Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:22])([CH3:21])[CH:6]=[C:5]2[CH3:23]
Reactant: Oc1ccccc1
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc2c(c1COc1ccccc1)C(C)=CC(C)(C)N2
Temperature: 80 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound 5-1, 52 mg, 0.16 mmol), phenol (42 μL, 0.48 mmol) and potassium carbonate (88 mg, 0.64 mmol) was suspended in anhydrous N,N-dimethylformamide (2 mL), and stirred 80° C. for 5 hours. After cooling down, the reaction mixture was diluted with ethyl acetate (60 mL). The whole was washed with water (50 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (24 mg) as a colorless oil. (Yield 39%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a white solid (174 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:22][CH:21]=1)(=[O:19])[C:17]1[CH:26]=[CH:27][CH:14]=[CH:15][CH:16]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 26.2 %

Procedure:
A solution of N-(4-pyridyl)piperazine (815 mg), 4-fluorobenzophenone (1.2 g) and powdered potassium carbonate (912 mg) was stirred at 95° C. in DMSO (10 ml) overnight. The solution was poured into water (150 ml) and extracted with dichloromethane (3×50 ml). The dichloromethane extracts were combined, washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (ICN Alumina N 32-63) using 1% methanol in dichloromethane as eluant to give a solid. The solid was recrystallised from a mixture of ethyl acetate/isohexane to give 1-(4-benzoylphenyl)-4-(4-pyridyl)piperazine (450 mg) as a solid. m.p.136-137° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1
Reactant: Cc1ccccc1C(C)Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O
Temperature: 0 °C

Procedure:
A mixture of 650 mg of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-methylphenyl)ethoxy]thiophene-2-carboxamide in 50 ml THF is cooled to 0° C. At 0° C. 0.45 ml tetra-n-butylammonium fluoride (˜75% in H20) is added. The reaction mixture is allowed to warm to room temperature and stirred over night.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]#[CH:27])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22](=[O:23])[NH2:3])[CH2:25][C:26]#[CH:27])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCN=C=NCCCN(C)C
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22.1 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (563 mg, 2.94 mmol) was added to a solution of commercially available (S)-2-(tert-butyoxycarbonylaminopent-4-ynoic acid (e.g. Acros, 626 mg, 2.94 mmol) and 1-hydroxybenzotriazole (397 mg, 2.94 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred at 0° C. for 20 min. A 25% aqueous solution of ammonia (2.38 ml) was added. The reaction mixture was stirred for 16 h, while warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (150 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (250 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with a mixture of brine (75 ml) and water (75 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (50 g), using dichloromethane/methanol (10:1) as eluent, to give 138 mg of ((S)-1-carbamoylbut-3-ynyl)carbamic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=1[CH2:8]Cl.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH2:26])(=[O:25])=[O:24])([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]1[CH2:2][C:3]2[CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=2[CH2:8]1)(=[O:24])=[O:25])([O-:16])=[O:15]
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)c1cc(CCl)c(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(s1)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate (4.106 g, 17.17 mmol) and 2-nitrobenzenesulfonamide (3.825 g, 18.92 mmol) in acetone (40 mL) was added 2.5 M of potassium carbonate in water (20 mL, 50 mmol). The resulting biphasic mixture was stirred at room temperature for 1 hour then further heated at 45° C. overnight resulting in formation of precipitate. The reaction mixture was cooled to room temperature and the precipitate was collected by vacuum filtration. The solid obtained was washed with water followed by cold methanol and dried under vacuum to afford an off white solid (3.352 g, 53%). LCMS (FA) ES+ 369; 1H NMR (400 MHz, DMSO) δ 8.02 (ddd, J=7.8, 4.9, 1.4 Hz, 2H), 7.90 (td, J=7.7, 1.5 Hz, 1H), 7.84 (td, J=7.7, 1.4 Hz, 1H), 7.63 (s, 1H), 4.79 (t, J=2.9 Hz, 2H), 4.60 (t, J=2.9 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: [C:1]([O:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]#[N:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[C:1]([O:9][C:10]1[N:15]=[C:14]([O:16][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=2)[C:13]([C:17]#[N:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OC(=O)c2ccccc2)nc1O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: N#Cc1ccc(OC(=O)c2ccccc2)nc1OC(=O)c1ccc(Cl)cc1
Yield: 82.8 %

