Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[I-:30].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][I:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: ICCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-benzyloxy-phenyl)-ethanol (78.72 g, 0.34 mol) in methylene chloride (400 ml) is added triethylamine (67.3 ml, 0.44 mol, 1.4 eq), then at 0° C. is added mesylchloride (34.8 ml, 0.44 mol, 1.3 eq). The reaction mixture is stirred at 0° C. for 30 minutes and allowed to rise to room temperature. The reaction mixture is extracted with methylene chloride (2×300 ml), the combined organic layers are then washed with brine (2×300 ml) and concentrated under vacuum. To the crude product in solution in ethyl acetate (600 ml) is added sodium iodide (67.2 g, 0.44 mol, 1.3 eq) and the reaction mixture is stirred under reflux for 6 hours. After filtration, the organic layer is washed with brine (3×400 ml), dried with Na2SO4, filtered and concentrated under vacuum. 1-Benzyloxy-4-(2-iodo-ethyl)-benzene is isolated after crystallization with diethyl ether (116.5 g, 86%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C1(S(O[CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:23][CH:22]=2)(=O)=O)C=CC=CC=1>>[CH3:33][C:30]1([CH3:32])[C:29]([CH3:34])([CH3:35])[O:28][B:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:26][CH:25]=2)[O:31]1
Reactant: CC1(C)OB(c2ccc(OCCOS(=O)(=O)c3ccccc3)cc2)OC1(C)C
Reactant: OC1CCOCC1
Product: CC1(C)OB(c2ccc(OCCOC3CCOCC3)cc2)OC1(C)C
Yield: 68.3 %

Procedure:
Using tetrahydropyran-4-ol (3.7 g, 36.2 mmol) and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl benzenesulfonate (6 g, 14.3 mmol) synthesized in Reference Example 2 (2c), the desired title compound (3.4 g, yield 68%) was obtained by the same method as in Reference Example 2 (2a).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C:14]([O:18][C:19]([N:21]([CH2:28][C:29](O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>CN(C)C=O.O>[O:30]=[C:29]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)[CH2:28][N:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19](=[O:20])[O:18][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[4-(4-Pyridinyl)phenyl]amine (5.35 g) and [(tert-butoxycarbonyl)(phenyl)amino]acetic acid (7.90 g) were dissolved in N,N-dimethylformamide (250 mL), then N,N-diisopropylethylamine (12.0 mL) and N-[(dimethylamino) (3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (13.1 g) were added to the mixture at ambient temperature. After stirring at ambient temperature overnight, water (250 mL) was added to the resulting mixture and the mixture was extracted with ethyl acetate (500 mL). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (250 g, n-hexane/ethyl acetate (1:1) then 2% methanol in chloroform). The combined fraction was concentrated in vacuo. The residue was crystallized from 5% ethyl acetate in n-hexane (100 mL). The crystals were collected by filtration and washed with 5% ethyl acetate in n-hexane (20 mL) to afford tert-butyl (2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl)phenylcarbamate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg]Cl>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: C[Mg]Cl
Product: CC1(O)CCN(Cc2ccccc2)C1

Procedure:
Benzyl-3-methyl-pyrrolidin-3-ol was prepared as described in Tett Lett 1996, 37, 8, 1297, by addition of 1-benzylpyrolidin-3-one to methyl magnesium chloride.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1C)=[C:8](OCC1OC1)[CH:7]=[CH:6][CH:5]=2.[CH2:17](O)C>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC=C2C=1C(C)=C(C)N2>[NH2:3][CH:2]1[CH2:1][CH2:17][C:8]2[C:9](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10]1
Reactant: Cc1[nH]c2cccc(OCC3CO3)c2c1C
Reactant: CCO
Agent: Cc1[nH]c2cccc(OCC(O)CNC3CCc4ccccc4C3)c2c1C
Agent: Cl
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure described in Example 27, but starting from 2,3-dimethyl-4-(2,3-epoxypropoxy)indole (10 g) and 2-aminotetralin (6.9 g) in ethanol (100 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2,3-dimethylindol-4-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 14 wherein Z is methyl, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]([NH:26][CH3:27])=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH3:30]N(C=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]([N:26]([CH3:30])[CH3:27])=[O:25])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CNC(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2Sc2ccc(Cl)cn2)cc1

Procedure:
[11C]MeI (from Step 1) was trapped in a RT mixture of (1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-1-methyl-1H-imidazol-4-yl}phenyl)-N-methylcyclopropane-carboxamide (product of Example 6, 0.25 mg) in DMF (0.25 mL) containing 16 ul of NaH (0.5 g/20 mL DMF). The reaction mixture was transferred to a 2 mL v-vial at 65° C., heated for 5 minutes, diluted with H2O (0.8 mL) and injected onto the HPLC (Gemini C18, 10×150 mm, Phenomenex). The desired peak was eluted with a solvent system containing 25% A and 75% B (A=MeCN, B=95:5:0.1H2O:MeCN:TFA, 5 ml/min, retention time ˜6.5 minutes) and collected in a heated round bottom flask on a rotary evaporator. The solution was concentrated and vacuum transferred to a septum capped 5 mL v-vial. The round bottom flask was rinsed with ethanol (0.1 mL) and saline (1-2 mL) and vacuum transferred to the same v-vial to give 13.6 mCi of [11C] (1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-1-methyl-1H-imidazol-4-yl}phenyl)-N,N-dimethyl-cyclopropanecarboxamide.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[CH:25][CH:24]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(-c3ccc(F)cc3)cc2)CC1
Reaction time: 1 h
Yield: 79.4 %

