Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:8]([CH3:18])[C:7]=1[O:19]C>ClCCl>[CH3:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[C:8]([CH3:18])[C:7]=1[OH:19]
Reactant: COc1c(C)cc(-c2ccccc2)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)cc(C)c1O
Temperature: 25 °C
Yield: 97.3 %

Procedure:
T-butyllithium (1.3M in pentane, 17.9 ml, 23.2 mmol) was added slowly to a solution of 2,6-dimethyl-4-bromo-methoxybenzene (2.5 g, 11.6 mmol) in anhydrous THF (50 ml) at −78° C. under an atmosphere of argon, then after 1 hour a solution of anhydrous zinc chloride (1.6 g, 11.7 mmol) in THF (40 ml) was added by cannula and the clear solution allowed to warm to room temperature and stir for 1 hr. This solution was then added by cannula to iodobenzene (2.37 g, 11.6 mmol) and bis(triphenylphosphine)palladium (II)chloride (81 mg, 116 μmol) in THF (40 ml) and allowed to stir overnight. The reaction was added to 1N HCl (150 ml) and extracted into dichloromethane (2×300 ml). The organic phase was washed with water (150 ml), brine (150 ml) and dried (Na2SO4). The crude product was concentrated and purified by chromatography on silica gel (100 g), eluent 10% dichloromethanelhexanes to give 2,6-dimethyl-4-phenyl-methoxybenzene (2.11 g, 9.9 mmol) in 86% yield. 1H nmr (CDCl3): δ=7.6-7.2 (m, 7H); 3.78 (s, 3H) and 2.37 (s, 6H). Boron tribromide (4.72 g, 19 mmol) was added dropwise to a solution of 2,6-dimethyl-4-phenyl-methoxybenzene (2.35 g, 11.1 mmol) in dichloromethane (45 ml) at −78° C. under argon, then the solution was allowed to warm to room temperature overnight. Ice/water (75 g) was added to quench the reaction, then the reaction was extracted with dichloromethane (2×200 ml). The organic layer was washed with water (50 ml), brine (50 ml) and dried (Na2SO4). Removal of the solvent gave 2,6-dimethyl-4-phenyl-phenol (2.15 g, 10.8 mmol) in 98% yield as a white solid, a single component by TLC Rf (0.13) eluent 4:1 dichloromethane/hexanes and 1H nmr. 1H nmr (CDCl3): δ=7.6-7.2 (m, 7H); 4.70 (s, 1H) and 2.37 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][NH2:3].O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:42])=[C:10]([C@:12]23[CH2:21][O:20][C@@H:19]([CH:22]([CH:28](OC)OC)[CH:23](OC)OC)[CH2:18][C@H:17]2[CH2:16][S:15][C:14]([NH:33]C(=O)C2C=CC=CC=2)=[N:13]3)[CH:11]=1.S(=O)(=O)(O)O>C(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:42])=[C:10]([C@:12]23[CH2:21][O:20][C@@H:19]([C:22]4[CH:23]=[N:3][N:2]([CH3:1])[CH:28]=4)[CH2:18][C@H:17]2[CH2:16][S:15][C:14]([NH2:33])=[N:13]3)[CH:11]=1
Reactant: CNN
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cc(Br)ccc2F)CO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cn1cc([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3cc(Br)ccc3F)CO2)cn1
Temperature: 60 °C

Procedure:
Methylhydrazine (0.0834 mL, 1.60 mmol) followed by water (2.2 mL) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C44) (0.65 g, 1.06 mmol) in ethanol (5 mL). Sulfuric acid (0.110 mL, 2.07 mmol) was then added in a drop-wise manner to the reaction mixture. The resulting solution was heated to 60° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). The layers were separated and the resulting aqueous layer was further extracted with ethyl acetate (3×100 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated to give a mixture of product and benzoylated product (0.79 g), which was taken directly to the following step. LCMS m/z 427.1 [M+H+] (product) and m/z 527.1 [M+H+] (benzoylated product).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol (353 mg, 1.05 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (200 mg, 1.05 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (302 mg, 1.58 mmol) and 1-hydroxy-1H-benzotriazole (161 mg, 1.05 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (166 mg, 31%).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)[N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12.C(OCC)(=O)C.O.C[C:35]([N:37](C)C)=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.[C-]#N.[Zn+2].[C-]#N>[C:35]([C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([C:18]3[CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[S:21][CH:22]=3)[N:11]=[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12)#[N:37]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(Br)cnc(OC)c32)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-n2nc(C3CCCC3)c3c(C#N)cnc(OC)c32)cs1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl 4-(4-bromo-3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxylate (65 mg), tetrakis(triphenylphosphine)palladium(0) (34.4 mg) and zinc cyanide (26.2 mg) in DMA (3 mL) was stirred under microwave irradiation at 120° C. for 30 min. To the reaction mixture were added ethyl acetate and water, and the mixture was filtered through Celite. The filtrate was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (40 mg).
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:10]([O:12]N1C(=O)CCC1=O)=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH2:30][C@H:31]([C:38]([O:40][CH3:41])=[O:39])[CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35].Cl.C(OCC)(=O)C>C(N(CC)CC)C>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:2]([C:10]([NH:30][C@H:31]([C:38]([O:40][CH3:41])=[O:39])[CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:12])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Temperature: 20 °C
Reaction time: 15 h

