Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N1CCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCCCCCCCC=O
Solvent: CCO
Solvent: C1CCNC1
Product: CCCCCCCCCC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.527 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 1.11 ml (5.0 mmol) of decanal in 20 ml of ethanol, 0.04 ml (0.5 mmol) of pyrrolidine was added, followed by refluxing for 20 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate 3/1→ethyl acetate). The resulting residue was crystallized from n-hexane to yield 0.13 g (5.8%, white crystal) of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl>[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[O:22])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(aminomethyl)-Boc-piperidine (0.313 g, 1.458 mmol), 4-aminobenzoic acid (0.200 g, 1.458 mmol) and N-methyl morpholine (0.242 mL, 2.187 mmol) in dichloromethane (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.422 g, 2.187 mmol) and the reaction mixture stirred at room temperature overnight. The reaction was then washed with water and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-100% EtOAc in hexane gradient to afford tert-butyl 4-((4-aminobenzamido)methyl)piperidine-1-carboxylate. LCMS (3) Rt: 1.91 min; m/z (ES+) 334.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N+:12]([O-])[C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[OH:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=3)[N:11]=[N:12][C:13]=2[CH:19]=1
Reactant: O=C(O)c1ccc(-c2nc3ccc(O)cc3[n+]([O-])n2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2nnc3cc(O)ccc3n2)cc1
Reaction time: 0.5 h

Procedure:
3-(4-Carboxyphenyl)-7-hydroxybenzo[e][1,2,4]triazine 1-oxide (Compound VII-1, 350 mg, 1.23 mmol) was dissolved in 70% ethanol in water (20 ml) at reflux. 5.0 equivalents of Na2S2O4 were added. The reaction turned dark brown. After 30 minutes, the solution was concentrated to remove ethanol and the solid was filtered and washed with water and dried (12 mg). 1H NMR (DMSO-d6 400 MHz): δ 8.67 (d, 2H), 8.16 (d, 2H), 8.09 (d, 1H), 7.77 (d, 1H), 7.67 (s, 1H). MS (ESI): m/z 268.43 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:22])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]([SH:34])=[N:32][N:33]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[C:16]1([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:22])[C:2]([S:34][C:31]3[NH:30][C:29]([C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)=[N:33][N:32]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: Sc1nnc(-c2ccncc2)[nH]1
Reactant: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Sc1nnc(-c2ccncc2)[nH]1
Temperature: 55 °C
Yield: 27 %

Procedure:
A solution of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (150 mg, 0.46 mmol, from Step 1 below), 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (82 mg, 0.46 mmol), and triethylamine (64 □L, 0.46 mmol) dissolved in DMF (5 mL) was heated to 55° C. under N2 for 8 h. The resulting mixture was concentrated and purified by Prep HPLC to give the title compound (58 mg, 27%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[F:18][C:19]([F:24])([F:23])[C:20](O)=[O:21].Cl>O1CCCC1.C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:20](=[O:21])[C:19]([F:24])([F:23])[F:18])=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCc1cc(N)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1O
Reaction time: 2 h

Procedure:
t-Butyl 3-(1-hydroxy-4-aminobenzen-2-yl)propionate was dissolved in a mixture of tetrahydrofuran (100 ml) and triethylamine (7.1 ml). Anhydrous trifluoroacetic acid (6.0 ml) was added to the solution at 0° C. in an atmosphere of argon gas. The solution was stirred for 2 hr. at 0°0 C. The reaction solution was poured into a mixture of ice and 1N hydrochloric acid (100 ml). The reaction mixture was extracted with ethyl acetate (300 ml). The extract was washed with water, saturated aqueous solution of sodium bicarbonate, followed by brine, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixture of ethyl acetate-n-hexane (1:5) to give the title compound having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])([O-:13])=[O:12]>C1(C)C(C)=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:18])([O-:13])=[O:12]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1cccc([N+](=O)[O-])c1
Yield: 69.1 %

