Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][C:14]#[CH:15].C(N(CC)C1C=CC=CC=1)C>C(OCC)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]2[C:3]=1[O:12][CH2:13][CH:14]=[CH:15]2
Reactant: C#CCOc1cc(C(=O)OC)ccc1F
Solvent: CCN(CC)c1ccccc1
Solvent: CCOCC
Product: COC(=O)c1ccc(F)c2c1C=CCO2
Temperature: 220 °C

Procedure:
Methyl 4-fluoro-3-propargyloxybenzoate (14.0 g, 67.2 mmol) was mixed with N,N-diethylaniline and the reaction was heated to 220° C. for 5 hours. The black reaction mixture was allowed to cool, dissolved in diethyl ether (600 mL) and washed with 2 M HCl in portions (1 L). The aqueous washings were re-extracted with diethyl ether, the combined ether phases were washed with H2O until neutral, treated with brine, dried with MgSO4, filtered, and the solvent was removed in vacuo to give a dark brown crude residue. The crude solid was chromatographed on silica (eluent: methylene chloride/carbon tetrachloride 1:1) to give 11.9 g (85% yield) of a tannish yellow solid as the title compound (mp 73.5-74.5° C.). EIMS (70 eV) m/z (relative intensity) 208 (65, M+), 207 (42), 194 (12), 193 (100), 177 (32), 149 (10), 148 (12).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].Br[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCOC(=O)CCCOc1ccccc1OCCCBr
Reactant: CCc1nc(N)nc(N)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(N)nc(N)c1OCCCOc1ccccc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
2,4-Diamino-6-ethyl-5-hydroxypyrimidine (0.4625 g, 3 mmol) was added to a stirred solution of lithium hydroxide monohydrate (0.4406 g, 10.5 mmol) in DMF (4 mL) and the reaction mixture was stirred at 25° C. for 1 hour. A solution of ethyl 4-(2-(3-bromopropoxy)phenoxy)butanoate (1.0357 g, 3 mmol) in DMF (1 mL) was added and the reaction mixture was left stirring at 25° C. overnight. DMF was partially removed under reduced pressure to give residue. The residue was diluted with water and extracted with dichloromethane. The aqueous layer was neutralized with dilute HCl to give white solid. Recrystallization with acetone afforded the desired diaminopyrimidine as white solid (0.6911 g, 59%, m.p. 204-206° C.). 1H NMR (400 MHz, DMSO-d6): 1.10 (3H, t, J=7.5 Hz), 1.91 (2H, m), 2.14 (2H, m), 2.31-2.39 (4H, m), 3.78 (2H, t, J=6.1 Hz), 3.96 (2H, t, J=6.4 Hz), 4.13 (2H, t, J=6.1 Hz), 5.60 (2H, s), 6.09 (2H, s), 6.86-6.90 (2H, m), 6.95-7.01 (2H, m).
