromatography using a gradient elution of 0:100 to 5:95 MeOH:EtOAc to give 2-(1,2,4-triazol-1-yl)cyanobenzene (1H NMR (DMSO-d6) δ 9.19 (s, 1H), 8.37 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.96–7.87 (m, 2H), 7.71 (t, J=7.7 Hz, 1H); mass spec m/z=171 (M++H)) and 2-(1,2,4-triazol-4-yl)cyanobenzene (1H NMR (DMSO-d6) δ 9.03 (s, 2H), 8.13 (d, J=7.6 Hz, 1H), 7.93(t, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H); mass spec m/z=171 (M++H)), both as white solids.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O1CCOCC1.[CH2:18]([N:24]=[C:25]=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:25](=[O:26])[NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CCCCCCN=C=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 32 °C
Reaction time: 48 h

Procedure:
Mixture of quinolin-6-ol (0.58 g., 4 mmol), dry dioxane (20 ml), hexyl isocyanate (0.698 ml, 4.8 mmol) and dry pyridine (0.2 ml) was stirred at room temperature (32° C.) for 48 hours. Reaction mixture was concentrated under vaccum, titurated with water (1 ml) and crystallised with ether, to give 1a; yield: 0.80 g. (73.5%), m.p. 89° C., C16H20N2O2; 1H NMR δ ppm (CDCl3): 0.91 (bs, 3H), 1.33-1.34 (bs, 6H), 1.56-1.62 (m, 2H), 3.24-3.34 (m, 2H), 5.21 (bs, 1H), 7.35-7.42 (m, 1H), 7.48-7.52 (m, 1H), 7.60-7.61 (m, 1H), 8.07-8.12 (m, 2H), 8.86-8.89 (m, 1H); IR vmax (KBr) (cm−1): 478, 530, 674, 730, 788, 839, 909, 970, 1002, 1040, 1158, 1215, 1258, 1300, 1356, 1462, 1495, 1543, 1709, 1919, 2373, 2861, 2961, 3032, 3286, 3346, 3777, MS: m/z: 273 (M+).
Reaction SMILES: CS(O[CH:6]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)(=O)=O.O.[CH3:31][NH2:32]>>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([CH2:7][CH:6]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[NH:32][CH3:31])[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccc(F)cc2)CCN(C)C1
Reactant: CN
Solvent: O
Product: CNC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethyl methane sulfonate (250 mg, 0.6 mmol) in methyl amine (40% solution in water, 5 mL) was heated at 100° C. for 4 h. The progress of the reaction was monitored by TLC and LCMS. 10 mL of water was added to the reaction mixture and then extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase HPLC to obtain 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)-N-methyl ethanamine (30 mg) as the TFA salt. 1H NMR (CDCl3, freebase): δ (ppm): 7.32 (t, 2H), 7.24 (m, 1H), 7.21 (s, 1H), 7.01 (m, 3H), 3.91 (m, 2H), 3.65 (dd, 2H), 2.80 (m, 3H), 2.62 (m, 1H), 2.54 (s, 3H), 2.45 (s, 3H), 2.14 (s, 3H). Chiral HPLC separated the racemate into enantiomers II-12a-b.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[CH:11]=[CH:12][O:13]CC[Si](C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C.O>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[CH2:11][CH:12]=[O:13]
Reactant: Cc1nc2ccccn2c1C=COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1nc2ccccn2c1CC=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.7 %

