Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:11][C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:3]([OH:5])=[O:4].N[C@@H](CCCCN(C(OCC1C=CC=CC=1)=O)C[C@@H](O)CCNC(OCC1C=CC=CC=1)=O)C(O)=O.FC(F)(F)C(O)=O.O1C=CCCC1>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[CH2:11][C@@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](CCCCN(C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Agent: C1=COCCC1
Agent: N[C@@H](CCCCN(C[C@@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCCCN(C[C@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Yield: 58 %

Procedure:
According to the method described for the preparation of 18a, 17b (37 mg, 73.8 μmol) was reacted with trifluoroacetic acid (17 mg, 0.15 mmol) and 3,4-dihydro-2H-pyran (46 mg, 50 μL, 0.55 mmol) in CH2Cl2 (2 mL) to give 18b (25 mg, 58%) as a colorless oil: 1H NMR δ 1.26-1.96 (m, 14H), 3.02-4.04 (m, 10H), 4.32-4.63 (m, 1H), 5.06 (s, 2H), 5.11 (s br, 2H), 7.22-7.40 (m, 10H); HRMS m/z calcd for C31H44N3O8 586.3128, found 586.3137.
Reaction SMILES: [C:1]([N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH:9]1[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([N:8]1[C:17]2[CH:12]([CH2:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH:9]1[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C=CC1CCC2CC=CC=C2N1C(=O)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCC2CC=CC=C2N1C(=O)C(=O)OCC
Yield: 94.4 %

Procedure:
N-Ethoxalyl-2-ethoxycarbonylethenyltetrahydroquinoline (4 g, 12.1 mmol) in ethanol (100 mL) was hydrogenated over 10% palladium on carbon (500 mL) under atmospheric pressure of hydrogen for 1.5 h at room temperature. The mixture was filtered through celite and the filtrate was concentrated to give 3.83 g of N-ethoxalyl-2-ethoxycarbonylethyltetrahydroquinoline (95%): 1H NMR (270 MHz, CDCl3) δ7.03~7.19 (m, 4H), 4.78 (m, 1H), 4.11(q, 4H, J 7 Hz), 2.73 (t, 2H, J=6 Hz), 2.47 (m, 1H), 1.69 (m, 1H), 1.25 (t, 3H, J=7 Hz), 1.11 (t, 3H, J=7Hz).
Reaction SMILES: [CH2:1]([O:19][C:20]1[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH:31]=[CH:30][C:21]=1[CH:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=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][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:72]([NH2:89])([O:74][CH2:75][CH:76]1[C:88]2[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=2)[C:82]2[C:77]1=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73].CS(O)(=O)=O.C(O)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:72]([NH:89][CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:21]1[CH:30]=[CH:31][C:32]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20]=1[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([O:74][CH2:75][CH:76]1[C:88]2[C:83](=[CH:84][CH:85]=[CH:86][CH:87]=2)[C:82]2[C:77]1=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73]
Reactant: NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(O)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: OC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC2c3ccccc3-c3ccccc32)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To 2,3,4-trioctadecanoxybenzhydrol (650 mg, 657 μmol) obtained in Example 1 were added toluene (10 ml) and Fmoc-NH2 (189 mg, 790 μmol), and the mixture was warmed to 50° C. in an oil bath. Methanesulfonic acid (6.4 μl, 99 μmol) was added, and the mixture was heated to 100° C. and stirred for 6 hours. After confirmation of disappearance of a benzhydrol type anchor, the mixture was cooled to room temperature. Toluene (5 ml) and 5% aqueous sodium hydrogen carbonate (10 ml) were added and the mixture was stirred. After partitioning, the organic layer was further washed with water (10 ml×2). The organic layer was evaporated under reduced pressure, and the residue was washed with methanol (10 ml) to give N-Fmoc-[phenyl(2,3,4-trioctadecanoxyphenyl)methyl]amine (788 mg, yield 98%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:16][O:17][C:18]1[CH:41]=[CH:40][C:21]([C:22](Cl)([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>N1C=CC=CC=1.O1CCOCC1>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:15][CH2:14][C:3]([CH2:2][OH:1])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:21]2[CH:40]=[CH:41][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(C(Cl)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)C(CO)(COC(c1ccc(OC)cc1)(c1ccc(OC)cc1)c1ccc(OC)cc1)C(=O)OCC
Yield: 28.5 %

