Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1.S(C)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].[NH4+].[Cl-]>CCOCC.[Cu]I.C1COCC1>[C:1]([C:3]1[CH:8]([C:12]2[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=2)[CH:7]=[CH:6][N:5]([C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH:4]=1)#[N:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1cccnc1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CSC
Product: Cc1ccc(C2C=CN(C(=O)Oc3ccccc3)C=C2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 3-cyanopyridine (10 g, 96 mmol), CuI (914 mg, 4.8 mmol), p-tolylmagnesium bromide (100 mL of a 1M solution in Et2O, 100 mmol), THF (200 mL), and Me2S (100 mL) under N2 at 23° C. was added phenyl chloroformate (12.6 mL, 100 mmol) over a 30 min. period. After 2 h, aqueous NH4Cl (20%, 100 mL) and Et2O (100 mL) were added and the mixture was warmed to room temperature. The organic layer was washed sequentially with 1N HCl (50 mL), H2O (50 mL), a 1:1 mixture of 20% aqueous NH4Cl and conc. NH4OH (3×50 mL), and brine (50 mL) then dried (MgSO4). Concentration gave the crude 3-cyano-1-phenoxycarbonyl-4-(p-tolyl)-1,4-dihydropyridine as a tan solid. A portion (8 g) of this crude dihydropyridine was treated with S8 (810 mg) in decalin (25 mL) at reflux for 6 h. This reaction was cooled to rt, EtOAc (100 mL) and H2O (50 mL) were added and the resulting mixture was filtered through celite®. The organic layer was washed sequentially with 1 N NaOH (30 mL), water and brine then dried over (K2CO3). Purification (flash chromatography, 20% EtOAc/hexanes) gave the titled compound as a tan solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([S:15](Cl)(=[O:17])=[O:16])=[CH:7]1>O1CCCC1>[C:1]([NH:5][S:15]([C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:6][CH:7]=1)(=[O:16])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1csc2ccccc12
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1csc2ccccc12
Temperature: 0 °C

Procedure:
To 25 g of tert-butyl amine in 100 ml of dry tetrahydrofuran was added dropwise with cooling 34 g of benzothiophene-3-sulfonyl chloride. The reaction mixture was allowed to come to room temperature and then poured into 200 g of ice. The phases were separated and the organic portion was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue thus obtained melted at 146°-148° after recrystallization from alcohol. It showed an absorption peak by NMR at 1.34 δ (singlet), for tert-butyl and 7.4-8.4 δ (multiplet) for benzothiophene consistent for the desired product.
Reaction SMILES: [Na].[Cl-:2].[NH2:3][C:4]([NH2:6])=[NH2+:5].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][C:18](OCC)=[O:19])[N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]2=[O:27]>C(O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][C:18]([NH:5][C:4]([NH2:6])=[NH:3])=[O:19])[N:12]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:11]2=[O:27].[Cl:2][C:16]1[CH:15]=[C:14]2[C:10]([C:11](=[O:27])[N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH:13]2[CH2:17][C:18]([NH:5][C:4]([NH2:6])=[NH:3])=[O:19])=[CH:9][CH:8]=1
Reactant: [Cl-]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccc(Cl)cc2C(=O)N1CC(C)C
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(Cl)ccc2C1CC(=O)NC(=N)N
Product: CC(C)CN1C(=O)c2ccc(Cl)cc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 18 h

Procedure:
N-[(5-Chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine and N-[(6chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are prepared as described in Example 9, starting with 20 cm3 of absolute ethanol, 0.35 g of sodium, 1.46 g of guanidinium chloride and 3.1 g of ethyl (5-chloro-2-isobutyl-3-oxo-2,3dihydro-1-H-isoindol-1-yl)acetate and ethyl (6-chloro-2-isobutyl-3-oxo-2,3-dihydro-1isoindol-1-yl)acetate in 15 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 15 cm3 of water and 45 cm3 of diethyl ether and then stirred at a temperature in the region of 0° C. for 4 hours. The precipitate obtained is filtered off, washed with twice 20 cm3 of ice-cold water and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 1 g of N-[(5-chloro-2isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]quanidine and N-[(6-chloro-2-isobutyl-3-oxo-2,3-dibydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a white powder. (Analysis: C15 H19 Cl N4 O2, % calculated C: 55.81, H: 5.93, Cl: 10.98, N: 17.36, O: 9.91% found C: 55.67, H: 6.18, Cl: 11.32, N: 17.05). Mass spectrum: DCI: m/e 323 (M+H)+.
Reaction SMILES: O.[OH-].[Na+].[O:4]=[C:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[N:13](S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]=1>C1COCC1.C(OCC)(=O)C>[O:4]=[C:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[CH:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CC3CCCC3=O)c3cc(C#N)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]cc(C=C3CCCC3=O)c2c1
Reaction time: 16 h
Yield: 66.1 %

Procedure:
Water (50 mL) and sodium hydroxide (50 mL, 10 N) were added to a solution of 3-(2-oxo-cyclopentylmethyl)-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (1.0 g, 2.56 mMol) in THF (200 mL), and the mixture was stirred for 16 h. The reaction was diluted with ethyl acetate (300 mL), quenched with 1N HCl (100 mL), and then poured into a mixture of saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL). The aqueous layer was extracted with ethyl acetate (4×250 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a step gradient of 20% ethyl acetate/hexanes-85% ethyl acetate/hexanes to give 3-(2-oxo-cyclopentylidenemethyl)-1H-indole-5-carbonitrile as a yellow solid (400 mg, 67%) after drying under vacuum. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (1H, s), 7.96 (1H, m), 7.63 (2H, m), 7.55 (1H, m), 2.85 (2H, m), 2.35 (2H, m), 2.00 (2H, m); LCMS (4.6×50 mm XTERRA C-18 S5 column, 5 mL/min, 0–100% MeOH/H2O/0.1% TFA, 2 min gradient): Tr=1.50 min, m/e 237 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH2:20]([O:24][C:25]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=O)[CH:21]([CH3:23])[CH3:22].[O-]CC.[Na+]>>[CH2:20]([O:24][C:25]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=1/[CH:27]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Reactant: COc1cccc(C=O)c1OCC(C)C
Agent: CC[O-]
Agent: [Na+]
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C#N)cc2)c1OCC(C)C
Yield: 44.5 %

Procedure:
The title compound was prepared by the reaction of Intermediate 4 (350 mg, 1.325 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (409 mg, 1.961 mmol) in presence of sodium ethoxide (178 mg, 2.264 mmol) according to the procedure described in Example 9 to give 270 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.85 (d, J=3.9 Hz, 4H), 2.03 (d, J=7.8 Hz, 3H), 3.77 (s, 3H), 3.83 (d, J=6.3 Hz, 2H), 6.84 (d, J=15.6 Hz, 1H), 6.95-7.00 (m, 3H), 7.50-7.58 (m, 3H), 7.92-8.04 (m, 3H), 8.14 (d, J=15.3 Hz, 1H); ESI-MS (m/z) 470.45 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([I:14])=[CH:12][N:13]=[C:7]2[CH:6]=1)=O.O.[NH2:16][NH2:17]>CO>[I:14][C:11]1[N:8]2[CH:9]=[CH:10][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]2=[N:13][CH:12]=1
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccn2c(I)cnc2c1
Yield: 90.3 %

