Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:4](=[O:18])[NH:3]1.[NH2-].[Na+].N.[CH3:22]I>CN(C)P(=O)(N(C)C)N(C)C.O>[CH3:22][N:3]1[CH:2]([CH3:1])[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:5][C:4]1=[O:18]
Reactant: CI
Reactant: CC1NC(=O)OC12CCCCC2c1ccccc1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1N(C)C(=O)OC12CCCCC2c1ccccc1
Reaction time: 1 h

Procedure:
4-Methyl-6-phenyl-1-oxa-3-azaspiro [4.5] decan-2-one (Example XXIII) (23.6 g) in hexamethylphosphoric triamide (HMPT) is added dropwise to 5 g sodium amide in 35 ml HMPT. The mixture is stirred until NH3 evolution is essentially finished and 11 ml methyl iodide added at about 40° over a 1/2 hour period. The mixture is stirred 1 hour, added to 700 ml water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give 25 g crude product. A sample of the crude product, recrystallized from cyclohexane, gave the crystalline product, m. 85°-6°.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=[O:9])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C(#N)C.C(OCC)(=O)C>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:5]=1)[CH3:14]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(C=O)c(OCCN2CCCCC2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In 90 mL of acetonitrile was dissolved 2.8 g (14.6 mmol) of 4-diethylaminosalicylaldehyde. To this solution were added 14.3 g (43.8 mmol) of cesium carbonate and 2.8 g (15.3 mmol) of 1-(2-chloroethyl)piperidine hydrochloride at room temperature and the mixture was stirred at 80° C. for 4 hours. Water (150 mL) was added to the resulting reaction mixture and extraction with ethyl acetate (100 mL×3) was performed. The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to quantitatively give 4.5 g of the title compound.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18]([O:20]CC)=O)=[N:16][N:15]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1>ClCCl.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18]([NH:2][CH3:1])=[O:20])=[N:16][N:15]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)c1nn(-c2cccnc2)c(=O)c2c1c1ccc(F)cc1n2C
Reactant: CN
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1nn(-c2cccnc2)c(=O)c2c1c1ccc(F)cc1n2C

Procedure:
A stream of gaseous methylamine is introduced into a solution of 0.28 g (0.76 mmol) of ethyl 7-fluoro-5-methyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate (obtained in stage 4.1.) in 30 ml of dichloromethane and 70 ml of methanol. Stirring is maintained for 4 h. The reaction medium is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/methanol: 100/0 to 90/10). The solid obtained is recrystallized from a mixture of dichloromethane and ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.[NH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[OH:33]>>[OH:33][C@@H:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@H:27]1[NH:26][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: O=c1c2c(ncn2Cc2ccccc2)nc(Cl)n1Cc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=c1c2c(ncn2Cc2ccccc2)nc(N[C@@H]2CCCC[C@H]2O)n1Cc1ccccc1

Procedure:
Treat 2-chloro-1,7-bis(phenylmethyl)purin-6-one with trans-2-aminocyclohexanol as described in Preparative Example 5 to give the title compound, a tan foam. FAB MS: M+1=430.
Reaction SMILES: [CH3:1][CH:2]([CH:41]([OH:43])[CH3:42])/[CH:3]=[CH:4]/[CH2:5][CH:6]1[CH:11]([OH:12])[CH:10]([OH:13])[CH:9]([CH:14]([OH:40])/[C:15](/[CH3:39])=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]2[C:37](=[O:38])[NH:36][C:32]3=[CH:33]S[S:35][C:31]=23)=[O:28])=[O:18])[O:8][CH2:7]1.O[O:45][S:46]([O-:48])=O.[K+].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH3:1][C@@H:2]([C@@H:41]([OH:43])[CH3:42])/[CH:3]=[CH:4]/[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([C@H:14]([OH:40])/[C:15](/[CH3:39])=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]2[C:37](=[O:38])[NH:36][C:32]3=[CH:33][S:46]([S:35][C:31]=23)(=[O:48])=[O:45])=[O:28])=[O:18])[O:8][CH2:7]1
Reactant: C/C(=C\C(=O)OCCCCCCCC(=O)Nc1c2sscc-2[nH]c1=O)C(O)C1OCC(C/C=C/C(C)C(C)O)C(O)C1O
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C/C(=C\C(=O)OCCCCCCCC(=O)NC1=C2SS(=O)(=O)C=C2NC1=O)[C@@H](O)[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Yield: 75 %

