Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:22])[CH2:6][CH2:7]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 146, 60 mg crude, 0.20 mmol), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol), and sodium triacetoxy borohydride (130 mg, 0.60 mmol) were reacted as described for Example 69 to give the free base of the title compound as an oil. The free base was taken up in isopropanol and treated with 4.0M HCl in dioxane (3 eq). Solvent was removed under reduced pressure to give 28 mg (27% yield) of the bis-hydrochloride salt of the product.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH3:6])#[N:2].[NH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH:9][C:4](=[N:3][C:1]#[N:2])[NH:5][CH3:6])=[CH:16][N:15]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CNC(=NC#N)SC
Product: CNC(=NC#N)NCc1ccc(Cl)nc1
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of 3-cyano-1-methyl-2-methylisothiourea (0.65 g) and 5-aminomethyl-2-chloropyridine (0.72 g) was stirred under heating at 100° C. for three hours. Then, the reaction product was cooled to room temperature and then purified on silica gel column chromatography (eluent: ethanol/chloroform) to obtain the desired 3-(2-chloro-5-pyridylmethyl)-1-methyl-2-cyanoguanidine (0.5 g) having a melting point in the range of from 193° to 197° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:21]C(OC(C)(C)C)=O)[CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH2:21])[CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)C(N)Cc2c[nH]cn2)CC1
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq. ), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCl (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(N2CCNCC2)c(Cl)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
A solution of 4-(2-Chloro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.164 mmol) in MeCl2 (0.8 ml) was treated with trifluoroacetic acid (63 μl), heated up to 40° C. and stirred for 4 h. The solvent was removed in vacuo. The residue was dissolved in water and basified with NaOH 1N. The aqueous layer was extracted twice with MeCl2. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to provide the title compound (20 mg, 46%) as a yellow oil, MS (m/e): 265.0 (MH+, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](O)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 57.5 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-methoxy-ethyl)-amide (38 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (58 mg), 2-methoxyethylamine (12 mg), HBTU (65 mg), and DIEA (37 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.49 (t, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.78 (d, 1H), 7.64 (d, 1H), 7.50 (d, 1H), 7.37 (d, 1H), 3.67 (s, 3H), 3.54-3.40 (m, 4H), 3.29 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:23]2[CH2:22][CH2:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)([OH:26])[CH2:25][CH2:24]2)=[CH:5]1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)cc2)CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 59.1 %

Procedure:
A mixture of 3-(2-bromoethyl)indole (1.06 g; 4.73 mM), 4-(p-chlorophenyl)piperidin-4-ol (1.0 g; 4.72 mM), potassium carbonate (0.75 g; 5.42 mM) and dimethylformamide (12 ml) was stirred in an oil-bath maintained at 75° for 19.5 hours under a nitrogen blanket. The mixture was poured onto water (50 ml) and cooled in ice. The sticky, yellow solid which formed was filtered off and washed well with water. It was then promptly transferred to a new flask (the solid tended to gum) and dissolved in ethanol, acidified with ethanolic HCl and the solvents evaporated. The residue was crystallised from iso-propanol/ethyl acetate, then twice triturated well with ethanol/ethyl acetate. Filtration gave the title compound as the hydrochloride (0.99 g; 53.5%) as very pale pink plates, m.p. 248°-252° (dec; decomposition occurred above 235°).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[CH3:11][C:2]([O:1][C:23](=[O:24])[CH2:22][CH2:21][Cl:20])([CH3:12])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)CCCl
Reactant: CC(C)(O)C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(OC(=O)CCCl)C(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 72 h
Yield: 6.5 %

Procedure:
9.9 g (60 mmol) 2-hydroxy-2-methyl-1-phenyl-1-propanone (DAROCUR™ 1173) was dissolved in 60 ml tetrahydrofuran. 6.1 g (60 mmol) triethyl amine was added and the reaction mixture was cooled to −10° C. 7.6 g (60 mmol) 3-chloro-propionyl chloride was added while the temperature was kept below −5° C. The reaction was allowed to continue for 30 minutes at 0° C. and for 72 hours at 40° C. The precipitated salts were removed by filtration and the solvent was evaporated under reduced pressure. 3-chloro-propionic acid 1,1-dimethyl-2-oxo-2-phenylethyl ester was purified by preparative column chromatography on a Prochrom LC80 column, using n.-hexane/ethyl acetate 80/20 as eluent at a flow rate of 150 ml/min and Kromasil 60A 10 micron as silica. 1 g of 3-chloro-propionic acid 1,1-dimethyl-2-oxo-2-phenylethyl ester was isolated.
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:11]=[C:10]3[C:26]2[CH:31]=[N:30][CH:29]=[C:28]([CH:32]3[CH2:34][CH2:33]3)[N:27]=2)=[N:5][N:6]=1.[NH:35]1[CH:39]=[CH:38][C:37](B(O)O)=[N:36]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH:32]1([C:28]2[N:27]=[C:26]([C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:4]5[O:3][C:2]([C:37]6[NH:36][N:35]=[CH:39][CH:38]=6)=[N:6][N:5]=5)[CH:8]=4)[N:12]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:11]=3)[CH:31]=[N:30][CH:29]=2)[CH2:34][CH2:33]1
Reactant: OB(O)c1cc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(Br)o4)ccc32)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(-c5ccn[nH]5)o4)ccc32)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 41.1 %

