Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8][CH2:9][CH3:10])([OH:7])[CH2:5][CH2:4][NH:3]1.F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[OH:7][C@@:6]1([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:4][N:3]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][CH3:21])[CH:13]=2)[C@H:2]1[CH3:1]
Reactant: CCC[C@]1(O)CCN[C@H]1C
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCC[C@]1(O)CCN(c2ccc(C#N)c(OC)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-methyl-3-propylpyrrolidin-3-ol 0.5 oxalate (250 mg), 4-fluoro-2-methoxybenzonitrile (399 mg) and lithium carbonate (195 mg), the title compound was obtained as colorless oil (yield: 303 mg, yield: 83%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32]CC1N=CNC=1>>[NH:31]1[CH:32]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[N:8]=[CH:9]1
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCc1c[nH]cn1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using histamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 353 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69-11.97 (1H, m) 11.52 (1H, br. s.) 10.35 (1H, s) 8.24 (1H, br. s.) 8.02 (1H, d, J=5.37 Hz) 7.77 (1H, d, J=5.47 Hz) 7.44-7.54 (2H, m) 7.31 (1H, dd, J=3.32, 2.83 Hz) 6.88 (1H, br. s.) 6.82 (1H, d, J=5.37 Hz) 6.44 (1H, dd, J=3.47, 1.71 Hz) 3.41-3.52 (2H, m) 2.71 (2H, t, J=6.98 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.C([S:39][C:40]([CH3:48])([CH3:47])[C@@H:41]([C:43]([O:45][CH3:46])=[O:44])[NH2:42])C1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:42][C@H:41]([C:43]([O:45][CH3:46])=[O:44])[C:40]([SH:39])([CH3:48])[CH3:47])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)C(C)(C)SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)(C)S
Temperature: -70 °C

Procedure:
146 g of t-butoxycarbonyl proline are dissolved in 1500 ml of methylene chloride. 150 ml of N-methylmorpholine are added to the solution. The solution is cooled to -70° C. 89 ml of isobutylchloroformate are added. The reaction mixture is warmed to -15° C. and then cooled to -70° C. 197 g of methyl S-benzylpenicillaminate hydrochloride are added to the reaction mixture. The reaction mixture is stirred for sixteen hours at room temperature. The reaction mixture is extracted three times with 1.0 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in a minimum of diethyl ether. The ether solution is added to cold rapidly stirring hexane. The white precipitate is filtered and dried to afford the product, methyl t-butoxycarbonylprolylpenicillaminate.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[N+:19]([O-])([OH:21])=[O:20].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: O=[N+]([O-])O
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)Cn1cnc2c(N)nc3ccc([N+](=O)[O-])cc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (28.3 g, 0.118 mol) in concentrated sulfuric acid (150 mL) was cooled to 5° C. A solution of 70% nitric acid (8.4 mL, 0.130 mol) in sulfuric acid (30 mL) was added in portions over a period of one hour. The reaction temperature was maintained below 10° C. The solution was allowed to warm to ambient temperature, stirred for two hours, and then poured into 500 g of ice. The resulting solution was made basic with the addition of ammonium hydroxide while keeping the solution cold. A precipitate formed, was isolated by filtration, washed with water, and dried to provide 1-(2-methylpropyl)-8-nitro-1H-imidazo[4,5-c]quinolin-4-amine as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: C1CCNCC1
Product: c1cc(N2CCC(CN3CCCCC3)CC2)ccc1CN1CCCC1

Procedure:
Prepared from the product of Example 16 and piperidine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCO.CO>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CO
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Yield: 84.9 %

Procedure:
Step-1 A solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (1) (0.25 g, 1.1 mmol) and aniline (2) (0.16 g, 1.7 mmol) in n-BuOH (25 mL) was heated at 120° C. for 12 h in a pressure tube. The reaction mixture was cooled, was dissolved in methanol (10 mL) and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (35 mL) and was washed successively with 10% sodium bicarbonate solution (20 mL), water (20 mL), and saturated brine (20 mL). The ethyl acetate extract was dried over Na2SO4 and was concentrated under reduced pressure to give a residue, which was triturated with diethyl ether to give (260 mg, 83%) N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (3) as an off-white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([Br:23])[CH:9]=[C:10]2[C:14]=1[N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:12]=[CH:11]2)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>>[Br:23][C:8]1[CH:9]=[C:10]2[C:14](=[C:6]([CH2:5][OH:4])[CH:7]=1)[N:13]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:12]=[CH:11]2
Reactant: CC(=O)OCc1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(CO)c21
Reaction time: 0.33 h