Procedure:
100.9 mg of thiomarinol (prepared as described in Example 6) were dissolved in a mixture of 5 ml of acetone and 5 ml of water, and then the resulting solution was ice-cooled. 112.2 mg of OXONE (a trade name for a product of Aldrich Chemical Co., Inc.) were added to the resulting solution, and then the mixture was stirred, whilst ice-cooling, for 40 minutes. At the end of this time, 1.2 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to this mixture, and the mixture was again stirred, whilst ice-cooling, for 30 minutes. 5 ml of water were then added to the reaction mixture, which was then extracted with a 10:1 by volume mixture of methylene chloride and tetrahydrofuran. The extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was then isolated and purified by reverse phase, high performance liquid chromatography (using a Senshu Pak ODS-5251-N column, and 40% v/v aqueous acetonitrile as the eluent), to obtain 79.5 mg (yield 75%) of thiomarinol B having a light yellow color and having the physico-chemical properties listed above.
Reaction SMILES: C([N:8]([CH3:41])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[NH2:42][C:43]1[N:48]=[C:47](C)[C:46](Br)=[CH:45][CH:44]=1>>[ClH:27].[ClH:27].[CH2:36]([O:35][C:34]1[CH:33]=[CH:32][C:31]([C:46]2[CH:47]=[N:48][C:43]([NH2:42])=[CH:44][CH:45]=2)=[CH:30][C:29]=1[CH2:28][N:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][CH3:41])[CH2:14][CH2:13]1)[C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[Cl:27])=[O:17])[CH3:37]
Reactant: Cc1nc(N)ccc1Br
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2ccc(N)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
The title compound was prepared from boronic acid (12) (25 mg, 42 μmol) and 6-amino-3-bromo-2-methylpyridine (6.5 mg, 40 μmol) in accordance with Method L2.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH:14]1N=CN(C(N2C=NC=C2)=O)C=1.CO>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSc1ccc(CCC(=O)O)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.9 %

Procedure:
In a 100 mL round bottom flask, 3-(4-(methylthio)phenyl)propanoic acid (1.00 g, 5.10 mmol) was dissolved in DMF (17 mL) under N2(g). CDI (1.24 g, 7.65 mmol) was then added to the reaction mixture and the resulting mixture was allowed to stir at room temperature for ˜45 min. MeOH (6 μL) was then added in dropwise fashion to the reaction. The reaction was allowed to stir for an additional 1 h, after which time it was extracted with EtOAc (3×50 μL) and brine (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4(s), filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution mixture: 10% EtOAc in Hexanes to 100% EtOAc) to give the title compound (0.771 g, 72%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([Li])CCC.[CH2:11]([Li])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CCCCCC>[CH3:6][C:2](=[CH:3][CH2:4][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:1][OH:5]
Reactant: [Li]CCCCCCCC
Reactant: CCCCO
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: CCCCCCCCCC=C(C)CO
Temperature: 0 °C
Yield: 75 %

Procedure:
A hexane solution of n-butanol (77.1 mg; 1.0 mmol) was cooled to 0° C. under an argon atmosphere, and a hexane solution of n-butyllithium (1.0 ml) was added dropwise thereto and stirred. To the resulting solution, there was further dropwise added a hexane solution of n-octyllithium (1.2 mmol) and a hexane solution of 3-methyl-3,4-epoxybutene-1 (88.1 mg; 1.0 mmol), and after the addition was completed, the resulting mixture was cooled at 0° C. for 1 hour and at room temperature for 1.5 hours, followed by the usual work up. Removal of the solvent and distillation of the residue gave 150 mg of 2-methyl-2-dodecen-1-ol (yield, 75%; Z/E=93.0/7.0).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4](=O)[NH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[C:5]2[NH:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2cc[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc[nH]c12
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one, (1.8 g, 13.5 mmol, 1 equiv.) and 50 mL of POCl3 was warmed at reflux for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue was then diluted with 200 mL of water, made basic with solid potassium carbonate and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo to provide 1.18 g (57%) of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine as a yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]([C:4]1([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[OH-].[Na+].Cl>CO.C(Cl)Cl>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[NH:1][C:2](=[O:3])[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[N:9]=1
Reactant: NC(=O)C1(NC(=O)c2ccccc2Cl)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C1NC(c2ccccc2Cl)=NC12CCCC2
Temperature: 90 °C

Procedure:
Into a solution of N-[1-(aminocarbonyl)cyclopentyl]-2-chlorobenzamide from Step A (0.51 g, 1.912 mmol) in methanol (10 mL) was added NaOH (1.15 mL, 5 N). This solution was heated at 90° C. for 2.5 h. After allowing the reaction mixture to cool, the bulk of the solvent was removed in vacuo to give a residue, which was then neutralized by the addition of 1 N HCl and diluted with DCM. The layers were separated and the aqueous layer was extracted with an additional volume of DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound as a white solid. MS: m/z=249 (M+1).
Reaction SMILES: Cl.[CH:2]1([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(Cl)Cl.C(N(CC)CC)C>[C:19]([C:8]1([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)(=[O:22])[CH:20]=[CH2:21]
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)C1(C2CCCCC2)NCCc2ccccc21

