Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([CH:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17]C(OC)=CC=3OCC)=NC2CC(C)C)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47][CH2:46]N(C)[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]2[CH2:65]CC[CH2:62]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:43][CH2:44][CH:8]([N:12]4[CH2:11][CH2:13][CH2:18][CH2:17]4)[CH2:46][CH2:47]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]([CH3:65])[CH3:62])=[CH:31][CH:30]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Product: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-1H-imidazole (Example 10) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 567.3103, calculated for C32H43N4O3Cl [(M+H)+]567.3097.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:26][C:25]=2[CH3:39])[CH:21]=[CH:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:39][C:25]1[CH:26]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CCl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (85.00 g) and 3′-chloromethyl-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (149.91 g) in N,N-dimethylformamide (255 mL) was added tripotassium phosphate (130.00 g), and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, ethyl acetate (1020 mL) and water (1020 mL) were added, and the mixture was partitioned. The organic layer was washed with water (1020 mL) and 10% brine (1020 mL) and concentrated under reduced pressure. To the concentrated residue were added dimethyl sulfoxide (510 mL) and 2M aqueous sodium hydroxide solution, and the mixture was stirred at 60° C. for 1 hr. The mixture was allowed to cool to room temperature, and washed with ethyl acetate (1020 mL). The organic layer was washed with water (1223 mL). 6M Hydrochloric acid was added, and the mixture was extracted with ethyl acetate (1020 mL). The organic layer was washed with water (1020 mL) and 10% brine (1020 mL) and concentrated to give [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid (212.60 g). 100% ee. (high performance liquid chromatography conditions)
Reaction SMILES: NC1C=CC(Cl)=CN=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Cl-].C([NH+](CC)CC)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]=[C:37]=[O:38])=[N:34][CH:35]=1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47]2)=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>ClC(Cl)C.ClCCl.C(N(CC)CC)C>[C:54]([O:53][C:51]([N:48]1[CH2:49][CH2:50][CH:46]([C:43]2[CH:44]=[CH:45][C:40]([NH:39][C:37]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][N:34]=3)=[O:38])=[CH:41][CH:42]=2)[CH2:47]1)=[O:52])([CH3:57])([CH3:55])[CH3:56]
Reactant: O=C=Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Agent: CC[NH+](CC)CC
Agent: Nc1ccc(Cl)cn1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)Nc3ccc(Cl)cn3)cc2)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred suspension of 2-amino-5-chloro-pyridine (1.01 g) in dichloroethane (20 ml) was added portionwise triphosgene (831 mg). Triethylamine (2.22 ml) was then added dropwise and the mixture was stirred at 50° C. for 1 h. The mixture was then concentrated in vacuo to afford a beige solid containing a mixture of triethylammonium chloride and 5-chloro-2-isocyanato-pyridine. This solid was then added to a stirred solution of (RS)-tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (350 mg, CAS 908334-28-1) and N,N-diisopropylethylamine (0.68 ml) in dichloroethane (6 ml) and the resulting mixture was stirred at 60° C. overnight. The mixture was then diluted with dichloromethane and washed with water. The phases were separated and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-3-{4-[3-(5-chloro-pyridin-2-yl)-ureido]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (212 mg, 38%) as an off-white solid. MS (ISP): 419.2 ([{37Cl}M+H]+), 417.2 ([{35Cl}M+H]+).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([CH2:12][NH2:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([CH2:12][NH:13][CH2:3][CH2:2][C:1]#[N:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CC#N
Reactant: NCCc1ccccc1
Solvent: CCO
Product: N#CCCNCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.3 g of acrylonitrile are added dropwise to a solution of 12.1 g of N-benzylmethylamine in 20 ml of ethanol. The reaction mixture is stirred for three hours at room temperature and then concentrated under vacuum to give 17 g (Y=97%) of the expected product.
