Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH3:15])=[C:10]([N+:26]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:29])[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:15][N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:2]([CH3:1])[CH2:3][C:4](=[O:29])[NH:5][N:6]=3)=[CH:9][C:10]=2[N:26]=[C:16]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)N(C)c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc3cc(C4=NNC(=O)CC4C)ccc3n2C)cc1

Procedure:
A mixture of 6.4 gm of 5-methyl-6-{3-nitro-4-[N-methyl-(4-methoxy-benzoyl)-amino]-phenyl}-4,5-dihydro-2H-pyridazine-3-one and 0.6 gm of 10% palladium charcoal in 100 ml of ethanol was treated for 2.5 hours at room temperature with hydrogen at 5 bar. The catalyst was suction filtered off, and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silicagel (eluting agent: methylene chloride/ethanol 19:1 to 9:1). The corresponding fractions were evaporated and the product was crystallized by trituration with ether.
Reaction SMILES: [OH-].[K+].[N+](=[CH2:5])=[N-].C(O)C.[C:9]([C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:12][OH:13])#[N:10]>O.C(OCC)C>[CH3:5][O:13][CH:12]=[C:11]([C:9]#[N:10])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CC(=CO)CCCCc1ccccc1
Reactant: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: COC=C(C#N)CCCCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3.0 grams of potassium hydroxide in 6 mL of water was placed in a commercially available diazomethane generator. Ethanol, 8 mL, was added to the generator, and the contents of the generator were slowly warmed to 60° C. to 70° C. To this was added dropwise a solution of 4.6 grams (0.021 mole) of Diazaid® in a minimum amount of diethyl ether. The diazomethane generated was condensed on a cold finger and, in turn, was allowed to drip into a stirred, cooled solution of 2.5 grams (0.012 mole) of 2-cyano-6-phenyl-1-hexen-1-ol in a minimum of diethyl ether. The complete generation of diazomethane required about 30 to 45 minutes. Upon completion of the diazomethane generation, the reaction mixture was allowed to warm to ambient temperature. After this time the reaction mixture was concentrated under reduced pressure, yielding 2.4 grams of 1-methoxy-2-cyano-6-phenyl-1-hexene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CCN(CC=C)c1nc(NC(C)=O)n2oc(=O)nc2n1

Procedure:
6 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are stirred at room temperature for 18 hours with 60 ml. of absolute pyridine and 8 ml. of acetic acid anhydride. The solvents are distilled off at 40° C. and the residue is dissolved in 220 ml. of methylene chloride. The solution obtained is washed with 1-N hydrochloric acid, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}acetamide having a melting point of 164°-165° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH2:22]([NH2:25])[CH2:23][NH2:24].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH2:24][CH2:23][CH2:22][NH:25][C@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])[CH2:12]1
Reactant: NCCN
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@]12CC[C@H](NCCN)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17β-Hydroxy-5α-androstan-3-one (403 mg, 1.39 mmol)(Aldrich Chemical Company) was added to a stirred solution of 0.745 mL 1,2-ethylenediamine (11.1 mmol) and 1.44 mL acetic acid (25.2 mmol) in 16.0 mL dry methanol (MeOH), followed by 104 mg (1.65 mmol, 1.19 equiv.) of sodium cyanoborohydride. After stirring at room temperature for 15 h, the reaction concentrated under reduced pressure. The residue was partitioned between methylene chloride and aqueous 1N sodium hydroxide, shaken, and separated. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[CH2:29][O:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Yield: 74.7 %

Procedure:
A mixture of 3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetic acid (428 mg, 1.36 mmol), methyl (S)-4-(2-pyrrolidinylmethoxy)benzoate (330 mg, 1.40 mmol), EDC (312 mg, 1.63 mg), HOBt (220 mg, 1.63 mmol), and a catalytic amount of DMAP in DMF (15 mL) was stirred for 6 hr. The resulting mixture was diluted with EtOAc, washed with 0.5 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo to give an oily residue, which was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 540 mg (75%) methyl (S)-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate as an oil. 1H-NMR (CDCl3) δ 1.81–2.12 (m, 4 H) 2.88 (bs, 3 H), 3.48–3.61 (m, total 7 H), 3.88 (s, 3 H), 4.10–4.21 (m, 2 H), 4.42–4.46 (m, 1 H), 6.75–8.08 (series of m, total 13 H).
Reaction SMILES: [Cl:1][C:2]1[S:12][C:5]2[NH:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH:3]=1.Cl.[NH2:14][C@@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17].O.[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C>[CH2:24]([C@H:15]([NH:14][C:9]([C:7]1[NH:6][C:5]2[S:12][C:2]([Cl:1])=[CH:3][C:4]=2[CH:8]=1)=[O:11])[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1
Reactant: O=C(O)c1cc2cc(Cl)sc2[nH]1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)c1cc2cc(Cl)sc2[nH]1

