Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[O:38][C:39]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:40][CH:41]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[CH:40][CH:41]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)o2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-c3ccc(CN4CCOCC4)o3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-[5-(morpholin-4-ylmethyl)fur-2-yl]naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:8]([C:10]1[CH:39]=[CH:38][C:13]2[N:14]([CH3:37])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:36])[NH:26][C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:28])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[CH3:47][S:48]([OH:51])(=[O:50])=[O:49]>CC(C)=O>[CH3:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:27](/[N:26]=[C:25](\[NH2:36])/[C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH2:17][C:15]2[N:14]([CH3:37])[C:13]3[CH:38]=[CH:39][C:10]([C:8]([N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:9])=[CH:11][C:12]=3[N:16]=2)=[CH:24][CH:23]=1)=[O:28].[CH3:47][S:48]([OH:51])(=[O:50])=[O:49]
Reactant: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 20 °C

Procedure:
100 g of 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]amino methyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl) amide was dissolved in 890 ml of acetone under heating. A solution of 15 g of methane sulfonic acid in 200 ml of acetone was added to the reaction mixture. The solution is filtered and after the addition of 77 ml of acetone cooled to approximately 20° C. The precipitated product was filtered and washed with acetone then dried at 50° C. under reduced pressure.
Reaction SMILES: [N:1]([CH:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][CH:16]=1)[CH2:5][CH:6]1OCC[O:7]1)=[N+:2]=[N-:3].Cl.C(OCC)C>O1CCCC1>[N:1]([CH:4]([C:11]1[CH:16]=[N:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=1)[CH2:5][CH:6]=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(CC1OCCO1)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(CC=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-(1-azido-2-(1,3-dioxolan-2-yl)ethyl)-2-(trifluoromethyl)pyridine (7.44 g, 25.8 mmol) in tetrahydrofuran (60 mL) was treated with 20% aq. HCl (60 mL) at 0° C. The mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, ethyl ether was added and the organic layer was separated, dried over MgSO4, and concentrated to yield a crude oil without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:12][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a mixture of 5-trifluoromethyl-pyridine-2-ylamine (65 g) and chloroform (100 mL), N-bromosuccinimide (71 g) was added in 5 parts under ice-cooling. The mixture was heated to room temperature, and stirred for 1 hour, then heated to 80° C., and stirred with heating for 30 minutes. After the mixture was allowed to cool to room temperature, into the mixture, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution were poured, and extracted with chloroform. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 96 g of 3-bromo-5-trifluoromethyl-pyridine-2-ylamine.
Reaction SMILES: O[C:2]1[C:10]([C:11](=[O:25])[CH2:12][C:13](=[O:24])[C:14]2[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].Cl.[C:27](O)(=O)C>>[O:25]=[C:11]1[C:10]2[C:2](=[C:3]([C:4]([O:6][CH3:27])=[O:5])[CH:7]=[CH:8][CH:9]=2)[O:24][C:13]([C:14]2[C:15]([C:20]([F:23])([F:21])[F:22])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:12]1
Reactant: CC(=O)O
Reactant: O=C(CC(=O)c1cccc(C(=O)[O-])c1O)c1cccnc1C(F)(F)F
Agent: Cl
Product: COC(=O)c1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Yield: 23 %

Procedure:
A mixture of 2-hydroxy-3-(3-oxo-3-(2-(trifluoromethyl)pyridin-3-yl)propanoyl)benzoate 39 (600 mg, 1.46 mmol) and con. HCl (1 mL) in acetic acid (5 mL) was heated at 100° C. for 4 hours. The reaction mixture was concentrated and sat. aq NaHCO3 was added. The mixture was extracted with ethyl acetate and the combined organics were washed with brine, dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography to give 40 (120 mg, 23% yield).
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[CH:14]=[C:13]3[C:26]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:29]=[CH:28][N:27]=2)=[N:7][N:6]=1)(=O)=O.[NH3:38].O>CS(C)=O>[O:35]1[CH2:34][CH2:33][N:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:8]5[S:9][C:5]([NH2:38])=[N:6][N:7]=5)[CH:11]=4)[NH:15][CH:14]=3)[N:31]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2nccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Reactant: N
Solvent: CS(C)=O
Solvent: O
Product: Nc1nnc(-c2ccc3[nH]cc(-c4nccc(N5CCOCC5)n4)c3c2)s1
Temperature: 110 °C
Yield: 5 %