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:6][C@H:5](/[CH:7]=[CH:8]/[C@@H:9]([OH:21])[C@@H:10]([CH3:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([CH2:22][CH2:23][CH2:24][C:25]2[S:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=2)[C:3]1=[O:33].[H][H]>C(O)C.[Pd]>[F:34][C:2]1([F:1])[CH2:6][C@H:5]([CH2:7][CH2:8][C@@H:9]([OH:21])[C@@H:10]([CH3:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([CH2:22][CH2:23][CH2:24][C:25]2[S:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=2)[C:3]1=[O:33]
Reactant: C[C@@H](CCCc1ccccc1)[C@H](O)/C=C/[C@H]1CC(F)(F)C(=O)N1CCCc1ccc(C(=O)O)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](CCCc1ccccc1)[C@H](O)CC[C@H]1CC(F)(F)C(=O)N1CCCc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
To a solution consisting of 5-(3-((R)-3,3-difluoro-5-((3S,4S,E)-3-hydroxy-4-methyl-7-phenylhept-1-en-1-yl)-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylic acid (15.2 mg, 0.031 mmol) in ethanol (12 mL) and covered with an atmosphere of nitrogen was added palladium (12 mg, 10% on activated carbon). The nitrogen atmosphere was replaced with hydrogen and the reaction mixture was stirred vigorously for 5 hours at room temperature. The hydrogen was replaced with nitrogen and mixture was filtered through a small pad of celite which was washed with ethanol. The combined filtrate was concentrated under vacuum and the residue was purified by silica gel chromatography eluting with ethyl acetate-heptane-acetic acid (45:55:0.4 v/v/v) to give 9.5 mg (62%) of the title compound as a colorless oil; TLC Rf 0.29 (solvent system: 45:55:1 v/v/v ethyl acetate-heptane-acetic acid); MS (ESI−) m/z 492.2 (M−H)−; 1H NMR (CD3OD) δ 7.47 (d, J=3.66 Hz, 1H), 7.18-7.01 (m, 5H), 6.80 (d, J=3.30 Hz, 1H), 3.72-3.63 (m, 1H), 3.16-3.03 (m, 1H), 2.79 (t, J=7.32 Hz, 2H), 2.61-2.45 (m, 3H), 2.19-2.05 (m, 1H), 1.98-1.78 (m, 2H), 1.78-1.57 (m, 2H), 1.53-1.39 (m, 4H), 1.34-1.14 (m, 5H), 1.10-1.00 (m, 1H), 0.81-0.76 (m, 3H); 19F NMR (CD3OD) δ−103.2 (ddd, 1F), −105.9 (ddd, 1F).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Li]CCCC.[B:21]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])OC(C)C.OC(C(O)(C)C)(C)C>O1CCCC1.CC(O)=O>[CH3:33][C:31]1([CH3:32])[C:27]([CH3:28])([CH3:29])[O:26][B:21]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[O:30]1
Reactant: CC(C)Oc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-1-[(1-methylethyl)oxy]-2-(trifluoromethyl)benzene (D41) (5.21 g) in dry tetrahydrofuran (THF) (50 mL) was added n-BuLi (12.65 mL) dropwise at −78° C. (maintaining the temperature <−60° C.). The resulting solution was stirred at −78° C. for 30 min before triisopropyl borate (5.13 mL) was added dropwise (<−60° C.). The reaction mixture was allowed to warm to room temperature, then pinacol (0.70 g) and AcOH (2.107 mL) was added and the reaction mixture stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl, the mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine, the organic phase was dried over sodium sulphate and concentrated. The residue was purified by column chromatography to give 4,4,5,5-tetramethyl-2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,2-dioxaborolane (D42) (5.3 g) as a clear oil. δH (CDCl3, 600 MHz): 1.33 (12H, s), 1.36 (6H, d), 4.69 (1H, m), 6.97 (1H, d), 7.88 (1H, d), 7.99 (1H, s). MS (ES): C15H22BF3O3 requires 330. found 331.2 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:6]#[N:7].[C-:12]#[N:13].[K+]>C(O)C>[C:12]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:6]#[N:7])#[N:13]
Reactant: [C-]#N
Reactant: Cc1cc(C#N)cc(CBr)c1
