Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]Br.[C:4]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>ClCCl.O1CCCC1.CCCCC.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH2:2]=[C:4]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1CCCCCCCCCCCC1
Reactant: BrCBr
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CCCCC
Solvent: C1CCOC1
Product: C=C1CCCCCCCCCCCC1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a stirred mixture of 3 g of zinc dust, 50 ml of anhydrous tetrahydrofuran and 2.66 g of dibromomethane, was added dropwise a solution of 2.13 g of anhydrous titanium tetrachloride in 5 ml of dichloromethane. After 15 minutes, to the resulting solution was added dropwise a solution of 2 g of cyclotridecanone in 8 ml of anhydrous tetrahydrofuran. The mixture was allowed to react at room temperature for 12 hours. The reaction mixture was diluted with 50 ml of pentane, admixed with 100 ml of 1-M hydrochloric acid, and intermixed by shaking. The organic layer was washed successively with water, dilute aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, then dried, and concentrated to yield methylenecyclotridecane. To a solution of this substance in 40 ml of anhydrous dichloromethane, after having been cooled to -15° C., was added dropwise with stirring a solution of 2.64 g of m-chloroperbenzoic acid in 40 ml of anhydrous dichloromethane. After 3 hours of reaction, the organic layer was washed successively with 10-% sodium sulfite solution, 7-% sodium hydrogencarbonate solution, and saturated sodium chloride solution, then dried and concentrated under reduced pressure. The residue was purified by the silica gel chromatography [developed with a petroleum ether-ethyl acetate (20:1) mixture] to yield 2.04 g (95% yield based on the ketone compound) of an epoxide. To a solution of the epoxide in anhydrous dichloromethane, after having been cooled to -18° C., was added dropwise a borontrifluoride-ether complex. After completion of the addition, water was added to the reaction mixture. The organic layer was separated, then concentrated, and purified by the silica gel chromatography to yield only cyclotridecanecarbaldehyde in a yield of 60-70%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:5]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16].[CH3:25]I.O>CN(C)C=O>[CH3:3][C:4]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:5]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([O:19][CH3:25])[C:15]([O:17][CH3:18])=[O:16].[CH3:3][C:4]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:5]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16]
Reactant: CI
Agent: COC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reaction time: 0.5 h

Procedure:
60% oily sodium hydride (0.13 g, 3.3 mmol) was added to a solution of methyl 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-hydroxyacetate (0.72 g, 2.4 mmol) and methyl iodide (0.68 g, 4.8 mmol) in N,N-dimethylformamide (6 ml) at 0° C. with stirring. After 30 minutes, ice and water were added in this order, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=9/1) to give the desired compound methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetate (0.69 g, 92%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:41])(C)C.CCOCC>CC(CC)=O>[ClH:41].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(CCc1ccccc1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOCC
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(3-phenylpropionyl)-1,4,8-triazaspiro[4,5]decan-2-one (360 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (2.9 mL), water (8 μL), TMSCl (107 μL), and ether (10 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(3-phenylpropionyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 323 mg (83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:27][CH2:28]CS([O-])(=O)=O)[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:9]1.Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:27][CH2:28][N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]2)[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:9]1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccccc3F)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccccc3F)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([NH:38][CH2:37][CH2:36][N:33]3[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:35][CH2:34]3)=[O:3])[C:5]=12
Reactant: NCCN1CCC(CCCCN2CCCCC2)CC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Solvent: CC#N
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCCN3CCCCC3)CC1)c1ccccc1NC2=O
Yield: 20 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[4-(piperidin-l-yl)butyl]-piperidin-l-yl]ethanamine in a yield of 20% of theory. Colourless crystals, m.p. 186°-187° C. (acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[N:36][CH:37]=[C:38]([CH:42]=1)[C:39]([NH2:41])=[O:40].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:34]4[CH:35]=[N:36][CH:37]=[C:38]([CH:42]=4)[C:39]([NH2:41])=[O:40])[CH:19]=3)[O:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3cncc(C(N)=O)c3)ccc1O2
Temperature: 100 °C