Procedure:
To a solution of (5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methyl acetate (1.04 g, 2.60 mmol) in methanol (15 mL, 371 mmol) at room temperature was added potassium carbonate (200 mg, 1.45 mmol). After 20 min, the reaction was concentrated and the resulting residue partitioned between water and diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 0.73 g (78%) as a colorless oil that solidified to an amorphous white solid upon standing. 1H-NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.81 (d, J=1.5, 1H), 7.43 (d, J=1.8, 1H), 5.90 (s, 2H), 4.97 (d, J=6.4, 2H), 3.49 (m, 2H), 3.43 (t, J=6.4, 1H), 0.83 (m, 2H), −0.09 (s, 9H); 13C NMR(126 MHz, CDCl3) δ ppm 136.7, 133.5, 131.1, 128.1, 125.9, 123.6, 114.4, 80.0, 66.6, 62.5, 17.8, −1.4.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH:8]=2)[N:3]=1.[BH4-].[Na+].CC(C)=O>CO>[NH2:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: Cc1cccc(C(O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice bath) solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (0.246 g, 0.581 mmol, prepared as in Example 15, Step 1) in MeOH (10.0 mL) was added sodium tetrahydroborate (0.044 g, 1.162 mmol) in one portion. The reaction mixture was then allowed to warm to RT and stirred for 17 h (overnight). Additional 4 eq of NaBH4 was added and stirred for 7 h until the conversion was completed, determined by LCMS. Acetone was added to quench the excess NaBH4. The resulted solution was concentrated and dried in vacuum to afford crude (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl) (phenyl)methanol as light yellow solid which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C1N2CCN(CC2)C1.C1C=CC=CC=1>[CH3:9][S:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:19])[O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:16]=1
Reactant: OCc1cccnc1
Reactant: CSc1ccc(N=C=O)cc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CSc1ccc(NC(=O)OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 4.4 g. (0.04 mole) of 3-pyridylcarbinol in 50 ml. of benzene containing 0.1 g. of Dabco catalyst was added, dropwise, a solution of 6.6 g. (0.04 mole) of p-methylthiophenyl isocyanate (New Haven Chemicals) in 50 ml. of benzene. During the addition a white solid separated and the temperature rose from 23°C. to 34°C. The mixture was stirred at ambient temperature for 16 hrs. and the product was filtered off. After oven-drying in vacuo there was obtained 10.4 g. melting at 133° -135°C. This is a 95% yield of 3-pyridylmethyl N-(4'-methylthiophenyl)-carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:25](=[O:26])[CH2:24][Cl:23])[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccc(C#N)c(Br)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CCc1ccc(C#N)c(Br)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-Butyl (2-{[2-(3-bromo-4-cyanophenyl)ethyl]amino}ethyl)carbamate (30 mg, 0.081 mmol) and TEA (30 mg, 0.30 mmol) in DCM (1 mL) was added chloroacetyl chloride (10 mg, 0.089 mmol) to the mixture at 0° C. The mixture was stirred at RT for 0.5 hour. Then the residue was diluted with DCM (20 mL) washed with water (5 mL×2) dried over Na2SO4 and concentrated in vacuo to give the desired product. MS m/z: 444 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[NH3:16].C(O)C.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([NH2:16])[CH2:8][CH2:7][CH2:6]2
Reactant: N
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(N)CCC2
Temperature: 0 °C
Yield: 4 %

Procedure:
3,4-Dihydro-6,7-dimethoxynaphthalen-1(2H)-one (5.00 g, 24.2 mmol), titanium(IV) isopropoxide (14.1 mL, 48.5 mmol) and 2 M solution of ammonia in ethanol (60.6 mL, 121 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0° C. and sodium borohydride was added portionwise during 10 min. (1.37 g, 36.4 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 130 mL), the precipitate that formed was filtered off and washed with ethyl acetate (25 mL×3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (25 mL×2). The combined organic extracts were washed with 1 M HCl (50 mL). The acidic aqueous extracts were washed with ethyl acetate (100 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (75 mL×3). The combined organic extracts were washed with brine (75 mL), dried (Na2SO4), and concentrated in vacuo to afford the desired product (200 mg, 4% yield). 1H NMR (400 MHz, CDCl3): δ 6.95 (s, 1H), 6.56 (s, 1H), 3.92 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.71 (m, 2H), 1.97 (m, 2H), 1.76 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]([NH2:21])[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13].[S:22](Cl)(Cl)(=[O:24])=[O:23]>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]([NH:21][S:22]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:24])=[O:23])[C:12]([N:14]1[CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH2:19]1)=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1CCN(C(=O)C(N)CCc2ccccc2Cl)CC1
Agent: Cl
Product: CC1CCN(C(=O)C(CCc2ccccc2Cl)NS(=O)(=O)c2ccccc2)CC1

