Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([NH:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:20])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>ClCCl>[CH2:31]([O:30][C:28]([NH:20][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC(CNC(=O)c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(CNC(=O)c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
0.12 g of triethylamine was added to 10 ml of a solution of 0.25 g of N-benzoyl-2-phenyl-1,2-ethylenediamine hydrochloride and 0.17 g of benzyl chloroformate in dichloromethane under ice cooling, and the mixture was stirred at 5° C. for 30 minutes and at room temperature for 3 hours. The reaction mixture was rinsed with water, the organic layer was dried over magnesium sulfate anhydrous, and the residual oily material obtained under a reduced pressure was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to obtain 0.28 g of the title compound as colorless crystals.
Reaction SMILES: [Na+].[Cl-].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH:15]([CH:17]([CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[OH-].[Na+]>S([O-])([O-])(=O)=O.[Zn+2].C(OCC)(=O)C>[OH:16][CH2:15][C@@H:17]([CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCCCC(C=O)C(=O)OCC
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Product: CCCC[C@H](CO)C(=O)OCC
Temperature: 30 °C
Reaction time: 40 h
Yield: 90 %

Procedure:
Recombinant Escherichia coli HB101 (PNTRS) (Accession Number: FERM BP-08545) was inoculated in 50 ml of 2× YT medium (containing 1.6% of tripeptone, 1.0% of yeast extract, 0.5% of NaCl, and 50 mg of zinc sulfate.7H2O, pH=7.0) sterilized in a 500-ml Sakaguchi Flask and incubated while shaking at 30° C. for 40 hours. To 25 ml of the resultant culture solution, 1,000 units of glucose dehydrogenase (manufactured by Amano Enzyme Inc.), 2.5 g of ethyl 2-formylhexanoate, 3 mg of NAD, 4 g of glucose, and 50 mg of zinc sulfate.7H2O were added, the culture solution was stirred at 30° C. for 24 hours while adding 2.5 M aqueous solution of sodium hydroxide dropwise to the culture solution to adjust to pH 6.5. After completion of the reaction, 100 ml of ethyl acetate was added to the reaction solution for extraction and the organic layer was distilled off under reduced pressure. Thereafter, the product was purified by silica gel chromatography to obtain an oily ethyl (R)-2-hydroxymethylhexanoate. The yield was 90% and the optical purity was 93.6% e.e. Note that analysis for optical purity was performed as follows. The product was derivatized with a HPLC labeling agent (3,5-dinitrobenzoyl chloride), and analyzed by HPLC using a Chiralcel OD-H column, 0.46×25 cm I.D. (manufactured by Daicel Chemical Industries, Ltd.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10](O)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.NC1C=CC=[C:20]2C=1C=[CH:23][C:22]([OH:26])=[CH:21]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:9]=2[CH:20]=[CH:21][C:22]([OH:26])=[CH:23]3)[CH2:4][CH2:3]1
Reactant: Nc1cccc2cc(O)ccc12
Reactant: CN1CCN(c2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc3cc(O)ccc23)CC1
Yield: 37 %

Procedure:
Compound 53A is prepared according to the same procedure as that for 13A, using the following reactants: 8-aminonaphthalen-3-ol (10 g, 62.8 mmol), 2-chloro-N-(2-chlorethyl)-N-methylethananine hydrochloride (11.8 g, 62.8 mmol), sodium carbonate (3.32 g, 31.4 mmol), 1-butanol (200 ml).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:14][C:15]([C@@H:17]1[CH2:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:20][C:19](=O)[NH:18]1)=O)C1C=CC=CC=1>O1CCCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH2:22][C@@H:17]([CH2:15][OH:14])[NH:18][CH2:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(C2=CC(=O)N[C@H](C(=O)OCc3ccccc3)C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C2=CCN[C@H](CO)C2)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a stirred suspension of 10.9 g of lithium aluminium hydride in 1 l of tetrahydrofuran is added a solution of 43 g of (S)-4-(4-methoxy-phenyl)-6-oxo-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid benzyl ester in 1 l of tetrahydrofuran at 70° C. The reaction mixture is stirred for another 3-4 hours at this temperature, cooled to 0° C. and quenched by the slow addition of 12.4 ml of water, 12.4 ml of 2N sodium hydroxide and 37 ml of water. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a white solid. Rf=0.17 (dichloromethane-methanol-25% ammonia conc. 90:10:1); