Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9]CC)=O.C(O)(=O)C.[CH:16](N)=[NH:17]>CCO>[CH:5]1[N:4]=[C:3]2[C:7]([N:17]=[CH:16][NH:1][N:2]2[CH:6]=1)=[O:9]
Reactant: CCOC(=O)c1nccn1N
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1nc[nH]n2ccnc12
Temperature: 25 °C

Procedure:
A mixture of ethyl 1-amino-1H-imidazole-2-carboxylate (C-4) (800 mg, 5.16 mmol, 1.0 eq) and formamidine acetate (2.68 g, 25.78 mmol, 5.0 eq) in EtOH (100 mL) is stirred at reflux overnight. The resulting mixture is cooled to RT. The solid is collected by filtration, rinsed with EtOH (3×2 mL) and petroleum ether (2 mL×3), and then dried in vacuo to afford the product, imidazo[1,2-f][1,2,4]triazin-4-ol (C-5). Imidazo[1,2-f][1,2,4]triazin-4-ol (C-5) (400 mg, 2.94 mmol, 1.0 eq) is dissolved in POCl3 (10 mL, 109.2 mmol, 37.1 eq) and the resulting mixture is stirred at reflux for 2 h. The mixture is concentrated in vacuo to remove POCl3. The residue is poured into ice water (30 mL) and neutralized with saturated aqueous NaHCO3 solution to adjust the pH to 6-7 while keeping the temperature below 5° C. The mixture is extracted with ethyl acetate (30 mL×4). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (16% ethyl acetate in petro ether) to afford the product, 4-chloroimidazo[1,2-f][1,2,4]triazine (C-6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:21]1([OH:31])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:21]1([O:31][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:19]=[N:18][CH:17]=2)[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(Oc3cccc4c3CCCC4)n2)cc(OC)c1OC
Yield: 13 %

Procedure:
Using Method X with 150 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine and 5,6,7,8-tetrahydro-1-naphthol, the title compound was obtained (27 mg). Yield: 13%. 1H NMR (250 MHz, DMSO-d6) δ 1.65-1.69 (m, 4H), 2.53-2.56 (m, 2H), 2.72-2.77 (m, 2H), 3.42 (s, 6H), 3.54 (s, 3H), 6.74 (s, 2H), 6.89 (d, 1H, J=7.9 Hz), 6.95 (d, 1H, J=6.6 Hz), 7.11 (t, 1H, J=7.8 Hz), 7.71 (s, 1H), 7.91 (s, 1H), 9.55 (bs, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 22.01, 22.26, 23.12, 28.78, 55.36, 60.03, 95.72, 118.40, 120.56, 125.66, 126.09, 127.60, 129.06, 132.10, 136.39, 138.76, 150.59, 151.46, 152.70, 157.65. m/z 408.2 [(M+H)+ calcd for C23H25N3O4 407.2].
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21]OS(C)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C-:27]#[N:28].[Na+].O>CS(C)=O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C@H:11]([CH2:21][C:27]#[N:28])[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CC#N
Temperature: 80 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
The mixture of tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (13.95 g, 32.6 mmol, J. Med. Chem. 1988, 31, 1598-611) and sodium cyanide (3.20 g, 65.2 mmol) in dimethylsulfoxide (100 mL) was stirred at 80° C. for 20 h. After cooling to room temperature, water (200 mL) was added to the mixture. The resulting mixture was extracted with ethyl acetate (400 mL×2). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (5:1) to give 7.81 g (70%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:9][C:10]1[NH:15][C:14](=[O:16])[NH:13][C:12](=[O:17])[C:11]=1[CH:18]([CH3:20])[CH3:19].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O.CC(C)=O>[CH:18]([C:11]1[C:12](=[O:17])[NH:13][C:14](=[O:16])[NH:15][C:10]=1[O:9][C:8]1[CH:7]=[C:6]([CH:23]=[C:22]([CH3:24])[CH:21]=1)[CH:2]=[O:1])([CH3:20])[CH3:19]
Reactant: Cc1cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)cc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C=O)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A mixture of 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1H-pyrimidine-2,4-dione (1.33 g, 4 mmol), PPTS (201 mg, 0.8 mmol), and water (10 drops) in acetone (20 ml) was heated under reflux for 4 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, CHCl3: methanol (95:5)) to afford 1.03 g (89%) of a white solid. m.p. 241-242° C.; 1H NMR (200 MHz, CD3OD/CDCl3) δ 1.03 (6H, d, J=7.2 Hz), 2.34 (3H, s), 2.84 (1H, m), 6.99 (1H, s), 7.17 (1H, s), 7.38 (1H, s), 9.81 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([CH3:21])=[CH:23][CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 83 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-methylbenzoyl chloride (1.1 g, 8.0 mmol) in THF (40 mL) was heated to reflux for 36 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-methyl-benzamide as a yellow solid (1.3 g, 83% yield): mp, 322–324° C.; 1H NMR (DMSO-d6) δ 2.06–2.10 (m, 1H, CHH), 2.41 (s, 3H, CH3), 2.50–2.65 (m, 2H, CH2), 2.83–2.97 (m, 1H, CHH), 5.19 (dd, J=5.3, 12.6 Hz, 1H, NCH), 7.42 (d, J=8.1 Hz, 2H, Ar), 7.67 (d, J=7.2 Hz, 1H, Ar), 7.86–7.93 (m, 3H, Ar), 8.62 (d, J=8.4 Hz, 1H, Ar), 10.37 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.07, 21.99, 30.93, 48.99, 117.57, 118.58, 125.94, 127.28, 129.58, 130.44, 131.33, 136.34, 136.77, 142.96, 164.80, 166.65, 168.29, 169.69, 172.72; Anal Calcd for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.65; H, 4.17; N, 10.70.