Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28](O)=[O:29])[CH2:25][CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCCC1>[NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[NH:8][C:28](=[O:29])[CH:27]([CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(CCC)C(=O)O
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCCC(CCC)C(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(O)cc1
Yield: 65 %

Procedure:
Prepared analogously to Example 5d), but using tetrahydrofuran instead of acetonitrile, from (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl]-ornithinamide, 2-propyl-pentanoic acid and TBTU in a yield of 65% of theory. Colourless crystalline substance which was further processed without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1.[H][H]>C(OCC)(=O)C.[Rh]>[CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: COCc1ccc(C(=O)O)o1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COCC1CCC(C(=O)O)O1
Yield: 102.5 %

Procedure:
A solution of 5-methoxymethylfuran-2-carboxylic acid (3.10 g) in ethyl acetate (40 ml) was hydrogenated over 5% rhodium on carbon (200 mg) until hydrogen uptake ceased. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated to give the title compound as a colourless oil (3.26 g); νmax (film) 1750 cm-1 ; δH (CDCl3) 1.75-2.1 (2H,m), 2.1-2.6(2H,m,), 3.45 (3H,s), 3.47 (1H,dd, J 3 and 10 Hz), 3.74 (1H,dd, J 4 and 10 Hz), 4.15-4.43 (1H,m) and 4.43-4.63 (1H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[N:30]1([CH2:36][CH2:37][OH:38])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:9]([C:27]([N:33]3[CH2:34][CH2:35][N:30]([CH2:36][CH2:37][OH:38])[CH2:31][CH2:32]3)=[O:29])[NH:10][CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:12]2([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)N2CCN(CCO)CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 63.5 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with 2-piperazin-1-yl-ethanol (65.0 mg, 0.50 mmol), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2S,3R,4R,5R)-4-(3-chloro-phenyl)-3-(4-chloro-phenyl)-2-(2,2-dimethyl-propyl)-5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyrrolidine-3-carbonitrile (48.3 mg, 63.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([CH2:24][NH2:25])[CH2:12]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:26]([S:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)(=[O:30])=[O:29])[CH3:27]>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]([CH2:24][NH:25][S:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][S:28]([CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:37][CH:36]=3)(=[O:40])=[O:39])[CH2:12]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(OC)cc(N2CCN(Cc3ccccc3)C(CN)C2)c1
Product: CCS(=O)(=O)Nc1ccc(S(=O)(=O)NCC2CN(c3cc(OC)cc(OC)c3)CCN2Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 3, react 4-(3,5-dimethoxyphenyl)-1-(phenylmethyl)-2-piperazinemethanamine with 4-[(ethylsulfonyl)amino]benzenesulfonyl chloride to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([CH:18]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:8]1[N:15]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[I:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[O:19])[N:6]([CH:18]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[C@H:8]1[NH2:15]
Reactant: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c(=O)[nH]c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 5-iodo,2′-azido,2′-deoxyuridine (2.48 g, 6.3 mmoles) in dioxane (33 ml) is added triphenylphosphine (5.8 g, 22 mmoles, 3.5 eq.) and the mixture is stirred at room temperature for 1 h, during which time a white precipitate forms. The precipitate is collected and washed three times with diethyl ether (3×50 ml). The filtrate is evaporated to dryness, taken up in a minimum amount of dioxane, and stored at −20° C. for 48 h. The precipitate is collected and washed with diethyl ether. The combined precipitates gave 1.81 g of 5-iodo,2′-amino,2′-deoxyuridine (78% yield). The spectral properties agreed with those reported in the literature (Verheyden et al. (1971) supra).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].Br[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.O>CN(C=O)C>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:8]2[C:9]3[N:5]4[C:4](=[N:3][C:2]([CH3:1])=[C:6]4[C:7]2=[O:13])[CH:12]=[CH:11][CH:10]=3)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3n(CC4CCN(C(=O)OC(C)(C)C)CC4)c(=O)c1n23
Yield: 62.9 %