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C#N)cc(CC#N)c1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a stirred ethanol (150 mL), was added 3-(bromomethyl)-5-methylbenzonitrile (48 g, 0.228 M), potassium cyanide (27 g, 0.42 M), and distilled water (77 mL). The mixture was then refluxed for 3 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue was partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:1)) to afford 18.3 g (51%) of 3-(cyanomethyl)-5-methylbenzonitrile as a pale yellow solid. m.p. 63-64° C. 1H NMR (300 MHz, CDCl3) δ 2.42 (3H, s), 3.77 (2H, s), 7.42 (2H, s), 7.45 (1H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:29]([Cl:30])=[CH:28][C:13]3[NH:14][C:15]([O:17][C:18]4[CH:19]=[CH:20][C:21]([CH3:27])=[C:22]([CH:26]=4)[C:23]([OH:25])=[O:24])=[N:16][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:31][Mg+].[Br-]>C1COCC1.CCOCC>[Cl:30][C:29]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:31])[CH3:2])=[CH:9][CH:8]=2)=[CH:11][C:12]2[N:16]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([CH3:27])=[C:22]([CH:26]=3)[C:23]([OH:25])=[O:24])[NH:14][C:13]=2[CH:28]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1ccc(-c2cc3nc(Oc4ccc(C)c(C(=O)O)c4)[nH]c3cc2Cl)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(Oc2nc3cc(-c4ccc(C(C)(C)O)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. suspension of 5-{[5-(4-acetylphenyl)-6-chloro-1H-benzimidazol-2-yl]oxy}-2-methylbenzoic acid (52 mg, 0.124 mmol) and CeCl3 (244 mg, 0.988 mmol) in THF (4 mL) was added MeMgBr (1.4 M in THF) (0.618 mL, 0.865 mmol) dropwise via syringe. The reaction was stirred at rt for 30 min, diluted with Et2O (50 mL) and washed with 1 M HCl (10 mL). The aqueous phase was extracted with Et2O. The combined organics were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. Purification by reverse phase HPLC eluting with MeCN:H2O afforded the desired product as an off-white solid. LC-MS: calculated for C24H21ClN2O4 436.89, observed m/e 437.2 (M+H)+ (Rt: 1.81 min). 1 H NMR (500 MHz, CD3OD): δ 7.89 (d, 1H), 7.54 (d, 2H), 7.49 (s, 1H), 7.47-7.39 (m, 2H), 7.37 (m, 2H), 7.32 (s, 1H), 2.62 (s, 3H), 1.57 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.O>N1C=CC=CC=1>[CH:18]1([C:21]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
A solution of 0.300 gm (1.30 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 40 mL pyridine was heated to 50° C. To this solution was added 0.13 mL (1.43 mMol) cyclopropanecarbonyl chloride and the reaction mixture was stirred for 1.5 hours. An additional 0.10 mL of cyclopropanecarbonyl chloride were added and the reaction mixture was stirred for an additional hour. The reaction mixture was treated with 1.0 mL of water and was then concentrated under reduced pressure. The residue was diluted with 3:1 chloroform:isopropanol and the solution washed sequentially with water, dilute aqueous sodium hydroxide, and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 1 mm), eluting with a gradient of dichloromethane (5-10% methanol) containing 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol/water to provide 0.22 gm (55.9%) of the title compound as a crystalline solid.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[O:28][CH3:29].Cl>O.C(O)C>[CH3:29][O:28][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])[C:23]([OH:25])=[O:24]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Temperature: 25 °C

Procedure:
10-chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 76; 739 mg, 2.9 mmol), 4-amino-3-methoxy-benzoic acid (Aldrich, 534 mg, 3.2 mmol), 4:1 Water/Ethanol (6 mL) and concentrated aqueous hydrochloric acid (0.485 mL, 5.8 mmol) were combined and heated at reflux overnight under nitrogen. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with water followed by diethylether to give the title compound as an off white solid as the Hydrochloride salt (673 mg, 55%)
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16]3[C:11](=[C:12]4[CH:21]=[C:20]5[O:22][CH2:23][O:24][C:19]5=[CH:18][C:13]4=[N:14][CH:15]=3)[N:10]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:9](=[O:30])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[C:17]2[C:16]3[C:11](=[C:12]4[CH:21]=[C:20]5[O:22][CH2:23][O:24][C:19]5=[CH:18][C:13]4=[N:14][CH:15]=3)[N:10]([CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[C:9](=[O:30])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)CCn1c(=O)c2cccc([N+](=O)[O-])c2c2cnc3cc4c(cc3c21)OCO4
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCn1c(=O)c2cccc(N)c2c2cnc3cc4c(cc3c21)OCO4