Procedure:
A solution of 21.8 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 18.6 g (0.1 mole) 3-nitrobenzoyl chloride in 250 ml xylene was heated at reflux for 20 hours. Unreacted starting amino compound was recovered by cooling the reaction mixture and filtering the resulting precipitate. The filtrate was concentrated in vacuo and the residue recrystallized from xylene. After washing with petroleum ether, 25.4 g (69% yield) of pure product was obtained; m.p. 198° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:44][C:45]1[C:46](=[O:60])[N:47]([CH2:53][C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)[C:48]([CH3:52])=[CH:49][C:50]=1O>C1COCC1.CN(C=O)C>[Br:44][C:45]1[C:46](=[O:60])[N:47]([CH2:53][C:54]2[CH:55]=[CH:56][N:57]=[CH:58][CH:59]=2)[C:48]([CH3:52])=[CH:49][C:50]=1[O:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: OCc1ccc(F)cc1F
Reactant: Cc1cc(O)c(Br)c(=O)n1Cc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccncc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a cold solution of 2,4-difluorobenzylalcohol (0.569 mL, 5.1 mmol) in THF (5 mL) was added PPh3 (resin, 2.55 g, 7.65 mmol) followed by the addition of DIAD (1.48 mL, 7.65 mmol). The reaction mixture stirred at −10° C. for 15 minutes under nitrogen. A solution of 3-bromo-4-hydroxy-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one (1.0 g, 3.4 mmol), in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at 0° C. for 1.5 hours and then allowed to stir at room temperature overnight. The resin was filtered and rinsed with fresh MeOH and the filtrate was concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (ethyl acetate). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 8.47 (d, 2H, J=5.6 Hz), 7.63 (q, 1H), 7.15 (d, 1H, J=5.6 Hz), 7.05 (m, 2H), 6.55 (s, 1H), 5.45 (s, 2H), 5.31 (s, 2H), 2.35 (s, 3H); ES-HRMS m/z 421.0366/423.0355 (M+H calculated for C19H16N2O2F2Br requires 421.0358/423.0339).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1Br)[CH3:2].[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[B:17]([OH:20])[OH:18])[CH3:2]
Reactant: COB(OC)OC
Reactant: CCc1cccc(CC)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
2,6-Diethyl bromobenzene (38.2 g, 180.2 mmol) is added dropwise through an additional funnel over a 1 hour period to a solution of n-BuLi (2.0 M in cyclohexane, 99.1 ml, 198.2 mmol) in THF (380 mL) at −75° C. After addition, the reaction mixture is stirred at −75° C. for 30 minutes; trimethyl borate (28.1 g, 270.3 mmol) is added slowly over a 40 minute period. The reaction mixture is warmed to room temperature overnight. 2N HCl (250 mL) is added slowly and the resulting mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ether (2×200 mL). The combined organic layers are dried over anhydrous Na2SO4 and the solvents are removed in vacuo. Hexane (400 mL) is added to the residue and a white precipitate is formed. Filtration and drying in vacuo gives 19.0 g of 2,6-diethylphenyl boronic acid as a white solid. 1H NMR: (CDCl3) 7.22 (t, 1H), 7.04 (s, 2H), 4.65 (s, 2H), 2.64 (q, 4H), 1.22 (t, 6H).
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4][NH:3][CH2:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17].CO>C(O)(=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][CH2:17][N:3]1[CH2:2][CH2:1][N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: O=C1Nc2ccccc2N2CCNCC12
Reactant: C=Cc1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2ccccc2N2CCN(CCc3ccccn3)CC12

Procedure:
2,3,4,4a-Tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (7 g.) and 2-vinylpyridine (12 g.) in 150 ml. of methanol containing 5 ml. glacial acetic acid were heated under reflux for 24 hours. After removing solvent under reduced pressure, the residue was slurried with water and the insoluble material filtered off and washed with water. After drying there was obtained 9.3 g. of the title compound. A portion recrystallized from ethanol gave a m.p. of 167°-69° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][S:23][CH3:24])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([CH2:22][S:23][CH3:24])[CH:5]=1
Reactant: [H][H]
Reactant: CSCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CSCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The mixture of 3.0 g of N-(4-nitro-2-methylmercaptomethylphenyl)-4-chlorophthalimide, 1.5 g of Raney nickel and 250 ml of ethyl acetate is hydrogenated at room temperature and atmospheric pressure until the hydrogen uptake ceases. It is filtered, the filtrate evaporated and the residue recrystallized from benzene, to yield the N-(4-amino-2-methylmercaptomethylphenyl)-4-chlorophthalimide melting at 134°-137°. Analogously the N-(4-amino-2-methylsulfonylmethylphenyl)-4-chlorophthalimide is prepared, m.p. 253°-257° (acetonitrile); as well as the N-(4-amino-2-hydroxymethylphenyl)-4-chlorophthalimide, m.p. 228°-230° (ethyl acetatediethyl ether).
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C(OO)(=[O:24])C>>[O:24]1[C:19]([CH3:21])([CH3:20])[CH:18]1[CH2:17][CH2:16][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)=CCCC(C)=CCOc1ccc2c(c1)OCCC2
Reactant: CC(=O)OO
Product: CC(=CCOc1ccc2c(c1)OCCC2)CCC1OC1(C)C

Procedure:
Following the procedure of Example 17, 7-(3,7-dimethyl-2,6-octadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3,7-dimethyl-2-octenyloxy)-chromane, nD20 = 1.5341.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:7]=1.[OH-].[NH4+:14]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][NH2:14])[CH:5]=[N:4][CH:3]=1
Reactant: ClCCCOc1cncc(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCCCOc1cncc(Cl)c1
Temperature: 100 °C
Yield: 63.4 %

Procedure:
The 3-chloro-5-(3-chloropropoxy)pyridine (5.74 g, 28.0 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 3.30 g (63.4%) of an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH2:13]([O:16][C:17]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])[CH:14]=[CH2:15]>>[CH2:13]([O:16][C:17]1[C:24]([O:25][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])[CH:14]=[CH2:15]
Reactant: C=CCOc1c(O)cccc1C=O
Reactant: BrCc1ccc2ccccc2c1
Product: C=CCOc1c(C=O)cccc1OCc1ccc2ccccc2c1
Yield: 95 %

Procedure:
2-Bromomethylnaphthalene was reacted with 2-allyloxy-3-hydroxybenzaldehyde using the conditions described in Example 1 to give 2-allyloxy-3-(naphth-2-ylmethoxy)benzaldehyde as an oil in 95% yield. A mixture of the product so obtained (1.3 g), p-toluenethiol (0.8 g), sodium hydride (55% w/w dispersion in oil, 0.28 g) and dimethylformamide (10 ml) was heated to 100° C. for 1.3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 4:1 v/v mixture of methylene chloride and ethyl acetate as eluent. There was thus obtained 2-hydroxy-3-(naphth-2-ylmethoxy)benzaldehyde (0.7 g), m.p. 105° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH3:11])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N1([C:68]2[CH:79]=[CH:78][C:74]([N+:75]([O-:77])=[O:76])=[CH:73][C:69]=2[N+:70]([O-:72])=[O:71])CCC[C@H]1C(N[C@H](C(NCC(O)=O)=O)CCC(=O)N)=O>>[NH:1]([C:68]1[CH:79]=[CH:78][C:74]([N+:75]([O-:77])=[O:76])=[CH:73][C:69]=1[N+:70]([O-:72])=[O:71])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH3:11])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: NC(=O)CC[C@H](NC(=O)[C@@H]1CCCN1c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)NCC(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Product: CC[C@H](C)[C@H](Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
Boc-Ile-Ala-Gly-D-Arg(NO2)-OBzl (900 mg, 1.4 m mol) was demasked with respect to the N-masking group, and coupled with DNP-Pro-Gln-Gly-OH (580 mg, 1.4 m mol) in the manner similar to that of Example 1, paragraph 7).
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:28]([O:30]C(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.I[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:25][C:24]([F:26])([F:27])[S:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:14][C:10]2[N:9]3[C:5](=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:28]1=[O:30])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N(CCCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1c2cnc3cccc(n23)CN1CCCCNS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.1 %