Procedure:
To a suspension of 735 mg (4.24 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 15 ml of DMF was added, while stirring under ice-cooling, 187 mg (4.68 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 20 minutes at the same temperature. To the mixture was added a solution of 1.18 g (4.24 mmol) of 4-bromomethyl-1-tert-butoxycarbonylpiperidine in 5 ml of DMF. The mixture was stirred for one hour at 100° C. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 988 mg of the desired compound (62.8%, pale yellow solid).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>>[OH:26][C:22]1[CH:21]=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(O)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(O)c1
Yield: 66.4 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 418 mg of 3-aminophenol in place of the 2,4-difluoroaniline. 210 mg of N-(3-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[C:12]1(=O)[O:16][CH2:15][CH2:14][CH2:13]1.N>Cl>[CH3:3][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=[C:12]1[CH2:13][CH2:14][CH2:15][OH:16]
Reactant: CNc1ccccc1N
Reactant: O=C1CCCO1
Agent: Cl
Agent: N
Product: Cn1c(CCCO)nc2ccccc21
Yield: 71.2 %

Procedure:
N-Methyl-ortho-phenylenediamine dihydrochloride (4.88 g), and butyrolactone (3.22 g) were stirred at reflux for 18 hours in 4N hydrochloric acid (25 ml). The reaction mixture was cooled, the pH adjusted to 8 with concentrated aqueous ammonia and filtered. The solid was recrystallised from ethyl acetate to yield the title compound as a white solid (3.39 g 71%), m.p. 107° C. Found: C, 69.22; H, 7.38; N, 14.73. C11H14N2O requires C, 69.45; H, 7.42; N, 14.72%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:28])[C:17]3=[C:18]([F:27])[CH:19]=[N:20][C:21]4[CH:22]=[C:23]([Cl:26])[C:24](=[O:25])[N:15]([C:16]=43)[CH2:14]2)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1.[Na].O>C(O)C>[Cl:26][C:23]1[C:24](=[O:25])[N:15]2[CH2:14][C:13]([CH2:12][N:29]3[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:33][CH2:34]3)([OH:28])[C:17]3=[C:18]([F:27])[CH:19]=[N:20][C:21]([CH:22]=1)=[C:16]23
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)c(Cl)cc4ncc(F)c2c43)CC1
Reaction time: 8 h

Procedure:
To a solution of crude ((4R/S)-8-chloro-3-fluoro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl 4-methylbenzenesulfonate (˜2.5 g, assumed 6.10 mmol) in ethanol (50 mL), at room temperature, under argon was added 1,1-dimethylethyl 4-piperidinylcarbamate (1.22 g, 6.10 mmol) and sodium hydrogenocarbonate (1.94 g, 18.31 mmol). The reaction mixture was stirred for 8 hours. A further 0.5 equivalent of 1,1-dimethylethyl 4-piperidinylcarbamate (0.61 g, 3.05 mmol) and 1.5 equivalent of sodium hydrogenocarbonate (0.97 g, 9.15 mmol) were added. The reaction mixture was stirred for an additional 18 hours, treated with water (200 mL) and extracted with a 10% solution of methanol in dichloromethane (3×200 mL). The combined organic layers were dried over magnesium sulphate, evaporated and chromatograped affording an impure material which used crude in the following step.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([C:14](O)=O)[CH2:8][CH2:7]2)=[O:5])C.Cl.[NH2:18][C:19]1[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=1[NH2:25]>>[O:29]=[C:22]1[N:23]([CH2:26][CH2:27][CH3:28])[C:24]2[N:25]=[C:14]([CH:9]3[CH:10]4[CH2:13][C:6]([C:4]([OH:3])=[O:5])([CH2:12][CH2:11]4)[CH2:7][CH2:8]3)[NH:18][C:19]=2[C:20](=[O:33])[N:21]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCOC(=O)C12CCC(C1)C(C(=O)O)CC2
Agent: Cl
Product: CCCn1c(=O)c2[nH]c(C3CCC4(C(=O)O)CCC3C4)nc2n(CCC)c1=O
Yield: 110.3 %