Procedure:
16.25 g of Z-Thr(But)-OSu and 8.47 g of H-Ser(But)-OMe. HCl are added to 200 ml of ethyl acetate, 5.6 ml of triethylamine are added at 0°C and the solution is stirred for 15 hours at 20°C and washed with 1 N citric acid, 1 N sodium bicarbonate and water. After drying over sodium sulphate, the solution is evaporated, whereupon the product, which is pure according to thin layer chromatography, is obtained as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=3)=[CH:13][C:12]=2[F:39])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C1COCC1>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[N:19]=3)=[CH:13][C:12]=2[F:39])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: CS(=O)(=O)c1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2ccc(Nc3nc(N4CCOCC4)ncc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a suspension of 4-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-2-(methylsulfonyl)pyrimidine-5-carboxamide (75 mg, 0.13 mmol) in THF (4 mL) was added morpholine (100 mg, 1.1 mmol) and the reaction mixture was stirred 15 min. The solvent was removed in vacuo and the resulting solid was triturated in methanol/ether to give the desired product (55 mg, 75%) as a white solid. MS(ESI+) m/z 566 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH:5]([C:11](OCC)=[O:12])[C:6](OCC)=[O:7].[CH:20]([NH2:22])=[NH:21]>>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[C:11](=[O:12])[NH:22][CH:20]=[N:21][C:6]=1[OH:7]
Reactant: N=CN
Reactant: CCOC(=O)C(Cc1ccccc1Cl)C(=O)OCC
Product: O=c1[nH]cnc(O)c1Cc1ccccc1Cl

Procedure:
Condensation of diethyl o-chlorobenzylmalonate with formamidine yielded 5-(o-chlorobenzyl)-6-hydroxy-4(3H)-pyrimidinone which, by reaction with phosphorus oxychloride, yielded 4,6-chloro-5-(o-chlorobenzyl)pyrimidine, melting point 110°-112° C.
Reaction SMILES: O=[CH:2][C:3]1C=CC(O)=C(OC)[CH:4]=1.[CH:12]1[CH:17]=[C:16]([CH2:18]N)C=[C:14]([CH2:20][NH2:21])[CH:13]=1>>[CH3:2][CH2:3][CH2:4][CH2:18][CH2:16][CH2:17][CH2:12][CH2:13][CH2:14][CH2:20][NH2:21]
Reactant: NCc1cccc(CN)c1
Reactant: COc1cc(C=O)ccc1O
Product: CCCCCCCCCCN

Procedure:
according to the general preparation protocol for the reductive alkylation, 30.4 g of vanillin (=4-hydroxy-2-methoxybenzaldehyde) and 13.6 g of MXDA were reacted. There was obtained a clear, orange oil with a viscosity of 62,380 mPa·s at 60° C. and an amine content of 5.0 mmol N/g.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[C:4]([S:15][CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>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>[Cl:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:3]=[C:4]([S:15][CH3:16])[N:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(Cl)n1
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: O
Product: CSc1nc(Cl)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 35.1 %

Procedure:
To a mixture of 4,6-dichloro-2-(methylthio)-5-phenylpyrimidine (2.71 g, 10.0 mmol), 4-chlorophenylboronic acid (1.72 g, 11.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in toluene (25 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 10 mL, 20.0 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 6 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to obtain 1.22 g of the title compound as a white solid. HPLC/MS: retention time=4.32 min, [M+H]30 =347.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:14]([O:16][C:17](=[O:22])[CH:18]=[C:19](Cl)[CH3:20])[CH3:15]>O1CCCC1>[CH2:14]([O:16][C:17](=[O:22])/[CH:18]=[C:19](/[O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)\[CH3:20])[CH3:15]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1
Temperature: 23 °C
Yield: 88.4 %

Procedure:
Potassium t-butoxide (11.9 g, 0.106 mol) was added to a stirred solution of phenol (7.86 g, 0.053 mol) in tetrahydrofuran (25 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-phenoxy-but-2-enoic acid ethyl ester (6.20 g, 89%) as a yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][C:9](=[O:32])[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].[Br:33]Br.Br.O>C(O)(=O)C>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH:8]([Br:33])[C:9](=[O:32])[C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C(Br)[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 121.9 %