Procedure:
To a solution of 5.25 g (8.81 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[4-(trifluoromethanesulfonamido)butan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 25 ml of chloroform was added dropwise 2.5 ml (17.62 mmol) of iodotrimethylsilane at room temperature. The reaction mixture was stirred for 10 minutes, which was poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. This solution was extracted with 250 ml of ethyl acetate. The organic layer was washed with 100 ml of a 1.0N aqueous solution of sodium thiosulfate, then with 100 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 2.16 g (65.0%) of the desired compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17](Br)=[CH:18][N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1C2C(=O)N(COCC[Si](C)(C)C)N=CC=2N(COCC[Si](C)(C)C)C=1.CB(O)O>>[CH2:1]([O:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([CH3:30])=[CH:18][N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(=O)n(COCc3ccccc3)ncc21
Agent: CB(O)O
Product: Cc1cn(COCC[Si](C)(C)C)c2cnn(COCc3ccccc3)c(=O)c12
Yield: 96 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 20-(b) except for using 30.8 g (66.3 mmol) of 5-benzyloxymethyl-3-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(b) in place of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and using 12.0 g (200 mmol) of methylboronic acid in place of propylboronic acid, respectively, whereby 25.3 g of the title compound was obtained as a brownish oil. (Yield: 96%)
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:16][O:17][C:18](=[O:30])[NH:19][C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:11][C:12](OC)=[O:13])[CH3:8].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[C:20]([NH:19][C:18](=[O:30])[O:17][CH2:16][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:2]=2[F:1])=[O:31])[CH2:10][CH2:11][CH2:12][OH:13])[N:21]=1
Reactant: COC(=O)CC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)NCc1cccc(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCO)COC(=O)Nc1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
To a solution of (S)-methyl 4-(3-(2,3-difluorobenzyl)-1-methylureido)-5-(isoquinolin-3-ylcarbamoyloxy)pentanoate (1.0 g, 2.0 mmol) in THF (10 mL) was added LAH (2.0 M in THF, 1.5 mL, 3.0 mmol) at 0° C. and stirred at 0° C. for 20 min. The mixture was quenched with H2O (0.12 mL), NaOH (3 N, 0.12 mL), and H2O (0.36 mL) and the resulting suspension was stirred at RT for 30 min and filtered. The filtrate was concentrated and the residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-5-hydroxypentyl isoquinolin-3-ylcarbamate (0.52 g, 55%). LRMS (M+H+) m/z 473.2.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH2:14][C:15]2[C:16](=O)[N:17]([CH3:32])[CH2:18][CH2:19][CH:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=4)[C:21]=23)[O:13][CH2:12][CH2:11][O:10]1.O.[OH-].[Na+]>C1C=CC=CC=1.O1CCCC1>[CH3:8][C:9]1([CH2:14][C:15]2[CH2:16][N:17]([CH3:32])[CH2:18][CH2:19][CH:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=4)[C:21]=23)[O:10][CH2:11][CH2:12][O:13]1
Reactant: COc1ccc2c(c1)CCC1CCN(C)C(=O)C(CC3(C)OCCO3)=C21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CCC1CCN(C)CC(CC3(C)OCCO3)=C21

Procedure:
The starting material is prepared as follows: 105 ml of a 1.1 M solution of alane-triethylamine in benzene are added dropwise to the solution of 31.2 g of 1-(2-methyl-1,3-dioxolan-2-yl-methyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth-[1,2-d]azepin-2-one in 200 ml of anhydrous tetrahydrofuran at 0°. The mixture is stirred at 0° for 4 hours whereupon 44 ml of water are added slowly, followed by 88 ml of 3 N aqueous sodium hydroxide at 0°. The resulting mixture is extracted with diethyl ether, the extract dried and evaporated to give the 1-(2-methyl-1,3-dioxolan-2-yl-methyl)-9-methoxy-3-methyl-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[O:7][CH2:6][CH2:5]2.[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH:28]([CH:34]=O)[O:27][CH2:26][CH2:25]2.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:34][CH:28]3[C:29]4[C:24](=[CH:23][C:22]([Br:21])=[C:31]([O:32][CH3:33])[CH:30]=4)[CH2:25][CH2:26][O:27]3)[CH2:19][CH2:20]1)[O:7][CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1Br)CCOC2C=O
Reactant: COc1cc2c(cc1Br)CCOC2CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCOC2CN1CCN(CC2OCCc3cc(Br)c(OC)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{[6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromen-1-yl]methyl}piperazine (100 mg, 0.3 mmol) in 5 mL of DCM was added 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carbaldehyde (81 mg, 0.30 mmol) and NaBH(OAc)3 (127 mg, 0.6 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 1,4-bis{[6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromen-1-yl]methyl}piperazine.