Procedure:
Using the procedure described in Example 50, Step D, bicyclo[3.2.1]octane-1,4-dicarboxylic acid 1-ethyl ester (0.84 mmol, 0.19 g) was reacted with 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (0.84 mmol, 0.22 g) to provide the desired product (0.36 g, 100%) as a mixture of axial and equatorial amides. MS (ESP+, 60V): 456.95 (M+Na, 45%), 435.00 (M+H, 8%), 325.12 (42%), 280.05 (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH3:23])[C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: CI
Reactant: N#Cc1cc(Br)cc(NC(=O)OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)c1cc(Br)cc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a stirring solution of 773 mg (2.33 mmol) of benzyl 3-bromo-5-cyanophenylcarbamate in 10 mL of THF at 0° C. was added 231 mg of NaH (60% dispersion in mineral oil). After 1 h, 300 μL (4.82 mmol) of methyl iodide was added, the ice bath was removed, and the red mixture was stirred at r.t. with the light off. After 17 h, saturated NH4Cl, H2O, and EtOAc were added and the layers separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 195 mg of benzyl 3-bromo-5-cyanophenyl(methyl)carbamate in 24% yield.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)CBr>CN.CO.CN(C)C=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH2:7][CH2:6][NH2:3]
Reactant: CCN(CC)CC
Reactant: BrCc1cc(Br)cc(Br)c1
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Product: NCCc1cc(Br)cc(Br)c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
Triethylamine (5.28 g; 52.2 mmol) was dissolved in 40% methylamine in methanol (100 ml). While the mixture was stirred at room temperature, 3,5-dibromobenzyl bromide (17.2 g; 52.2 mmol) in N,N-dimethylformamide (20 ml) was added dropwise. The mixture was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in 2N hydrochloric acid (150 ml), and the mixture was extracted with diethyl ether (150 ml), to thereby exclude impurities. The aqueous layer was alkalinized with aqueous sodium hydroxide solution, and extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 11.3 g of the target compound as orange oily matter (yield: 77.7%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH:10]=3
Reactant: O=c1ccn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=c1ccn2c3c(cc(OCc4cccnc4)cc13)Sc1ccc(Br)cc1-2
Yield: 72.2 %

Procedure:
According to Example 34, the compound (170 mg) produced in Example 58 was reacted with 3-chloromethylpyridine hydrochloride (155 mg) to obtain the title compound (155 mg; 72%).
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCC>[OH:11][CH:4]([CH:13]1[CH2:14][CH2:15][CH2:16][C:12]1=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC=O
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: CCCCCCC(O)C1CCCC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
Into a 2-litter four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were added sodium hydroxide (3.2 g) and water (300 ml). Then, a mixture of heptanal (114 g) and cyclopentanone (152 g) was added dropwise thereto under stirring at 0-5° C. over a period of 2 hours. After the addition, the reaction mixture was stirred at room temperature for 1 hour to complete the reaction. Hexane (150 ml) was added to the reaction mixture and the layers were separated from each other. The resulting organic layer was washed with an aqueous solution (200 ml) of acetic acid (1 g) and separated. Then, the resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover hexane and unreacted cyclopentanone, whereby a product (202 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 154 g of 2-(1-hydroxyheptyl)cyclopentanone (boiling point: 112-114° C./666 Pa; GC purity: 92%). The remaining 8% was 2-heptylidenecyclopentanone which is a dehydration product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[S:28][C:27]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=4[C:25]=3[CH3:34])(=[O:23])=[O:22])=[C:16]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39].C(OCC)(=O)C.CCOCC>C(OCC)(=O)C>[ClH:39].[CH3:38][S:35]([C:16]1[CH:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][C:17]=1[NH:20][S:21]([C:24]1[S:28][C:27]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:26]=2[C:25]=1[CH3:34])(=[O:22])=[O:23])(=[O:36])=[O:37]
Reactant: Cc1c(S(=O)(=O)Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1c(S(=O)(=O)Nc2ccc(C3CCNCC3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-[4-(5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-3-methanesulfonyl-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (0.025 g) in ethyl acetate (1 ml) was treated with 2.5 N HCl/ethyl acetate (2 ml). The reaction mixture was stirred at rt for 2 h. Ether (20 ml) was added, the precipitate was filtered off, washed with ether and dried under high vacuum over P2O5 to obtain the title compound (0.020 g) as a yellowish powder. MS (ISP): 483.3 (M+H)+
Reaction SMILES: C([O:8][C:9](=[O:44])[CH2:10][C@@H:11]([C:25]1[CH:29]=[CH:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[CH:26]=1)[C:12]([NH:14][C@H:15]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])C1C=CC=CC=1>CCO.C1COCC1>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH:28]=[CH:29][C:25]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20]4[NH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[CH2:10][C:9]([OH:44])=[O:8])=[CH:26]3)=[CH:35][CH:34]=2)=[CH:37][CH:38]=1)#[N:43]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)c1ncc[nH]1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)c1ncc[nH]1
Yield: 54 %