Procedure:
12.5 g of acetyl-4-piperidinecarbonyl chloride were added portionwise to a mixture of 10 g of 4-fluoro-1,1′-biphenyl, 17.5 g of aluminum-(III)-chloride and 60 g of 1,2-di-chloroethane. Upon completion, stirring was continued for 1 hour at reflux temperature. The reaction mixture was poured into a mixture of crushed ice and hydrochloric acid. The product was extracted with DCM. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 15 g (80.8%) of 1-acetyl-4-[(4′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl]piperidine (interm. 3).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](Cl)=[O:24]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:24]
Reactant: CCOC(=O)CCc1ccc(CN)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCc1ccc(CCC(=O)O)cc1

Procedure:
By reaction of ethyl β-[4-(aminomethyl)-phenyl]-propionate hydrochloride (m.p. 192°-193° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained β-[4-(5-chloro-2-methoxybenzamidomethyl)-phenyl]-propionic acid; m.p. 152°-153° C., after recrystallization from isopropanol.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][Cl:24]>CCO>[ClH:24].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Fc1ccc(CCl)cc1F
Solvent: CCO
Product: Cl
Product: Fc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1F
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3,4-difluorobenzyl chloride (0.255 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 207 mg of the product 214. 1H NMR (DMSO-d6) δ 11.38 (s, 2H), 7.90-7.65 (m, 1H), 7.65-7.40 (m, 2H), 7.20-6.90 (m, 6H), 6.90-6.65 (m, 4H), 5.79 (s, 2H), 4.85 (s, 2H); MS: m/z 381 (M++1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.C(O[C:13]([C:15]1[CH:19]=[CH:18][NH:17][C:16]=1[CH3:20])=[O:14])C.Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13]([C:15]1[CH:19]=[CH:18][NH:17][C:16]=1[CH3:20])=[O:14])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1cc[nH]c1C
Reaction time: 0.33 h

Procedure:
To a solution of 1.6 ml of diethylamine in 30 ml of toluene was added 7.5 ml of 2M trimethylaluminum in hexane, and the mixture stirred for 20 minutes. To this mixture was added 1.53 g of 2-methylpyrrole-3-carboxylic acid ethyl ester, and the reaction mixture refluxed overnight. The mixture was cooled, acidified with aqueous 2N hydrochloric acid and extracted twice with ethyl acetate and three times with methylene chloride. Solvent was removed from the combined extracts under reduced pressure, and the residue was flash chromatographed on silica gel, eluting with 75% ethyl acetate/hexane, giving 1.5 g of 2-methylpyrrole-3-carboxylic acid diethylamide, m.p. 120°-121° C., the compound of formula (b).
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][C:7]#[N:8].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[O-].[Na+]>CN(C=O)C.CO>[NH2:8][C:7]1[CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[Se:1][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)(C)C(Cl)=CC#N
Reactant: CCOC(=O)CCl
Reactant: [Se-2]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1[se]c(C(C)(C)C)cc1N
Temperature: 65 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a suspension of sodium selenide (4.4 g, 34.84 mmol, prepared from 2.78 g of selenium as described above) in DMF (35 mL) was added a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (5 g, 34.84 mmol) in DMF (10 mL) at rt for 5 min and stirred the mixture at 60-70° C. for 2 h. Then ethyl chloroacetate (3.71 mL, 34.84 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (1.88 g, 34.84 mmol) in methanol (25 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to rt and poured into ice cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to give the product as a yellow color solid (6.2 g, 65%), mp 66-68° C. 1H NMR (400 MHz, CDCl3): δ 6.59 (1H, s, H-4), 5.52 (2H, br s, —NH2), 4.24 (2H, q, J=7.1 Hz, —COOCH2CH3), 1.33 (9H, s, tert-butyl), 1.31 (3H, t, J=7.1 Hz, —COOCH2CH3).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]([CH3:8])[CH2:6][C:5](=[O:9])[CH2:4][C:3]1=[O:10].C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])([O-:21])=[O:20].[C-]#N.[K+]>C(Cl)Cl.C(#N)C>[CH3:11][C:2]1([CH3:1])[CH:7]([CH3:8])[CH2:6][C:5](=[O:9])[CH:4]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:22]=2[N+:19]([O-:21])=[O:20])[C:3]1=[O:10]
Reactant: CC1CC(=O)CC(=O)C1(C)C
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC1CC(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])C(=O)C1(C)C
Temperature: 25 °C
Yield: 23.5 %