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a solution of compound 6a (40 mg, 0.1 mmol) in ethanol (10 mL), Ra—Ni (˜50 mg) and then hydrazine hydrate (0.2 mL) were added and reaction was stirred at room temperature for 3 h. The catalyst was filtered through the Celite and filtrate was concentrated in vacuo to provide 28 mg of a solid (74.4% yield); mp 223–224° C.; 1H NMR (CDCl3) δ 2.31 (s, 6H), 2.90 (t, 2H, J=7), 4.34 (s, 2H), 4.65 (t, 2H, J=7.4), 6.18 (s, 2H,), 7.16 (d, 1H, J=8), 7.4 (dd, 2H, J=7.6, 9.8) 7.74 (s, 1H), 8.02 (d, 1H, J=7.8), 10.03 (s, 1H); HRMS m/z calcd for C21H20N4O3H: 377.1614. found 377.1631.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:1]([C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([OH:2])=[O:10])=[O:11])=[CH:15][CH:14]=1
Reactant: Fc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 25 parts of 1,3-isobenzofurandione and 108.5 parts of fluorobenzene were added portionwise 50 parts of aluminium chloride. Upon completion, the whole was heated slowly to reflux and stirring was continued for 1.50 hours at reflux temperature. The reaction mixture was cooled and poured onto a mixture of crushed ice and 60 parts of concentrated hydrochloric acid. The product was extracted twice with dichloromethane. The combined extracts were washed with a sodium hydroxide solution 10%. The aqueous phase was separated, washed with 2,2'-oxybispropane and acidified with concentrated hydrochloric acid while cooling. The whole was stirred for 1 hour at room temperature. The precipitated product was filtered off and dissolved in benzene. The solution was distilled azeotropically to dry. The solid residue was stirred in hexane. The product was filtered off and dried in vacuo at about 50° C., yielding 33.5 parts (87.7%) of 2-(4-fluorobenzoyl)benzoic acid; mp. 129.2° C. (intermediate 90).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[NH2:1])=[CH:20][CH:19]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2N)cc1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a solution of 2-amino-3-nitrophenoi (10 g) in dimethylformamide (100 ml) was added potassilum carbonate (17.9 g) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added 4-methoxybenzyl chloride (10.7 g) at ambient temperature, and the mixture was stirred for 30 minutes under ice-cooling and then overnight at ambient temperature. To the reaction mixture was added water, and the mixture was extracted with dichloromethane, and purified by silica gel column chromatography (ethyl acetate—n-hexane). The residue was crystallized with ethanol to give 2-(4-methoxybenzyloxy)-6-nitroaniline (13.6 mg) as yellow needles.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33][C@H:34]2[CH2:39][C@H:38]([N:40]3[CH2:45][CH2:44][CH:43]([CH:46]4[C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=5[CH2:50][CH2:49][N:48]5[C:57]6[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=6[N:59]=[C:47]45)[CH2:42][CH2:41]3)[CH2:37][CH2:36][NH:35]2)[CH:29]=[CH:30][C:31]=1[Cl:32]>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:35]1[CH2:36][CH2:37][C@@H:38]([N:40]2[CH2:41][CH2:42][CH:43]([CH:46]3[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[CH2:50][CH2:49][N:48]4[C:57]5[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=5[N:59]=[C:47]34)[CH2:44][CH2:45]2)[CH2:39][C@@H:34]1[CH2:33][C:28]1[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=1)=[O:7]
Reactant: Clc1ccc(C[C@H]2C[C@H](N3CCC(C4c5ccccc5CCn5c4nc4ccccc45)CC3)CCN2)cc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@@H](N2CCC(C3c4ccccc4CCn4c3nc3ccccc34)CC2)C[C@@H]1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
3,5-di(trifluoromethyl)benzoyl chloride (0.003 mol) and then triethylamine (0.0045 mol) were added dropwise to a mixture of (±)-trans-6-[1-[2-[(3,4-dichlorophenyl)-methyl]-4-piperidinyl]-4-piperidinyl]-11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepine (0.003 mol) in CH2Cl2 (25ml). The mixture was stirred at RT overnight, washed with water and separated into its layers. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 98/2 to 96/4). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 1.23 g (51%) of (±)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-1-piperidinyl]piperidine (comp. 63).