Procedure:
Referring to scheme 1, diethyl bis-(hydroxymethyl)malonate (11.5 g, 55 mmol) was treated overnight with 4,4′,4″-trimethoxytrityl chloride (19.2 g, 52 mmol) in pyridine (16 mL) and dioxane (100 mL), and the solvent was evaporated. The residue was dissolved in CH2Cl2 (500 mL), washed with 5% aqueous NaHCO3 (3×100 mL), washed with brine (2×100 mL), dried over Na2SO4 and evaporated. The residue was purified on a silica gel column using a step gradient of ethyl acetate (0 to 15%) in toluene to give 1 (8.2 g, 67.5%) as an oil. HR MALDI MS: calculated for C31H36O9 (M+H+) 553.2442, found 553.2438. 1H NMR (CDCl3) δ 7.29 (6H, d, J=8.8 Hz), 6.83 (6H, d, J=8.8 Hz), 4.26-4.11 (6H, m), 3.80 (9H, s), 3.62 (2H, s), 2.11 (1H, t, J=5.8 Hz), 1.24 (6H, t, J=7.0 Hz). 13C NMR (CDCl3) δ 169.3 (C), 158.5 (C), 136.1 (C), 129.8 (CH), 113.2 (CH), 86.0 (C), 63.7 (CH2), 61.9 (CH2), 61.6 (CH2), 60.6 (C), 55.2 (CH3), 14.1 (CH3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[N:3]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: O=[N+]([O-])c1cccc(Br)n1
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: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2c(F)cccc2F)n1
Temperature: 120 °C

Procedure:
To a solution of 2-bromo-6-nitropyridine [21203-78-1] (200 mg, 0.99 mmol) and 2,6-difluorophenylboronic acid [162101-25-9] (311 mg, 1.97 mmol) in dioxane (4 mL) and water (1 mL) was added potassium carbonate (340 mg, 2.46 mmol) and Pd(PPh3)4 (114 mg, 0.099 mmol). The solution was heated for 60 min at 120° C. under microwave irradiation. More 2,6-difluorophenylboronic acid (622 mg, 3.94 mmol) was added to the mixture followed by heating at 120° C. for 120 min under microwave irradiation. The reaction mixture was then diluted with EtOAc and the resulting solution was washed successively with saturated aqueous NaHCO3 solution and brine, the organics were then dried (Phase separator) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 9:1) to give the title compound. MS (LC-MS): 237 [M+H]+, 259 [M+Na]+; tR (HPLC conditions k): 3.44 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2N)[CH2:4][CH2:3]1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:21]>O.[Cu](Br)Br>[Br:21][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCN(c2ccccc2N)CC1
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccccc2Br)CC1
Temperature: 22.5 °C

Procedure:
A solution of 2-(4-methylpiperazin-1-yl)-aniline (23.77 grams, 0.124 mol) in 80 mL of 48% hydrobromic acid was cooled to 20° C. and treated with a solution of sodium nitrite (8.6 grams, 0.124 mol) in 35 mL of water while maintaining a temperature of 20-25° C. To this was added a solution of copper (II) bromide (3.5 grams, 0.024 mol) in 12 mL of 48% HBr. The mixture was heated to 85° C. for approximately 30 minutes, poured over crushed ice in a large beaker and neutralized with dilute aqueous sodium hydroxide. The crude product was extracted into diethyl ether and concentrated in vacuo to a black oil which was chromatographed on silica gel using triethylamine.methanol.methylene chloride (0.5:10:90) as the eluent. The product, 1-bromo-2-(4-methylpiperazin-1-yl)benzene, was obtained as a brown oil 20 grams Mass spectrum: 254 (M+), 256 1H-NMR (CDCl3, 300 MHz) δ 7.55 (1H, d), 7.30 (1H, t), 7.05 (1H, d), 6.9 (1H, t), 3.05 (4H, br s), 2.55 (4H, t), 2.35 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=O.C(N(CC)CC)C.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([N:34]=[N+:35]=[N-:36])=[O:12]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(=O)/C=C/c1ccccc1Cl
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of (E)-3-(2-chlorophenyl)acrylic acid (13 g, 71.2 mmol) in benzene (100 ml) was added triethylamine (14.4 g, 141 mmol) followed by DPPA (19.5 g, 71.2 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as pale yellow solid (14 g, 95%). 1H NMR (400 MHz, CDCl3): δ ppm 8.19-8.15 (d, J=16 Hz, 1H), 7.63-7.61 (d, J=8 Hz, 1H), 7.44-7.42 (m, 1H), 7.36-7.26 (m, 2H), 6.44-6.40 (d, J=16 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]1[O:22][C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:15][CH:13]1[CH3:14]>>[CH2:12]1[O:22][C:16]2([CH2:21][CH2:20][N:19]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17]2)[O:15][CH:13]1[CH3:14]
Reactant: CC1COC2(CCNCC2)O1
Reactant: COC(=O)c1ccccc1F
Product: COC(=O)c1ccccc1N1CCC2(CC1)OCC(C)O2
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A mixture of methyl 2-fluorobenzoate (16.0 g, 103.8 mmol) and 4-piperidone propylene ketal (9.8 g, 62.3 mmol) was stirred at room temperature (8 d). Flash chromatography on silica gel (10% MeOH-90% CHCl3) afforded the title compound (44).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:11][C:12](=[O:26])[CH2:13][CH2:14][C:15]1[NH:19][C:18]2[CH:20]=[C:21]([Cl:25])[C:22](Br)=[CH:23][C:17]=2[N:16]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:21]1[C:22]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:23][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]([OH:11])=[O:26])[NH:19][C:18]=2[CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCc1nc2cc(Br)c(Cl)cc2[nH]1
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: COCCOC
Product: O=C(O)CCc1nc2cc(-c3ccccc3)c(Cl)cc2[nH]1
Temperature: 85 °C
Reaction time: 10 h