Reaction SMILES: N1CCC(C2C=CC3N(C=NN=3)C=2)CC1.[N:16]1[N:20]2[CH:21]=[CH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:24][C:19]2=[CH:18][N:17]=1.N1N=CN2C=C(C3CCN(C(OC(C)(C)C)=O)CC3)C=CC=12>>[NH:28]1[CH2:27][CH2:26][CH:25]([C:23]2[CH:22]=[CH:21][N:20]3[N:16]=[N:17][CH:18]=[C:19]3[CH:24]=2)[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccn3nncc3c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(c2ccc3nncn3c2)CC1
Agent: c1cc2nncn2cc1C1CCNCC1
Product: c1cn2nncc2cc1C1CCNCC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 36.2, except tert-butyl 4-([1,2,3]triazolo[1,5-a]pyridin-5-yl)piperidine-1-carboxylate (compound 40.3) was used in place of tert-butyl 4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)piperidine-1-carboxylate (compound 36.1). m/z (ES+) 203(M+H)+.
Reaction SMILES: C(C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1OCCCC)(=O)C1C=CC=CC=1.[CH2:26]([O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([N+:49]([O-])=O)[C:39]=1[C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:34]([OH:36])=[O:35])[CH2:27][CH2:28][CH3:29]>>[NH2:49][C:38]1[C:39]([C:40](=[O:48])[C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)=[C:31]([O:30][CH2:26][CH2:27][CH2:28][CH3:29])[CH:32]=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35]
Reactant: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(Cl)cc1
Agent: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Product: CCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccc(Cl)cc1

Procedure:
By replacing in Example 1, step C, 4benzoyl-3-n-butoxy-5-nitrobenzoic acid with 3-n-butoxy-4-(4'-chlorobenzoyl)-5-nitrobenzoic acid and following the procedure described, 5-amino-3-n-butoxy-4-(4'-chlorobenzoyl)benzoic acid is obtained with a melting point of 286°-287.5° C.
Reaction SMILES: [CH2:1]([N:3]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.[F:22][C:23]1[C:28]([F:29])=[C:27]([F:30])[CH:26]=[CH:25][C:24]=1[CH2:31][NH2:32].C(N1CCOCC1)C.Cl.CN(C)CCCN=C=NCC>ClCCl.Cl.CN(C)C=O>[CH2:1]([N:3]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:4]1[C:5]([NH:32][CH2:31][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[C:28]([F:29])[C:23]=1[F:22])=[O:7])[CH3:2]
Reactant: CCN1C(=O)CC[C@H]1C(=O)O
Reactant: NCc1ccc(F)c(F)c1F
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)c(F)c1F
Temperature: 25 °C
Yield: 33.3 %

Procedure:
1-Ethyl-5-oxo-proline (0.050 g, 0.32 mmol) was dissolved in anhydrous dichloromethane (˜7 ml) and dimethylformamide (1 ml) and to this was added 1-hydroxybenzotriazole (0.052 g, 0.38 mmol), [(2,3,4-trifluorophenyl)methyl]amine (0.103 g, 0.64 mmol), N-ethyl morpholine (0.151 ml, 0.95 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.073 g, 0.38 mmol). The mixture was shaken at room temperature over the weekend. A further aliquot of [(2,3,4-trifluorophenyl)methyl]amine (0.051 g, 0.32 mmol) was added to the mixture and stirring continued for a while longer until HPLC indicated that no further product was forming. The mixture was diluted with 2M aqueous hydrogen chloride (5 ml) and then filtered through a phase separator. The organic layer was then washed with saturated aqueous sodium hydrogen carbonate and again filtered through a phase separator. The organic layer was then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure 1-ethyl-5-oxo-N-[(2,3,4-trifluorophenyl)methyl]-prolinamide (0.032 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1.Cl.CN(C)CCCN=C=NCC>ClCCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=1)=[O:27]
Reactant: NC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Reactant: Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cccc(C(=O)Nc2cccc(-c3cc4ccccc4n3C(N)=O)c2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the solution of 2-(3-aminophenyl)-1H-indole-1-carboxamide (50.2 mg, 0.2 mmol, 1 eq) and m-toluic acid (27.5 mg, 1 eq) in anhydrous DCE (2 mL) was added 4-(dimethylamino)pyridine (4.9 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.1 mg, 1.2 eq). After the reaction was stirred at 60° C. for 1 hour, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:10 to 1:1) to give 2-{3-[(3-methylbenzoyl)amino]phenyl}-1H-indole-1-carboxamide as a clear oil which turned into a white foam in vacuo in amount of 34 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].C(O)C.