Procedure:
The general procedure of Example 90 was followed using 1.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine and 0.72 g of 4-chlorobenzoyl chloride, thereby producing 1.29 g of the title compound in a yield of 82%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][N:7]1[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: Fc1ccc2nc[nH]c2c1
Reactant: ClCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Fc1ccc2ncn(CCCCCl)c2c1
Temperature: 60 °C
Yield: 62.6 %

Procedure:
6-fluoro-1H-benzimidazole (13.2 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Post treatment was performed based on common method one for synthesis. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 14.2 g of 1-(4-chlorobutyl)-6-fluoro-1H-benzimidazole, with a yield of 62.6%.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][CH2:7][NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(2-nitrophenethylamino)piperidine-1-carboxylate (10.5 g) in EtOH (180 ml) was added 10% Pd/C (1.05 g) and the reaction mixture was stirred at RT under an atmosphere of H2 overnight. The reaction mixture was filtered and the resulting solution was evaporated to dryness giving the desired product (9.6 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=320; tR=2.06.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH2:22]1COCC1.CO.O[Li].O>O>[CH3:22][CH:6]1[CH2:7][CH2:8][C:5]1([NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:3]([OH:2])=[O:4]
Reactant: C1CCOC1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CCC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC1CCC1(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
methyl-1-(2-nitrophenylsulfonamido)cyclobutanecarboxylate (500 mg, 1.59 mmol) was charged and dissolved through addition of THF (5 ml), and methanol (5 ml). LiOH.H2O dissolved in H2O (5 ml) was added thereto, followed by stirring for 12 hours at room temperature. After the stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Then, through vacuum distillation, the solvent was removed so as to obtain methyl-1-(2-nitrophenylsulfonamido)cyclobutanecarboxylic acid (468 mg, 1.56 mmol, 98%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([O:45]C)=O)=[N:8]1.O.[OH-].[Li+].[CH3:53][C@@H:54]([NH2:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[C:55]1([C@H:54]([NH:61][C:43]([C:42]2[CH:47]=[CH:48][CH:49]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=6)([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:45])[CH3:53])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenyl methyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (R)-(+)-α-methylbenzyl amine (0.240 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30–60% ethyl acetate/hexanes gave the title compound (0.393 g, 86% yield). ES-MS (m/z) 493 [M+1(−Tr)]+
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26]O)[O:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>ClCCl.O>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26][N:53]5[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]5)[O:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CNC1
Reactant: OCc1cc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)co1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CN(Cc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)co2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of (4-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-furyl)methanol (0.20 g, 0.50 mmol) that was obtained in Example 1 (1e), carbon tetrabromide (0.20 g, 0.60 mmol), and triphenylphosphine (0.16 g, 0.60 mmol) in dichloromethane (1.0 ml) was stirred at 0° C. for 1 hour. Subsequently, to the reaction mixture were added successively ethyl 3-azetidinecarboxylate hydrochloride (0.12 g, 0.75 mmol) and N,N-diisopropylethylamine (0.26 ml, 1.5 mmol) at the same temperature with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, a saturated aqueous solution of sodium hydrogencarbonate (1.0 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1) as the eluent to afford the title compound (0.21 g) in a yield of 84% as a white crystalline solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 34.6 %

