Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[CH3:8][O:9][C:10](=[O:61])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:41][C:42]([CH:45]5[CH2:49][NH:48][CH2:47][N:46]5[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=[N:43][CH:44]=4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14].Cl[C:63]([O:65][CH3:66])=[O:64]>ClCCl>[CH3:66][O:65][C:63]([N:48]1[CH2:49][CH:45]([C:42]2[NH:41][C:40]([C:37]3[CH:36]=[CH:35][C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:25]5[NH:24][C:23]([CH:19]6[CH2:20][CH2:21][CH2:22][N:18]6[C:16](=[O:17])[CH:12]([NH:11][C:10]([O:9][CH3:8])=[O:61])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:29][CH:30]=4)=[CH:39][CH:38]=3)=[CH:44][N:43]=2)[N:46]([C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[CH2:47]1)=[O:64]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CNCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)OC)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Yield: 16.8 %

Procedure:
4-Methylmorpholine (31 μL, 0.28 mmol) was added to a suspension of {1-[2-(5-{4′-[3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-3H,1′H-[2,4′]biimidazolyl-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (41.1 mg, 0.056 mmol) [prepared via reaction of 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester with HCl-solution] in dichloromethane (5 mL). Methyl chloroformate (16.5 μL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed in vacuo. The residue was taken into tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 2 hours the organic solvents were removed in vacuo and the aqueous phase was decanted. The residue was dissolved in dimethylformamide (2 mL) and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA). The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid methyl ester (7.5 mg) C41H51N9O8 calculated 797.4 observed [M+1]+ 798.4; 1H (DMSO-d6): δ=8.08 (s, 1H), 7.83 (m, 8H), 7.58 (d, J=8.0 Hz, 1H), 7.29 (s, J=8.4 Hz, 1H), 5.42 (dd, J=7.6, 3.6 Hz, 1H), 5.26 (d, J=4.8 Hz, 1H), 5.18 (d, J=6.0 Hz, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.88 (m, 1H), 4.08 (t, J=7.6 Hz, 2H), 3.94 (m, 1H), 3.82 (m, 4H), 3.65 (s, 3H), 3.52 (s, 3H), 3.51 (s, 3H), 2.36 (m, 1H), 2.01 (m, 5H), 0.83 (m, 12H).
Reaction SMILES: [Cl-].[Li+].C1(C)C=CC(S(O)(=O)=[O:10])=CC=1.C12CC(CC1)C=C2.[OH2:21].C[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=CC=1>CC(=O)CC>[CH:32]12[CH2:23][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]2[C:26]([OH:10])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: Cc1cccc2ccccc12
Agent: C1=CC2CCC1C2
Agent: [Cl-]
Agent: [Li+]
Solvent: CCC(C)=O
Product: O=C(O)C1CC2CCC1C2
Temperature: 65 °C
Yield: 39 %

Procedure:
Lithium chloride (8.4 mg, 0.20 mmol), para-toluenesulfonic acid (34.4 mg, 0.20 mmol), [(Ph—(R)-Phanephos)Pd2Cl4] (0.01 mmol) and norbornene (94.2 mg, 1 mmol) were weighed into a Biotage 5 ml microwave vial. A stirring bar was added and the vial was sealed with a crimp cap and put under inert atmosphere. Degassed water (between 2.5 equiv. and 15 equiv.), degassed 2-butanone (1.5 ml) and internal standard (approximately 10 μl of 1-methylnaphtalene) were added using a syringe. The solution was mixed before 20 μl of the solution was diluted in CDCl3 and analysed using NMR (to give a t0 spectra that calibrates the internal standard against starting material). The caps were pierced with two needles and quickly placed in an autoclave that had previously been placed under an argon atmosphere before being opened under a flow of argon. The autoclave was sealed, purged three times with CO and then pressurised to 30 bar and heated in a preheated oil bath or heating jacket at 65° C. with constant magnetic stirring. After the desired time, the autoclave was cooled to room temperature and the pressure released slowly. The mixture was then analysed by taking a sample, diluting with CDCl3 and obtaining an 1H NMR spectrum. This shows the formation of the desired acid as a 99:1 mixture of exo and endo isomers (52% conversion to acid, 48% oligomeric dimer-acid) The solvent was carefully removed from the reaction mixture and the residue was purified by column chromatography (SiO2, using hexane: ethylacetate 8:1 as eluent) to give colourless crystals of bicyclo[2.2.1]heptane-2-carboxylic acid (39% isolated yield). The ratio of optical isomers was determined by forming the mandelate ester of the carboxylic acid and calculating the diastereomeric excess by 1H-NMR integration, and in this case was 89:11.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)CCCC(C)(C)N1.C([Li])CCC.Cl[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]>O1CCCC1.CCCCCC.O>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([O:38][CH3:39])[CH:32]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCCN1Cc1ccccc1
Reactant: COc1ccccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2CCCCN(Cc3ccccc3)C2=O)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-Benzylhexahydro-2H-azepin-2-one (10.2 g) in tetrahydrofuran (100 ml) was added dropwise to a stirred, cooled solution of lithium-2,2,6,6-tetramethylpiperidide [prepared by the addition of 2,2,6,6-tetramethylpiperidine (8.5 g) to butyl lithium (0.05 mole) in hexane (32 ml)] under nitrogen. When the addition was completed a further portion of butyl lithium (0.05 mole) in hexane (32 ml) was added. The solution was cooled to 0° C. and o-chloroanisole (6.2 ml) added dropwise. After stirring at room temperature for four hours the reaction was decomposed with water and the solvents removed under reduced pressure. The resulting oil was partitioned between 5 M hydrochloric acid and toluene. After drying (MgSO4) the toluene was removed to leave an oil which was distilled affording 5.02 g b.p. 180°-220° C. at 0.2 mm. The oil was crystallised from methanol, affording 3.15 g m.p. 120°-122° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: CC(C)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCOc1ccc(N)cc1
Reaction time: 4 h
Yield: 99.8 %