Procedure:
A sealed tube was charged with tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(4-morpholinopyrimidin-2-yl)-1H-indole-1-carboxylate (1.7 g, 3.3 mmol) in DMSO (17 mL) saturated with NH3. The reaction was heated at 110° C. for 7 h, then the mixture was poured into H2O. The mixture was extracted with EtOAc and the combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography to give 5-(3-(4-morpholinopyrimidin-2-yl)-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (65 mg, 5%). MS (ESI, pos. ion) m/z: 380.1 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ: 11.89 (1H, s), 8.79 (1H, s), 8.28 (1H, d, J=6.3 Hz), 8.24 (1H, d, J=2.4 Hz), 7.75 (1H, dd, J=8.4, 1.5 Hz), 7.52 (1H, d, J=8.7 Hz), 7.32 (2H, s), 6.66 (1H, d, J=6.3 Hz), 3.81 (8H, brs).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][C:15]=2[N+:25]([O-:27])=[O:26])[C:4]1=[O:28].O1CCOCC1.Cl>O>[Cl:1][CH2:2][CH:3]1[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:6][N:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:15]=2[N+:25]([O-:27])=[O:26])[C:4]1=[O:28]
Reactant: CCOC(=O)c1ccc(N2OC(c3ccccc3)C(CCl)C2=O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(N2OC(c3ccccc3)C(CCl)C2=O)c([N+](=O)[O-])c1

Procedure:
270 g (0.67 mols.) of 4-chloromethyl-5-phenyl-2-(4-ethoxycarbonyl-2-nitrophenyl)isoxazolin-3-one was added to 2.5 liters of 1,4-dioxane, and 300 ml of concentrated hydrochloric acid was added thereto, followed by refluxing the mixture for 8 hours under heating. After cooling, water was added to the reaction solution, and the crystals which precipitated were collected by filtration, washed with water, and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[N+:21]([O-])=O)[CH:9]=2)[CH:4]=1>O1CCCC1.CO.[Pd]>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[C:14]([NH2:21])[CH:15]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 2-methoxy-6-(4-methoxy-2-nitrophenyl)naphthalene (390 mg) in tetrahydrofuran (6 ml) and methanol (6 ml) was added 10% palladium-activated charcoal (100 mg), and the solution was stirred overnight at room temperature under a hydrogen atmosphere at ambient pressure. After filtration through celite pad, the solvent was evaporated in vacuo, and the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (285 mg).
Reaction SMILES: [Cl:1][C:2]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[C:29]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17]CC1C=CC(OC)=C(OC)C=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][C:2]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[C:29]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[OH:17]
Reactant: COc1ccc(COc2cc(C)nc3c(OCc4c(Cl)ccc([N+](=O)[O-])c4Cl)cccc23)cc1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)c2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Yield: 34.2 %

Procedure:
A mixture of 8-(2,6-dichloro-3-nitrobenzyloxy)-4-(3,4-dimethoxybenzyloxy)-2-methylquinoline (106 mg), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (50 mg) and dichloromethane-water (18:1, V/V, 2.85 ml) was heated under reflux for 19 hours. The reaction mixture was partitioned into dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a preparative thin-layer chromatography (dichloromethane-methanol) followed by washing with ethanol to give a brownish powder (26 mg) of 8-(2,6-dichloro-3-nitrobenzyloxy)-4-hydroxy-2-methylquinoline.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[CH2:11][O:10][CH3:9])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COCC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCC1CCCN1c1cncc(Cl)n1
Yield: 80.4 %