Procedure:
1′-tert-butoxycarbonyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chroman-2,4′-piperidin]-4-one (1.43 g, 3.23 mmol), 5-bromonicotinamide (778 mg, 3.87 mmol), Pd(PPh3)4 (372 mg, 0.322 mmol), and aqueous 2M Na2CO3 (10 ml) solution were suspended in dioxane (20 ml) and heated at 100° C. for 4 h. The reaction mixture was diluted with CHCl3 and H2O, the aqueous layer was extracted with CHCl3. The combined organic layer was dried over MgSO4. The desiccant was removed through celite filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (EtOAc/Acetone) to obtain the intended compound as a pale yellow foam.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:29])[NH:7][C:8]2[CH:28]=[CH:27][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])=[CH:27][CH:28]=2)=[O:29])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
tert-Butyl 4-(4-(3-(cyclopropylmethyl)ureido)benzoyl)piperazine-1-carboxylate (46.7 mmol, 18.78 g) was dissolved in dichloromethane (30 mL) and trifluoroacetic acid (233 mmol, 17.33 ml, 26.6 g) was added. The reaction was stirred for 1 hour and then was concentrated under reduced pressure. The crude material was triturated with ether to give a white powder after high vacuum drying. The white powder was taken up in water and carefully taken to pH 10 with sodium carbonate. The aqueous was then extracted with dichloromethane and the combined organic phases were dried, filtered and concentrated under reduced pressure to give the title compound (13.4 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[N:5][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[CH:7]=1)#[N:2].C([Li])CCC.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>O1CCCC1.ClCCl>[C:1]([C:3]1[C:4]([C:20]([F:23])([F:21])[F:22])=[N:5][N:6]([C:8]2[C:9]([Cl:19])=[CH:10][C:11]([C:15]([F:17])([F:18])[F:16])=[CH:12][C:13]=2[Cl:14])[C:7]=1[Si:30]([CH3:32])([CH3:31])[CH3:29])#[N:2]
Reactant: C[Si](C)(C)Cl
Reactant: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 0.03 h

Procedure:
A stirred solution of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (1.5 g) in dry tetrahydrofuran cooled to -78° C. was treated with a solution of n-butyl lithium (2.6 M in hexane, 1.71 ml) dropwise under nitrogen. The temperature was kept below -65° C. during the addition, and the resultant solution kept at -78° C. for 1 hour. A solution of trimethylsilyl chloride (0.56 ml) in dry tetrahydrofuran (2 ml) was then added, dropwise, during 2 minutes. The mixture was allowed to reach room temperature over 2 hours, left overnight and evaporated in vacuo to give a pale yellow solid. This was dissolved in dichloromethane, washed with water, dried over anhydrous magnesium sulphate, and evaporated in vacuo. The product was recrystallized from hexane to give 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethyl-5-trimethylsilylpyrazole as white crystals, m.p. 108-110° C.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:38]2[CH:39]=[C:40]([CH2:44]O)[CH:41]=[CH:42][CH:43]=2)=[N:25][C:26]=1[C:27]1[NH:31][C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:29][N:28]=1.[C@@H:46]1([NH:55][S:56]([C:59]2[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][C:60]=2[N+:68]([O-:70])=[O:69])(=[O:58])=[O:57])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][CH2:47]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[NH2:20][C:21]1[N:22]=[CH:23][C:24]([C:38]2[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=2)[CH2:44][N:55]([C@@H:46]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][CH2:47]2)[S:56]([C:59]2[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][C:60]=2[N+:68]([O-:70])=[O:69])(=[O:58])=[O:57])=[N:25][C:26]=1[C:27]1[NH:31][C:30]([CH2:32][C:33]2[CH:1]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:29][N:28]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ncc(-c2cccc(CO)c2)nc1-c1nnc(-c2ccccc2)[nH]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N[C@H]2CCc3ccccc32)c([N+](=O)[O-])c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2cccc(CN([C@H]3CCc4ccccc43)S(=O)(=O)c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])c2)nc1-c1nnc(Cc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triphenylphosphine (47 mg, 0.17 mmol) was added to a stirred solution of {3-[5-amino-6-(5-phenyl-4H-1,2,4-triazol-3-yl) pyrazine-2-yl]phenyl}methanol (50 mg, 0.14 mmol) and N-[(1S)-2,3-dihydro-1H-inden-1-yl]-2,4-dinitrobenzen sulfonamide (60 mg, 0.16 mmol) in THF. Diethyl azodicarboxylate (31 mg, 0.17 mmol) was then added and mixture was stirred at ambient temperature 4 h. Ethyl acetate (20 mL) was added, and the organic layer was washed with saturated aqueous sodium chloride, and then dried (Na2SO4). Filtration and concentration followed by chromatography on silica gel afforded the title compound: MS (EI) for C35H29N9O6S: 704 (MH+).
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:8]=2[N:9]=1.Br[CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([OH:21])=[O:20]>C(N(CC)CC)C>[N+:14]([C:12]1[CH:11]=[CH:10][C:8]2[N:9]=[C:5]([S:4][CH:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([OH:21])=[O:20])[S:6][C:7]=2[CH:13]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2ccc([N+](=O)[O-])cc2s1)c1ccccc1
Yield: 18.4 %

Procedure:
A methylene chloride solution of 5.0 g (0.235 m) 2-mercapto-6-nitrobenzothiazole, 5.2 g (0.235 m) α-bromophenylacetic acid and 5.0 g (0.05 m) triethylamine is heated to gentle reflux overnight. The solution is washed twice with a dilute hydrochloric acid solution and once with water. The solution is dried over anhydrous MgSO4 and then concentrated. The residue is recrystallized once from benzene and then from acetonitrile. 1.5 g (18% yield) of title compound, having a melting point of 152°-5° C., is obtained.
Reaction SMILES: [H-].[Na+].C(O)(C)(C)C.[CH3:8][O:9][C:10]([CH2:12][O:13][C:14]1[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18](OC)=[O:19])=[O:11].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[O:19]=[C:18]1[CH:12]([C:10]([O:9][CH3:8])=[O:11])[O:13][C:14]2[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=2[O:16][CH2:17]1
Reactant: COC(=O)COc1ccccc1OCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: COC(=O)C1Oc2ccccc2OCC1=O
Yield: 74.4 %

Procedure:
To a mixture of 4.1 g of 60% sodium hydride in 150 ml of xylene is added 0.3 ml of tert-butanol, and a solution of 10 g of methyl 2-methoxycarbonylmethyloxyphenoxyacetate in 100 ml of xylene is added dropwise to the mixture at 140°-150° C. (for 8 hours). To the reaction mixture 7 g of acetic acid is added and the precipitates are filtered off. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1 2:1), to give 6.5 g of methyl 3-oxo-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate as a colorless oil. Mass spectrum m/e: 222 (M+). IR νmaxneat cm-1 : 1750. NMR (CDCl3) δ: 3.75(3H, singlet, OCH3), 4.68 (2H, double doublet, C4 --H), 5.32 (1H, singlet, C2 --H).
Reaction SMILES: [CH2:1]1COC[CH2:2]1.CO.[Br:8][C:9]1[S:10][C:11](SCC)=[CH:12][CH:13]=1.O.O[O:19][S:20]([O-:22])=O.[K+]>C(Cl)Cl>[Br:8][C:9]1[S:10][C:11]([S:20]([CH2:1][CH3:2])(=[O:22])=[O:19])=[CH:12][CH:13]=1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CCSc1ccc(Br)s1
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 25 mL THF/MeOH (2:1) solution of 2-Bromo-5-ethylsulfanyl-thiophene (CAS 19991-60-7) is stirred at 0-10° C. while 8 mL H2O, then 3 equivalents of Oxone are added. The reaction mixture is stirred three hours at room temperature, then is diluted with CH2Cl2, filtered, washed with aq. NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo. The crude mixture is purified by silica gel column chromatography (gradient: 0-20% EtOAc/CH2Cl2) to give title intermediate that is confirmed by NMR.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[CH3:19][C:15]1[CH:14]=[C:13]([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Oc1cccc2ccccc12
Reactant: Cc1cccc(N)c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: Cc1cccc(Nc2cccc3ccccc23)c1
Yield: 94 %