Procedure:
5% Palladium on charcoal (100 mg) was added in one portion to a stirred solution of 1-[(3-methylbutyl)oxy]4-nitrobenzene (intermediate 4, 2.00 g, 9.56 mmol) in ethyl acetate (40 mL) at room temperature under a nitrogen atmosphere. The nitrogen was replaced with hydrogen and stirring was continued for 4 h. The hydrogen was replaced with nitrogen then the crude reaction mixture was filtered through a plug of celite. The solute was evaporated to dryness to give the title compound as a colourless oil (1.71 g, 100%) which was used without purification. LC/MS: 2.29 min; z/e 180, calcd (M+1) 180. 1H NMR (400 MHz; CDCl3): 0.95 (6H), 1.65 (2H), 1.85 (1H), 3.10 (2H), 3.90 (2H), 6.65 (2H), 6.75 (2H).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][Si:17]([CH3:26])([CH3:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:6](=O)[CH3:7])[CH3:2].[Cl-].[OH:28][NH3+:29]>N1C=CC=CC=1>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][Si:17]([CH3:26])([CH3:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:6](=[N:29][OH:28])[CH3:7])[CH3:2]
Reactant: [NH3+]O
Reactant: CCON=C(C(C)=O)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCON=C(C(C)=NO)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1

Procedure:
14.3 g of 1-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-propane-1,2-dione-1-ethyl-oxime in 50 ml of pyridine are stirred with 3.5 g of hydroxylammonium chloride for 2 hours at 70° C. The reaction mixture is concentrated in vacuo and ethyl acetate is added to the residue; the organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off. Recrystallisation from hexane yields the title product having a melting point of 100-102° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[NH:7][NH:8][C:9]2=[O:14])([O-:3])=[O:2].[OH2:16]>C(O)(=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]([O:16][C:6](=[O:15])[C:5]=12)=[O:14])([O-:3])=[O:2].[OH2:2].[NH2:7][NH2:8]
Reactant: O=c1[nH][nH]c(=O)c2c([N+](=O)[O-])cccc12
Solvent: O
Solvent: CC(=O)O
Product: NN
Product: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]

Procedure:
where M is Li, Na, K wherein 5-nitro-2,3-dihydrophthalazine-1,4-dione is solved in water solution of MOH, where M has the above mentioned meaning, with forming solution of 5-nitro-2,3-dihydrophthalazine-1,4-dione alkaline salt which is catalytically transformed in 5-amino-2,3-dihydrophthalazine-1,4-dione salt at the temperature of 40-90° C. by means of hydrogen under the pressure of 1-4 MPa at the presence of a transition metal catalyst (Pt, Pd) on active carbon, and separation of 5-amino-2,3-dihydrophthalazine-1,4-dione crystalline salt is performed by dilution of the water solution with lower alcohol or cyclic lower ether while cooling to the temperature −5° C. to −15° C., providing that there is used 5-nitro-2,3-dihydrophthalazine-1,4-dione obtained in the reaction of 3-nitrophthalic acid anhydride with hydrazine hydrate in anhydrous acetic acid at the temperature 100-110° C. with distilling the mixture of acetic acid and water off.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:29][CH2:30][CH3:31])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:38][N:37]=[N:36][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:31]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A mixture of methyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (1.85 g) and trimethyltin azide (2.80 g) in toluene (15 ml) were heated under reflux for one day. The reaction mixture was concentrated to dryness. To the residue were added methanol (50 ml) and 1N—HCl (20 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to ab out pH 3–4 with 1N—NaOH. After removal of the solvent, the residual syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene gave colorless crystals (1.16 g, 56%), m.p. 191–193° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:34]=[CH:33][CH:32]=[CH:31][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH2:29][CH3:30])[CH3:28])=[CH:23][CH:22]=1)=[O:19]>CCO>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:18](=[O:19])[C:17]3[C:16](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:15]=[C:7]2[C:6]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:22][CH:23]=1)([CH2:29][CH3:30])[CH3:28]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Yield: 48.9 %

