Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([C:27]([F:28])([F:29])[F:30])[CH:16]=2)=[N:22]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc(N)c(C(F)(F)F)c2)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc(N)c(C(F)(F)F)c2)cc1C
Reaction time: 6 h
Yield: 48.2 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and ethyl isocyanate (0.09 g, 1.3 mmol) were added to a solution of 3-(4-amino-3-trifluoromethylphenyloxy)-5-methylpyrazole (0.30 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellowish solid of N-ethyl-3-(4-amino-3-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.19 g, yield: 50.5%). mp: 102-104° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.3 Hz, 3H), 2.56 (d, J=0.8 Hz, 3H), 3.37 (dq, J=5.9 and 7.3 Hz, 2H), 4.11 (br s, 2H), 5.61 (q, J=0.8 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.93 (br s, 1H), 7.14 (dd, J=2.7 and 8.8 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:34]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)Cl>[F:33][C:2]([F:1])([F:32])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[C:16]([Br:34])=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1c(Br)c(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide (Comp. No. 16e) (200 mg, 0.43 mmol) in chloroform (5 ml) was added N-bromo-succinimide (76 mg, 0.43 mmol) and the mixture was stirred for 18 h at 25° C. Then excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The crude product was purified by reverse phase HPLC to give 200 mg (86%) of 7-bromo-6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 3): Rt=1.81 min; m/z=543.1 (M+H+).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][N:14]=1>C1COCC1>[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][N:14]=1
Reactant: CC(=O)c1cnc(C)nc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ncc(C2(C)CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(2-methylpyrimidin-5-yl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=O.C(=O)([O-])[O-].[K+].[K+].[C:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][CH:30]=1)(=[NH:27])[NH2:26]>CCOCC>[C:33]([C:32]1[CH:36]=[CH:37][C:29]([NH:28][C:25]2[N:26]=[C:5]([C:7]3[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=3)[CH:4]=[CH:3][N:27]=2)=[CH:30][CH:31]=1)(=[O:34])[NH2:35]
Reactant: N=C(N)Nc1ccc(C(N)=O)cc1
Reactant: CCOC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2ccnc(Nc3ccc(C(N)=O)cc3)n2)cc1
Yield: 46 %

Procedure:
A mixture of ethyl 4-acetylbenzoate (3.00 g, 15.62 mmol) and N,N-dimethylformamide dimethyl acetal (6.2 g, 52.10 mmol) was refluxed for 18 hours, cooled and concentrated to give ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate quantitatively. A solution of ethyl 4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzoate, potassium carbonate (3.55 g, 25.74 mmol), and 4-(amidinoamino)benzamide (3.10 g, 12.87 mmol) in ETOH (120 mL) was refluxed for 18 hours. The mixture was cooled, filtered, and washed with ETOH, water, then ether respectively to give ethyl 4-{2-[(4-carbamoylphenyl)amino]pyrimidin-4-yl}benzoate (2.60 g, 46% yield). This compound was refluxed for 2 hours in ETOH (30 mL), water (20 mL), and NaOH (0.640 g, 16 mmol). The reaction mixture was cooled, acidified to pH 3, and filtered to give 1.00 gram (42% yield) of the titled compound. HPLC/ES-MS (20-100% acetonitrile): R.T. 4.7 min.(Method A); (m/z) 335 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:8](=[C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]=1[CH3:11])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:5]2.[Cl:28]S([N:32]=[C:33]=[O:34])(=O)=O.Cl.O>C(Cl)Cl>[ClH:28].[CH3:27][C:3]1[C:2]([NH:1][C:33]([NH2:32])=[O:34])=[C:10]([CH3:11])[C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCCCCCN1CCc2c(C)c(N)c(C)c(NC(=O)C(C)(C)C)c21
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCN1CCc2c(C)c(NC(N)=O)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 3 h

Procedure:
N-(5-Amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide (500 mg) was dissolved in methylene chloride (5.0 mL), and chlorosulfonyl isocyanate (0.14 mL) was added dropwise at −60° C. The mixture was stirred at the same temperature for 3 hr and 6M hydrochloric acid (0.45 mL) was added. The mixture was stirred at room temperature for 30 min. Water (50 mL) was added to the reaction solution and the mixture was extracted with chloroform (100 mL). The chloroform layer was washed with saturated brine and dried over sodium sulfate. Chloroform was evaporated under reduced pressure and the obtained crystalline residue was recrystallized from a mixture of chloroform-diisopropyl ether to give the title compound as crystals (407 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[C:12]([O-])([O-])=O.[K+].[K+].CI.CN([CH:23]=[O:24])C>>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:24][CH3:23])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccccc1O
Agent: [K+]
Solvent: CI
Product: COC(=O)Cc1ccccc1OC
Reaction time: 72 h
Yield: 92 %