Procedure:
A 4 mL vial with a septum cap and a stirring bar was charged with phenylboronic acid (4.5 mg, 0.037 mmol) and Pd(PPh3)4 (2.0 mg, 5 mol %) and was purged briefly with N2. A solution of 3-(5-bromo-6-chloro-1H-benzimidazol-2-yl)-propionic acid methyl ester (Intermediate 9, 10.0 mg, 0.032 mmol) in DME (200 uL) was added to the vial, followed 1M aqueous K2CO3 (100 uL). The resulting mixture was stirred at 85° C. for 10 h. The mixture was allowed to cool down to rt, and was partitioned with EtOAc (1 mL) and 10% aqueous AcOH (1 mL). The organic layer was separated and evaporated to dryness in vacuo. The resulting oily residue was dissolved in DMSO (1.0 mL), filtered and purified by reverse-phase HPLC to give the title compound. LR-MS (API-ES): calculated for C16H13ClN2O2 300.0, observed m/e 301.0 (M+H)+ (Rt 2.42 min).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[C:2]=[S:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>C(#N)C>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[S:3]
Reactant: Nc1ccccc1O
Reactant: S=C=NCc1ccncc1
Solvent: CC#N
Product: Oc1ccccc1NC(=S)NCc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 15 parts of 4-(isothiocyanatomethyl)pyridine, 9.5 parts of 2-aminophenol and 160 parts of acetonitrile was stirred for 3 hours at room temperature. The precipitated product was filtered off, washed with 2,2'-oxybispropane and crystallized from acetonitrile, yielding 8.22 parts of N-(2-hydroxyphenyl)-N'-(4-pyridinylmethyl)thiourea; mp. 179.6° C. (intermediate 73).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]#[N:8])=[O:5].C([O-])(=O)C.[NH4+].C(O)(=O)C.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](=O)[CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>C1C=CC=CC=1.O>[C:7](/[C:6](=[C:31](/[C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)=[CH:30][CH:29]=1)\[CH3:32])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])#[N:8]
Reactant: CC(=O)c1ccc(N2CCN(C)CC2)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)/C(C#N)=C(/C)c1ccc(N2CCN(C)CC2)cc1
Temperature: 137.5 °C
Reaction time: 36 h
Yield: 31.9 %

Procedure:
Ethyl cyano acetate (3.12 g, 27.6 mmol), ammonium acetate (123 mg, 1.76 mmol), acetic acid (0.2 ml, 3.5 mmol) were added successively to a stirred solution of 1-(4-(4-methylpiperazin-1-yl)phenyl)ethanone (5.0 g, 23 mmol) in benzene (25 ml) and stirred for 36 h at 135-140° C. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. This was purified by column chromatography using 2% methanol in CHCl3 as eluent to afford (Z)-ethyl 2-cyano-3-(4-(4-methylpiperazin-1-yl)phenyl)but-2-enoate as yellow liquid 2.30 g (32.4%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:25][CH2:24][CH2:23][C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:16]=3[N:17]=[C:18]([NH2:20])[N:19]=2)[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:25][CH2:24][CH2:23][C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:16]=3[N:17]=[C:18]([NH2:20])[N:19]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(N)nc3c2CCCc2ccccc2-3)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(c(N3CC[C@@H](N)C3)n1)CCCc1ccccc1-2
Reaction time: 16 h

Procedure:
A solution of the product from Example 4D (68 mg, 0.17 mmol) in CH2Cl2 (3 mL) was treated with trifluoroacetic acid (0.2 mL) and stirred for 16 hours. The mixture was diluted with CH2Cl2, washed H2O, dried, concentrated and chromatographed on silica gel eluting with eluting with NH4OH/MeOH/CH2Cl2 (0.8/8/92) to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH:32][CH3:33]>CCN(C(C)C)C(C)C.O>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([N:32]([CH2:31][CH2:30][O:29][CH3:28])[CH3:33])[C:7]=3[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Reactant: CNCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCN(C)c1cc(C(=O)O)nc2c(-c3cccc(O)c3)nc(N3CCOCC3)nc12