Procedure:
Examples 6-38 are prepared from 4-(2-chlorophenyl)-1-(4-methylpiperidin-1-yl)-1-oxobutan-2-amine hydrochloride and the appropriate sulfonyl chloride in a manner similar to the synthesis of Example 5.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][O:21]CC3C=CC=CC=3)[C:10]=2[CH2:9][CH:8]([CH3:29])[CH2:7]1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][OH:21])[C:10]=2[CH2:9][CH:8]([CH3:29])[CH2:7]1)=[O:5])[CH3:31]
Reactant: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C(=O)C1CC(C)Cc2c1c1ccccc1n2CCO
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To a solution of 9-(2-benzyloxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (48) (460 mg, 1.1 mmol) in methanol (25 mL) was added a slurry of Pd/C (100 mg) in methanol (5 mL). The mixture was placed on the Parr hydrogenator and shaken for 24 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and concentrated in vacuo to afford 250 mg (79%) of 9-(2-hydroxy-ethyl)-2-methyl-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (49) as a yellow oil which was used in the next step without purification. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.20-1.40 (9H, m, CH3 and N(CH2CH3)2), 1.90-2.20 (3H, m, 2-CH and 3-CH2), 2.35-2.45 (1H, m, 1-CH2), 2.85-2.95 (1H, m, 1-CH2), 3.40-3.70 (4H, m, N(CH2CH3)2), 3.70-3.80 (1H, m, 4-CH), 4.10-4.30 (4H, m, NCH2CH2OH), 6.91 (1H, t, J=7 Hz, NCCHCHCHCH), 7.00 (1H, t, J=7 Hz, NCCHCHCHCH), 7.12 (1H, d, J=7 Hz, NCCHCHCHCH), and 7.15 (1H, d, J=7 Hz, NCCHCHCHCH).
Reaction SMILES: [NH2:1][CH:2]([CH3:42])[CH2:3][O:4][C@@H:5]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH:14][C@@H:15]([CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:16][N:17]([CH3:27])[C:18](=[O:26])[O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:13])[CH2:7]1.CCN(C(C)C)C(C)C.Cl[C:53]([O:55][CH3:56])=[O:54]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:56][O:55][C:53]([NH:1][CH:2]([CH3:42])[CH2:3][O:4][C@@H:5]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH:14][C@@H:15]([CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:16][N:17]([CH3:27])[C:18](=[O:26])[O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:13])[CH2:7]1)=[O:54]
Reactant: CC(N)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of crude 2-(trimethylsilyl)ethyl (2S)-2-((3R)-3-((1R)-(2-aminopropoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (0.1340 g), obtained as, described above, DMAP (0.151 g), DIPEA (2 mL), and methyl chloroformate (0.483 g) in CH2Cl2 was stirred at rt for 2 d. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to give 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(2-(methoxycarbonylamino)propoxy)(3-chlorophenyl)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate. MS ESI +ve m/z 705 (M+Na).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].[Cl:14][C:15]1[CH:16]=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][CH:20]=1.Cl>C(Cl)Cl>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][C:18]=1[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][Br:5])=[O:12]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1cccc(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(Cl)ccc1C(=O)CCCCCBr

Procedure:
Aluminum chloride (70 g.) was added portionwise to a solution of 110 g. of 6-bromocaproyl chloride in 250 ml. of methylene dichloride. To the resulting solution was added slowly, with cooling and stirring, 72 g. of m-chloroanisole in 250 ml. of methylene dichloride. The reaction mixture was stirred for 1 hour and poured into 500 ml. of 2N hydrochloric acid and 500 ml. of ice. The organic layer was separated and the aqueous layer extracted with ether. The combined organic layers were washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The product containing isomeric mixtures was chromatographed on silica gel and eluted with ethyl acetate-hexane. The first compound eluted (72 g.) was the desired isomer, 5-(2-methoxy-4-chlorobenzoyl)pentyl bromide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][N:8]=[C:9]=[O:10]>ClCCl>[CH3:7][NH:8][C:9]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:10]
Reactant: CN=C=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: CNC(=O)N1CCNCC1

