Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH2:22])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]([C:25]#[N:26])[K]>O>[C:2]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([CH2:21][NH:22][C:25]([NH2:26])=[O:23])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CO[K]
Reactant: NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: Cl
Solvent: O
Product: NC(=O)NCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
C-(7-Benzenesulfonyl-chroman-4-yl)-methylamine HCl salt (75 mg, 0.22 mmol) was dissolved in 8 mL water and KOCN (36 mg, 0.44 mmol) was added. The reaction mixture was stirred at 100° C. for 30 minutes., then cooled, partitioned between EtOAc and water, and dried over MgSO4. After concentration, the product was precipitated from Et2O/hexanes. After formation of the HCl salt, 24 mg (32%) of (7-Benzenesulfonyl-chroman-4-ylmethyl)-urea was collected. MS: 347 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH3:28])[CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][C@H:3]1[OH:29].[NH2:30][C:31]1[C:39]([C:40]#[N:41])=[CH:38][C:34]([C:35](O)=[O:36])=[C:33]([OH:42])[CH:32]=1.ClC(Cl)Cl.C(O)(=O)C>O>[OH2:12].[NH2:30][C:31]1[C:39]([C:40]#[N:41])=[CH:38][C:34]([C:35]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([CH:8]([CH3:28])[CH2:9][C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][C@H:3]2[OH:29])=[O:36])=[C:33]([OH:42])[CH:32]=1
Reactant: N#Cc1cc(C(=O)O)c(O)cc1N
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](NC(=O)c2cc(C#N)c(N)cc2O)[C@H](O)C1
Yield: 10 %

Procedure:
To a stirred solution of 3.95 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide and 1.78 parts of 4-amino-5-cyano-2-hydroxybenzoic acid in 150 parts of trichloromethane were added 3.1 parts of N,N'-methanetetraylbis[cyclohexanamine] and stirring was continued over weekend at room temperature. The reaction mixture was acidified with an acetic acid solution in water. The separated organic layer was washed with water, dried, filtered and evaporated. The residue was taken up in acetonitrile and the precipitate was filtered off. The filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.55 parts (10%) of trans-4-[(4-amino-5-cyano-2-hydroxybenzoyl)amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide monohydrate; mp. 211.4° C. (compound 42).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.N[C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.CC1C=CC(N=C=S)=CC=1>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][C:6]([CH3:37])=[CH:7][CH:2]=4)=[S:35])=[CH:12][CH:13]=3)[CH:18]=2)[C:22]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: Cc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(C)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 274 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-methyl phenyl isothiocyanate. The compound of example 274 was used directly without isolation, for the preparation of compound of example 275.
Reaction SMILES: C([O:4][C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(C)C>C(Cl)Cl>[OH:4][C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][C:6]=1[O:15][CH3:16]
Reactant: COc1ccc2cc(C)sc2c1OC(C)C
Solvent: ClCCl
Product: COc1ccc2cc(C)sc2c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 140.1 %

Procedure:
To a mixture of the product of Step D (0.033 g; 0.0941 mmol) in CH2Cl2 (1 ml) TiCl4 (0.02 ml; 0.182 mmol) was added at room temperature under N2. After stirring for 10 min at room temperature, the mixture was diluted to 15 ml with CH2Cl2 and quenched with H2O (5 ml) and the organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure to give 7-hydroxy-6-methoxy-2-methyl-benzo[b]thiophene (0.0256 g; 100%). This was diluted to 1 ml with CH2Cl2 and tosyl chloride (0.03 g; 0.158 mmol), followed by triethylamine (0.022 ml; 0.158 mmol) of were added to it. The resulting mixture was stirred for 1 h at room temperature, washed with H2O, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from hexane/ethyl acetate mixture (9.5:0.5) to give the title compound (0.035 g; 68%), as creamy crystals. 1H-NMR (CDCl3) 2.45 (s, 3H); 2.48 (s, 3H); 3.63 (s, 3H); 6.83 (s, 1H); 7.32 (d, 2H, J=8.27 Hz); 7.43 (d, 1H, J=8.62 Hz), 7.87 (d, 2H, J=8.62 Hz).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.S(=O)(=O)(O)O>>[C:13]1(=[N:2][NH:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5][N:4]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NNC1=NCCc2ccccc21
Reactant: O=C1CCCCC1
Agent: O=S(=O)(O)O
Product: c1ccc2c(c1)CCN=C2NN=C1CCCCC1

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (9.4 g.) and cyclohexanone (6.3 g.) and treatment of the reaction mixture with sulfuric acid gave an oil, which was crystallized, then recrystallized, from isopropyl alcohol-ether, affording 1-(2-cyclohexylidenehydrazino)-3,4-dihydroisoquinoline [(I: X=X'=CH2 (CH2)4C,] Y=Y'=Z=Z'=H) sulfate (15.3 g., m.p. 139°-141° C. with decomposition).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[S:7][CH2:6][CH2:5][O:4]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:8]([O:1][CH2:2][C@@H:3]1[S:7][CH2:6][CH2:5][O:4]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@H]1OCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC[C@H]1OCCS1)c1ccccc1
Reaction time: 1 h
Yield: 44.6 %

Procedure:
2(S)-(Hydroxymethyl)-1,3-oxathiolane (0.25 mmol, 30 mg, 1.0 equiv.) recovered from Example 3 was treated with benzoyl chloride (0.25 mmol, 35 mg, 1.0 equiv.), triethylamine (0.25 mmol, 25 mg, 1.0 equiv.) in dichloromethane (1 mL) at ambient temperature while monitoring the reaction progress by TLC. After 1 h, the reaction was extracted with saturated ammonium chloride solution and brine. The organic phase was concentrated and chromatographed on silica gel to give 2(S)-(benzoyloxymethyl)-1,3-oxathiolane (25 mg, 44.6%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].C1([O-])C=CC=CC=1.[Br:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[Br:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: Oc1cccc(Br)c1
Reactant: O=Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1cccc(COc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.4 g of 3-bromomethylbenzaldehyde was dissolved in 3 ml of dimethylformamide, and the solution was added to 5 ml of a tetrahydrofuran solution of phenolate, prepared from 1.5 g of 3-bromophenol and 0.36 g of 60% oily sodium hydride. The mixture was stirred for 2 hours at room temperature. The solvent was evaporated, and water and ethyl acetate were added to the residue to extract it. The extract was worked up in a customary manner to give crude 3-(3-bromophenoxymethyl)benzaldehyde. When the same reaction as in Referential Example 12 was performed using 440 mg of the resulting aldehyde compound, 747 mg of tributyl(3-thienyl)stannane and 10 mg of tetrakis(triphenylphosphine)palladium, 341 mg (yield 77%) of 3-[3-(3-thienyl)phenoxymethyl)benzaldehyde was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[CH:20]([O:19][CH:13]([CH2:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH2:3][CH2:2][O:1][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])[CH:5]=1)[C:14]([OH:16])=[O:15])([CH3:21])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)OCCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(NC1C=CC(O)=CC=1)(=O)C.[N+](C1C=CC(O[C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[C:33]([N+:38]([O-:40])=[O:39])[CH:32]=2)=CC=1)([O-])=O>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:37]1[CH:31]=[CH:32][C:33]([N+:38]([O-:40])=[O:39])=[C:34]([CH:36]=1)[NH2:35])(=[O:3])[CH3:2]
Reactant: Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Reactant: CC(=O)Nc1cccc(O)c1
Agent: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])c(N)c2)c1

Procedure:
3-Acetamidophenol was utilized instead of 4-acetamidophenol, according to the same procedure for Intermediate 1 to prepare Intermediate 1A: MS m/e 286 (M−1).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][C:8]3=O)=[CH:3][CH:2]=1.[CH3:15][Li].[BH4-].[Na+].[ClH:19]>CCOCC.CO>[ClH:19].[CH3:15][CH:8]1[NH:9][CH2:10][CH:11]2[C:7]1([C:4]1[CH:5]=[CH:6][C:1]([CH3:14])=[CH:2][CH:3]=1)[CH2:12]2
Reactant: Cc1ccc(C23CC2CNC3=O)cc1
Reactant: [Li]C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(C23CC2CNC3C)cc1

Procedure:
Using the method of M. Takeda, et al., Chem. Pharm. Bull., 24, 2312 (1976), 1-(p-tolyl)-3-azabicyclo[3.1.0]hexan-2-one is reacted with methyllithium followed by sodium borohydride. Excess reagents are decomposed with methanol, followed by 1 N hydrochloric acid, and then 1 N sodium hydroxide and then evaporation of the solution gives a residue which is dissolved in ether. This solution is dried over sodium sulfate and filtered, and to the filtrate is added dry hydrogen chloride. Filtration of this suspension gives 2-methyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[CH2:29][CH:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][NH:25]1>C1(C)C=CC=CC=1>[NH:25]1[CH2:26][CH2:27][CH:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:29][C:24]1=[S:10]
Reactant: COC(=O)C1CCNC(=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CCNC(=S)C1
Yield: 176.7 %