Procedure:
To a solution of 2-hydroxyphenylacetic acid (25 g, 0.16 mol) in DMF (300 mL) was added K2CO3 (56.7 g, 0.41 mol), followed by methyl iodide (46.7 g, 0.32 mol). The reaction mixture was stirred for about 3 days, filtered and the filtrate was stripped. The residue was taken up in ethyl acetate, washed with water, saturated Na2CO3, then brine, and then the organic layer was dried over MgSO4, filtered and stripped to afford 26.4 g (92%) of methyl 2-methoxyphenylacetate.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:16])([O:6][C:7]([NH:9][C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][OH:12])=[O:8])[CH3:5].I[CH3:18]>CN(C=O)C.Cl>[CH3:5][C:4]([CH3:16])([O:6][C:7]([NH:9][C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][O:12][CH3:18])=[O:8])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
Sodium hydride (60% dispersion, 4.3 g, 0.107 mol) was added portionwise at 0° C. to a stirred solution of (S)-N-(1,1-dimethylethoxy)carbonylserine (10 g, 48.7 mmol) in anhydrous DMF (250 ml). A solution of iodomethane (6.1 ml, 0.1 mol) in anhydrous DMF (10 ml) was then added dropwise. The mixture was allowed to warm to RT and stirred overnight, then diluted with 1N hydrochloric acid to pH3 and the solution concentrated in vacuo to ca. 100 ml. The mixture was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine (100 ml), dried (MgSO4) and evaporated in vacuo to provide the title compound as a yellow oil (7.48 g, 70%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([C:17]3[C:18]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([OH:24])=O)[NH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:42]([C:41]1[CH:40]=[CH:39][C:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:22]([C:21]3[C:20]([CH3:26])=[CH:19][C:18]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:17]([C:15]4[NH:16][C:10]5[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12][C:11]=5[N:14]=4)[CH:25]=3)=[O:24])[CH2:33][CH2:34]2)=[CH:45][CH:44]=1)#[N:43]
Reactant: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C2CCC2)c(-c2nc3c([nH]2)CN(C(=O)OC(C)(C)C)CC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 8 h
Yield: 126.9 %

Procedure:
To a solution of 5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoic acid (compound 406.1, 1.00 g, 1.22 mmol, 1.00 equiv, 50%) in N,N-dimethylformamide (5 mL) were added 4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5, 270 mg, 1.21 mmol, 1.00 equiv), EDC.HCl (460 mg, 2.40 mmol, 2.00 equiv), and 4-dimethylaminopyridine (296 mg, 2.42 mmol, 2.00 equiv). The resulting mixture was stiffed at 25° C. overnight. The mixture was then diluted with 30 mL of ethyl acetate, washed with 3×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 890 mg (63%) of the title compound as a brown solid.
Reaction SMILES: [C:1]([N:18]1[CH2:21][CH:20]([C:22](O)=[O:23])[CH2:19]1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][C:56](=[C:59]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:60]([NH:62][NH2:63])=[O:61])[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl.O>[C:46]([O:50][C:51]([N:53]1[CH2:54][CH2:55][C:56](=[C:59]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:60]([NH:62][NH:63][C:22]([CH:20]2[CH2:21][N:18]([C:1]([O:3][CH2:4][CH:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:2])[CH2:19]2)=[O:23])=[O:61])[CH2:57][CH2:58]1)=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NN)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NNC(=O)C2CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 101.6 %