Procedure:
2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid and (2S)-amino-1-morpholin-4-yl-3-phenyl-propan-1-one hydrochloride (See, for example, Suzuki, K.; Fujita, H.; Sasaki, Y.; Shiratori, M.; Sakurada, S.; Kisara, K,. Chem. Pharm. Bull., 36, 4834-40 (1988)) were coupled according to Procedure C (solution of product in ethyl acetate washed with water, dried over MgSO4, concentrated).
Reaction SMILES: S(=O)(=O)(O)O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:12]([N:15]([CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[C:20]#[N:21])[CH2:16][CH:17]=[CH2:18])[CH:13]=[CH2:14].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:16]([N:15]([CH2:12][CH:13]=[CH2:14])[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:29])=[O:30])=[CH:26][CH:27]=1)[CH2:20][NH2:21])[CH:17]=[CH2:18]
Reactant: C=CCN(CC=C)C(C#N)c1ccc(S(=O)(=O)CCC)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(CC=C)C(CN)c1ccc(S(=O)(=O)CCC)cc1
Reaction time: 0.25 h

Procedure:
Anhydrous THF (5 mL) was cooled to 0° C. and treated with 98% sulphuric acid (0.28 mL, 5.25 mmol). After stirring for 15 mins, lithium aluminium hydride (10.5 mL of 1.0M solution in THF, 10.5 mmol) was added drop wise over 10 mins. The mixture was stirred at 0° C. for 60 minutes before addition of a solution of (diallylamino)[4-(propylsulphonyl)phenyl]acetonitrile (1.22 g, 3.83 mmol) in THF (3+2 mL washing). The mixture was stirred at 0° C. for 30 mins then at 40° C. for 1 h. The reaction was allowed to cool and carefully treated with powdered sodium sulphate decahydrate (3 g). The mixture was stirred at ambient temperature for 15 h, then filtered and the filtrate concentrated to give a pale yellow oil. Used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.01 (3H, t, J=7.4 Hz), 1.75-1.81 (2H, m), 2.82 (2H, dd, J=14.6, 7.6 Hz), 2.95 (1H, dd, J=13.0, 6.0 Hz), 3.06-3.10 (2H, m), 3.18 (1H, dd, J=13.1, 7.5 Hz), 3.28-3.33 (2H, m), 3.86 (1H, br t, J=67 Hz), 5.15-5.20 (4H, m), 5.77-5.85 (2H, m), 7.44 (2H, d, J=8.3 Hz), 7.88 (2H, d, J=8.3 Hz); m/z (ES+) 323 (M+H), 306 (M−NH2).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([CH:15]([CH3:17])[CH3:16])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[N+:18]([O-])=O>CC(O)C.O.[Fe]>[NH2:18][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][C:2]=1[F:1])[NH:12][C:11]1[C:10]([CH:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][C:6]2=1
Reactant: CC(C)c1cccc2c1[nH]c1cc(F)c([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: CC(C)O
Solvent: O
Product: CC(C)c1cccc2c1[nH]c1cc(F)c(N)cc12
Yield: 65.2 %

Procedure:
3-Fluoro-benzohydrazine (3.3 g) and cyclohexanone (2.2 g) were added to ethanol (30 ml) and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the resulting residue was recrystallized from hexane to obtain 7-fluoro-carbazole (1.81 g, 48%). Then, concentrated sulfuric acid (20 ml) was cooled to 0° C. and added with 7-fluoro-carbazole (2.1 g) and sodium nitrate (900 mg), and then the mixture was stirred for 10 minutes. The reaction mixture was poured on an ice layer and filtered to obtain 7-fluoro-6-nitro-carbazole (1.1 g, 42%). The resulting 7-fluoro-6-nitro-carbazole (500 mg) and KOH (200 mg) were stirred in acetonitrile as a solvent, and then the mixture was added dropwise with 2-iodopropane (500 mg) and stirred for 8 hours. The reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 7-fluoro-1-isopropyl-6-nitro-carbazole (254 mg, 43%). The resulting 7-fluoro-1-isopropyl-6-nitro-carbazole (500 mg) and Fe (400 mg) were stirred in i-PrOH/water solvent (1:1) under reflux. The reaction mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 6-amino-7-fluoro-isopropyl-carbazole (290 mg, 65%). The resulting amino compound (500 mg) was dissolved in chloroform (10 ml), and the solution was added dropwise with phenyl chloroformate (190 mg) and stirred for 2 hours. The reaction mixture was added with water and extracted. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain phenylurethane (263 mg, 61%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:37])=[CH:25][CH:24]=1)=[O:38]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(C(=O)Nc4ccccc4)cc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(C(=O)Nc4ccccc4)cc3)c2c1
Yield: 88.2 %