Procedure:
To a solution of 2-methyl-3-[2-(2-trimethylsilanyl-ethoxy)-vinyl]-imidazo[1,2-a]pyridine (1.8 g, 6.56 mmol) in a mixture of acetonitrile and water (1:1 by volume, 16 mL) in a 100 mL plastic bottle was added HF (8 mL, 48% solution in water). The reaction mixture was stirred at room temperature for 96 h and solid sodium bicarbonate was added in batches until the mixture reached pH 6. The mixture was washed twice with ether, basified to pH 8 with solid sodium hydroxide, and extracted three times with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulfate and concentrated in vacuo to give (2-methyl-imidazo[1,2-a]pyridin-3-yl)-acetaldehyde (922 mg) as a deep brown semi-solid that was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1Br.[C:15]1([NH:21][C:22](=O)[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:22]([CH3:23])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:14]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: CC(=O)Nc1ccccc1
Product: COC(=O)c1cccc2nc(C)n(-c3ccccc3)c12
Yield: 30 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 2-Bromo-3-nitrobenzoic acid methyl ester and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as viscous oil (40 mg, 30%). 1H NMR (DMSO) δ 2.41 (s, 3 H), 3.08 (s, 3 H), 7.39-7.63 (m, 7 H), 7.96 (br s, 1 H); 13C NMR δ 14.1, 51.8, 117.2, 121.1, 123.0, 124.9, 137.0, 139.3, 139.6, 137.0, 140.2, 155.2, 165.7.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13]>C1COCC1>[Cl:13][C:12]1[N:11]=[C:18]([Cl:19])[N:17]=[C:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=2)[N:14]=1
Reactant: C=Cc1ccc(Br)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A solution formed by dissolving 4-bromostyrene (18.3 g, 0.1 mol) and magnesium (2.64 g, 0.11 mol) into THF (200 mL) was stirred at 30° C. for two hours, and then, refluxed for two hours. This solution was added to a solution of cyanuric chloride (21.58 g, 0.120 mol) into THF (200 mL) at −20° C., and the mixture was stirred at −20° C. for five hours. The solvent was distilled off under a reduced pressure, the remaining solid was dissolved into dichloromethane and washed with water twice. The organic layer was dried over anhydride MgSO4, and the solvent was distilled off.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[C:15]([CH3:19])([CH2:17][CH3:18])[CH3:16].[C:20](#[N:23])[CH:21]=[CH2:22]>C1C=CC=CC=1>[CH3:16][C:15]([CH3:19])([CH2:17][CH3:18])[CH2:22][CH2:21][C:20]#[N:23]
Reactant: CCC(C)(C)Br
Reactant: C=CC#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCC(C)(C)CCC#N

Procedure:
Tri n-butyl tin hydride (19.6 ml.) and α-azo-iso-butyronitrile (0.5 g.) were added succesively to a stirred solution of 2-bromo-2-methylbutane (10 g.) and acrylonitrile (43.5 ml.) in dry benzene (200 ml.). The mixture was heated at reflux for 6 hours, cooled and filtered. The residue was washed with diethyl ether (50 ml.) and the combined filtrates evaporated under reduced pressure. 4,4-Dimethylhexanenitrile was obtained as a colourless liquid (2.1 g.), b.p. 85°-94°/20 mm.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19]Cl.O.[SH:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[NH:31][CH:32]=[N:33]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:18])[N:9]=[C:8]1[CH2:19][S:28][C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1-c1ccccc1
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1-c1ccccc1
Yield: 84.1 %

Procedure:
Prepared according to Procedure C using Intermediate 2i (400 mg, 1.05 mmol), 6-mercaptopurine monohydrate (196 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was chromatographed in MeOH/CH2Cl2 and subsequently recrystallized from EtOH to provide 439 mg of a pale yellow crystalline solid (84%), mp 222.0-222.5° C. (dec). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.55 (s, 1H); 8.45 (s, 1H); 7.73 (t, J=8.0 Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.50-7.59 (m, 4H); 7.41-7.48 (m, 1H); 7.25-7.38 (m, 5H); 4.41 (d, J=16 Hz, 1H); 4.16 (d, J=16 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 157.0, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134.1, 133.3, 131.5, 130.5, 130.3, 130.1, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ES): m/z 497.0 (M+). Anal. calcd. for C26H17ClN6OS: C, 62.84; H, 3.45; Cl, 7.13; N, 16.91; S, 6.45. Found: C, 62.60; H, 3.47; Cl, 7.15; N, 16.65; S, 6.41.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:14])[C:11]([OH:13])=O)[C:4](=[O:15])[CH:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:14])[C:11]([NH:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:19][CH:18]=2)=[O:13])[C:4](=[O:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(C#N)c(Br)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(Br)cc1=O