Procedure:
To a suspension of Methyl-3-Iodo-imidazo[1,2-a]pyridine-7-carboxylate (0.4 g, 1.32 mmol) in MeOH (6 ml) was added hydrazine hydrate (0.25 ml, 5.28 mmol). The mixture was refluxed for 4 h then further hydrazine hydrate (0.25 ml, 5.28 mmol) was added, the mixture heated o/n, allowed to cool, solid was filtered off and washed with MeOH and dried to afford 0.36 g of product. MS: [M+H]+ 303.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1.[H][H].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].[Cl-].[Na+]>CN(C)C=O>[CH3:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[S:3][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cn1ccnc1S
Reactant: [H][H]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a slurry of 0.8 g (20 mmoles) of sodium hydride (60% dispersion in mineral oil) in 10 ml of N,N-dimethylformamide, stirred in an ice bath, and under a nitrogen atmosphere, was added dropwise a solution of 2.28 g (20 mmoles) of 2-mercapto-1-methylimidazole in 5 ml of N,N-dimethylformamide. After the evolution of hydrogen gas had ceased, the ice bath was removed and the reaction mixture stirred at room temperature for 0.5 hours. To the reaction was added, dropwise, a solution of 2.82 g (20 mmoles) of 1-fluoro-2-nitrobenzene in 10 ml of N,N-dimethylformamide. After stirring at room temperature for 16 hours, the mixture was poured into a saturated sodium chloride solution (100 ml) and extracted with dichloromethane. The organics were dried and the solvents were removed in vacuo. The resulting yellow solid was triturated with ether and collected by filtration to give 3.5 g (74%) of product as yellow prisms, mp 117°-119° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:37]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:36]=2[Cl:35])=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (53 mg, yield 62%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=1.[O:20]1[C@H:22]2[CH2:23][C@@:24]3([CH3:46])[CH:28]([CH:29]4[CH2:30][C@H:31]([F:40])[C:32]5[C@@:37]([CH3:38])([C@:21]124)[CH:36]=[CH:35][C:34](=[O:39])[CH:33]=5)[CH2:27][C@@H:26]([CH3:41])[C@:25]3(O)[C:42]([OH:44])=[O:43].Cl>CN(C=O)C>[O:20]1[C@H:22]2[CH2:23][C@@:24]3([CH3:46])[CH:28]([CH:29]4[CH2:30][C@H:31]([F:40])[C:32]5[C@@:37]([CH3:38])([C@:21]124)[CH:36]=[CH:35][C:34](=[O:39])[CH:33]=5)[CH2:27][C@@H:26]([CH3:41])[C@:25]3([O:18][C:17]([C:14]1[CH:13]=[N:12][C:11]([CH3:10])=[CH:16][N:15]=1)=[O:19])[C:42]([OH:44])=[O:43]
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N,N-Diisopropylethylamine (2.3 mL) is added to a cooled (0° C.) solution of 5-methylpyrazine-2-carboxylic acid (736 mg) in DMF (7 mL), followed by O-(7-azabenzotriazo-1-lyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2.26 g). The suspension is stirred at room temperature for 10 minutes, then a solution of (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid (2 g) in DMF (7 ml) is added. After 2 hours, the reaction mixture is added dropwise to a solution of 1M HCl. The product is collected by filtration, washed repeatedly with water and dried to yield 5-methyl-pyrazine-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-carboxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected H-NMR signals (CDCl3) δ 0.95 (3H, d), 1.10 (3H, s) 1.40 (3H, s), 2.65 (3H, s).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C1C=CC(C(F)(F)F)=CC=1)[N:6]=[C:5]2C1CCN(C)CC1.[Cl:28][CH:29](OC(Cl)=O)[CH3:30]>ClCCCl>[ClH:28].[N:6]1([C:3]2[CH:2]=[CH:10][CH:9]=[C:8]3[C:4]=2[CH:5]=[N:6][NH:7]3)[CH2:30][CH2:29][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccc(F)cc23)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: c1cc(N2CCCCC2)c2cn[nH]c2c1
Reaction time: 0.25 h

Procedure:
To a solution of 5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(1-methyl-4-piperidinyl)-1H-indazole (13.2 g, 0.035 moles) in 1,2-dichloroethane (35 ml) at 0° C. was added 1-chloroethylchloroformate (3.9 ml, 0.035 moles). The reaction was stirred for 15 minutes at 0° and then for 4 hours at ambient temperature. The solvent was removed and then methanol (90 ml) was added. The mixture was refluxed for 1 hour and then the methanol was removed which left 17.8 g of a solid. The product was recrystallized twice from isopropyl alcohol to yield 6.3 g (45%) of 5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl-1H-indazole hydrochloride, mp 276°-278°.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH2:7])=[N:5][N:6]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH3:18][N:19](C)C=O>>[CH3:18][NH:19][C:2]1[S:3][C:4]2=[N:7][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][N:5]2[N:6]=1
Reactant: Nc1nnc(Br)s1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccccc1
Product: CNc1nn2cc(-c3ccccc3)nc2s1
Temperature: 25 °C