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([N:13]([CH3:23])[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)[CH:10]=[CH:11][CH:12]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:52])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:39]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[NH4+].[Cl-]>C1COCC1.O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH:39]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14](=[O:22])[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=3)[CH3:23])[CH:16]=2)[OH:52])[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C(=O)c1cccc(I)c1)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cccc(C(O)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
n-Butyllithium (1.61 mL of 1.92 M solution; 3.10 mmol) was added to a mixture of N-(3-fluorophenyl)-3-iodo-N-methylbenzamide (1.0 g; 2.82 mmol) and 4-[3-(tert-butyl-dimethyl-silanyloxy)benzoyl]-piperidine-1-carboxylic acid tert-butyl ester (1.182 g; 2.82 mmol) in THF (150 mL) at −78° C. under nitrogen in one portion. The reaction was stirred under nitrogen overnight while the temperature warmed to room temperature. Saturated NH4Cl solution (25 mL) was added to the reaction mixture, followed by the addition of 25 mL of water. The mixture was extracted by ether (300 mL×2). The ether layer was washed by water (200 mL×2) and brine (200 mL×1), dried by Na2SO4 and concentrated to give 2.03 g of crude product, which was purified by silica gel column chromatography eluted with 30% EtOAc in pentane to give 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methylcarbamoyl]phenyl}hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (763 mg; 42%). 1H NMR (600 MHz, DMSO-d6) δ 7.34 (bs, 1H), 7.29 (s, 1H), 7.23-7.16 (m, 3H), 7.09 (m, 2H), 6.94 (m, 2H), 6.85 (m, 2H), 6.60 (d, 1H, J=7.0 Hz), 5.25 (s, 1H), 3.88 (m, 2H), 3.35 (s, 3H), 2.60 (bs, 2H), 2.34 (m, 1H), 1.37 (s, 9H), 1.36 (m, 2H), 1.16 (m, 2H), 0.91 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20][CH3:21])=[C:13]([C:22]([F:25])([F:24])[F:23])[CH:12]=3)[N:7]=[C:6]([C:26]#[N:27])[C:5]=2[N:4]=[CH:3]1.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>C1COCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([C:37](=[O:40])[CH2:38][CH3:39])[CH3:21])=[C:13]([C:22]([F:23])([F:25])[F:24])[CH:12]=3)[N:7]=[C:6]([C:26]#[N:27])[C:5]=2[N:4]=[CH:3]1
Reactant: CCC(=O)Cl
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N(C)CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.053 mmol, 20 mg) in THF (1 mL) was added DIPEA (0.266 mmol, 47 μL) and propionyl chloride (0.16 mmol, 15 mg). The mixture was stirred at r.t. for 16 h and the product was then purified by HPLC to give 1-methyl-6-(4-(2-(N-propionyl-N-methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (CD3OD) δ: 8.37-8.46 (m, 4H), 7.31 (d, 1H), 4.31-4.37 (m, 2H), 3.90 (s, 3H), 3.82-3.90 (m, 2H), 3.01, 3.30 (2xs, 3H), 2.42-2.58 (m, 2H), 1.10-1.15 (m, 3H). MS m/z 432 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[NH2:11].N1C=CC=CC=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:10][N:8]([CH3:9])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:11]=[C:19]=[O:21])[CH:4]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)c1ccc(F)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1ccc(F)c(N=C=O)c1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1.09 g (7.1 mmol) of 4-fluoro-N1,N1-dimethylbenzene-1,3-diamine followed by 4.6 cm3 of pyridine are added, at a temperature in the region of 5° C., under an argon atmosphere, to 2.82 g (9.5 mmol) of triphosgene in solution in 150 cm3 of dichloromethane. After stirring for 18 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), to give a residue which is triturated in 40 cm3 of tetrahydrofuran. After filtration, a solution of 5-dimethylamino-2-fluorophenyl isocyanate in approximately 0.14 N tetrahydrofuran is obtained, which solution is used directly in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45]C(=O)C)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[OH:45])[CH:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1cccnc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
3-Aminopyridine (0.151 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.065 g, 0.159 mmol, 30%).