Procedure:
Add Lawesson's reagent (9.2 g, 22.7 mmol) to a solution of methyl 2-oxopiperidine-4-carboxylate (6.5 g, 41.4 mmol) in toluene (83 mL) and heat to reflux for 2 hours. Cool the solution and concentrate to dryness under reduced pressure. Purify the residue by flash chromatography on silica gel, eluting with ethyl acetate:dichloromethane (gradient 5-15%) to afford the title compound (6.95 g). 1H NMR (CDCl3) δ 1.97 (m, 1H), 2.17 (m, 1H), 2.78 (m, 1H), 3.03 (m, 1H), 3.24 (m, 1H), 3.39 (m, 1H), 3.49 (m, 1H), 3.72 (s, 3H), 8.48 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH-].[Na+].[CH3:17]OS(OC)(=O)=O>>[CH3:17][O:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: O=C(O)c1cc(O)cc2c1CCCC2
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(c(C(=O)O)c1)CCCC2
Reaction time: 24 h

Procedure:
A mixture of 0.02 mole of 3-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid, and 40 ml. of 2 N sodium hydroxide solution is treated with 0.04 mole of dimethylsulfate over a 5 minutes period, and the mixture is stirred for 24 hours. The mixture is washed with 3 × 50 ml. of ether and acidified with dilute hydrochloric acid. The precipitate is collected, washed with water, dried at room temperature and 100μ pressure and recrystallized from cyclohexane.
Reaction SMILES: Br[C:2]1[C:11]([OH:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[Cl:13][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2)=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[C:11]=1[OH:12]
Reactant: Cc1ccc2c(Br)c(O)c(Cl)cc2n1
Reactant: OB(O)c1ccc(Cl)cc1
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: [K+]
Solvent: COCCOC
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(Cl)cc2n1
Temperature: 80 °C
Yield: 46.5 %