Procedure:
1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (800 mg) was dissolved in methylene chloride (12 mL), to which triethylamine (1.1 mL) and acryloyl chloride (0.28 mL) were then added under ice-cooling, followed by stirring under ice-cooling for 30 minutes and then stirring at room temperature for 14 hours. Water was added to the reaction liquid which was then extracted with chloroform. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated to obtain 2 acryloyl-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (856 mg).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[N:19]1([CH2:18][CH2:17][CH2:16][CH2:15][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCn1ccnc1
Agent: Br
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Reaction time: 3 h

Procedure:
A mixture of 0.02 mole of potassium phthalimide, 0.01 mole of N-(4-bromobutyl)imidazole hydrobromide and 100 ml. of dimethyl formamide was gradually heated to 80° C. and held at this temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by HPLC using ethyl acetate and a silica gel column.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=2)=[CH:4][CH:3]=1.[NH2:16][CH:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]1>>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:16][CH:17]3[CH2:18][C:19]([CH3:26])([CH3:25])[NH:20][C:21]([CH3:24])([CH3:23])[CH2:22]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)c1nccc(-c2ccc(Br)s2)n1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1

Procedure:
4-(5-Bromo-thiophen-2-yl)-2-methanesulfinyl-pyrimidine (110 mg, 0.36 mmol) and 4-amino-2,2,6,6,-tetramethyl piperidine (0.6 ml) were heated to 130° C. for 45 minutes. Evaporation and chromatography on silicagel (TBDME/MeOH/ammonia:90/9/1) gave the title compound as slightly coloured crystals. Yield: 100 mg (70%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1.N1C=CC=CC=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32](Cl)=[O:33])[CH:28]=1>C(Cl)Cl.CCOC(C)=O>[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:15]2)=[C:2]([NH:1][C:32]([C:29]2[CH:28]=[C:27]([CH3:26])[O:31][N:30]=2)=[O:33])[CH:7]=1)=[O:9]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: COC(=O)C1CCN(c2ccc(C=O)cc2N)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(C=O)cc2NC(=O)c2cc(C)on2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a solution of methyl 1-(2-amino-4-formylphenyl)piperidine-4-carboxylate 59 (0.488 g, 1.9 mmol) in DCM (10 mL) at 0° C. was added pyridine (0.300 mL, 3.7 mmol) and 5-methylisoxazole-3-carbonyl chloride (0.185 g, 1.3 mmol). The reaction mixture was stirred at 0° C. for 30 min, additional acid chloride (88 mg) was added and stirring was continued at 0° C. After 30 min, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 50% EtOAc in hexanes) gave methyl 1-(4-formyl-2-(5-methylisoxazole-3-carboxamido)phenyl)piperidine-4-carboxylate 60 (0.268 g, 39% yield) as a pale yellow solid. Mass spectrum: calculated for C19H21N3O5 371.2. found 372.2 (M++1).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2>N1C=CC=CC=1>[C:1]1([C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Brc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: c1ccc(-c2cccc3cnccc23)cc1
Temperature: 90 °C
Yield: 53.6 %

Procedure:
Cupric oxide (0.2 g) was added in one portion to a mixture of phenol (2 g, 21 mmol), potassium carbonate (2.7 g, 20 mmol), and 5-bromoisoquinoline (2.1 g, 10 mmol) in pyridine (20 ml) heated at 90° C. under nitrogen. The mixture was then heated at 140° C. for 18 h. After this time the pyridine was removed in vacuo, the residue suspended in ether and the mixture filtered through a pad of silica gel. The solvent was evaporated and the residue purified by column chromatography on silica with ethyl acetate/hexane (1:3-1:1) as eluant to give the title compound as a colourless solid (1.1 g, 49%); δH (CDCl3) 7.1-7.5 (7H, m, ArH), 7.75 (1H, d, J 8 Hz, ArH), 8.02 (1H, d, J 8 Hz, ArH), 8.57 (1H, d, J 8 Hz, ArH), and 9.3 (1H, s, 1-H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:21]([O-])=[O:22].[Na+].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)=O.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1OC[C@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(L-arabinopyranosyl)urea are dissolved in 15 ml of formic acid, and 1.5 g of sodium nitrite are added gradually thereto at 0° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, 15 ml of ethanol are added to the reaction mixture. Said mixture is neutralized with potassium carbonate under ice-cooling. Then, 150 ml of ethyl acetate are added to the mixture, and insoluble materials are removed by filtration. The filtrate is washed with an aqueous sodium bicarbonate solution, dried and evaporated to remove solvent. The residue thus obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol (5:2:1)). 1.5 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[F-].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C@@H:21]1[C@@H:26]([NH:27]C(=O)OC(C)(C)C)[CH2:25][C@@H:24]([N:35]2[CH2:42][C:41]3[C:37](=[N:38][N:39]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:40]=3)[CH2:36]2)[CH2:23][O:22]1.C(N(CC)CC)C>ClCCl.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C@@H:21]1[C@@H:26]([NH2:27])[CH2:25][C@@H:24]([N:35]2[CH2:42][C:41]3[C:37](=[N:38][N:39]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:40]=3)[CH2:36]2)[CH2:23][O:22]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Agent: O=S(=O)(O)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)n1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)ccc3F)[C@@H](N)C1)C2
Temperature: 32.5 °C
Reaction time: 8 h