Procedure:
Anhydrous CuCl2 (0.370 g, 2.70 mmol) and 3,4-dinitrobenzaldehyde (0.270 g, 1.38 mmol) were added to a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (0.370 g, 1.38 mmol) in anhydrous EtOH (20 mL). After heating to reflux temperature for 3 hours, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 60% EtOAc in heptane, afforded 3-(4-sec-butylphenyl)-2-(3,4-dinitrophenyl)quinazolin-4(3H)-one (0.300 g, 49%).
Reaction SMILES: C(C1(C(O)=O)CC1)(OCC)=O.ClC(OCC)=O.NC1C=CC=CC=1.C(N(CC)CC)C.Cl[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([C:42]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:44][CH2:43]2)=[O:41])=[C:35](CC)[CH:34]=1>>[C:36]1([NH:39][C:40]([C:42]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:43][CH2:44]2)=[O:41])[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2CC)CC1
Agent: CCOC(=O)C1(C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Product: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1

Procedure:
1-Carboethoxycyclopropanecarboxylic acid (3.95 grams, 0.025 mole), ethyl chloroformate (2.71 grams, 0.025 mole) and aniline (2.33 grams, 0.025 mole) were reacted sequentially in the presence of triethylamine (2.53 grams, 0.025 mole) in a manner similar to that described for ethyl 1-(4-chloro-2-ethylphenylaminocarbonyl)cyclopropanecarboxylate in Example XXXIII to give ethyl 1-(phenylaminocarbonyl)cyclopropanecarboxylate which was then hydrolyzed in a manner similar to that described in Example VII to give 2.42 grams (0.01 mole) of 1-(phenylaminocarbonyl)cyclopropanecarboxylic acid having a melting point of 178° C.-181° C. NMR analysis of the product indicated the following:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].O>B(F)(F)F.CCOCC>[C:1]([C:16]1[C:17]([OH:19])=[CH:18][C:9]([OH:8])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(O)cc1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc(C(C)=O)c(O)cc1O
Temperature: 25 °C
Yield: 41.6 %

Procedure:
Acetic anhydride (3.06 g, 30.0 mmol) was added to methyl 2,4-dihydroxybenzoate (5.04 g, 30.0 mmol) in boron trifluoride diethyl etherate (7.6 ml) and the mixture was stirred and held at reflux for 3 hours and then allowed to cool to room temperature. Water (80 ml) was added and the mixture stirred at room temperature for 30 minutes. The resulting yellow solid was removed by filtration and sucked as dry as possible under vacuum. The solid was dissolved in dichloromethane and was washed with water, the organic layer was separated and the solvent removed in vacuo to afford methyl 5-acetyl-2,4-dihydroxybenzoate as a bright yellow solid (2.62 g, 42%) which was used without further purification. 1H NMR (DMSO-d6) 12.58 (1H, s), 11.22 (1H, s), 8.33 (1H, s), 6.45 (1H, s), 3.90 (3H, s), 2.62 (3H, s). MS: [M+H]+ 211.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.CCOCC>O1CCOCC1>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([C:4]([CH2:3][O:2][CH3:1])=[O:5])=[C:15]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26]
Reactant: COCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: CCOCC
Solvent: C1COCCO1
Product: COCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Yield: 82.8 %

Procedure:
3-methoxyacetyl-4-chloro-8-methoxyquinoline (19.0 g, 0.07 mol) and o-toluidine (9.0 ml, 0.08 mol) were heated under reflux in 1,4-dioxan (250 ml) for 1 hour. The solvent was removed and the residue taken up in dichloromethane, washed with dilute hydrochloric acid, sodium hydrogen carbonate solution, and brine. Evaporation of the solvent gave an oil, which afforded 8-methoxy-3-methoxymethylcarbonyl-4-(2-methylphenylamino)quinoline (19.5 g, 81%) as yellow crystals from ether, m.p. 122°-3°.
Reaction SMILES: Br[CH:2]([CH2:24][CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:26][NH:27][CH3:28].C1COCC1>C(OCC)C>[CH3:26][N:27]([CH3:28])[CH:2]([CH2:24][CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCC(Br)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)O)cc2)cc1
Reactant: CNC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)O)cc2)cc1)N(C)C

