Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.N[C@@H:29]([CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C@@H:30]([OH:40])[CH:31]([OH:39])[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(N(CC)CC)C>CN(C=O)C>[NH2:2][CH:32]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH:31]([OH:39])[CH:30]([OH:40])[CH2:29][CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: On1nnc2ccccc21
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
50 mg of L-N-[(2S or-R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine was dissolved in 0.2 ml of dry DMF, and 28.2 mg of 1-hydroxybenzotriazole and 33.2 mg of DCC were added thereto at 0° C. under stirring. Then, 55.2 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was dissolved in 0.2 ml of dry DMF, and 31.1 mg of triethylamine was added thereto for neutralization. This mixture was added to the previous reaction solution, and the mixture was stirred at 0° C. for two hours and at room temperature overnight. The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (chlorofrom/methanol= 20/1) to obtain 20.1 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucyl}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].[Br-].[Na+].C([Br:32])C>CN1CCCC1=O>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:32])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: CCBr
Reactant: C=C(C)C(=O)OCCCCCCCl
Agent: C=C(C)C(=O)OCCOC(=O)C(=C)C
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=C(C)C(=O)OCCCCCCBr

Procedure:
6-Chlorohexyl methacrylate ethylene glycol bismethacrylate co-polymer (4.1 meq Cl/g, approximately 1.9 molar % cross-linking) (c.f. Example 17) (14.1 g) was reacted with sodium bromide (6 g) and ethyl bromide (63.2 g) in N-methylpyrrolidone (200 ml) at 65° for 6 days. The slurry was then sieved and the fraction <53 μM discarded. The remaining polymer was washed with water, methanol, acetone and diethylether and dried under vacuum for 16 hours to give 6-bromohexyl methacrylate ethylene glycol bismethacrylate co-polymer (14.97 g, 3.47 meq Br/g, no Cl detected).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.Cl.[C:12]([O:16][NH2:17])([CH3:15])([CH3:14])[CH3:13]>CO.C(OCC)(=O)C>[C:12]([O:16][N:17]=[CH:4][C:3]1[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:2]=1[Br:1])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)ON=Cc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To the solution of 2-bromo-5-hydroxy-benzaldehyde (402 mg, 2 mmol) in methanol (10 ml) is added O-tert-butyl-hydroxylamine hydrochloride (125 mg, 10 mmol). The mixture is stirred at room temperature overnight. The resulting mixture is diluted with ethyl acetate, washed with brine, dried over MgSO4, and evaporated to afford the titled compound (360 mg) as colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:5][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cccc(Oc2ccccc2)c1NC(C)=O