Procedure:
A mixture of Example 9 (0.1 g, 0.25 mmol) and N-(2-methoxyethyl)methyl amine (34 mg, 0.38 mmol) in DIEA (1 mL) and water (0.5 mL) was stirred at 170° C. for 2 hours. The two phases were separated and the aqueous layer concentrated in vacuo. Purification by column chromatography (increasing amount of MeOH in DCM) followed by washing with Et2O afforded the title compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:36])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:16](=[O:36])[CH2:17]2)(=[O:23])=[O:22])=[CH:29][CH:28]=1)#[CH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(C#C[Si](C)(C)C)cc3)CC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C#Cc1ccc(S(=O)(=O)N2CCN(CC3CCNCC3)C(=O)C2)cc1
Reaction time: 1 h
Yield: 124.4 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)-4-(4-iodobenzenesulfonyl)-4-piperidylmethyl]-2-piperazinone (1.13 g), which was produced according to a method described in Reference Example 54 using 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone and 4-iodobenzenesulfonyl chloride, in diethylamine (20 ml)-DMF (5 ml) were added trimethylsilylacetylene (244 mg), bis(triphenylphosphine)palladium chloride (II) (69 mg) and copper iodide (2 ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane:acetone=1:1) to give brown crystals of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-[2-(trimethylsilyl)ethynyl]benzenesulfonyl]-2-piperazinone (825 mg). To a solution of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-[2-(trimethylsilyl)ethynyl]benzenesulfonyl]-2-piperazinone (534 mg) in toluene (10 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred for 1 hour. The reaction solution was concentrated, and the residue was dissolved in ethanol (20 ml). To the solution was added 1N sodium hydroxide (2 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added ethyl acetate, and the mixture was washed with 10% sodium carbonate solution and saturated brine, dried (MgSO4) and concentrated. Precipitated crystals were washed with ethanol-ether to give brown crystals of 4-(4-ethynylbenzenesulfonyl)-1-[4-piperidylmethyl]-2-piperazinone (450 mg). To 10% sodium carbonate solution was added bromopyridine hydrochloride (272 mg), and the mixture was extracted with ethyl acetate, dried and concentrated. To the residue were added 4-(4-ethynylbenzenesulfonyl)-1-[4-piperidylmethyl]-2-piperazinone (289 mg) and isoamylalcohol (10 ml), and the mixture was allowed to react at 130% overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added 10% sodium carbonate solution. The mixture was extracted with ethyl acetate-THF, and the extract was washed with saturated brine, dried and concentrated. The residue was purified with silica gel column chromatography (acetone:methanol=9:1→1:1), washed with water, and precipitated crystals were washed with acetone-ether to give powder of 4-(4-ethynylbenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (85 mg).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])=[N:15][CH:14]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 55 %

Procedure:
Prepared as described in general procedure P using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (1.0 g, 3.0 mmol), piperazine-1-carboxylic acid tert-butyl ester (838 mg, 4.5 mmol), acetic acid (40 μL, 0.6 mmol) and sodium triacetoxyborohydride (765 mg, 3.6 mmol) to afford 835 mg (55%) of the desired product after purification.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C:7](=[CH:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O>CCOCC>[CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@@]12CCC[C@H]1C1=CCc3cc(O)ccc3[C@H]1CC2
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCc3cc(O)ccc3[C@H]1CC2
Reaction time: 1 h

Procedure:
This synthesis is depicted in FIG. 11. A solution of the ketone 10 (800 mg, 3.10 mmol) in dry ether (5 ml) was added dropwise at RT. to a slurry of LiAlH4 (38 mg, 1 mmol) in ether (3 ml) (e). After 1 h, the mixture was hydrolyzed with 10% aq. H2SO4. After workup (ether), the crude product (802 mg, 9:1-mixture of 12 and 11) was chromatographed on silica gel with CH2Cl2. A small fraction of 11 (70 mg) was eluted first, followed by the main fraction of 12 (705 mg, 87%). M.p. 113°-115°, [a]- +36.3° (C=1.0). - IR. (CHCl3): 3640 m, 3500 br., 1585w. -1H-NMR. (90 MHz) : 0.78 (s, 3 H); 3.60 (m, w1/2 ≈(m, 20, 1 H); 5.71 (m, 1 H), 5.87 (m, 1 H).