Procedure:
4,4,5-trimethyl-cyclohexane-1,3-dione (0.98 g, 6.36 mmole) and triethylamine (0.77 g, 7.26 mmole) were dissolved in methylene chloride (30 ml). Into the resulting solution cooled with ice, a methylene chloride solution (5 ml) of 2-nitro-4-methylsulfonylbenzoyl chloride (1.68 g, 6.38 mmole) was dropped, and then this solution was stirred at room temperature for an hour. The resulting solution was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile (40 ml), into which triethylamine (0.77 g, 7.62 mmole) and potassium cyanide (0.1 g, 1.54 mmole) were added to stir at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved by adding ethyl acetate and water. To the resulting solution, diluted hydrochloric acid was added until the aqueous layer became acidic (pH 2 or below). The organic layer was washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. Methanol was added to the residue to crystallize to give crystal (0.57 g, mp: 166°-7° C.).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Yield: 97 %

Procedure:
To a solution of tert-butyl (3S)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 17 (0.28 g, 0.59 mml) in methanol (20 mL) was added 5% Pd/C (0.25 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl (3S)-3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 18 (0.22 g, 97%) as a white solid.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: Cl
Product: Fc1cc(CO[C@H]2CCN(Cc3ccccc3)C[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1

Procedure:
The compound (28.8 mg) obtained in Example 26 and benzyl alcohol (12.4 μl) were reacted and treated in the same manner as in the method described in Example 54 to obtain the title compound.
Reaction SMILES: Cl.CC(O)=O.[NH:6]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@@H:7]([C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:41]([OH:43])=[O:42])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:40])[NH2:39])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:8][CH2:9][CH2:10][NH:11]C(OC(C)(C)C)=O.Cl>>[NH:6]([C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[C@@H:7]([C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:41]([OH:43])=[O:42])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:40])=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])[CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCN)NC(=O)OCc1ccccc1)C(=O)O
Yield: 102.6 %

Procedure:
Into 5.2 ml (10.4 mmoles) of 2N HCl/AcOH was dissolved 2.3 g (2.6 mmoles) of Z-D-Orn(BOC)-Phe-Arg-CHA.HCl. After reacting it at room temperature for 2 hours, the product was precipitated in dry ether and the deposited crystalline product was collected by filtration and dried. Thus, crude Z-D-Orn-Phe-Arg-CHA.2HCl was obtained. It was purified by means of Toyopearl HW40F column with 30% AcOH as a developing solvent. Thus, 1.52 g (74.9%) of Z-D-Orn-Phe-Arg-CHA.2HCl was obtained.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCCCCI
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Temperature: 25 °C

Procedure:
To 500 ml of toluene in a one liter round bottom flask, fitted with a condenser and magnetic stirrer, are added 7.6 g (0.03M) of the potassium salt of 4-hydroxy-4'-nitrobiphenyl, 4.9 g (0.035M) of 6-iodo-1-hexanol, and 0.5 g of 18-crown-6ether. The mixture is refluxed for about 20 hours until all of the potassium salt has dissolved and reacted as evidenced by the absence of the blue crystalline solid. The solution is filtered hot, and then cooled to room temperature. After solvent removal, the solid residue is recrystallized from ethanol to yield a purified product, m.p. 117°-119° C.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].C(O)(=O)C.O>[Zn].C(Cl)(Cl)Cl>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH2:9][CH2:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 1, were suspended in 150 ml. of glacial acetic acid and then this mixture was poured into 20 g. of zinc dust suspended in 150 ml. of distilled water. A slight exotherm occurred during stirring and the temperature was maintained at 50° C. for 3 hours by external heating. Then 200 ml. of chloroform were added and stirring was continued for 30 minutes more. The chloroform layer was separated and washed with a saturated sodium carbonate solution and dried over anhydrous magnesium sulfate. Evaporation of the chloroform left a white solid. One recrystallization from methanol gave white crystals, m.p. 169°-170° C. Infrared spectrum showed carbonyl at 1740 cm-1. The nmr indicated two bridgehead protons at 431 Hz (singlet) and four α - protons at 303 Hz and 245 Hz (as a multiplet).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:35](I)[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:35]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])=[CH:3][C:2]=1[F:1])[CH3:36]
Reactant: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and ethyl iodide (0.53 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.44 g), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.96 g, 91%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:22])=[CH:11][C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[C:13]=2[C:20]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:8][C:9]1[C:10]([CH3:22])=[CH:11][C:12]2[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([OH:19])[C:13]=2[C:20]=1[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(c(C)c1NCc1ccccc1)C(=O)C(C)(C)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(c(C)c1NCc1ccccc1)C(O)C(C)(C)O2
Reaction time: 2 h

Procedure:
To a solution of 5-(benzylamino)-2,2,4,6-tetramethyl-1-benzofuran-3 (2H)-one obtained in Reference Example 51 (8.5 g, 28.8 mmol) in methanol (20 mL) was added sodium borohydride (2.18 g, 57.6 mmol) at room temperature, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, 5-(benzylamino)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3-ol. To a mixture of said compound with trifluoroacetic acid (30 mL) was added triethylsilane (10 mL, 64 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue was added a saturated sodium hydrogen carbonate solution to alkalify the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was crystallized with ethyl acetate-hexane to obtain 4.1 g (yield 51%) of the title compound. Melting point: 80-81° C. (ethyl acetate-hexane).