Procedure:
350 mg of the compound obtained in Example 80 dissolved in 7 ml of methylene chloride was reacted with 7 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 50 ml of saturated aqueous sodium bicarbonate for 30 mins, filtered under a reduced pressure, and dried to obtain the title compound (250 mg, 89%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30].CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH:30][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: COc1ccccc1CCN
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CCNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(2-methoxy-phenyl)-ethylamine and DIEA to give 2-[2-(2-methoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([Cl:20])[CH:13]=1)P(OCC)(=O)OCC.[CH:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[C:22]1=O)[CH2:28]2.C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:20][C:14]1[CH:13]=[C:12]([C:3]([O:2][CH3:1])=[C:22]2[CH:23]3[CH2:29][CH:27]4[CH2:26][CH:25]([CH2:30][CH:21]2[CH2:28]4)[CH2:24]3)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CCOP(=O)(OCC)C(OC)c1cc(Cl)cc(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=C1C2CC3CC(C2)CC1C3)c1cc(Cl)cc(OC)c1
Temperature: -68 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Phosphonoate 8 (4.62 g, 14 mmol) and 2-adamantanone (2.58 g, 17 mmol) were dissolved in anhydrous THF (35 ml) under argon and cooled to -68° C. Dropwise addition of lithium diisopropylamide (18.6 mmol) in anhydrous THF (20 ml) at -68° C. generated the ylid, followed by subsequent olefination of the ketone. The reaction was slowly warmed to room temperature over 2 h and then stirred at 75° C. for 1 h. The solution was partitioned between EtOAc/NH4Cl, dried over Na2SO4, evaporated and purified by silica gel chromatography (2% EtOAc/hexanes), yielding 2.5 g (55%) of enol ether 9 as an oil.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:9][C@@H:6]1[CH2:7][CH2:8][NH:1][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@H]1NCC[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The reaction mixture was composed of 100 mM TES buffer (pH 7.0), 5 mM L-proline, 5 mM2-ketoglutaricacid, 1 mM ferrous sulfate, 5 mM L-ascorbic acid and a predetermined amount of the pure enzyme, the total volume being 100 μl. The reaction was initiated by addition of the enzyme and continued for 10 minutes at 35° C. The reaction was stopped by heating the reaction mixture at 100° C. for 2 minutes. The amount of cis-3-hydroxy-L-proline formed in the reaction mixture was determined by the pre-column derivatization method using HPLC. One hundred microliters of 0.3 M boric acid buffer (pH 10.7), 4 μl of an aqueous solution of 10% (v/v) mercaptoethanol and 16 μl of ethanol solution of 5% (w/v) OPA were added to 100 μl of the reaction mixture, and the mixture was allowed to stand at 60° C. for 30 seconds. In addition, 50 μl of ethanol solution of 2% (w/v) NBD was added thereto and the mixture was allowed to stand at 60° C. for 40 minutes. The reaction was stopped by adding 30 μl of 1 N HCl to the reaction mixture, and the precipitates formed were removed therefrom by centrifugation and filtration. The cis-3-hydroxy-L-proline formed by the reaction was quantitatively determined by HPLC analysis.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].[Cl:19][C:20]1[S:21][C:22]([Cl:28])=[CH:23][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1.CCOCC>[C:1]([N:5]([C:25]([C:24]1[CH:23]=[C:22]([Cl:28])[S:21][C:20]=1[Cl:19])=[O:26])[NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)NNC(C)(C)C)cc1
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C(=O)NN(C(=O)c2cc(Cl)sc2Cl)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N'-t-butyl-N-4-methylbenzoylhydrazine (0.7 g) was dissolved in 35 ml toluene. Water (5 ml) and 50% aqueous sodium hydroxide (0.8 g) were added followed by 2,5-dichlorothiophene-3-carbonylchloride (2.0 g). After stirring for 3 hours at room temperature, ether was added and the organic layer separated. Evaporation afforded a solid which was triturated with 10% ether-hexane to afford N'-t-butyl-N-(4-methylbenzoyl)-N'-(2,5-dichlorothiophene-3-carbonyl)hydrazine. m.p. 163-165° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([C:42](O)=[O:43])[C:22]3[C:27](/[CH:28]=[CH:29]/[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:26][N:25]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[C:23]=3[N:24]=2)=[CH:15][CH:14]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C1COCC1.CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:42]([C:21]2[C:22]3[C:27](/[CH:28]=[CH:29]/[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:26][N:25]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[C:23]=3[N:24]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=3)[CH:20]=2)=[O:43])[CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)nc2c1c(/C=C/c1ccccc1)nn2C1CCCCO1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C)C(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccccc2)nn3C2CCCCO2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.24 mmol of piperazine-1-carboxylic acid dimethylamide were weighted into a reaction tube and dissolved/suspended in 1 ml THF. 1 ml of a DMF stock solution containing 0.24 mmol of 6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, 1 mmol N-methyl morpholine, 0.01 mmol 4-dimethylaminopyridine, and 0.3 mmol 1-hydroxybenzotriazole were added, followed by 0.3 mmol EDC. The tube was closed and shaken at 50° C. overnight. The THF was left to evaporate, 0.1 ml TFA was added, the volume was adjusted to 2 ml with DMF. The solution was filtered and submitted to prep. RP HPLC purification to give 4-[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid dimethylamide. In order to transform the trifluoro acetic acid salt into a hydrochloric acid salt and—for other examples to cleave acid labile protecting groups—the product obtained above was shaken with 3 ml methanol and 0.5 ml 4M HCl in dioxane at 65° C. for 30 minutes. Then 10 ml diethyl ether was slowly added to the cooled solution, and the formed precipitate was filtered off, washed with 1 ml diethyl ether, and dried in vacuo to afford 0.085 mmol of 4-[6-(4-Hydroxy-phenyl)-3-((E)-styryl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid dimethylamide (35%).
Reaction SMILES: [OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17](OCC)=[O:18])=[CH:10][CH:11]=2)[CH2:6]1.[CH3:29][NH:30][CH3:31]>O1CCCC1>[OH:1][CH:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([N:30]([CH3:31])[CH3:29])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: CNC
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)cc1)CC2
Solvent: C1CCOC1
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)cc1)CC2