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:42]1[CH2:62][CH2:61][CH2:60][C@H:43]1[C:44]([NH:46][C@H:47]([C:56]([O:58][CH3:59])=[O:57])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=1)=[O:45]>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:42]1[CH2:62][CH2:61][CH2:60][C@H:43]1[C:44]([NH:46][C@H:47]([C:56]([O:58][CH3:59])=[O:57])[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=1)=[O:45])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3.5 g of Boc-Ile (16 mmol) is reacted with 3.8 g of 1-hydroxybenzotriazole (2.4 mmol) and 3.7 g of N,N'-dicyclohexylcarbodiimide (18 mmol) for 1 hour at 0° C., and then the solution of Pro-Tyr-OMe in 15 cm3 of dimethylformamide, prepared earlier, is added. After stirring for 1 hour at 0° C. and then for 10 hours at 20° C., the precipitate of dicyclohexylurea is separated off by filtration and the filtrate is concentrated. The residue obtained is dissolved in ethyl acetate and the solution obtained is washed successively with a 1M solution of citric acid, a solution of sodium bicarbonate and a solution of sodium chloride. The organic layer is dried over sodium sulphate. After removal of the solvent, the crude product is purified by chromatography on a column of silica gel (height 45 cm, diameter 2.5 cm), by eluting with ethyl acetate and mixtures of ethyl acetate with hexane. 3.8 g of Boc-Ile-Pro-Tyr-OMe are obtained, the properties of which are as follows:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([OH:53])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:54]([C:56](=[O:69])[CH2:57][CH:58]1[CH2:61][N:60]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:59]1)[NH2:55]>C(Cl)Cl>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:55][NH:54][C:56](=[O:69])[CH2:57][CH:58]1[CH2:61][N:60]([C:62]([O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[O:63])[CH2:59]1)=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NN)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
HATU (19.6 g, 52.2 mmol) and DIPEA (16.6 g, 130.5 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (12.0 g, 43.5 mmol), tert-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-1-carboxylate (11.3 g, 49.8 mmol) in CH2Cl2 (360 mL). The mixture was allowed to warm to rt then the mixture was stirred at rt for 12 hrs. The mixture was then diluted with CH2Cl2 (300 mL), washed with water (2×) and saturated sodium chloride(2×), dried and concentrated. The residue was purified by silica gel column chromatography (0-20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)azetidine-1-carboxylate (19.3 g, 93%) as a white solid. ESI-MS (EI+, m/z): 488 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])/[CH2:18][CH2:19][CH2:20][C:21]2[C:26]/1=[CH:25][CH:24]=[CH:23][CH:22]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:14][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C1\CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (2.112 ml, 8.26 mmol) and ethyl(2E)-3,4-dihydronaphthalen-1(2H)-ylideneacetate (1.785 g, 8.26 mmol) in CH2Cl2 (33.3 ml) at 0° C. was added TFA (0.064 ml, 0.826 mmol) dropwise. Removed the ice bath and stirred at room temperature for 4 hours. Dilute with CH2Cl2 and wash twice with saturated NaHCO3. The organics were dried over sodium sulfate, concentrated, and purified on silica gel 20% EtOAc/Hex.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]1([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1>>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:8]([C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=2)[C:12]2[CH:11]=[CH:10][C:9]([C:16]3[CH:22]=[CH:21][C:19]([N:20]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[C:9]4[CH:15]=[CH:14][C:12]([NH2:8])=[CH:11][CH:10]=4)=[CH:18][CH:17]=3)=[CH:15][CH:14]=2)=[CH:2][CH:1]=1
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Reactant: Nc1ccc(N)cc1
Product: Nc1ccc(N(c2ccc(N)cc2)c2ccc(-c3ccc(N(c4ccc(N)cc4)c4ccc(N)cc4)cc3)cc2)cc1

Procedure:
The same reaction as in Synthesis example 1 was carried out except for changing p-phenylenediamine used in Synthesis example 1 to benzidine to obtain 12 parts of orange tetrakis (p-aminophenyl)benzidine.