Procedure:
Benzenesulfonic acid (32.95 kg, 271 mol) was dissolved in dichloromethane (1020 kg) under nitrogen. Then, 880 g of water was added such that the solution KF was 0.2%. Next, tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate (38.4 kg, 100 mol) was added in three equal portions over 30 min. The reaction was then aged overnight at room temperature. Next, water (733 kg) was added over 1 h and the reaction stirred rapidly for 1 h. The layers were then separated, discarding the resulting organics layer. To the aqueous layer was charged dichloromethane (510 kg) followed by triethylamine (22.4 kg, 592 mol). After agitation, the layers were separated and the aqueous extracted with dichloromethane (510 g). The combined organics were washed with 7% aqueous NaHCO3 (2×410 kg) and 5% brine (386 kg). The organics were then dried with Na2SO4, filtered, and treated with activated carbon (6.2 kg of C-941). The carbon was filtered off and the filtrate was concentrated under vacuum to 154-193 L. This solution was then warmed to 30-35° C. Next, iso-propylacetate (338 kg) was added and the solution stirred at room temperature for 1.5 h. Then, n-heptane (159 kg) was charged to the vessel drop-wise and stirred for 3 h. The slurry was then filtered and the cake washed with n-heptane. This wet cake was then recrystallized again by dissolving it into dichloromethane and adding iso-propylacetate and n-heptane as before, filtering, and washing with n-heptane. The solids were dried under vacuum at to give crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine was washed with cold 2:1EtOAc/hexanes to give the title compound as a solid. 1H NMR (500 MHz, CD3OD): 1.71 (q, 1H, J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48 (t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H, J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88 (s, 1H). LC-MS: 399.04 [M+1].
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[NH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])=[CH:3][CH:2]=1.[OH:15]P(O)(O)=O>>[C:12]([NH:14][C@H:8]([C:9]([OH:15])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:13])[NH2:11]
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Reactant: O=P(O)(O)O
Product: NC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
The assay of the D-hydantoinase activity was conducted by incubating a reaction mixture containing 120 mg/dl D-5-benzylhydantoin (BH), 50 mM KPB (pH 8.0) and an enzyme solution at 37° C. for 30 minutes, adding 9 volumes of 1.1 mMCuSO4, 11.1 mM H3PO4, centrifuging at 20,000G for 10 minutes to remove the pellet, and then quantifying the resultant N-carbamylphenylalanine (N—Car—Phe) by HPLC. One unit of the enzyme activity was defined as an enzymatic activity capable of producing 1 μmol of N-carbamylphenylalanine per 1 minute under the condition described above.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10])#[N:2].O.[C:22]1(O)C=C(C)C=[C:24]([OH:25])[CH:23]=1.C(C1C=CC=CC=1S([Cl:42])(=O)=O)#N>C([O-])(O)=O.[Na+].C(OCC)C.O>[ClH:42].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:22][CH2:23][CH2:24][OH:25])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1cc(O)cc(O)c1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C#N)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
3-(2-Cyanophenylsulfonyloxy)-5-methylphenol: Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-cyanobenzenesulfonyl chloride (2.02 g, 10.0 mmol) were mixed in saturated NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a white solid (1.65 g, 57%). 1H-NMR (300 MHz, CDCl3) δ 8.07 (m, 1H), 7.94 (m, 1H), 7.75-7.80 (m, 2H), 6.57 (s, 1H), 6.53 (s, 1H), 6.49 (s, 1H), 5.69 (br s, 1H), 2.22 (s, 3H).