Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([N:7]2[N:11]=[C:10]([OH:12])[CH:9]=[N+:8]2[O-:13])=[CH:3][CH:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI.S(=O)(=O)(O)O>CN(C)C=O.O>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([N:7]2[N:11]=[C:10]([O:12][CH3:15])[CH:9]=[N+:8]2[O-:13])=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-n2nc(O)c[n+]2[O-])cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1c[n+]([O-])n(-c2ccc(C)cc2)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
81.4 g of 2-(p-tolyl)-4-hydroxy-2H-1,2,3-triazole-1-oxide (m.p. 150°-154° C. with decomp., prepared in accordance with Synthesis 1974 (March), pp. 198-199) are dissolved in 810 ml of dimethyl formamide at room temperature. Then 141.3 g of potassium carbonate are suspended in this solution and 48.3 ml of methyl iodide are poured into the suspension with good stirring. The batch is then heated to 60° C. over 30 minutes and kept thereat for 6 hours. The fine suspension is thereafter poured into 6 liters of water, and the pH is adjusted to 4-5 with 2N sulphuric acid. After cooling to room temperature, the solid is collected with suction, washed with water and dried to yield 56.5 g of 2-(p-tolyl)-4-methoxy-2H-1,2,3-triazole-1-oxide with a melting point of 62°-64° C. After recrystallisation from alcohol/water the product melts at 70°-72° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(Cl)([Cl:11])=O.[CH3:13]O>>[ClH:11].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: NCCCCC(=O)O
Product: COC(=O)CCCCN
Product: Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5-Aminovaleric acid (7.35 g) is dissolved in methanol (50 ml), and thereto is added dropwise thionyl chloride (4.9 ml) under ice-cooling. The reaction solution is then warmed to room temperature and stirred for 17 hours. The reaction solution is concentrated under reduced pressure. The resulting residue is suspended in diethyl ether and the precipitates are collected by filtration to give methyl 5-aminovalerate hydrochloride (9.93 g).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[C:16](=O)(OC1C=CC=CN=1)[O:17]C1C=CC=CN=1.C(N(CC)CC)C>ClCCl>[N:14]([C:12]1[CH:11]=[N:10][N:9]([CH2:8][C:7]2[C:3]([CH3:2])=[N:4][O:5][C:6]=2[CH3:15])[CH:13]=1)=[C:16]=[O:17]
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(N=C=O)cn1

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (400 mg, 2.08 mmol), dipyridin-2-yl carbonate (450 mg, 2.08 mmol) and triethylamine (0.290 mL, 2.08 mmol) were stirred in dichloromethane (7 mL) for 12 hours at room temperature. The reaction was concentrated under vacuum to afford 4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole as an off-white solid in quantitative yield. Ethanol (1 mL) was added along with methyl 2-amino-3-(3-methoxyphenyl)propanoate (68 mg, 0.327 mmol) and triethylamine (0.064 mL, 0.461 mmol). The reaction was stirred at reflux for 12 hours, then allowed to cool to room temperature. The solvent was removed under a stream of nitrogen. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 16 minutes gradient). The pure fractions were combined and solvent removed under vacuum to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-(3-methoxybenzyl)imidazolidine-2,4-dione as a white solid yield: 50% 1H NMR (CDCl3, 400 MHz): δ 2.19 (s, 3H), 2.41 (s, 3H), 3.34-3.33 (d, J=3.2 Hz, 1H), 3.31-3.29 (d, J=8 Hz, 1H), 3.76 (s, 3H), 4.33-4.30 (m, 1H), 5.05 (s, 2H), 5.95 (bs, 1H), 7.25-7.21 (t, 1H), 6.82-6.78 (m, 3H), 7.85 (s, 1H), 7.99 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[C:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 100 °C
Yield: 80.7 %