Procedure:
A solution of acetyl chloride (1.38 g.) in methylene chloride (10 ml.) was added to a mixture of ethyl 2-(2-amino-3-phenoxyphenyl)acetate (4.3 g.), pyridine (1.9 g.) and dried methylene chloride (50 ml.) over 10 minutes at 5° C. with stirring and stirred for 30 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added 10% hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and then evaporated. The residue was crystallized with a mixture of benzene and n-hexane to give the captioned compound (3.65 g.). mp 106° to 107° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]([CH:17]3[CH2:20][O:19][CH2:18]3)=[N:14][C:13]=2[CH3:21])=[CH:7][C:3]=1[C:4]([OH:6])=O.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[F:40][C:41]1([C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[CH2:44][NH:43][CH2:42]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]([CH:17]3[CH2:20][O:19][CH2:18]3)=[N:14][C:13]=2[CH3:21])=[CH:7][C:3]=1[C:4]([N:43]1[CH2:42][C:41]([C:45]2[CH:46]=[CH:47][C:48]([C:49]#[N:50])=[CH:51][CH:52]=2)([F:40])[CH2:44]1)=[O:6]
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1cc(C)c(-c2[nH]c(C3COC3)nc2C)cc1C(=O)O
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]c(C3COC3)nc2C)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 2,4-dimethyl-5-(4-methyl-2-(oxetan-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 180.4) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 445 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 11.80 (br, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 7.18 (d, J=7.2 Hz, 2H), 4.87-4.75 (m, 4H), 4.60-4.36 (m, 4H), 4.31-4.21 (m, 1H), 2.35 (s, CH3, 3H), 2.90 and 2.20 (2 singlets, CH3, 3H), 2.13 and 2.02 (2 singlets, CH3, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:48][N:49]([CH3:55])[C@H:50]1[CH2:54][CH2:53][NH:52][CH2:51]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:48][N:49]([CH3:55])[C@H:50]1[CH2:54][CH2:53][N:52]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:51]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COC(=O)c1cccc(Br)c1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N2CC[C@H](N(C)C)C2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-bromobenzoate (1.0 g, 4.7 mmol), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (0.037 g, 0.093 mmol), tris(dibenzylidineacetone)dipalladium (0) (0.021 g, 0.023 mmol), anhydrous K3PO4 (1.4 g, 6.5 mmol) in 9.3 mL toluene under argon was added (S)—N,N-dimethylpyrrolidin-3-amine (0.71 mL, 5.6 mmol). The reaction was sealed and heated to 80 deg. C. for 3 days. The reaction was cooled to ambient temperature, was diluted with ethyl acetate, and filtered through celite. The filtrate was concentrated in vacuo to give a brown oil, which was further purified by silica gel chromatography, using 90/10/1 dichloromethane/methanol/sat'd ammonium hydroxide as eluent to give (S)-methyl 3-(3-(dimethylamino)pyrrolidin-1-yl)benzoate as a light brown oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(F)c(F)cc2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Chloro-4,5-difluoro-benzoic acid. LC-MS (basic): tR=0.94 min; [M+H]+=502.0.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.N1(C2CCCCCCCCCC2)CCCCCC[CH2:18][CH2:17][CH2:16]N1.BrC(C)C>C1C=CC=CC=1>[CH:17]([N:3]1[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=[C:2]1[Br:1])([CH3:18])[CH3:16]
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Reactant: Cc1nc(Br)[nH]c1C(=O)OC(C)C
Solvent: c1ccccc1
Solvent: CC(C)Br
Product: Cc1nc(Br)n(C(C)C)c1C(=O)OC(C)C
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of 2 g (8.1×10-3 moles) of isopropyl 2-bromo-4-methyl-5-imidazolecarboxylate in 20 ml of benzene was added 1.2 ml (8.2×10-3 moles) of diazabicycloundecane, followed by 1.0 g. (8.1×10-3 moles) of 2-bromopropane. The resulting mixture was heated to reflux overnight, cooled to room temperature and filtered. Concentration in vacuo gave a golden oil. This residue was purified by medium pressure liquid chromatography on silica gel to yield 1.6 g (70%) isopropyl 1-isopropyl-2-bromo-4-methyl-5-imidazolecarboxylate as a yellow oil, but only 466 milligrams (20%) of the desired product, isopropyl 2-bromo-3-isopropyl-4-methyl-5-imidazolecarboxylate (also a yellow oil), wherein S1 and S3 and R were all CH(CH3)2.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH3:12])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CCOCC>[OH:8][CH2:9][C@@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)[CH3:12]
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To tert-butyl (2S,3S)-1-(tert-butyldimethylsilyloxy)-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (2000 mg, 4.5 mmol) in 25 mL ether at 0° C. was added 1.0 M tetrabutylammonium fluoride in THF (8.9 mL, 8.9 mmol). After the addition, the ice-bath was taken away. The reaction progress was monitored by TLC. After 60 minutes, the solvent was evaporated and 100 mL diethyl ether was added. The organic layer was washed with water and brine solution, and then dried over sodium sulfate. The crude product was then chromatographed eluting with 30% EtOAc in hexane. After removing the solvent, the desired product was obtained as a white solid (1.25 g, 84%). 1H NMR (400 MHz, CD3OD) 8 ppm 1.26-1.31 (m, 9 H) 1.34 (d, J=7.04 Hz, 3H) 3.02-3.13 (m, 1H) 3.61-3.67 (m, 2H) 3.75 (dd, J=8.71, 4.60 Hz, 1H) 7.44 (d, J=8.02 Hz, 2H) 7.57 (d, J=8.22 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1>CN(C)C=O>[N:30]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:3]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: c1cn[nH]c1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cccn2)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Yield: 54.9 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), pyrazole (0.25 g) and dimethylformamide (35 ml). The product (0.62 g) was obtained as a colorless amorphous solid, MS, m/z: 423.2 (M+H)+, 445.2 (M+Na)+, 845.3 (2M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14](O)=[O:15])[C:6]1=2>C(O)C>[CH2:1]([O:3][C:14]([C:13]1[C:6]2[S:5][CH:9]=[CH:8][C:7]=2[CH:10]=[CH:11][CH:12]=1)=[O:15])[CH3:2]
Reactant: O=C(O)c1cccc2ccsc12
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1cccc2ccsc12
Yield: 86.4 %