Procedure:
Pd(PPh3)4 (120 mg, 0.1 mmol) was added to a mixture of 5-bromo-7-chloro-2-methylquinolin-6-ol (1D) (345 mg, 1.04 mmol), 4-chlorophenylboronic acid (326 mg, 2.09 mmol) and K2CO3 (2.3 mL 2 M in water, 4.7 mmol) in 1,2-dimethoxyethane (10 mL). The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with a NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide 1E as a white solid (147 mg, 47%). LCMS-ESI+ (m/z): 304.2, 306.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:44])[C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:44])[C:35]([NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[CH:13]1[CH2:25][O:26]C(=O)C1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH:14]([CH2:15][OH:16])[CH:13]1[CH2:25][OH:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1C(COC(=O)c2ccccc2)C1COC(=O)c1ccccc1)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC1C(CO)C1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
7 N-(Benzyloxycarbonyl)-2,3-bis(benzoyloxymethyl) cyclopropylamine (0.22 g, 479 mmol) from Step F was dissolved in 5 mL of methanol. Sodium methoxide (52 mg, 95.9 mmol) was added to this solution and the reaction mixture was stirred at ambient temperature for 0.5 h. TLC analysis (on silica gel plates eluted with 10% methanol in chloroform) indicated that the starting material had been consumed in the reaction. The reaction mixture was concentrated in vacuo and the residue dissolved in water. The aqueous solution was acidified with Amberlite® IR-120(plus) acidic ion exchange resin. The resin was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by column chromatography on a 2×20 cm silica gel column eluted with 5% methanol in methylene chloride. Fractions numbered 9 -14 were combined and concentrated in vacuo to give 51 mg (33.3% yield) of N-benzyloxycarbonyl 2,3-bis(hydroxymethyl) cyclopropylamine. DCI NH3MS, M/Z: 252 (M+H)+, 269 (M+NH4)+. 1H NMR (CDCl3) 1.10 (m, 1H, 1.40 (m, 1H), 1.59 (s, O-H), 2.60 (dd, 1H), 2.75 (N-H), 3.31 (ddd, 2H), 3.77 (dd, 1H), 4.00 (dd, 1 H), 5.12 (s, 2H), 7.32 (m, 5H) ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:15][C:14]([CH3:16])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([OH:18])=[O:17]
Reactant: BrCc1ccccc1
Reactant: CC(C)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(Cc1ccccc1)C(=O)O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (12.6 g, 125 mmol) in tetrahydrofuran (100 ml) under anhydrous conditions at 0° C. was added n-butyllithium (80.6 ml, 1.55M in hexane, 125 mmol). The reaction mixture was stirred for 30 minutes at 5° C. and then isobutyric acid (4.4 g, 50 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and then benzyl bromide (17.1 g, 100 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at ambient temperature, quenched with saturated aqueous ammonium chloride (60 ml) and then acidified with 6N hydrochloric acid with cooling. The aqueous phase was saturated with sodium chloride and extracted with diethyl ether (2×100 ml). The combined organic phase was washed with saturated aqueous sodium chloride (2×25 ml) and then dried over magnesium sulfate and concentrated in vacuo to give viscous oil. The oil was distilled at 0.2 mmHg and the product was collected at 160°-170° C. The product was purified by chromatography on a 5×15 cm column of silica gel eluted with 10 percent diethyl ether/hexane (1 L) and 50 percent diethyl ether/hexane (1 L) to afford the desired product as a colorless solid. m.p. 58°-9° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:30][C:31]([N:33]2[CH2:37][CH2:36][CH2:35][CH:34]2[CH2:38]O)=[O:32])[CH:16]=[CH:17][C:18]=1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:21].C(N(CC)CC)C.[NH2:47][C@@H:48]1[CH2:53][CH2:52][C@H:51]([C:54]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])[CH2:50][CH2:49]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.ClCCCl.CC(O)=O.O>[CH2:57]([O:56][C:54]([C@H:51]1[CH2:52][CH2:53][C@@H:48]([NH:47][CH2:38][CH:34]2[CH2:35][CH2:36][CH2:37][N:33]2[C:31](=[O:32])[CH2:30][C:15]2[CH:16]=[CH:17][C:18]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[O:21])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:49][CH2:50]1)=[O:55])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Reactant: COc1cc(CC(=O)N2CCCC2CO)ccc1NC(=O)Nc1ccccc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)N2CCCC2CN[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)ccc1NC(=O)Nc1ccccc1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
To a stirred solution of oxalyl chloride (0.3 ml, 3.3 mmol) in CH2Cl2 (30.0 ml) was added DMSO (6.6 ml, 0.51 mmol) at −78° C. After 5 minutes, to the mixture was added 1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinemethanol (1.2 g, 3.0 mmol) in CH2Cl2 (5.0 ml). The mixture was stirred for 30 minutes at −78° C., and triethylamine (2.1 ml, 15.0 mmol) was added. The mixture was stirred for 30 minutes at −78° C., and stirred for 30 minutes at room temperature. Water was added to the mixture, and extracted with CH2Cl2. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, benzyl cis-4-aminocyclohexanecarboxylate (769 mg, 3.3 mmol), and AcOH (0.32 ml) in DCE (10 ml) was added NaBH(OAc)3 (1.1 g, 5.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. Sat. NaHCO3 was added to the residue, and extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH—CH2Cl2 (1:9, v/v) as eluent to give benzylcis-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]cyclohexanecarboxylate (1.5 g, 83%) as an amorphous solid. 1H-NMR (CDCl3) δ 1.40–1.65 (m, 6H), 1.80–1.98 (m, 6H), 2.26 (s, 3H), 2.45–2.65 (m, 3H), 2.81–2.86 (m, 1H), 3.44–3.46 (m, 2H), 3.56 (s, 2H), 3.67 (s, 3H), 3.90–4.15 (m, 1H), 5.09 and 5.11 (each s, total 2H), 6.74–6.83 (m, 3H), 7.07–7.20 (m, 4H), 7.31–7.35 (m, 5H), 7.53–7.55 (m, 1H), 8.02–8.06 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:33])N(C)[C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=2)=[CH:3]1.[OH-:34].[K+]>CCO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[O:33][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:17]=2)=[CH:3]1
Reactant: [OH-]
Reactant: CN1C(=O)C(c2cccc(OCCN3CCOCC3)c2)=C(c2cn(C)c3ccccc23)C1=O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1cc(C2=C(c3cccc(OCCN4CCOCC4)c3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C

Procedure:
3-(1-Methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]-1-methylpyrrole-2,5-dione (0.22 g, 0.5 mmol) was dissolved in EtOH (10 mL) and a solution of KOH (1.5 g) in H2O (2.5 mL) was added. After the reaction mixture was refluxed for 3 h, it was cooled to room temperature, followed by evaporation of EtOH. The residue was acidified with aq. HCl to pH=4.5. The product was extracted with EtOAc and the EtOAc layer was dried over sodium sulfate and concentrated to give 3-(1-methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]furan-2,5-dione which was in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].C(OC([NH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:33][CH:34]([O:38][CH:39]([CH3:41])[CH3:40])[C:35]([O-:37])=[O:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])=O)(C)(C)C>>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([NH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:33][CH:34]([O:38][CH:39]([CH3:41])[CH3:40])[C:35]([OH:37])=[O:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])=[O:8])[CH3:2]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Reactant: CCOc1ccc(C(=O)O)c(OCC)c1
Product: CCOc1ccc(C(=O)NCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)c(OCC)c1

Procedure:
Using 2,4-diethoxybenzoic acid and 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl)-2-isopropoxypropanoate, 3-(3-[(2,4-diethoxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).