[CH3:16][C:17]1([CH3:31])[CH2:22][CH2:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:16][C:17]1([CH3:31])[CH2:22][CH2:21][C:20]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: CC1(C)CC=C(OS(=O)(=O)C(F)(F)F)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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)CC=C(c2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-nitrophenylboronic acid (14.2 g, 85.19 mmol) in toluene (250 mL)-ethanol(125 mL) were added trifluoromethanesulfonic acid 4,4-dimethylcyclohex-1-enyl ester (20 g, 77.44 mmol) prepared in Example (1a), tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.87 mmol) and 2N aqueous sodium carbonate (128 mL, 256 mmol). The mixture was stirred at an external temperature of 100° C. for 1 hour and 45 minutes under a nitrogen atmosphere.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:31](=[O:39])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[C:8]([CH3:30])[N:9]2[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][O:17][C:18]2([C:22]([O:24]CC)=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1.C1COCC1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:31](=[O:39])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[C:8]([CH3:30])[N:9]2[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[CH2:16][O:17][C:18]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1(OCc2cccc(Cn3c(C)c(C(=O)c4ccc(C)cc4)c4ccc(OC)cc43)c2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(C(=O)c3ccc(C)cc3)c(C)n(Cc3cccc(COC4(C(=O)O)CCC4)c3)c2c1
Reaction time: 20 h
Yield: 40.2 %

Procedure:
The compound of Example 63-1 (14 mg, 0.03 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 1N aqueous sodium hydroxide solution (1 ml), followed by stirring for 20 hours. The reaction mixture was diluted with water and washed with diethyl ether. The aqueous layer was adjusted to around pH 4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (6 mg, 45%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12](=O)([O-:14])[O-:13].[K+].[K+].C(=O)=O>O.CC(C)=O>[OH:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:12]([OH:14])=[O:13]
Reactant: Oc1cccc2c1CCCC2
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc2c(c1O)CCCC2
Temperature: 145 °C
Yield: 90 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-1-naphthol (7.42 g, 50 mmol) and potassium carbonate (25.5 g, 185 mmol) were placed in a glass tube inside a stainless steel pressure reactor. The reactor was charged with CO2 at 40 bar and then heated to 145° C. The pressure rose to 60 bar and then slowly dropped to 20 bar over the 3 day reaction period. The bomb was cooled and the solid product was taken up in water (˜500 ml) and acetone (˜500 ml). The mixture was evaporated in vacuo to remove the acetone and then washed with DCM (3×150 ml). The aqueous was acidified with 2M hydrochloric acid to give a white suspension. This was extracted with DCM (4×250 ml), which was then dried over sodium sulphate and evaporated in vacuo to give the crude product. This was recrystallised from aqueous ethanol and dried under high vacuum to provide 8.64 g (45 mmol, 90% yield) of the title compound as a pale brown powder. 1H NMR (200 MHz., d6-DMSO) δ 1.81 (4H, m); 2.67 (2H, m); 2.81 (2H, m); 6.73 (1H, d); 7.61 (1H, d); 11.78 (1H, bs). EIMS m/z=192 (M+); 174; 146
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)[CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:17][CH:18]=1)=[O:11])[CH2:28][CH3:29]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCNC(=O)Nc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCNC(=O)Nc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
The compound (101 mg) obtained in Example 12-3 was dissolved in anhydrous methanol (4.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (41.8 mg) and sodium cyanoborohydride (47.1 mg). The solution was adjusted to pH 5 by addition of acetic acid, followed by stirring at room temperature for 20 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (80.3 mg) of the subject compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([CH:21]([CH3:23])[CH3:22])[C:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([CH3:20])([CH3:19])[CH2:6]1)=[O:4].[S:24]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])(=[O:27])(=[O:26])[NH2:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@:8]2([OH:11])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:29]=3)[CH:21]([CH3:23])[CH3:22])[CH2:6][C:7]2([CH3:19])[CH3:20])=[CH:17][CH:16]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)c1cccc(S(N)(=O)=O)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 70.7 %

Procedure:
(R)-2-Amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (200 mg, 0.533 mmol), 3-sulfamoylbenzoic acid (129 mg, 0.639 mmol), HOBT (98 mg, 0.639 mmol), EDC (123 mg, 0.639 mmol) and triethylamine (0.149 mL, 1.066 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (1:1 Hexanes/EtOAc to 100% EtOAc) to obtain N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-sulfamoylbenzamide (197 mg, 0.377 mmol, 70% yield) as a white glass. MS found: (M+H)+=522.32.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:10][C:11]([NH:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1)=[CH:12]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Oc1ccccc1
Product: COc1ccc2c(Oc3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (6-methoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [ClH:1].[CH3:2][C:3]([CH3:16])([CH3:15])[CH2:4][CH2:5][N:6](C)[C:7](=O)OC(C)(C)C>O1CCOCC1>[ClH:1].[CH3:7][NH:6][CH2:5][CH2:4][C:3]([CH3:16])([CH3:15])[CH3:2]
Reactant: CN(CCC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4 M HCl in dioxane (4.05 mL, 16.2 mmol) was added dropwise to a solution of tert-butyl 3,3-dimethylbutyl(methyl)carbamate (436 mg, 1.62 mmol) in dry dioxane (4 mL) under a N2 atmosphere. The mixture was stirred at room temperature for 3 d. The mixture was evaporated to dryness, co-evaporated with DCM (15 mL) and the residue was stirred in Et2O for 30 min. The solids were filtered off, rinsed with Et2O and dried on air to yield AMN-38 (222 mg, 72%) as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl>CN(C)C=O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][N:5]1[CH2:6][CH2:7][O:3][C:4]1=[O:8]
Reactant: ClCCCCCl
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCCCCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Following the procedure of Piper et al. [J. Het. Chem. 4, p. 298 (1967)], sodium hydride (4.8 g of 50% dispersion in oil, 0.1 mole) was washed with pentane and suspended in 20 ml of dimethylformamide. A solution of 2-oxazolidinone (8.7 g, 0.10 mole) and 1,4-dichlorobutane (66 g, 0.52 mole) in 100 ml of dimethylformamide was then added dropwise over 30 minutes, maintaining the reaction temperature at 25°-30° C. The reaction was stirred for 18 hours at ambient temperature, then evaporated to an oil, and the oil taken up in ethyl acetate, treated with activated carbon, filtered over diatomaceous earth, and reevaporated in vacuo to yield the title product as an oil [16.5 g, contaminated with mineral oil from incompletely washed sodium hydride; pnmr/CDCl3 /delta: 0.67-1.0 and 1.03-1.4 (mineral oil), 1.4-1.83 (m, 4H), 3.03-3.72 (m, 6H), 4.10-4.43 (t, 2H)].
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:31][C:32]1[CH:39]=[C:38]([OH:40])[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17][O:40][C:38]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([F:31])[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: FC(F)(F)c1ccc(-c2nc(CCCOCc3ccccc3)c(CCl)s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCOCc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 0.82 g of 4-(3-benzyloxy-propyl)-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole in 12 mL of DMF at 0° C. was added 0.1 g NaH 55%. The reaction mixture was stirred at 0° C. for 10 min then 2-0.264 g of fluoro-4-hydroxybenzonitrile was added at this temperature. The reaction mixture was stirred at 0° C. for 1 h30, allowed to warm up to room temperature and then stirred for 4 h at room temperature. The solvent was removed and the resulting residue was taken up into dichloromethane then water was added. After decantation and separation, the aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.91 g of crude product as a yellow oil. Purification by column chromatography on silica gel (heptane 1/ether 1) gave 840 mg of 4-[4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-benzonitrile as a white foam.