Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-ethoxycarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[I:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>>[I:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1)=[O:23]
Reactant: O=C(Cl)c1ccccc1I
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccccc2I)CC1
Yield: 98 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 123, Step 3) was stirred at room temperature with 2-iodobenzoyl chloride (200 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude 2-[1-(2-iodo-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile was obtained as a solid. (320 mg; 98% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH:39]=[C:38]([C:40]2[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=2)[NH2:43])[CH:37]=[N:36]1.Cl.C([O-])(O)=O.[Na+]>C(O)C(F)(F)F.CCOC(C)=O>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)[CH:41]=3)[N:7]=2)[CH:18]=1
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c2)cn1
Temperature: 80 °C
Yield: 63.4 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.100 g, 0.217 mmol) and 3-(1-methyl-1H-pyrazol-4-yl)aniline (0.0563 g, 0.325 mmol) was dissolved in 4 mL of trifluoroethanol with stirring. HCl (0.11 mL, 4N in dioxane, 0.44 mmol) was added, and the vessel was sealed. The reaction was heated to 80° C. for 4.5 days and cooled to rt. The reaction was poured into half-saturated aqueous NaHCO3 solution and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded a solid that was triturated with diethyl ether to yield 0.0823 g (63%) of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.73 (s, 1H), 9.52 (d, J=5.1 Hz, 1H), 8.37-8.30 (m, 2H), 8.03 (d, J=7.3 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.69 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.54-7.43 (m, 2H), 7.42-7.32 (m, 1H), 7.26-7.11 (m, 4H), 7.00-6.92 (m, 1H), 6.61 (d, J=5.3 Hz, 1H), 3.80 (s, 3H). MS (M+H, ES+) 599.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:20])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1(I)[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C.CCOCC.[Ag-]=O>[CH:21]1([O:18][C:17](=[O:19])[CH:16]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: IC1CCCC1
Agent: O=[Ag-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OC1CCCC1)C(Cc1ccc(OCc2ccccc2)cc1)OC1CCCC1
Temperature: 55 °C
Yield: 17 %

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (1.0 g, 3.67 mmol), cyclopentyl iodide (7.2 g, 36.7 mmol) and silver (I) oxide (4.25 g, 18.3 mmol) in DMF (15 mL) was heated at 55° C. under N2 for 72 h. The reaction mixture was cooled, diluted with Et2O and filtered through hyflo. The filtrate was extracted with water and the organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 10:1 hexanes:acetone to afford 0.255 g (17%) 3-(4-benzyloxy-phenyl)-2-cyclopentyloxy-propionic acid cyclopentyl ester. Rf=0.67 (1:1 hexanes:acetone). 1H NMR.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][C:14]1([C:17]([OH:19])=O)[CH2:16][CH2:15]1.[Cl:20][C:21]1[CH:34]=[C:33]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:32]([Cl:41])=[CH:31][C:22]=1[O:23][C@H:24]1[CH2:27][C@H:26]([CH2:28][NH:29][CH3:30])[CH2:25]1>C1COCC1>[ClH:20].[Cl:20][C:21]1[CH:34]=[C:33]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:32]([Cl:41])=[CH:31][C:22]=1[O:23][C@H:24]1[CH2:25][C@H:26]([CH2:28][N:29]([CH3:30])[C:17]([C:14]2([CH3:13])[CH2:16][CH2:15]2)=[O:19])[CH2:27]1
Reactant: CNC[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1
Reactant: CC1(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C[C@H]1C[C@H](Oc2cc(Cl)c(CN3CCCC3)cc2Cl)C1)C(=O)C1(C)CC1
Product: Cl

Procedure:
CDI (71 mg, 0.43 mmol) was added to a solution of 1-methylcyclopropanecarboxylic acid CAS 6914-76-7 (66 mg, 65 mmol) in THF (2 ml) at RT under stirring, the mixture was stirred at RT for 1 h. Example 381, ({trans-3-[2,5-dichloro-4-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylamine (150 mg, 0.43 mmol) was added to the mixture and the solution was stirred at RT for 20 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 5 g, hexane/CHCl3 20:80→0:100, then CHCl3/MeOH 100:0→95:5). The residue was dissolved in ether (1 mL). 4N HCl/dioxane (0.20 mL) was added, and the reaction mixture was evaporated to dryness. The obtained crystals were washed with ether and dried in vacuo to give the title compound (65 mg, 32%) as beige crystals. LC/MS data: 425.1 (M+H) (calculated for C22H30Cl2N2O2 425.4). 1H NMR-data (DMSO-d6): 10.77 (br.s, 1H, NH+); 8.01 (s, 1H, NH); 7.09 (s, 1H, Ar—H); 4.80-4.92 (m, 1H), 4.42-4.56 (m, 2H); 3.33-3.55 (m, 4H); 2.95-3.18 (m, 5H); 2.60-2.70 (m, 1H); 2.17-2.34 (m, 4H); 1.84-2.17 (m, 4H); 1.25 (s, 3H); 0.92-0.96 (m, 2H), 0.46-0.52 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C(N(CC)CC)C.O.[NH2:20][NH2:21]>CS(C)=O.O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH:20][NH2:21])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: NN
Reactant: CSc1nc(Cl)c(F)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(Cl)c(F)c(NN)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
4,6-Dichloro-5-fluoro-2-(methylthio)pyrimidine (16.8 g, 78.85 mmol) and triethylamine (16.49 mL, 118.3 mmol) were dissolved in DMSO (200 mL) and stirred. The mixture was cooled to ˜5° C. with an ice water bath. To this solution was slowly added hydrazine monohydrate (4.59 mL, 94.62 mmol). After the addition was complete, the reaction mixture was warmed up to RT and stirring was continued for 1 h. The reaction mixture was diluted with water (500 mL), and the aqueous solution was extracted with CH2Cl2 (3×300 mL). The combined organic solution was washed with water (3×250 mL) and brine (250 mL), then dried (Na2SO4) and concentrated in vacuo to afford 4-chloro-5-fluoro-6-hydrazino-2-(methylthio)pyrimidine as a red foamy solid (9.70 g, 59%). LCMS: (M+H)+: 208.9.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][C:15]=2[CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[CH2:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:21][O:20][C:18]1[C:17]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:16][C:15]([CH:28]2[CH2:29][C:30]([CH3:36])([CH3:37])[CH2:31][C:32]([CH3:35])([CH3:34])[CH2:33]2)=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC(C)(C)CC(C)(C)C2)cc1N1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)cc1N1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
A mixture of the 4-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (88 mg, 0.17 mmol) produced in Example (72a), trifluoroacetic acid (0.25 mL, 3.2 mmol) and dichloromethane (0.5 mL) was stirred for 1 hour and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 56 mg of the title compound as a red solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6]3=[C:7]([C:12]([O:14][C:15](=[O:16])[C:5]3=[CH:4][CH:3]=1)=O)[CH:8]=[CH:9][CH:10]=2.[CH2:17]([CH:24]([NH2:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)CO.CO.O>[CH2:17]([CH:24]([N:32]1[C:12](=[O:14])[C:7]2=[C:6]3[C:11](=[CH:10][CH:9]=[CH:8]2)[C:2]([Br:1])=[CH:3][CH:4]=[C:5]3[C:15]1=[O:16])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Reactant: CCCCCCCC(N)CCCCCCC
Solvent: CO
Solvent: OCCO
Solvent: O
Product: CCCCCCCC(CCCCCCC)N1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
5 g (18 mmol) of 4-bromonaphthalene-1,8-dicarboxylic anhydride were heated to 160° C. with 6.1 g (27 mmol) of 1-heptyloctylamine in 50 ml of ethylene glycol for 4 hours. The resulting solution was allowed to cool to room temperature. Thereafter, the solution was diluted with 50 ml of methanol and 50 ml of distilled water. The aqueous solution was extracted with diethyl ether, the solution was dried over MgSO4 and the solvent was evaporated. The resulting yellow oil was purified by column chromatography with dichloromethane as the eluent, which afforded 5.5 g (63%) of the title compound as a colorless oil.