Procedure:
A solution of methyl 3α-acetoxy-7-keto-5β-cholanoate (5.6 g, 12.54 mmoles) in acetic acid (100 ml) was added with a bromine solution (2.8 g) in acetic acid (10 ml) and immediately after with 48% hydrobromic acid (0.74 ml). The resulting reaction mixture was left to react overnight under strong magnetic stirring, then it was poured into water (300 ml) and filtered under vacuum to obtain a solid (8,03 g) which was subjected to flash chromatography on silica, eluting with methylene chloride/methanol 99.5:0.5, to yield 6.0 g of a pure product (91%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Product: COc1cc([N+](=O)[O-])ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 84 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.12 mmol) was converted using 2-methoxy-4-nitro-benzoic acid instead of o-toluic acid to the title compound (2.92 g, 84%) which was obtained as a white solid. MS: m/e=379.2 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][NH+:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)[CH2:6]1>O.CO>[CH3:4][N:5]1[CH2:10][CH:9]=[CH:8][CH:7]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)[CH2:6]1
Reactant: C[NH+]1CCCC(c2cc3ccccc3o2)C1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC=CC(c2cc3ccccc3o2)C1

Procedure:
A solution of 50 g of sodium borohydride in 100 ml of water is added dropwise, with stirring and external cooling, to a solution of 56.0 g of 1-methyl-3-(2-benzofuranyl)-piperidinium-iodide in 600 ml of methanol, the manner of addition being such that the reaction temperature does not exceed 35°. The solution is subsequently stirred for 15 hours at room temprature and again a solution of 50 g of sodium borohydride in 100 ml of water is added dropwise at a temperature not exceeding 35°. The methanol is thereupon evaporated off in vacuo; the aqueous phase remaining behind is extracted twice with 300 ml of chloroform each time, the chloroform solution dried over sodium sulphate, filtered, and concentrated by evaporation. The 1-methyl-3-(2-benzofuranyl)-1,2,3,6-tetrahydropyridine obtained is recrystallised from di-isopropylether, and then melts at 63°. The hydrochloride prepared therefrom with a solution of hydrogen chloride in ethyl acetate melts, after recrystallisation from ethyl acetate, at 244°-246°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:10])=[C:7]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH:6]=1)(=[O:3])[CH3:2].[N:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[O:10])=[C:7]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[CH2:27][CH2:26]2)=[O:24])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)c2ccc(NC(C)=O)cc2NC(=O)C2CCN(Cc3ccncc3)CC2)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred suspension of 4-acetylamino-N-(4-methoxyphenyl)-2-[(4-piperidinylcarbonyl)amino]benzamide (0.4 g, 0.97 mmol), 4-pyridinecarboxaldehyde (0.11 mL, 1.17 mmol) and acetic acid (0.085 mL, 1.46 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (0.31 g, 1.46 mmol). After stirring overnight, the white solid was filtered off and the filtrate was concentrated in vacuo. The residue was suspended in diethyl ether, sonicated, and filtered. The combined solids were then washed with water, filtered and dried in vacuo to give 0.37 g (76%) of the title compound as a white solid.
Reaction SMILES: C(OC([N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:13]([O:28][C@@H:29]2[O:37][C@H:36]([CH2:38][O:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]2[OH:31])=[N:12]1)=O)C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[CH2:43]([O:42][C:40]([O:39][CH2:38][C@H:36]1[O:37][C@@H:29]([O:28][C:13]2[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:20][CH:19]=3)=[C:15]([CH3:16])[NH:11][N:12]=2)[C@H:30]([OH:31])[C@@H:32]([OH:33])[C@@H:34]1[OH:35])=[O:41])[CH3:44]
Reactant: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(=O)OCc3ccccc3)c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methylpyrazole (0.17 g) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder, and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The resulting insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (00.10 g).
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([C:19]#[N:20])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH2:22][CH2:23][CH2:24]Br.C(N(CC)CC)C>C(#N)C>[N:1]1([CH:2]2[CH:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10]3[CH:9]=[C:8]([C:19]#[N:20])[CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3]2)[CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Reactant: BrCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N1CCC1)CC2
Temperature: 120 °C

Procedure:
7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (790 mg, 3.03 mmol), 1,3-dibromopropane (0.4 mL, 3.93 mmol) and triethylamine (0.914 mL, 6.56 mmol) were dissolved in acetonitrile (8 mL) and the reaction mixture heated to 120° C. in the microwave for 2 h. The solvent was evaporated in vacuo. Water (30 mL) and ethyl acetate (40 mL) were added. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 346 mg (1.14 mmol, 37.6%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:35])[N:24]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:25][CH:26]([OH:29])[CH2:27][OH:28])[CH:20]=[C:19]([Cl:36])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:36][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1)[CH2:25][CH:26]([OH:29])[CH2:27][OH:28])=[O:35]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CC(O)CO)C2CCCC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CC(O)CO)C1CCCC1
Reaction time: 1 h

Procedure:
A solution of crude (2-{3-chloro-5-[cyclopentyl-(2,3-dihydroxy-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.044 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.007 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.