Procedure:
Acetyl chloride (14.8 mmol; 1.05 mL) is added to a solution of benzo[b]thiophene-7-carboxylic acid (4.94 mmol; 880 mg) in ethanol (20 mL) and the mixture is stirred at reflux for 24 h. The solvent is removed. Ethyl acetate is added to the residue and the resulting solution is washed with water, dried (Na2SO4), filtered and concentrated to obtain the title compound (880 mg, 92%) as colorless oil. 1H NMR (CDCl3): δ 8.12 (dd, 1H, J=7.2 Hz, 0.6 Hz), 8.03 (dd, 1H, J=7.6 Hz, 1.2 Hz), 7.58 (d, 1H, J=5.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.41 (t, 1H, J=5.2 Hz), 4.50 (c, 2H, J=7.3 Hz), 1.47 (t, 3H, J=7.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH2:14]1[CH:19]2[CH2:20][C:21]3([CH:24]=O)[CH2:23][CH:17]([CH2:18]2)[CH2:16][CH:15]1[CH2:22]3>>[C:21]12([CH:24]3[NH:1][C:2]4[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=4[S:10](=[O:12])(=[O:11])[NH:13]3)[CH2:20][CH:19]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:23]1)[CH2:22]2
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Reactant: O=CC12CC3CC(CC(C3)C1)C2
Product: O=S1(=O)NC(C23CC4CC(CC(C4)C2)C3)Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using 1-adamantylcarboxaldehyde). M.p. 270-273° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:31]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[N:32]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:36][C:33]3[NH:32][N:31]=[CH:35][CH:34]=3)=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Reactant: O=Cc1cc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ccn[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (72.0 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with pyrazole-3-carboxaldehyde (24.5 mg) and sodium cyanoborohydride (35.9 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (52.3 mg) of the subject compound as a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13]CC)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:20][CH2:19][CH2:18][NH2:21])=[O:13])=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: NCCN
Reactant: CCOC(=O)COc1ccc(NC(C)=O)cc1
Product: CC(=O)Nc1ccc(OCC(=O)NCCN)cc1

Procedure:
In a similar manner using 23.7 g. of ethyl 4-acetamidophenoxyacetate and 60 ml. of ethylenediamine as starting materials there is obtained β-(4-acetamidophenoxyacetamido)-ethylamine, m.p. 210°-212° C.
Reaction SMILES: C([N:8]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=[N:9]1)C1C=CC=CC=1.C(O)=O>[C].[Pd].C(O)C>[CH2:13]([C:12]1[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][NH:9][N:8]=1)[CH2:14][CH3:15]
Reactant: CCCc1c(/C=C/C(=O)OCC)cnn1Cc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: CCCc1n[nH]cc1CCC(=O)OCC
Yield: 81.6 %