Procedure:
A brown mixture of 2-bromo-5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (48.4 mg, 0.090 mmol), 1H-pyrazol-3-ylboronic acid (J&W Pharmlab, LLC, Levittown, Pa.; 30.3 mg, 0.271 mmol), Pd(PPh3)4 (20.85 mg, 0.018 mmol), and potassium carbonate (37.4 mg, 0.271 mmol) in a mixture of dioxane (1.0 mL) and H2O (0.250 mL) was stirred under argon at 100° C. for 1.5 h. The mixture was cooled to RT, concentrated onto silica gel, and purified chromatographically (silica gel, 0-100% (10% MeOH-EtOAc)/Hex) to provide 2-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(1H-pyrazol-5-yl)-1,3,4-oxadiazole (19.6 mg, 0.037 mmol, 42%) as a light-yellow solid: MS (ESI, pos. ion) m/z: 524.2 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:39])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][N:29]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:39])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(O[C@@H](C)COC)c3)[nH]2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ccc(C(=O)O)cn3)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Ethyl 6-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinate (42.0 mg, 0.076 mmol) synthesized in Example (11c) was dissolved in ethanol (4 mL). An aqueous sodium hydroxide solution (5M, 2 mL) was added, and stirring was carried out at 70° C. for 2 hours. After cooling to room temperature, hydrochloric acid (2M, 5 mL) and ethyl acetate (10 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to afford the desired compound (39.6 mg, yield 99%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=[O:5].Cl>C(O)C.[Pd]>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccc2cccnc2n1)c1c(F)cccc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccc2c(n1)NCCC2)c1c(F)cccc1F
Reaction time: 3 h

Procedure:
2,6-Difluoro-N-[1,8]naphthyridin-2-ylbenzamide (35 mg, 0.12 mmol) and 10% Pd/C (15 mg) were suspended in ethanol (5 mL). Concentrated HCl (0.02 mL, 0.24 mmol) was then added and the reaction mixture was stirred under hydrogen (1 atmosphere) for three hours. Next, the reaction mixture was filtered through Celite and concentrated to give 2,6-difluoro-N-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide. Yield 33 mg (95%). LCMS (ESI): calc. C15H13F2N3O=289; obs. M+H=290.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]1([Si:18]2(CCCC)[CH2:23][CH2:22][CH:21]([CH:24]3[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)C=C[CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C@H:27]2[CH2:26][CH2:25][C@H:24]([CH:21]3[CH2:20][CH2:19][SiH:18]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:23][CH2:22]3)[CH2:29][CH2:28]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCCC[Si]1(c2ccccc2)CCC(C2CCC(O)CC2)CC1
Product: CCCC[SiH]1CCC([C@H]2CC[C@H](OC(=O)c3ccc(OC)cc3)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-methoxybenzoic acid and 4-(4-phenyl-4-n-butyl-4-silacyclohexyl)cyclohexanol, thereby obtaining the intended product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:23]([O:30][C@H:31]1[CH2:35][N:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C@H:33]([CH2:41][CH2:42]Cl)[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[CH2:39]([O:38][C:36]([N:34]1[CH2:35][C@H:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:32][C@H:33]1[CH2:41][CH2:42][O:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:37])[CH3:40]
Reactant: Cc1cccc(CCc2ccccc2)c1O
Reactant: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCOc1c(C)cccc1CCc1ccccc1
Yield: 90.3 %