Procedure:
750 mg (purity 70%, 1.94 mmol) of 2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 704 mg (purity 70%, 57% of theory)
Reaction SMILES: C(OC(NCCC(O)=O)=O)(C)(C)C.[B-](F)(F)(F)F.CCO[C:22]([C:24]([C:34]#[N:35])=NOC(N(C)C)=[N+](C)C)=[O:23].[CH3:36][C:37]1[CH:46]=[C:45]([NH2:47])[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([NH2:48])[CH:43]=2)[N:38]=1.C(N1CCOCC1)C>CN(C=O)C>[NH2:35][CH2:34][CH2:24][C:22]([NH:48][C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[N:38]=[C:37]([CH3:36])[CH:46]=[C:45]2[NH2:47])=[O:23]
Reactant: Cc1cc(N)c2cc(N)ccc2n1
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN1CCOCC1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(N)c2cc(NC(=O)CCN)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 182.5 %

Procedure:
To a solution of 2.18 g (11.55 mmol) of 3-tert-Butoxycarbonylamino-propionic acid in 20 ml of DMF were added 3.78 g (11.55 mmol) TOTU. After 15 min at room temperature 2.0 g (11.55 mmol) of 2-methyl-quinoline-4,6-diamine and 2.66 g (23 mmol) of N-ethylmorpholine were added. After 24 h stirring at room temperature the solution was evaporated and the residue was treated with a saturated aqueous solution of NaHCO3. The aqueous solution was extracted with ethyl acetate. The separated organic layer was dried (Na2SO4) and evaporated. The residue was treated with 20 ml 90% trifluoroacetic acid for 2 h. After evaporation the residue was dissolve in water and extracted with ethyl acetate. The aqueous layer was lyophilized to yield 5.15 g (76%) of the title compound. MS 245.1 (M+1)+.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][CH:16]=2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+]>CO.O>[C:20]1([C:18]2[S:19][C:15]([CH:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)=[CH:16][N:17]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1)N1CCC(c2cnc(-c3ccccc3)s2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(-c2ncc(C3CCNCC3)s2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To 55 mg of 1-benzoyl-4-(2-phenyl-thiazol-5-yl)-piperidine in 4.5 ml of MeOH and 0.5 ml of H2O was added 354 mg of potassium hydroxide. The reaction was stirred at 70° C. overnight. The reaction was then cooled to room temperature and 20 ml of H2O was added. This aqueous layer was extracted with 4×25 ml EtOAc. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give 25 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH3:9][C:2]1[NH:1][CH:11]=[CH:12][CH:13]([C:14]2[CH:15]=[CH:4][CH:3]=[CH:2][CH:9]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)N
Reactant: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC=CC1c1ccccc1

Procedure:
(E)-3-Phenyl-2-propanol (13.8 ml, 0.11 mol) and ethyl 3-amino-2-butenoate (12.9 g, 0.1 mol) were dissolved in 150 ml of absolute ethanol containing 0.5 ml of piperidine. The mixture was heated under reflux for 18 hours followed by removal of the solvent under vacuum to yield 17.6 g of ethyl 1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate as a brown viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:33][N:34]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:33]#[N:34])=[CH:10][CH:9]=2)=[O:4]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C#N)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), zinc cyanide (50 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg) and 1-methyl-2-pyrrolidone (3 ml) was stirred at 100° C. for 2 hrs. under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and THF. The organic layer was washed with aqueous ammonia, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained crystals were washed with a mixture of ethyl acetate and diethyl ether to give the title compound (210 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH:18]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]O)([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH:18]([CH3:20])[CH3:19])[CH:23]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CC(C)Oc1cccc(CO)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(OC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-isopropyloxybenzyl alcohol (118 mg, 0.710 mmol) were dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (165 mg, 0.629 mmol) and a diethyl azodicarboxylate toluene solution (2.2 M, 290 μL, 0.640 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours.
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.CC(OC)(C)C>[F:17][C:16]([F:18])([F:19])[CH2:15][O:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:13])([F:11])[F:12])[C:4]#[N:5]
Reactant: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Agent: CC(C)CCON=O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Yield: 79.1 %

Procedure:
To a solution of 2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile from step 4 (14.47 g, 50.9 mmol) in dry THF (153 mL) was added isoamyl nitrite (15.0 mL, 112.0 mmol), and the mixture was refluxed for 20 h. The solvent was removed in vacuum to give an orange oil, which was dissolved in TBME, washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown solid (15.05 g), which was purified by Kugelrohr distillation (up to 155° C. bath temperature at 1.2 mbar) to give the title compound as alight yellow solid (10.83 g, 79%). MS (EI) 269 [M].