Procedure:
A mixture of ethyl(E)-3-(1-benzyl-5-propyl-1H-pyrazol-4-yl)propenoate (6.00 g), 5% palladium-carbon (12.0 g), formic acid (50 ml), and ethanol (100 ml) was refluxed for 16 hours. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-(3-propyl-1H-pyrazol-4-yl)propionate (3.45 g, yield: 82%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][C:5]1([CH3:18])[CH3:17])(=[O:3])[CH3:2].C[OH:20].O.OO>[O-][W]([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>[CH2:14]([CH:13]=[N+:12]([CH:7]1[CH2:6][C:5]([CH3:17])([CH3:18])[N:4]([C:1](=[O:3])[CH3:2])[C:9]([CH3:10])([CH3:11])[CH2:8]1)[O-:20])[CH2:15][CH3:16]
Reactant: CO
Reactant: CCCCNC1CC(C)(C)N(C(C)=O)C(C)(C)C1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC=[N+]([O-])C1CC(C)(C)N(C(C)=O)C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred mixture of 12.4 g (48.6 mmol) of 1-acetyl-4-n-butylamino-2,2,6,6-tetramethylpiperidine, 0.8 g (2.4 mmol) of sodium tungstate, 85 ml of methanol and 20 ml of water at 0° C. is added 19.9 ml (195 mmol) of 30% aqueous hydrogen peroxide. After stirring for one hour at 0° C., the reaction mixture is allowed to warm to room temperature and is stirred for an additional 2.5 hours. Ethyl acetate is added and the organic phase is then washed with water, and brine, dried over anhydrous sodium sulfate and concentrated. The crude product is purified by flash chromatography on silica gel (12:2:1, ethyl acetate:hexane: methanol) to yield 4.8 g (37%) of the title compound as a clear oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=[O:31].O>C(#N)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30](=[O:31])[CH2:29][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CC(=O)c2ccc(Cl)cc2)CC1
Yield: 13.1 %

Procedure:
K2CO3 (0.129 mol) was suspended in a solution of ethyl 4-(1H-benzimidazol-2-yl-amino)-1-piperidinecarboxylate (0.0347 mol) and 2-bromo-1-(4-chlorophenyl)ethanone (0.0647 mol) in acetonitrile (150 ml). The mixture was stirred and refluxed for 8 hours, then cooled, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The pure fractions were collected and the solvent was evaporated. Part of this fraction (3 g) was taken up in 2-propanone and diethyl ether. The precipitate was filtered off and dried, yielding 2 g of ethyl 4-[[1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (interm. 1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[CH:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]S([O-])(=O)=O.[Mg+2]>ClCCl>[CH3:2][O:3][C:4](=[O:13])[CH:5]([N:12]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C(N)c1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(N=Cc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 8 (40.3 g, 0.2 mol) in dichloromethane (600 mL) was added triethyl amine (24.24 g, 0.24 mol) dropwise. After stirring for 30 min, benzaldehyde (21.2 g, 0.2 mol) was added dropwise, followed by the addition of MgSO4 (240 g, 2 mol). The mixture was stirred overnight. After filtration, the filtrate was evaporated to give compound 9 (49 g, 96.8%). 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3 H), 5.22 (s, 1 H), 7.30-7.39 (m, 6 H), 7.53-7.56 (m, 2 H), 7.82-7.85 (m, 2 H), 8.34 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([NH:17][CH2:18][CH2:19][CH3:20])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[I:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([I:21])=[CH:23][CH:24]=2)=[O:30])[CH2:18][CH2:19][CH3:20])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCNN(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Reactant: O=C=Nc1ccc(I)cc1
Solvent: c1ccncc1
Product: CCCN(C(=O)Nc1ccc(I)cc1)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Yield: 84.6 %

Procedure:
2.0 g (7.273 mmol) of 404 are stirred at RT for 1.5 h in 5.0 ml of pyridine with 1.78 g (7.265 mmol) of 4-iodophenyl isocyanate. After customary work-up, 3.2 g (84.7%) of 405 are thus obtained as crystals having a melting point of 184-185° C.; MS(FAB)=521.