Procedure:
A mixture of 2.00 g (10.5 mmol) of 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared as described in Example 13, 1.60 g (11.6 mmol) of anhydrous K2CO3 and 2.30 g (11.8 mmol) of ethyl 4-bromobutyrate in 40 ml of DMF is heated at 100° C. for 2 hrs under N2. The DMF is removed under vacuum and the residue taken up in 150 ml of EtOAc and 75 ml of water. The organic phase is washed with 5% aqueous NaOH, then with saturated NaCl, dried (MgSO4), and the solvent removed to leave 2.58 g of 6-[4-[3-carboethoxy-propyloxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 81%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si](C(C)(C)C)(C)C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26](=[O:55])[N:27]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:28]=[C:29]([NH:31][C:32]([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH:38]=2)=[O:33])[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26](=[O:55])[N:27]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:53])([CH3:52])[CH3:54])[CH:28]=[C:29]([NH:31][C:32]([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH:38]=2)=[O:33])[CH:30]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(O[Si](C)(C)C(C)(C)C)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(O)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Intermediate (11d), 5-(tert-butyl-dimethyl-silanyloxy)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]-amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester (1.55 g, 1.97 mmol) was stirred in tetrahydrofuran (40 mL) and cooled to 0° C. Tetrabutylammonium fluoride solution 1.0M in tetrahydrofuran (2.08 mL, 2.08 mmol) was added drop wise at 0° C., and then the reaction was allowed to attain ambient temperature, where it was stirred for a further 2 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL), aqueous 0.5N hydrochloric acid solution (30 mL), brine, dried (Na2SO4) and concentrated in vacuo. The resultant green foam was purified via trituration using diethyl ether, to afford the title compound as a pale yellow solid, 0.946 g, 71%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[S:7][C:6]=2[CH:16]=1.[C:17]1(B(O)O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:10][C:9]1[C:5]2[CH:4]=[CH:3][C:2]([C:25]3[C:26]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:16][C:6]=2[S:7][C:8]=1[C:11]1[NH:12][CH2:13][CH2:14][N:15]=1
Reactant: Clc1c(C2=NCCN2)sc2cc(Br)ccc12
Reactant: OB(O)c1cccc2ccccc12
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: C1COCCO1
Product: Clc1c(C2=NCCN2)sc2cc(-c3cccc4ccccc34)ccc12
Temperature: 95 °C

Procedure:
A solution of 60 mg (0.19 mmol) of 2-(6-bromo-3-chlorobenzo[b]thiophen-2-yl)-4,5dihydro-1H-imidazole, 69 mg (0.4 mmol) of naphthalene-1-boronic acid, and 23 mg (0.02 mmol) of Pd(PPh3)4 in a mixture of 2.5 ml dioxane and 0.4 ml 2M aqueous sodium carbonate solution was heated at 95° C. for 24 h. After cooling it was concentrated to dryness under reduced pressure, and the title compound was obtained from the residue by column chromatography on silica gel with dichloromethane/ethanolic ammonia gradient.
Reaction SMILES: [C:1]([C:4]1O[C:6]([CH3:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)(=O)[CH3:2].[CH2:16]([NH2:19])[CH2:17][NH2:18].O.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:2][C:1]1[C:4]2[N:18]([C:6]([CH3:15])=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:8]=2)[CH2:17][CH2:16][N:19]=1
Reactant: NCCN
Reactant: CC(=O)c1cc(-c2ccccc2)c(C)o1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: O
Product: CC1=NCCn2c1cc(-c1ccccc1)c2C

Procedure:
2-Acetyl-5-methyl-4-phenylfuran (1.9 g) was heated to 150° C. for 1 hour under argon with 6.3 ml of 1,2-ethanediamine and 0.6 ml of water. After cooling the mixture was poured into 500 ml of water and the mixture was extracted three times with 80 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 1.9 g of brown oil, was chromatographed on 100 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. 0.6 g of a total of 1.2 g (56%) of crude product were dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.4 g of 3,4-dihydro-1,6-dimethyl-7-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt: 180°-182° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)=[N:6]1.OO.NC(N)=O.F[C:33](F)(F)[C:34]([O:36]C(=O)C(F)(F)F)=[O:35]>C(Cl)Cl.C(OC(=O)C)(=O)C>[C:34]([O:36][C:17]1[C:18]([F:21])=[CH:19][CH:20]=[C:15]([C:7]2[CH:8]=[C:9]([C:10]3[CH:14]=[CH:13][O:12][N:11]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:16]=1)(=[O:35])[CH3:33]
Reactant: Fc1ccc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1nc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)ccc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a cold mixture of 3-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole (1 equiv.) and urea compound with hydrogen peroxide (1:1) (3 equiv.) in DCM (1.7 ml) at 0° C., was added trifluoroacetic anhydride (3 equiv.). The mixture was allowed to warm to 25° C. and stirred for 3 days. The mixture was quenched with saturated solution of sodium bisulfate and extracted with dichloromethane (50 ml×3). The organic layers were combined, filtered and evaporated to give solid. The solid was dissolved in acetic anhydride (1.4 ml) and heated to 145° C. for 4 h. The mixture was cooled to 25° C., diluted with dichloromethane (100 ml) and washed with saturated solution of sodium bicarbonate (50 ml). The organic layer was dried (MgSO4), filtered and evaporated to give an oil. Purification of the oil by column chromatography (0 to 30% ethyl acetate in hexanes) gave 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl acetate as an yellow oil. The yellow oil was combined with methanol (1.7 ml) and potassium carbonate (1 equiv.). The mixture was heated to 65° C. for 30 min. The mixture was concentrated under vacuum. The resulting residue was diluted with dichloromethane (100 ml) and washed with 1N HCl (30 ml). The organic layer was dried (MgSO4), filtered and evaporated to give a solid. Purification of the solid by column chromatography (0 to 5% methanol in dichloromethane) gave 3-fluoro-6-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyridin-2(1H)-one as a yellow solid (7% overall yield).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH:6][C:7]1[CH:28]=[CH:27][C:10]([CH:11]=[CH:12][CH2+:13]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH:16]=[C:15]([CH3:26])O2)=[CH:9][CH:8]=1.O.[NH2:30][NH2:31]>C(O)C>[OH:6][C:7]1[CH:28]=[CH:27][C:10]([CH:11]=[CH:12][C:13]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:31][N:30]=2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: CC1=Cc2cc3c(cc2[CH2+](C=Cc2ccc(O)cc2)O1)OCO3
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC1=NN=C(C=Cc2ccc(O)cc2)c2cc3c(cc2C1)OCO3
Reaction time: 0.5 h