Procedure:
According to the procedure described in Example 1(a), 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid benzyl ester was hydrogenolyzed in EtOH/THF for 3 h to give a 54% yield of 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid: mp 206-210° C. (dec); 1HNMR (DMSO-d6): δ—12.0 (bs, 1H), 8.31 (d, 1H, J=8.45 Hz), 7.93 (s, 4H), 7.86 (d, H, J=8.5 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.33-7.30 (m, 2H), 6.81 (s, 2H), 6.18 (s, 1H), 5.02 (dd, 1H, J=15.8, 8.8 Hz), 3.86 (dd, 1H, J=9.6, 4.8 Hz), 2.87 (dd, 1H, J=16.9, 10.3 Hz), 2.60 (dd, 1H, J=16.5, 4.8 Hz), 1.7-1.5 (m, 3H), 0.87 (d, 3H, J=6.6 Hz), 0.84 (d, 3H, J=5.9 Hz); HRFABMS Calculated for C29H29N5O3Cs (M+Cs): 628.1325 Found: 628.1335
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH:13]1([C:19]([C:7]2[C:6]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:9][C:8]=2[CH3:10])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccc2cc(C)oc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COc1ccc2c(C(=O)C3CCCCC3)c(C)oc2c1
Reaction time: 1 h
Yield: 47 %

Procedure:
To a mixture of 6-methoxy-2-methyl-1-benzofuran (1.50 g), cyclohexanecarbonyl chloride (1.36 mL) and nitromethane (15 mL) was added aluminum chloride (1.85 g) at 0° C., and the mixture was stirred for 1 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% ethyl acetate/hexane) to give the title object compound (1.18 g, 47%) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([S:24][CH3:25])[C:12]=1[C:13](O)=[O:14]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:13](=[O:14])[C:12]1[C:16]([S:24][CH3:25])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:11]=1[O:10][CH3:9]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N

Procedure:
The title compound, yellow foam, MS: m/e=385.1 [(M+H)+], was prepared in accordance with the general method of intermediate G from cis-1,2-diaminocyclohexane and 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:15]([OH:17])[CH3:16]>C1COCC1>[CH2:15]([O:17][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]([F:11])=[CH:10][C:2]=1[F:1])[CH3:16]
Reactant: CCO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F

Procedure:
Prepared analogously to example 156a from 2,4-difluoro-5-nitro-benzoyl chloride (5.0 g, 22.6 mmol), ethanol and TEA in THF.
Reaction SMILES: [C:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])(O)=[O:2].C(Cl)(=O)C([Cl:57])=O.CN(C)C=O>ClCCl>[Cl:57][C:1]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl

Procedure:
The solution of 0.80 g of benzyl 3-[4-carboxy-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 15 ml of dichloromethane is cooled to 0° C. with stirring and admixed successively with 0.190 ml of oxalyl chloride and 0.008 ml of N,N-dimethylformamide. The reaction mixture is stirred at 0° C. over 6 hours. The reaction mixture is subsequently concentrated by evaporation at room temperature to obtain the crude title compound.