Reaction SMILES: IC.[H-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([O:35][C@H:36]3[C@H:40]4[O:41][CH2:42][C@@H:43]([OH:44])[C@H:39]4[O:38][CH2:37]3)=[N:24][C:9]2=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.[CH3:45]COC(C)=O.CCCCCC>CN(C=O)C.CCOC(C)=O>[CH3:45][O:44][C@@H:43]1[CH2:42][O:41][C@@H:40]2[C@H:36]([O:35][C:25]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:8]4[C:9]([N:24]=3)=[N:10][C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:14][CH:13]=3)=[C:6]([Cl:5])[CH:7]=4)[CH2:37][O:38][C@H:39]12
Reactant: CCOC(C)=O
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodomethane (40 μl, 0.640 mmol) and sodium hydride (7.7 mg, 0.193 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (35.6 mg, 0.061 mmol) in DMF (0.2 ml). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then partitioned between EtOAc (40 ml), water (10 ml), and 2 N HCl (10 ml). The organic layer was washed with water (2×20 ml) and brine (1×10 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a pale amber residue. The residue was dissolved in EtOAc and loaded onto a 500 micron 20 cm×20 cm silica gel plate, which was developed using 70% EtOAc/hexane. The silica containing the product bands was collected and eluted with EtOAc (80 ml). The solvent was evaporated under reduced pressure to give the desired product as a colorless residue. LC-MS: calculated for C31H36ClN3O5Si 593.21 observed m/e: 594.24 (M+H)+ (Rt 1.40/2 min)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:35]1([CH3:53])[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=[C:43]([C:49]([F:52])([F:51])[F:50])[N:42]=2)[CH:36]=1.C(N(CC)CC)C>C(#N)C.C(OC(=O)C)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:13])[C:10]([NH:48][CH2:47][C:46]2[C:41]([C:37]3[CH:36]=[C:35]([CH3:53])[CH:40]=[CH:39][CH:38]=3)=[N:42][C:43]([C:49]([F:52])([F:50])[F:51])=[CH:44][CH:45]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: CC(C(=O)O)c1ccc(C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a stirred solution of 2-(4-cyanophenyl)propanoic acid (148 mg, 0.85 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (243 mg, 1.27 mmol), 1-hydroxybenzotriazole (171 mg, 1.27 mmol), (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (247 mg, 0.93 mmol) and triethylamine (0.29 mL, 2.11 mmol). The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-Cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (311 mg) was obtained as 87% yield.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)CC.[CH2:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:18]1[O:20][CH2:19]1.[ClH:34]>O>[ClH:34].[OH:20][CH:18]([CH2:17][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:19][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CCCCCCCCCCCCOCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 0.5 h
Yield: 33108.2 %

Procedure:
L-arginine (17.4 g, 0.1 mmols) were dissolved in 100 ml of water in a three-necked round flask, and 100 ml of propanol were added thereto. Dodecyl glycidyl ether [made by Sakamoto Yakuhin Kogyo Co., Ltd., 24.2 g (0.1 mols)] was added thereto dropwise over a period of 30 minutes while being heat-stirred under reflux, and the mixture was stirred as such under reflux, for 3 hours. After it was identified through TLC and gas chromatography that dodecyl glycidyl ether disappeared, the residue was neutralized with 10.1 g (0.1 mols) of 36-% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (Kieselgel 60 made by Merck & Co., Inc., eluent--mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 15.0 g of N-(2-hydroxy-3-dodecyloxypropyl)-L-arginine hydrochloride in a yield of 36.0%.
Reaction SMILES: [CH:1]1([C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:5]([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45](OC)OC)=[CH:41][CH:40]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:12]1[C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[C@H:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:11][CH:45]1[C:42]1[CH:43]=[CH:44][C:39]([O:38][CH3:37])=[CH:40][CH:41]=1)=[O:14])([CH3:18])([CH3:17])[CH3:19]
Reactant: COc1ccc(C(OC)OC)cc1
Reactant: CCOC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Yield: 53 %

Procedure:
A solution of 2.07 g of ethyl (2R,3S)-3-cyclopropyl-3-tert -butoxycarbonylamino-2-hydroxypropionate and 213 mg of pyridinium p-toluenesulfonate in 125 ml of toluene is refluxed under heating. To the mixture is added dropwise a solution of 2.76 g of p-anisaldehydedimethylacetal in 25 ml of toluene for 20 minutes. The reaction mixture is evaporated to remove the generated methanol. The mixture is stirred under heating for 1.5 hours and cooled. After the reaction mixture is condensed under reduced pressure, ethyl acetate and water are added to the residue. The ethyl acetate layer is obtained by separation. The aqueous layer is extracted with ethyl acetate. The extract is washed with water and brine, dried and condensed under reduced pressure. The residue is purified by silica gel column chromatography (solvent; toluene:ethyl acetate=40:1) to give 1.572 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-cyclopropyl-5-oxazolidinecarboxylate (diastereomeric mixture).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH3:21][C:22]([CH3:24])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH:22]([CH3:24])[CH3:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication 88/08424, 2.0 g) is dissolved in 35 ml of methanol and acetone (0.48 g) is added. The reaction is cooled to 0° and acetic acid (to pH 4.0) is added. The reaction is stirred 15 min at 0° and then sodium cyanoborohydride (0.50 g) is added. The reaction is allowed to warm slowly to 20°-25° and followed by TLC until completion. Additional acetic acid, sodium cyanoborohydride and acetone are sometimes necessary to force the reaction to completion. The reaction is diluted with chloroform (100 ml), washed with saturated aqueous sodium bicarbonate (50 ml), saline (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (75 g silica gel, 4:1 hexane/ethyl acetate) affords the title compound, NMR (300 MHz, CDCl3) 7.67, 6.91, 4.15, 3.57, 3.00, 1.48 and 1.23 δ.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([O-:9])([O-:8])=[O:7])#N.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C[O:23][C:24](=[O:56])[C@H:25]([CH2:48][C:49]1C=CC(O)=[CH:51][CH:50]=1)[NH:26][C:27](=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1.Cl>C(#N)C.O>[C:27]([NH:26][C@H:25]([C:24]([OH:56])=[O:23])[CH2:48][C:49]1[CH:50]=[CH:51][C:4]([O:5][P:6]([OH:9])([OH:8])=[O:7])=[CH:3][CH:1]=1)(=[O:47])[CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC#N
Product: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 23 %

Procedure:
A solution of pyridinium cyanoethylphosphate (2 mmol) in anhydrous acetonitrile (3 ml) was added to dry N-arachidonoyl-L-tyrosine methyl ester. N,N′-Dicyclohexylcarbodiimide (413 mg, 2 mmol) was then added and the mixture was stirred at room temperature. After 5 days, the mixture was cooled to 0° C., water (0.5 ml) was added and, after stirring for 30 min at room temperature, the precipitated N,N′-dicyclohexylurea was separated by filtration. The filtrate was evaporated in vacuo and the residue obtained was fractionated by short column chromatography on silica gel. The desired phosphorylated N-acyl-L-tyrosine methyl ester was eluted from column with chloroform-methanol (70-60:30-40, v/v). The composition of the eluates was controlled by TLC on Silica gel 60 plates (system B) using a molybdate spray for detecting the spots. The appropriate fractions were combined, evaporated to dryness in vacuo and residue was dissolved in 1 ml tetrahydrofuran. The solution obtained was added, dropwise over a period of 5 min, to a cooled (ice-bath), stirred 1.5 M NaOHaq (4 ml). After a further 25 min, the mixture was acidified with 1 N HCl to pH 2-3 and extracted with chloroform-methanol (2:1, v/v). The extract was washed with methanol-water (10:9, v/v), concentrated in vacuo and applied to a column of silica gel. The desired products was eluted from column with chloroform-methanol (30-20:70-80, v/v), the fractions containing pure substance stained on the TC plates with molybdate spray were combined and evaporated to dryness to give 63 mg (23%) of (8): Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.3 (s, 8H, 4CH2); 2.0-2.4 (m, 6H, 2CH2CH═CH and CH2CO); 2.7-2.9 (br s, 6H, 3HC═CHCH2CH═CH); 2.9-3.1 (m, 2H, CH2Ar); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 8H, 4HC═CH); 7.0-7.2 (q, 4H, Ar); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].[Si]([O:26][C:27]([O:29][CH3:30])=[CH2:28])(C(C)(C)C)(C)C>>[CH3:30][O:29][C:27](=[O:26])[CH2:28][CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:6]1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Product: COC(=O)CC1c2ccccc2-c2ccccc2N1C(C)=O

Procedure:
(5-Acetyl-5,6-dihydro-phenanthridin-6-yl)-acetic acid methyl ester was prepared from phenanthridine, acetyl chloride, and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene according to GP 2. Yield, 43%. 1H-NMR (DMSO-d6): δ=2.12 (s, br., 3H), 2.28-2.43 (m, 2H), 3.54 (s, 3H), 6.22 (s, br., 1H), 7.28-7.56 (m, 6H), 7.90-7.98 (m, 2H); (+)-ESI-MS: m/z=296 [M+H]+, 254, 222, 180.