Procedure:
To a solution of Fmoc-azetidine-3-carboxylic acid (0.495 g, 1.53 mmol) in CH2Cl2 (10 mL) was added HOBt (0.290 g, 2.14 mmol) and EDCI (0.411 g, 2.14 mmol), and the mixture was allowed to stir for 10 min. To this solution was added 4-(1-phenyl-1-hydrazinocarbonyl-methylene)piperidine-1-carboxylic acid tert-butyl ester (0.507 g, 1.53 mmol), the mixture was stirred for 1 h and then it was diluted with H2O and the layers separated. The aqueous phase was extracted with CH2Cl2 (×3) and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated to give the title compound (0.99 g, 100%) which was of sufficient purity to be used as such in the following step:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[S:30][C:26]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[CH3:19])=[CH:27][CH:28]=3)=[O:32])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1ccncc1-c1ccc(C(=O)O)s1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccncc1-c1ccc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)s1
Yield: 55.8 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.116 g, 0.446 mmol), 5-(4-methylpyridin-3-yl)thiophene-2-carboxylic acid (0.098 g, 0.446 mmol), DIPEA (0.233 ml, 1.337 mmol), HOBt hydrate (0.102 g, 0.668 mmol) and EDCI (0.128 g, 0.668 mmol) as described in the previous Example affording 0.115 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 2.41 (s, 3H), 4.32 (m, 2H), 4.43 (m, 1H), 6.95 (d, 1H), 7.33 (d, 1H) 7.37 (d, 1H), 7.79 (d, 1H), 7.85 (d, 1H), 7.94 (m, 2H), 8.07 (d, 1H), 8.45 (m, 2H), 8.55 (s, 1H).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=O)=[O:4].Cl.[NH2:21][C@H:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24][CH2:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([NH:21][C@H:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCC[C@H](N)C(=O)OCC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Boc-Gly-Pro-OH (3.85 g, 0.014 mol), the HCl salt of Nleu-OEt (2.76 g, 0.014 mol) and HOBt (2.8 g, 0.02 mol.) were dissolved in 100 ml DMF and the solution was chilled to 0° C. on a water-ice bath. TEA (2.8 ml, 0.02 mol.) was added to the solution. After stirring the solution for 10 minutes, EDC (4.0 g, 0.021 mol.) was added. The stirring was continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 200 ml ethyl acetate. The organic layer was washed by H2O 2×30 ml, saturated NaHCO3 3×10 ml, brine 2×10 ml, saturated NaHSO4 3×15 ml and brine again until the pH value of the brine layer was approximately 7. The ethyl acetate solution was dried using Na2SO4 and the solvent was removed by distillation under reduced pressure. Column chromatography (elution solvents: E/H, 2:1) was performed to obtain the pure product (yellowish oil, 4.7 g, 81%). TLC Rf=0.54 (developing solvents: CMA, 85:15:3) and Rf=0.34 (developing solvents: E/H, 2:1).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([SH:11])[C:4]2=[CH:3][CH:2]=1.[H-].[Na+].[O:14]1[CH2:16][CH:15]1[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O>[C:10]1([S:11][CH2:16][CH:15]([OH:14])[CH2:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Sc1cccc2ccccc12
Reactant: c1cncc(CCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)CSc1cccc2ccccc12
Yield: 34.5 %

Procedure:
Prepared according to the method described in Example 1 from 1-thionaphthol (0.150 g), sodium hydride (0.044 g) and (±)-3-(2-oxiranylethyl)pyridine (0.150 g) in dimethylformamide (3 ml) at room temperature to give the title compound as an oil (0.100 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[CH3:22][O-:23].[Na+].CO>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:23][CH3:22])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: C[O-]
Reactant: Fc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 0 °C

Procedure:
A mixture of 6-bromo-2,4-dichloro-3-(4-fluorobenzyl)quinoline (0.350 g, 0.909 mmol, Intermediate 4: step c) and a 0.5 M sodium methoxide in methanol solution (9.09 mL. 4.55 mmol) was stirred at reflux for 16 hours. The mixture was poured into ice water and extracted with EtOAc (2×). The combined EtOAc extract was dried (Na2SO4), filtered and evaporated in vacuo and purified by column chromatography with silica gel (heptane/CH2Cl2) to provide the title compound as a white solid.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]4[C:41]=3[N:40]([CH3:42])[CH:39]=[C:38]4/[CH:43]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:29]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26]>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]4[C:41]=3[N:40]([CH3:42])[CH:39]=[C:38]4[C@@H:43]3[CH2:7][C@H:44]3[C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:29]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:26])[CH3:27]
Reactant: CCOC(=O)/C=C/c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C