Procedure:
A solution of 2,6-dichloropyrazine (1.18 g), 2-(methoxymethyl)pyrrolidine (1.0 g) and potassium carbonate (1.64 g) in DMA (15 mL) was stirred at 80° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→15% ethyl acetate/hexane) to give the title compound (1.45 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 129 c]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 124 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as light yellow solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[C:20]1([C:26]23[CH2:35][CH:30]4[CH2:31][CH:32]([CH2:34][CH:28]([CH:29]4[CH2:36][C:37](O)=[O:38])[CH2:27]2)[CH2:33]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]1([C:26]23[CH2:27][CH:28]4[CH2:34][CH:32]([CH2:31][CH:30]([CH:29]4[CH2:36][C:37]([N:12]4[CH2:13][CH:14]5[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]5)[CH2:11]4)=[O:38])[CH2:35]2)[CH2:33]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC1CC(c1ccccc1)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC1CC(c1ccccc1)(C4)C3)C2
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Triethylamine 14.0 gl was added to a methylene chloride 1 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 15.9 mg and stirred at O@C for 30 min. 5-phenyl-2-adamantyl acetic acid 22.6 mg and WSC 19.3 mg were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 64 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(5-phenyl-2-adamantylacetyl)1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 3 ml solution of lithium aluminum hydride 3.8 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: acetone 20:1) to obtain the product. Yield: 7.0 mg (Yield 21%)
Reaction SMILES: C(OC1CC2C3[C:15](=CC=CC=3)[NH:14][C:13]=2CC1)(=O)C1C=CC=CC=1.[H-].[Na+].ClC1C=CC(CCl)=CC=1.C(O[CH:43]1[CH2:55][C:54]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]([CH2:56][C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=3)[C:46]=2[CH2:45][CH2:44]1)(=O)C1C=CC=CC=1>O.CN(C)C=O>[Cl:63][C:60]1[CH:61]=[CH:62][C:57]([CH2:56][N:47]2[C:46]3[CH2:45][CH2:44][CH:43]([N:14]([CH3:15])[CH3:13])[CH2:55][C:54]=3[C:53]3[C:48]2=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:58][CH:59]=1
Reactant: O=C(OC1CCc2[nH]c3ccccc3c2C1)c1ccccc1
Reactant: O=C(OC1CCc2c(c3ccccc3n2Cc2ccc(Cl)cc2)C1)c1ccccc1
Agent: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCc2c(c3ccccc3n2Cc2ccc(Cl)cc2)C1

Procedure:
A mixture of 29.1 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole and 4.3 g. of sodium hydride (56% in mineral oil) in 200 ml. of dimethylformamide was heated on a steam bath and 16.1 g. of p-chlorobenzyl chloride in 30 ml. of dimethylformamide was added dropwise. The reaction mixture was heated two hours, cooled, and diluted with water. The resulting oil was washed with water and crystallized from isopropyl alcohol to give 12.7 g. of 3-benzoyloxy-9-(p-chlorobenzyl)-1,2,3,4-tetrahydrocarbazole, m.p. 150°-152° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5][OH:6].B(F)(F)F.[N+](=[CH:17][C:18](=[O:43])[CH:19]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=1)[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][C:25]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[N-].CCN(CC)CC>C(Cl)Cl>[Cl:42][C:37]1[CH:36]=[C:35]([CH:19]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][C:25]([OH:34])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)[C:18](=[O:43])[CH2:17][O:6][CH2:5][C:4]2[CH:7]=[C:8]([CH3:10])[CH:9]=[C:2]([CH3:1])[CH:3]=2)[CH:40]=[CH:39][C:38]=1[Cl:41]
Reactant: [N-]=[N+]=CC(=O)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C)cc(CO)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(COCC(=O)C(CCN2CCC(O)(c3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Dissolve 3,5-dimethyl benzyl alcohol (1.32 g, 9.71 mmoles) in 4.0 ml of dry CH2Cl2 and add BF3 etherate (0.44 ml, 3.56 mmoles). Add a dry CH2Cl2 solution (2.0 ml.) of the product of Step 5 (0.7 g, 1.62 mmoles) dropwise at room temperature, under N2, over a period of 4.5 h. Stir the mixture at room temperature for another 30 min, then quench the reaction with water (6.0 ml) followed, after 10 min of stirring, by Et3N (2.0 ml). Stir for 15 min, then dilute with 90 ml of CH2Cl2. Wash the organic layer with water and dry it over anhydrous Na2SO4. Purify the reaction mixture by flash chromatography (SiO2), eluting the column first with 30% EtOAc/hexanes, then, after elution of the excess of 3,5-dimethyl benzyl alcohol, change the eluent to 40% EtOAc/Hexanes. Yield: 0.435 g. HRMS (FAB, M+H+): m/e calc'd for [C31H36NO3Cl2 ]+ : 540.2072; found 540.2075.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH:37]1[C:49]2[CH:48]([CH2:50][O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[C@H:56]([CH2:58][CH3:59])[CH3:57])=[O:53])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:52]([NH:54][C@H:55]([C:60]([NH:1][C@@H:2]([CH2:3][OH:4])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:61])[C@H:56]([CH2:58][CH3:59])[CH3:57])([O:51][CH2:50][CH:48]1[C:49]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:53]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: N[C@@H](CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
(R)(+)-2-amino-3-phenyl-1-propanol (427 mg, 2.83 mmol) dissolved in dry DMF (20 mL), stirred under nitrogen, to this stirred mixture at 25° C. DCC (699 mg, 3.39 mmol), HOBt (457 mg, 3.38 mmol) was added with constant stirring. After 10 minutes of stirring N-(9-fluorenylmethoxycarbonyl)-L-isoleucine (1.0 g, 2.83 mmol) was added to the above mixture and then stirred at 25° C. for 14 h. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (2% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.6), LC/MS also showed molecular ion peak corresponding to the dipeptide 1a with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 2% MeOH: CH2Cl2 to give 650 mg of the dipeptide Fmoc-NH-L-Ile-D-Phe-CH2OH (1a) as a white solid. Checked on LC/MS which showed M++1 (487.4) and M++Na (509.2).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])(=O)C.[K+].[Cl-].[Li+].[CH3:18][Si:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]2[C:21]([CH3:22])=[C:20]([Si:19]([CH3:24])([CH3:23])[CH3:18])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Cc1c(Br)cnc(N)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1c(Br)cnc2[nH]c([Si](C)(C)C)c(C)c12
Temperature: 90 °C
Reaction time: 72 h