Procedure:
1200 mg of 6-methyl-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 700 mg of potassium t-butoxide and 1600 mg of (2S,4R)-4-benzyloxy-2-(2-chloroethyl)-1-ethoxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2260 mg (yield 90%) of the title compound as an oily substance.
Reaction SMILES: [C:1]([NH:3][C:4]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[N:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)#[N:2].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[C:1]([NH:3][C:4]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[N:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][CH:13]=1)#[N:2]
Reactant: N#CNC(=NCCc1ccc(N)cc1)c1cccnc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#CNC(=NCCc1ccc(NCc2ccccc2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
N-cyano-N'-[2-(4-aminophenyl)ethyl]-3-pyridinecarboximidamide (0.20 g, 0.75 mmol) was dissolved in methanol (15 ml), and benzaldehyde (0.12 g, 1.13 mmol) and sodium cyanoborohydride (0.10 g, 1.59 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue thus obtained was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.12 g, 0.34 mmol, yield: 75%) as colorless needles.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10]2
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: CC1(C)CCc2cc(C=C3C(=O)Nc4ccc(Cl)cc43)ccc2O1

Procedure:
2,2-Dimethyl-6-formylchromane was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-Chloro-3-(2,2-dimethylchroman-6-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH2:33][O:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([CH2:33][O:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COCC1(c2ccc(Br)cc2)CCOCC1
Product: COCC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)CCOCC1
Yield: 74.2 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (78 mg) was reacted with tetrahydro-4-(4-bromophenyl)-4-(methoxymethyl)-2H-pyran (88 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(tetrahydro-4-(methoxymethyl)-2H-pyran-4-yl)phenyl]pent-4-enoic acid methyl ester (97 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:34])[C:16]2[CH:21]=[N:20][C:19](S(C)(=O)=O)=[N:18][C:17]=2[N:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:27]=1)=[O:13])[CH3:10]>>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:34])[C:16]2[CH:21]=[N:20][C:19]([NH:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:18][C:17]=2[N:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:27]=1)=[O:13])[CH3:10]
Reactant: NCCN1CCCC1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCN3CCCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 2-pyrrolidin-1-yl-ethylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (25 mg, 0.07 mmol). 8-Cyclohexyl-5-oxo-2-(2-pyrrolidin-1-yl-ethylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (18 mg, 80%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H31N5O3: 414.24 (M+H). Found: 414.3.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].O.[CH3:7][C:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:28]#[N:29])=[C:11]([CH3:30])[O:10][N:9]=1>CS(C)=O>[CH3:7][C:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:28](=[N:2][OH:3])[NH2:29])=[C:11]([CH3:30])[O:10][N:9]=1
Reactant: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C(N)=NO
Temperature: 65 °C
Yield: 24 %

Procedure:
A neutral 2 M solution of hydroxylamine hydrochloride and NaOH in water (0.5 mL, 1.0 mmol) was added to 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (5.4 mg, 0.017 mmol) in DMSO (0.5 mL) and stirred at 65° C. over night. Crude LCMS on the reaction mixture show 41% product, 38% amide and 21% starting material. Purification using preparative HPLC gave E5 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carboximidamide (1.42 mg, 24%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 356.2 (M+H), 354.21 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.11 m 2H, 6.85 m 2H, 2.77 m 2H, 2.11 s 3H, 1.88 s 3H, 1.75 m 2H, 0.98 t (7.5 Hz) 3H.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:21])[CH2:19][OH:20])[CH:12]=[CH:11]2>>[S:1]([O:20][CH2:19][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)[CH:14]=1)[CH3:21])(=[O:4])(=[O:3])[NH2:2]
Reactant: COc1ccc2cc(C(C)CO)ccc2c1
Reactant: NS(=O)(=O)Cl
Product: COc1ccc2cc(C(C)COS(N)(=O)=O)ccc2c1
Yield: 21 %

Procedure:
The title compound was prepared by the procedure of Example 33 from sulfamoyl chloride and 2-(6-methoxy-2-naphthyl)propanol as white solid, mp 112°-115° C., in 21% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([NH:29][C:30]([CH3:35])([CH3:34])[C:31]([NH2:33])=[O:32])[CH2:26][CH2:27][CH3:28]>>[CH2:25]([N:29]1[C:30]([CH3:35])([CH3:34])[C:31](=[O:32])[N:33]=[C:21]1[C:10]1[C:9]([CH3:24])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCNC(C)(C)C(N)=O
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: CCCCN1C(c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)=NC(=O)C1(C)C

Procedure:
Compound 9 was synthesized from 4a (252 mg, 0.66 mmol) and 5d (161 mg, 1.01 mmol) as a white solid (141 mg, 42%) in a manner similar to that described in Example 36. 1H NMR (600 MHz, CDCl3) δ 7.44 (d, 1H), 7.29-7.24 (m, 3H), 7.13 (d, 1H), 7.05 (d, 2H), 3.80-3.78 (m, 2H), 2.39 (s, 3H), 1.69-1.64 (m, 2H), 1.40 (s, 6H), 1.26-1.22 (m, 2H), 0.81 (t, 3H); ESMS m/z: 503.1 (M+1).