Procedure:
Ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)-ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (250 mg) was dissolved in tetrahydrofuran (5 ml), and dimethylamine (1 ml) was added to the solution under ice-cooling. After reaction in sealed tube at 60° C. for 60 hours, the reaction mixture was concentrated in vacuo. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=10/1) gave 2-[(2S)-2-[[(2RS)-2-hydroxy-2-(4-hydroxyphenyl)-ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (189 mg) as an amorphous.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[CH2:16]1[C:20]2[CH2:21][NH:22][CH2:23][C:19]=2[CH2:18][N:17]1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33])=[O:25].FC(F)(F)C([O-])=O>>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:22]3[CH2:23][C:19]4[CH2:18][N:17]([C:24](=[O:25])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]([F:34])([F:33])[F:35])[CH2:16][C:20]=4[CH2:21]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: O=C([O-])C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nn1
Yield: 27 %

Procedure:
N-(2-Cyclopropylethyl)-6-chloropyridazine-3-carboxamide (150 mg, 0.665 mmol) and (3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)-(2-trifluoromethylphenyl)methanone, trifluoroacetate (263 mg, 0.665 mmol) were converted analogously to example 3b. Yield: 27%, M+H+: 472.08.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([Br:18])[C:14]([NH2:15])=[N:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:19].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](Cl)=[O:29]>O.ClCCl>[Br:18][C:16]1[C:14]([NH2:15])=[N:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:8]1[O:9][C@H:5]([CH2:4][NH:3][C:28](=[O:29])[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Br:20])[C@@H:6]([OH:19])[CH2:7]1
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: NC[C@H]1O[C@@H](n2cc(Br)c(N)nc2=O)C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3Br)O2)cc1Br
Reaction time: 0.17 h

Procedure:
0.84 ml of a 1M sodium hydroxide solution was added to a solution of 256 mg of 5'-amino-5-bromo-2',5'-dideoxycytidine in 3.3 ml of water. A solution of (2-bromophenyl)acetyl chloride (prepared from 185 mg of the acid) in 5 ml of dichloromethane was added, the mixture was shaken vigorously for 10 minutes and then filtered. The solid was recrystallized from 30 ml of ethanol to give 44 mg of 5-bromo-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxycytidine in the form of a white solid of melting point 164°-167° C.