Procedure:
A mixture of 5 g (12.3 mM) of 1-(4-hydroxystyryl)-3-methyl-6,7-methylenedioxy-2-benzopyrylium perchlorate (m.p. 306° to 308° C. d.), 100 ml of 99.5% ethanol and 1.85 ml (36.9 mM) of 100% hydrazine hydrate are refluxed for one hour. The end-product is beginning to precipitate already in the first minutes of the reaction. The mixture is evaporated at reduced pressure, the partially crystalline residue is suspended in 100 ml of water, the crystals are filtered, washed with 3×10 ml of water, the crude product is resuspended in 300 ml of hot water, stirred for 30 minutes, filtered hot, washed with 2×20 ml of hot water and dried at 80° to 100° C. Yield 2.18 g, m.p. 243 to 248° C. d. For further purification this product is refluxed in 10 ml of 99.5% of ethanol, filtered after cooling, washed with 3×2 ml of ethanol and dried. Yield 2.08 g (52.8%), m.p. 246° to 248° C. (decomp.).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[S:24][CH:25]=[C:26]([CH3:28])[N:27]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[S:24][CH:25]=[C:26]([CH3:28])[N:27]=2)[N:3]=1
Reactant: Cc1csc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) in DMF (8 mL) was added potassium carbonate (0.478 g, 3.46 mmol) at ambient temperature. After 15 minutes, 2-(chloromethyl)-4-methylthiazole hydrochloride was added. The mixture was allowed to stir at ambient temperature for 18 hours, concentrated under reduced pressure and diluted with DCM and brine. The organic phase was dried (phase separator silicone treated filter paper), and purified by silica gel chromatography (10-50% ether in DCM) to provide 2-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-4-methylthiazole (0.414 g, 60% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Oc1cccc(Cl)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2cccc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-chlorophenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].O.[C:32](OCC)(=[O:34])C>CO.N1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([O:34][CH3:32])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CCOC(C)=O
Agent: I[Cu]I
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: COc1cncc2cccc(S(=O)(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C

Procedure:
A solution of Intermediate 1a (337 mg) obtained in Example 1-1, Step A in methanol (2.7 ml) and pyridine (2.7 ml) was added with a solution of 28% sodium methylate (847 mg) in methanol, and then with copper iodide (70 mg), and the mixture was stirred at 65° C. for 30 hours. The reaction mixture was cooled to room temperature, and added with water (30 ml) and ethyl acetate (30 ml), and the insoluble solids were removed by filtration through Celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted 3 times with ethyl acetate (20 ml for each time). The combined organic layer was washed 3 times with saturated brine (30 ml for each time), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=30:1) to obtain the title compound (98 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][C:10](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(Br)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
5-Bromopyridine-2,3-diamine (2.45 g) was dissolved in THF (25 mL) and 1,1′-carbonyldiimidazole (2.54 g, 1.2 eq) was added. The reaction was stirred at room temperature under nitrogen gas overnight. Water was then added to the mixture and the product was collected by filtration. The solid was dried under vacuum delivering product (2.57 g, 92% yield). 1H-NMR (300 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.00 (s, 1H), 7.93 (s, 1H), 7.39 (s, 1H). MS (ES+) m/z 213.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([NH2:13])=[C:4]([Cl:14])[CH:3]=1.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[C@@H:36]([CH3:46])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:45][CH2:44][N:43]([C:20](=[O:21])[NH:13][C:5]3[CH:6]=[C:7]([O:8][C:9]([F:11])([F:12])[F:10])[C:2]([Br:1])=[CH:3][C:4]=3[Cl:14])[CH2:42][CH2:41]2)[C@@H:36]([CH3:46])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: Nc1cc(OC(F)(F)F)c(Br)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CCNCC1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CCN(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.7 %