Procedure:
18.0 g of 2-bromo-5-amino-1,3,4-thiadiazole (0.1 mol) and 20.0 g of ω-bromoacetophenone (0.1 mol) in 250 ml of dimethylformamide are heated to 100° C. for 4.5 hours. After cooling down to room temperature, 100 ml of ice-water are added and the precipitate is filtered off with suction. After drying, it is taken up in chloroform and, after the addition of ether, recrystallized. The crude 2-bromo-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole is then heated to reflux for 2 hours in 250 ml of ethanol with 25 ml of 30% strength methylamine solution. After cooling down, precipitation is by addition of 200 ml of water, the precipitate is filtered off with suction and recrystallized from chloroform/ether.
Reaction SMILES: [CH2:1]([NH:7][C:8]([CH2:13][OH:14])([CH2:11][OH:12])CO)[CH2:2]S(O)(=O)=O.N1CCC[C@H]1C(O)=[O:18].O=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:14][C@@H:13]1[CH2:2][CH2:1][NH:7][C@@H:8]1[C:11]([OH:12])=[O:18]
Reactant: O=S(=O)(O)CCNC(CO)(CO)CO
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(O)CCC(=O)C(=O)O
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@H]1NCC[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The cells, the treated cells or the enzyme preparation are added to 240 mM TES [N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid] buffer containing 12 mM L-proline, 24 mM 2-ketoglutaric acid, 4 mM ferrous sulfate and 8 mM L-ascorbic acid to make 250 μl in total. The mixture is kept at 35° C. for 10 minutes. The reaction mixture is heated at 100° C. for 2 minutes to stop the reaction, and the amount of cis-3-hydroxy-L-proline produced in the reaction mixture is determined by HPLC.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]4[CH2:29][CH2:28][CH2:27][N:26]4[C:30](=[O:40])[C@@H:31]([NH:35][C:36]([O:38][CH3:39])=[O:37])[CH:32]([CH3:34])[CH3:33])=[O:24])=[CH:18][CH:17]=3)[CH2:14][CH2:13][C@H:12]2[C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48]([C@@H:50]3[CH2:54][CH2:53][CH2:52][N:51]3[C:55](OC(C)(C)C)=[O:56])=[O:49])=[CH:43][CH:42]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:62](O)(C(F)(F)F)=[O:63].[C:69]([O:73][C:74]([N:76]1[CH2:80][CH2:79][CH2:78][C@H]1C(O)=O)=[O:75])(C)(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:15]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]([C@@H:25]4[CH2:29][CH2:28][CH2:27][N:26]4[C:30](=[O:40])[C@@H:31]([NH:35][C:36]([O:38][CH3:39])=[O:37])[CH:32]([CH3:34])[CH3:33])=[O:24])=[CH:20][CH:21]=3)[CH2:14][CH2:13][C@H:12]2[C:41]2[CH:42]=[CH:43][C:44]([NH:47][C:48]([C@@H:50]3[CH2:54][CH2:53][CH2:52][N:51]3[C:55](=[O:56])[C@@H:80]([NH:76][C:74](=[O:75])[O:73][CH3:69])[C@H:79]([O:63][CH3:62])[CH3:78])=[O:49])=[CH:45][CH:46]=2)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc([C@@H]2CC[C@@H](c3ccc(NC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)cc3)N2c2ccc(C(C)(C)C)cc2)cc1)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc([C@@H]2CC[C@@H](c3ccc(NC(=O)[C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)cc3)N2c2ccc(C(C)(C)C)cc2)cc1)C(C)C
Yield: 52 %