Procedure:
216 parts of α-naphthol, 214 parts of m-toluidine and 10 parts of triphenyl phosphite are mixed. The reaction is carried out analogously to Example 7. After removing 27 parts of water, the reaction has ended. After distilling off excess m-toluidine, 330 parts of N-m-tolyl-α-naphthylamine, corresponding to a yield of 94% of theory, are obtained at a boiling point of 203° - 206° C/5 mm Hg.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.[CH2:23]([O:30][C:31]1[CH:58]=[CH:57][C:56]([OH:59])=[CH:55][C:32]=1[C:33]([NH:35][C:36]1[CH:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.O>[CH2:23]([O:30][C:31]1[CH:58]=[CH:57][C:56]([O:59][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:55][C:32]=1[C:33]([NH:35][C:36]1[CH:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:46]=[CH:45][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN1CCN(CCCBr)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CCN(CCCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 31.2 %

Procedure:
N,N-Dimethylformamide (3.0 mL), potassium carbonate (0.12 g), and 1-(3-bromopropyl)-4-methylpiperazine (0.30 g) were sequentially added to tert-butyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate (0.15 g), followed by stirring at 100° C. for 1 hour and 20 minutes. Potassium carbonate (0.12 g) was added to the reaction mixture, followed by stirring at 100° C. for 50 minutes. Water and chloroform were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.060 g of tert-butyl 2-(2-(benzyloxy)-5-(3-(4-methylpiperazin-1-yl)propoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: [N:1]1([C:27]([O:29]C(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][CH2:20][C:21]([NH2:23])=[O:22])=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:41]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:42](C(ON1C(=O)CCC1=O)=O)[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CCN(CC)CC>[NH:41]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:42]([C:27]([N:1]1[CH2:26][CH2:25][CH2:24][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][CH2:20][C:21]([NH2:23])=[O:22])=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:29])[CH2:43][O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O

Procedure:
The desired compound was prepared from 6.0 g of Boc-Pro-Arg(NO2)-Gly-NH2, 35 ml of 4 N HCl-AcOEt, 1.8 ml of Et3N and 5.1 g of Boc-Ser(Bzl)-OSu in the same manner as in Example 26-(4).
Reaction SMILES: [CH2:1]([N:4]([CH3:10])[C:5](=O)[N:6]([CH3:8])[CH3:7])[CH:2]=[CH2:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:4]([CH3:10])[C:5]([N:6]([CH3:8])[CH3:7])=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: Nc1ccccc1N1CCOCC1
Reactant: C=CCN(C)C(=O)N(C)C
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-allyl-1,1,3-trimethylurea (7.17 g) in benzene (50 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) for 45 hours at 70° C. gave 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethylguanidine (bp. 148°-150° C. at 0.2 mm Hg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38](=[O:47])[N:39]([CH3:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38](=[O:47])[N:39]([CH3:46])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:35][CH:36]=2)=[O:9])[CH:2]=1
Reactant: O=C(O)c1cccnc1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A solution of 3-pyridinecarboxylic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (0.36 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stir-stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 15% yield as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.O.NN>CO.[Ni]>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1
Reactant: CN(C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 98.6 %

Procedure:
A solution of compound 112 (0.21 g, 0.735 mmol) in dry methanol (5 mL) was treated with Ra—Ni (0.05 g) followed by hydrazine hydrate (0.22 mL, 7.359 mmol) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 5 min. The reaction brought to room temperature, filtered through celite bed and washed with methanol (2 10 mL). The solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 113 (0.185 g, quantitative) as a foam. mp 63-65° C.; 1H NMR (DMSO-d6) δ 1.40-1.52 (m, 1H), 1.97-2.02 (m, 1H), 2.08-2.57 (m, 11H), 4.47 (s, 2H), 5.99 (brs, 1H), 6.47 (dd, 1H, J=1.8, 8.4 Hz), 6.99 (d, 1H, J=0.9 Hz), 7.04 (d, 1H, J=8.7 Hz), 7.13 (d, 1H, J=2.4 Hz), 10.55 (s, 1H); ESI-MS m/z (%): 256 (MH+, 100), 211 (41).