Procedure:
To a solution of 4-bromo-2-chloro-5-trifluoromethoxy-phenylamine (92.5 mg, 0.32 mmol) in DCM (0.82 mL) was added CDI (56.8 mg, 0.35 mmol). The reaction mixture was stirred at RT for 6 h and a solution of (S)-3-methyl-4-piperidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (99.3 mg, 0.35 mmol; Preparation 22) in DCM (1 mL) was added. The solution was concentrated under vacuum and purified by silica gel chromatography (0-5% MeOH/DCM). Product fractions were combined and concentrated under vacuum to provide the title intermediate (32 mg, 17% yield) as a clear oil. (m/z): [M+H]+ calcd for C23H31BrClF3N4O4 599.12, 601.11 found 601.4.
Reaction SMILES: [Cl:1]C(Cl)C.[O:5]=[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]([CH:17]=O)[CH2:7]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C@H:27]([NH2:29])[CH3:28])[CH:24]=[CH:25][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(O)(=O)C>[ClH:1].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C@H:27]([NH:29][CH2:17][CH:8]2[CH2:9][N:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:5])[CH2:7]2)[CH3:28])[CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: O=CC1CC(=O)N(c2ccccc2)C1
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc([C@@H](C)NCC2CC(=O)N(c3ccccc3)C2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 10 ml dichloroethane solution of 0.53 g of 5-oxo-1-phenylpyrrolidine-3-carboaldehyde was mixed with 508 mg of (1R)-1-(3-methoxyphenyl)ethanamine and 0.1 ml of acetic acid and stirred at room temperature for 1 hour. Successively this was mixed with 1.8 g of sodium triacetoxyborohydride and stirred overnight at room temperature. This was mixed with 40 ml of water and extracted with chloroform. The organic layer was concentrated, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol), treated with 4 M hydrogen chloride/ethyl acetate and concentrated to dryness to obtain 161 mg of 4-({[(1R)-1-(3-methoxyphenyl)ethyl]amino}methyl)-1-phenylpyrrolidin-2-one hydrochloride as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1CC(=O)[C@H](CC1C=CC=CC=1)NC(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].C(O)C.CO.[BH4-].[Na+]>C(O)(C)C>[C:1]([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
2 g (4.3 mmol) of N-[[N-(benzyloxycarbonyl)-L-phenylalanyl]methyl]-L-proline tert.butyl ester (prepared as described in Example 1) were dissolved in 25 ml of isopropanol, 25 ml of ethanol and 25 ml of methanol and the solution was stirred at room temperature for 4 hours in the presence of 0.4 g (10.7 mmol) of sodium borohydride. The solvent was removed by evaporation and the residue was partitioned between 50 ml of ethyl acetate and 25 ml of water. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The solvent was removed by evaporation and there were obtained 2 g of N-[3(S)-(benzyloxyformamido)-2(R and S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a clear gum: Rf (System C): 0.68 and 0.57.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([N:17]([CH3:19])[CH3:18])([C:15]#N)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:15]([C:12]1([N:17]([CH3:19])[CH3:18])[CH2:13][CH2:14][CH:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CN(C)C1(C#N)CCC(OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(Cc2ccccc2)CCC(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.00 g of 4-benzyloxy-1-dimethylaminocyclohexanecarbonitrile were dissolved in 40 ml of tetrahydrofuran, and 10.8 ml of two molar benzylmagnesium chloride solution in tetrahydrofuran were added dropwise under a nitrogen atmosphere, while cooling with an ice bath. After stirring overnight at room temperature, the mixture was again cooled in an ice bath, and 20 ml of cold ammonium chloride solution (20 percent by weight) were added. The phases were separated and extracted twice using 60 ml of diethyl ether each time, the combined organic phases were extracted three times using 50 ml of hydrochloric acid (5 percent by weight) each time, the combined acidic extracts were rendered weakly alkaline (pH 8–9) with aqueous ammonia solution (25 percent by weight) and extracted three times using 60 ml of diethyl ether each time, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. The resulting yellow solid (3.85 g) was separated on silica gel with diethyl ether/hexane (V:V=1:1). 2.45 g of (1-benzyl-4-benzyloxycyclo-hexyl)dimethylamine were obtained in the form of a white solid which, as described for Example 1, was converted into 2.03 g of the corresponding hydrochloride (white solid) using chlorotrimethylsilane and water in 2-butanone.