Procedure:
A solution of the product from Example 189A (30 mg, 0.036 mmol) in a 1:1 mixture of CH2Cl2:TFA (0.4 mL) was stirred at rt for 45 min. The mixture was concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO3 and EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a solid. The solid was subjected to the procedure described in Example 189A (27 mg), substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid, to give the title compound (17 mg, 52%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.85-0.97 (m, 6H), 1.08-1.19 (m, 12H), 1.60-1.66 (m, 2H), 1.80-2.05 (m, 8H), 2.08-2.20 (m, 2H), 3.25 (s, 3H), 3.42-3.50 (m, 2H), 3.52 (s, 3H), 3.53 (s, 3H), 3.58-3.72 (m, 2H), 3.76-3.87 (m, 2H), 3.98-4.06 (m, 1H), 4.26 (t, J=7.81 Hz, 1H), 4.38-4.46 (m, 2H), 5.15 (d, J=6.40 Hz, 2H), 6.17 (d, J=8.78 Hz, 2H), 6.94 (d, J=8.89 Hz, 2H), 7.13 (d, J=8.24 Hz, 4H), 7.32 (t, J=8.84 Hz, 2H), 7.49 (dd, J=8.57, 2.06 Hz, 4H), 9.96 (d, J=15.51 Hz, 2H). MS (ESI) m/z 910.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](Br)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd][P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1
Reactant: OB(O)Oc1ccccc1
Reactant: COCOc1cc(CC(=O)OC)c(Br)c(OCOC)c1
Agent: Cc1ccccc1[P]([Pd][P](c1ccccc1C)(c1ccccc1C)c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: COCOc1cc(CC(=O)OC)c(-c2ccccc2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-bromophenylacetate (15.0 g, 43.0 mmol) obtained in Example 3, Step 1 was dissolved in a mixed solvent of 1,2-dimethoxymethane (0.15 L) and water (6.0 mL). To the solution were added phenylboric acid (7.3 g, 60 mmol), bis(tri-o-tolylphosphine)palladium (II) dichloride (0.68 g, 0.86 mmol) and cesium carbonate (42 g, 0.13 mol) in an atmosphere of argon, followed by stirring for 16.5 hours under heating and reflux. After cooling to room temperature, the reaction mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. To the resulting residue was added water (0.50 L), followed by extraction with ethyl acetate (0.40 L×2). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/3) to obtain a quantitative yield of methyl 3,5-bis(methoxymethoxy)-2-phenylphenylacetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]=O.[OH:9][C:10]1[C:17]([OH:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>C(O)C>[OH:9][C:10]1[C:17]([OH:18])=[C:16]([OH:19])[C:15]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1ccc(O)c(O)c1O
Reactant: C1COCCN1
Reactant: C=O
Solvent: CCO
Product: O=Cc1cc(CN2CCOCC2)c(O)c(O)c1O

Procedure:
20.9 g (0.24 mol) of morpholine were added to 19.2 g (0.24 mol) of a 37% aqueous formaldehyde solution in 140 ml of ethanol. Then 25.0 g (0.16 mol) of 2,3,4-trihydroxybenzaldehyde were added thereto. The reaction mixture was refluxed for one hour, developing a dark brown color. After cooling, a beige-brown solid precipitated out, which was filtered out and dried.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][CH2:9][C@@H:10]1[CH2:24][C@H:23]2[C@@H:13]([CH2:14][C:15]3[C:25]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]2=4)[NH:17][CH:16]=3)[N:12]([CH3:26])[CH2:11]1>CN(C)C=O>[CH3:26][N:12]1[C@H:13]2[C@@H:23]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:25]=3[C:15]([CH2:14]2)=[CH:16][NH:17]4)[CH2:24][C@@H:10]([CH2:9][NH:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:11]1
Reactant: CCOC(=O)CBr
Reactant: CN1C[C@H](CN)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: CN(C)C=O
Product: CCOC(=O)CNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Yield: 72 %

Procedure:
A solution of 1.3 ml of ethyl bromoacetate in 30 ml of dimethylformamide was added to a warmed solution of 6 g of 8β-aminomethyl-6-methyl-ergoline in 90 ml of dimethylformamide. At the end of the reaction, the solution was reduced in volume by evaporation in vacuo, poured into iced water and extracted with chloroform. The organic layer was removed in vacuo and the residue was purified by column chromatography on silica gel, using ethyl acetate:methanol (9:1 by volume) as eluent, to give 3.5 g of 6-methyl-8β-(N-ethoxycarbonylmethyl-aminomethyl)-ergoline (II: R1 =R2 =R3 =H, R4 =CH3, n=1, A=CHR6, R6 =H, B=CO2C2H5), m.p. 174°-176° C., after crystallization from diethyl ether. 3.5 of 6-methyl-8β-(N-ethoxycarbonylmethyl-aminomethyl)-ergoline were treated with 1.75 g of potassium cyanate, as described in Example 1, and the title compound, m.p. >300° C., was obtained in 72% yield.