Reaction SMILES: O1CCN(C[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])CC1.C([O:23]C1(OC)C=CC(C(O)=O)=CC1OC)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:8]([NH2:9])(=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(CN1CCOCC1)c1ccccc1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-morpholino-1-phenylethanamine represented by Formula 113 (516.3 mg, 2.50 mmol, purchased from Enamine Co.) was slowly added to 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (793.75 mg, 2.75 mmol) prepared in Preparative Example 1 and diisopropylethylamine (1.75 mL, 10.01 mmol) in DMF (12 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 1.05 g, 2.75 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (25 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 20 as a desired product (VVZ-021; 355.2 mg, 30% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](Br)=[CH:24][C:23]([CH3:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH2:40])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](/[CH:38]=[CH:37]/[C:36](=[O:39])[NH2:40])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(N)=O
Reactant: Cc1cc(Br)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/C(N)=O)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
50 mg (0.09 mmol) {1-[4-(8-Bromo-6-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 13.4 mg (0.19 mmol) acryl amide, 4.86 mg (0.016 mmol) tri-2-tolylphosphane, 2.1 mg (0.009 mmol) palladium(II) acetate and 0.02 mL (0.1 mmol) triethylamine in 0.7 mL degassed acetonitrile were heated in the microwave at 110° C. for 60′. Due to an incomplete reaction additional 13.3 mg acrylamide and 4.2 mg palladium(II) acetate were added, and heating in the microwave was continued for two hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated and the aqueous phase was once more extracted with dichloromethane. The combined organic extracts were washed twice with brine, dried, and the solvent was removed. The crude product (76 mg) was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 24.2 mg (49.3%) of the desired compound.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20]>CO>[C:1]1([NH:7][C:11]([C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[Se:8][S:20][CH2:19][C@@H:18]([C:21]([OH:23])=[O:22])[NH2:17])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Solvent: CO
Product: N[C@@H](CS[Se]c1ccccc1C(=O)Nc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,74 g (10 mmol) 2-phenyl-1,2-benzoisoselenazole-3(2H)-one and 1,21 g (10 mmol) L-cysteine are dissolved in 25 ml trifluororacetic acid. This solution is stirred for 18 hours at room temperature. Then, 150 ml of an ice-water mixture are added to this solution. The deposited precipitate after some stirring becomes solid. It is sucked off and finally dissolved in methanol. After evaporation of the solvent, a residue remains which is washed with ether.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:21])[C@@H:17]([NH2:20])[CH2:18][OH:19].CCN(CC)CC.[CH3:29][C:30]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:20][C@H:17]([C@H:16]([OH:21])[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:18][O:19][Si:33]([C:30]([CH3:32])([CH3:31])[CH3:29])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC=C[C@@H](O)[C@@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
To a solution of D-erythro-sphingosine (46 mg, 0.153 mmol) in CH2Cl2 (1.5 mL) at room temperature, Et3N (32 μL, 0.230 mmol), TBDPSCl (44 μL, 0.169 mmol) and 4-DMAP (ca. 5 mg, cat.) were added. After stirring for 4 h, the reaction was quenched with H2O (10 mL), extracted with EtOAc (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography on silica (hexane/EtOAc 5:1 to 100% EtOAc) to obtain 136 as a colorless oil (33 mg, 40% yield).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][C@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])[CH:2]=1.[C:22](OC=C)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CC(C)=O>[C:22]([O:18][CH2:17][C@H:15]1[O:16][C@H:11]([O:10][C:3]2[CH:2]=[CH:1][C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=2)[C@H:12]([OH:21])[C@@H:13]([OH:20])[C@@H:14]1[OH:19])(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C=COC(=O)CCCCCCCCCCCCCCC
Reactant: O=[N+]([O-])c1ccc(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 84.9 %

Procedure:
In 40 ml of acetone were suspended 0.3 g (1 mmol) of 4-nitrophenyl-α-D-glucopyranoside (manufactured by Tokyo Kasei Ind., Ltd.) as marketed, 0.85 g (3 mmol) of vinyl palmitate and 30 mg of Lipase B, and the suspension was reacted in a shaking apparatus at 25° C. for 1 day. After the enzyme was filtered off, the solvent was concentrated to afford a crude product in a white wax form, which was purified by silica gel chromatography (5% methanol-dichloromethane) to give 0.458 g of 4-nitrophenyl 6-O-palmitoyl-α-D-glucopyranoside in a white wax form. Yield 81%
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[C:16](Cl)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C.[ClH:27]>>[Cl:27][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][C:15]=1[O:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2Cl)CC1
Product: N[C@H]1CC[C@H](Oc2cc3ccncc3cc2Cl)CC1
Reaction time: 48 h

Procedure:
18 mg (0.05 mmol) trans-[4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10) were stirred in 2 M HCl at room temperature. After 2 days, the solvent was removed i. vac. and the residue was purified by preparative HPLC. 8 mg of the title compound could be obtained as trifluoro acetate. Rt=0.69 min (Method #1). Detected mass: 277.2/279.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27]\[OH:28])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ncccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ncccc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-3-(3-methyl-pyridin-2-yl)-1-(2-methyl-pyridin-4-yl)-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound which contains less than 6% of the Z isomer as a colorless oil, MS (ESI+): m/z=410.0872 ([M+H]+, 1Br).