Procedure:
The compound obtained in step 1 of Example 36 (1.8 g) was dissolved in N,N-dimethylformamide (40 ml), and potassium acetate (1.7 g) and lithium chloride (0.3 g) were added. After replacing the atmosphere in the system with nitrogen, palladium acetate (0.13 g) and 1-trimethylsilyl-1-propyne (4.3 ml) were added and the mixture was stirred at 90° C. for three days. The reaction solution was cooled to room temperature and then N,N-dimethylformamide was distilled off. The resulting residue was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give the crude title compound (2.4 g).
Reaction SMILES: [C:1]([C:4]1[C:5]([I:21])=[C:6]([C:15]([I:20])=[C:16]([NH2:19])[C:17]=1[I:18])[NH:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])([OH:3])=[O:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>Cl(O)(=O)(=O)=O>[C:1]([C:4]1[C:5]([I:21])=[C:6]([C:15]([I:20])=[C:16]([NH:19][C:22](=[O:24])[CH3:23])[C:17]=1[I:18])[NH:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(NC(=O)CCC(=O)O)c(I)c(C(=O)O)c1I
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)Nc1c(I)c(NC(=O)CCC(=O)O)c(I)c(C(=O)O)c1I

Procedure:
Potassium iododichloride (335 ml. 2.23N in water), was added over a period of forty minutes to a stirred suspension of 57.3 g. of 3'-carboxy-5'-aminosuccinanilic acid in 435 ml. of water. The solid product was collected by filtration and recrystallized from water and from aqueous dimethylformamide. The product was purified by converting it to the diammonium salt and then to the disodium salt, m.p. 222°-225° C. (dec.). The latter was acidified to produce the free acid form of 3'-carboxy-5'-amino-2',4',6'-triiodosuccinanilic acid, cream colored solid, m.p. 156.2°-172.2° C. (dec.). 3'-Carboxy-5'-amino-2',4',6'-triiodosuccinanilic acid can be acylated with acetic anhydride, using a few drops of perchloric acid as a catalyst to obtain 3'-carboxy-5'-acetamido-2',4',6'-triiodosuccinanilic acid [B; R is CH3CONH, R' and R" are H, Y' is CH2CH2, Z is OH].