Procedure:
A solution of 7.9 g (0.0195 mol) of 2-bromo-1-{4-[4-(2-hydroxy-2-methyl-propionyl)-phenoxy]-phenyl}-butan-1-one in diethyl ether was added drop wise to a solution of 58.5 ml of dimethylamine 2M in THF (0.117 mol), maintaining the temperature between 0° C. and 5° C. After one night the reaction was diluted with ether, washed three times with water, dried with sodium sulphate and evaporated obtaining 7.47 g of an oil used without purification in the following step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.[Br:38][C:39]1[C:40]([NH2:46])=[N:41][CH:42]=[C:43]([Br:45])[N:44]=1>CN(C)C=O.ClCCl>[Br:38][C:39]1[C:40]([NH:46][C:14]([CH:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[N:41][CH:42]=[C:43]([Br:45])[N:44]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOCC1C(=O)Nc1ncc(Br)nc1Br
Temperature: 50 °C
Yield: 70.6 %

Procedure:
A solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (1.500 g, 6.49 mmol) and 1,1′-carbonyldiimidazole (1.578 g, 9.73 mmol) in N,N-dimethylformamide (2 mL) and dichloromethane (6 mL) was stirred 4.5 h at room temperature under nitrogen. N,N-Diisopropylethylamine (2.260 mL, 12.97 mmol) was added followed by 3,5-dibromopyrazin-2-amine (3.28 g, 12.97 mmol). The resulting mixture was stirred and heated at 50° C. under a reflux condenser under nitrogen for 2 d. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted 3 times with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-30-50% ethyl acetate in hexanes) to give the desired product (2.136 g, 4.58 mmol, 71% yield) as a slightly yellow foam-solid. MS (ESI) m/z 467 [M+1]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Cl:30])[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)OC[C@@H]1C[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C[C@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
(±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (850 mg, 1.92 mmol) in dry N,N-dimethylformamide (5 mL) was maintained at 95° C. while N-chlorosuccinimide (760 mg) was added in portions over 3 hours. Heating was continued for a total of 6 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Title compound was eluted with ethyl acetate:hexanes/3:7 as a yellow solid (160 mg, 17%), 1H-NMR consistent with structure and almost identical with that of title compound of Example 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Br[CH2:20][CH2:21][CH2:22][CH3:23]>C(#N)C>[C:1]([O:5][C:6]([NH:7][NH:8][CH2:20][CH2:21][CH2:22][CH3:23])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCBr
Reactant: CC(C)(C)OC(=O)NN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNNC(=O)OC(C)(C)C
Yield: 39 %

Procedure:
To a magnetically stirred solution of tert-butylcarbazate (47.5 gram, 359 mmol) in anhydrous acetonitrile (300 ml) was successively added DIPEA (Hünig's base) (37.6 ml, 216 mmol) and 1-bromobutane (19.3 ml, 180 mmol). The resulting mixture was reacted at 60° C. for 16 hours. The resulting mixture was allowed to attain room temperature and subsequently concentrated in vacuo and further purified by Sepacore chromatography (eluant: petroleum ether 40-60/ethylacetate=4/1 (v/v)) to give N′-butylhydrazine-carboxylic acid tert-butyl ester (intermediate XIII-1) (13.2 gram, 39%) as a pale yellow oil: 1H-NMR (400 MHz, CDCl3) δ 0.91 (t, J=7, 3H), 1.30-1.49 (m, 13H), 2.81-2.87 (m, 2H), 4.00 (br s, 1H), 6.20 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:16])[N:8]2[CH2:13][CH:14]=O.[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][N:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]2=[O:16])[CH2:26][CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cccc2c1ccc(=O)n2CC=O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
1H-NMR (CDCl3) δ: 3.96 (3H, s), 5.13 (2H, s), 6.63 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=9.8 Hz), 6.71 (1H, d, J=8.4 Hz), 7.45 (1H, t, J=8.4 Hz), 8.24 (1H, d, J=9.8 Hz), 9.66 (1H, s) (2) To 2.4 mL of dichloromethane solution containing 0.10 g of (5-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.16 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 24 μL of acetic acid were added, and stirred for 20 min. To the reaction mixture, 0.15 g of sodium triacetoxyborohydride was added, and stirred for 50 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:3], to give 0.18 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow oil.