Procedure:
4.8 g of 1-(2-chloroethyl)-3-n-butyl-3-D-galactopyranosylurea are dissolved in 15 ml of formic acid, and 2.4 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for 1.5 hours. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-galactopyranosylurea are thereby obtained as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](OC)=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=1.[OH-].[Na+].Cl.C([N:24](CC)CC)C.[Cl-].[NH4+].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CO.C(O)C.O.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:24])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NCc1ccncc1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)c1sc(Br)cc1NCc1ccncc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
To a solution of methyl 5-bromo-3-[(pyridin-4-ylmethyl)amino]thiophene-2-carboxylate (238 mg, 0.727 mmol) in MeOH (2 mL) and ethanol (10 mL) was added a solution of sodium hydroxide (87 mg, 2.18 mmol) in water (1 mL). After stirring at 100° C. for 5 h, 6 M aqueous HCl (0.23 mL) was added to the mixture to adjust the pH to 10. After removal of the solvent at reduced pressure, the residue was diluted with DMF (4 mL). Then, triethylamine (2.0 mL, 15 mmol) and ammonium chloride (777 mg, 15 mmol) were added. After stirring at room temperature for 5 min, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (836 mg, 4.4 mmol) and 1-hydroxybenzotriazole (589 mg, 4.4 mmol) were added to the mixture, and stirring was continued for 18 h. Then, water and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to EtOAc) to give the title compound (167 mg, 74%) as a brown solid:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(OO)(=[O:12])C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([OH:12])[CH:3]=1
Reactant: COc1ccc(C)cc1
Reactant: CC(=O)OO
Product: COc1ccc(C)cc1O

Procedure:
The procedure of Example 18 was repeated, except Victor Wet 35B (phosphur-containing ester) was used as a reaction catalyst and 4-methyl anisole was used in place of anisole. Consequently, the conversion of peracetic acid was 96.2%, the conversion of 4-methyl anisole was 8.02% and there was formed 4.55g of 4-methyl-2-hydroxy anisole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:36]=[C:35]([Cl:37])[C:9]([C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])=[O:11])=[C:8]([Cl:38])[CH:7]=1.O=C1CCC(=O)N1[O:46][C:47](=O)[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][NH:74][C:75](=[O:85])[CH2:76][CH2:77][N:78]1[C:82](=[O:83])[CH:81]=[CH:80][C:79]1=[O:84].CCN(C(C)C)C(C)C>>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C:9]2[C:8]([Cl:38])=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47](=[O:46])[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][NH:74][C:75](=[O:85])[CH2:76][CH2:77][N:78]3[C:82](=[O:83])[CH:81]=[CH:80][C:79]3=[O:84])=[CH:36][C:35]=2[Cl:37])[C:14]([OH:16])=[O:15])=[CH:23][CH:22]=1)=[O:34]
Reactant: NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (107 mg, 0.15 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (100 mg, 0.145 mmol), and DIPEA (194 mg, 261 uL, 1.5 mmol), and after HPLC purification, resulted in a white solid (50 mg, 28%). ES(+)-HRMS m/e calcd. for C52H65Cl4N5O17 (M+Na)+ 1194.3022, obsd. 1194.3028.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:22]=1[CH:23]=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])/[C:9](/[S:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:23]\[C:22]2[C:25]([O:31][CH3:32])=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Reactant: O=C(CSc1ccc(Br)cc1)c1ccc(Br)cc1
Product: COc1cc(OC)c(/C=C(/Sc2ccc(Br)cc2)C(=O)c2ccc(Br)cc2)c(OC)c1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 1. A solution of 1-(4-bromophenyl)-2-(4-bromophenylthio)ethanone (10 mmol) and 2,4,6-trimethoxybenzaldehyde (10 mmol) was subjected to the procedure described as Method B in part C of Synthesis Example 1 and the product obtained was purified by column chromatography. m.p 130-132° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24]C)=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2].[OH-].[Na+]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([OH:24])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2]
Reactant: CCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(CC(=O)O)ccc1OCc1ccc2ccccc2n1

Procedure:
The title compound is prepared from 1.5 g (4.48 mmol) of the compound from Example XXXIV and 10 ml (10 mmol) of 1N sodium hydroxide solution analogously to the procedure of Example V.