Procedure:
To the solution of piperazine (3 g) in dichloromethane (30 ml) was added methyl isocyanate (2.16 ml) in an ice water bath with stirring. After 10 minutes the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo. The residue was diluted with acetonitrile (15 ml) and crystals were filtered off. The filtrate was evaporated in vacuo. To the residue was added xylene and the solvent was azeotropically removed in vacuo to give N-methyl-1-piperazinecarboxamide (2.43 g) as an oil.
Reaction SMILES: [ClH:1].O[CH:3]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:4][O:5][N:6]=[C:7]([Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>S(Cl)(Cl)=O>[Cl:1][CH:3]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:4][O:5][N:6]=[C:7]([Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC(CON=C(Cl)c1ccccc1)CN1CCCCC1
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: ClC(=NOCC(Cl)CN1CCCCC1)c1ccccc1
Reaction time: 2 h

Procedure:
2.0 g of N-[2-hydroxy-3-(1-piperidinyl)propoxy]-benzimidoyl-chloride hydrochloride is dissolved in 10 ml of thionylchloride, then the solution is boiled for 2 hours. The thionylchloride is distilled off; the evaporation residue is taken up in 50 ml of methanol, then evaporated. The light yellow evaporation residue (m=2.48 g) is dissolved in 12.5 ml of ethanol and crystallized with 50 ml of ether. The separated precipitate is filtered off, and washed with a mixture of ethanol/ether.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34](O)=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:57][S:54]([CH:51]4[CH2:53][CH2:52]4)(=[O:56])=[O:55])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
A solution of 50 (151 mg, 0.257 mmol) and carbonyldiimidazole (162 mg, 0.437 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (58 mg, 0.482 mmol) and DBU (76 mg, 0.502 mmol) were added. The resulting solution was stirred at 50° C. for 12 h, then cooled to room temperature. The reaction mixture was quenched with water and extracted with AcOEtethyl acetate, dried (MgSO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2/EtOAc, 95:5). The solid obtained was triturated in water, filtered, dried under high vacuum, triturated in diethylether and dried again under high vacuum to give 138 mg (77%) of the title product 51 as a white powder: m/z=691 (M+H)+; 1H-NMR (CDCl3): 10.70 (br s, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.97 (d, J=6.3 Hz, 1H), 7.54 (d, J=6.3 Hz, 1H), 7.21 (d, J=9.1 Hz, 1H), 6.70 (bs, 1H), 5.88 (bs, 1H), 5.74 (dd, J=17.3 Hz, 8.3 Hz, 1H), 5.16 (t, J=10.4 Hz, 1H), 4.74 (dd, J=9.4 Hz, 7.3 Hz, 1H), 4.11-3.98 (m, 4H), 3.69-3.55 (m, 2H), 3.27-3.10 (m, 1H), 3.02-2.89 (m, 1H), 2.83 (s, 3H), 2.58-2.35 (m, 3H), 2.29-2.13 (m, 1H), 2.11-1.92 (m, 2H), 1.75-0.76 (m, 9H).
Reaction SMILES: N12CCCN=C1CCCCC2.CO[C:14](=[O:30])[C:15]1[C:16](=[C:21]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19]C)=O.Cl.[NH2:32][CH:33]1[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:34]1=[O:35]>CN(C=O)C>[O:35]=[C:34]1[CH:33]([N:32]2[C:17](=[O:19])[C:16]3[C:15](=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:25][NH:26][C:27](=[O:29])[CH3:28])[C:14]2=[O:30])[CH2:39][CH2:38][C:37](=[O:40])[NH:36]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COC(=O)c1cccc(CNC(C)=O)c1C(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C
Yield: 22.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.93 g, 6 mmol) was added dropwise to a stirred suspension of 3-(acetylamino-methyl)-phthalic acid dimethyl ester (1.61 g, 6.0 mmol) and aminoglutarimide hydrochloride (1.0 g, 6.0 mmol) in DMF (15 ml). The mixture was then heated to 120° C. for 24 hours. The cooled mixture was concentrated in vacuo and the residue was stirred with water (25 ml) and dichloromethane (20 ml). The resulting slurry was filtered to give 0.45 g (22%) of the product as a gray solid. Recrystallization from methanol gave a white solid: mp 177–179° C.; 1H NMR (DMSO-d6) δ (11.02 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.74–7.55 (m, 3H), 5.05–4.98 (dd, J=5.3 and 12.5 Hz, 1H), 4.57 9D, j=5.9 Hz, 2H), 2.84–2.70 (m, 1H), 2.51–2.34 (m, 2H), 1.95–1.91 (m, 1H), 1.79 (s, 3H); 13C NMR (DMSO-d6) δ (172.85, 169.89, 169.81, 167.56, 167.05, 139.37, 134.83, 133.35, 131.58, 127.14, 121.94, 48.91, 37.84, 30.98, 22.54, 22.05; Anal. Calcd. For C16H15N3O5+0.96 water: C, 55.45; H, 4.92; N, 12.12. Found: C, 55.27; H, 4.82; N, 12.00.