Procedure:
To a suspension of trimethylsulfoxonium iodide (132 mg) in DMSO (3 mL) stirred under nitrogen at 20° C. was added NaHMDS (1.0 mol/L in THF, 0.6 mL) dropwise during 5 mins. The reaction mixture was stirred at this temperature for 15 mins. A solution of ethyl (2E)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoate (D62) (140 mg) in DMSO was added dropwise. After addition was complete, the reaction was stirred at room temperature for 1.5 h, and then warmed to 50° C. for 2 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water, aqueous HCl (2 M) and brine, dried over sodium sulphate and evaporated to afford ethyl (1R,2R)-2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]cyclopropanecarboxylate (D64) (80 mg). MS (ES): C26H26ClN3O4 requires 479. found 480.2 (M+H+).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH2:11]1[NH:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([OH:18])[C@H:12]1[CH2:19][OH:20]>O>[CH2:11]1[NH:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([OH:18])[C@H:12]1[CH2:19][OH:20].[C:6]([C@H:4]([C@@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: OC[C@H]1CNC[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Reaction time: 0.17 h
Yield: 143.3 %

Procedure:
A solution of D-(-)-tartaric acid (102 mg, 0.679 mmol) in deionized water (1.0 mL) was added into the solution of isofagomine (200 mg, 2.0 equivalents) dissolved in deionized water (2.0 mL) at room temperature. The solution was stirred for 10 min and lyophilized overnight. The residue was further dried under vacuum at 45° C. for three days to afford the desired salt (287.2 mg, 95%). m.p. 94-95° C., 1H NMR (300 MHz, D2O): δ 4.22 (s, 2H), 3.71 (dd, J=12, 3.6 Hz, 1H), 3.67-3.59 (m, 2H), 3.44-3.36 (m, 3H), 2.85 (t, J=12 Hz, 1H), 2.75 (t, J=12 Hz, 1 H), 1.84 (m, 1H) (FIG. 8B).
Reaction SMILES: Cl[C:2]1[C:3]([C:19]#[N:20])=[N:4][N:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:6](=O)[CH:7]=1.[OH2:21].[NH2:22][NH2:23]>C(O)C>[NH2:20][C:19]1[C:3]2=[N:4][N:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)[C:6](=[O:21])[CH:7]=[C:2]2[NH:23][N:22]=1
Reactant: NN
Reactant: O
Reactant: COc1ccc(-n2nc(C#N)c(Cl)cc2=O)cc1OC
Solvent: CCO
Product: COc1ccc(-n2nc3c(N)n[nH]c3cc2=O)cc1OC
Temperature: 100 °C

Procedure:
The starting chloride (31) (190 mg) was dissolved in 500 μl of ethanol. 5 equivalents of hydrazine hydrate were added and the reaction mixture heated in a sealed tube at 100° C. for 18 hours. HPLC showed the reaction to be complete. The reaction was concentrated to dryness and purified by normal phase SiO2 chromatography eluting with (1:1) ethyl acetate-hexanes going to 100% ethyl acetate to give after drying 25 mg of desired product (I-10) as a solid. MS+: m/e=288.0 (M+H)+, 1H-NMR (500 MHz, MeOH-d4): δ 7.17 (s, 1H), 7.11 (d, 1H), 7.07 (d, 1H), 6.37 (s, 1H), 3.90 (s, 3H), ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:36]([F:37])=[CH:35][C:17]3[N:18]=[C:19]([C:21]4[C:25]([N+:26]([O-])=O)=[CH:24][N:23]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][O:30]5)[N:22]=4)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:36]([F:37])=[CH:35][C:17]3[N:18]=[C:19]([C:21]4[C:25]([NH2:26])=[CH:24][N:23]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][O:30]5)[N:22]=4)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])nc3cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4N)nc3cc2F)CC1
Yield: 177 %

Procedure:
A suspension of 540 mg of 4-{6-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester in 15 mL of methanol and 54 mg of palladium-on-charcoal is hydrogenated under 1 bar of hydrogen pressure at ambient temperature for 16 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 900 mg of 4-{2-[4-amino-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-fluoro-3H-benzimidazol-5-yl}piperazine-1-carboxylic acid tert-butyl ester are obtained in the form of a black solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): from 1.30 to 2.20 (m, 6H); 1.42 (s, 9H); 3.00 (m, 4H); 3.52 (m, 4H); 3.67 (m, 1H); 3.96 (m, 1H); 5.55 (broad d, J=10.0 Hz, 1H); 7.22 (d, J=7.5 Hz, 1H); 7.46 (d, J=12.5 Hz, 1H); 8.17 (s, 1H). ES mass spectrum: m/z=486 MH+ (base peak).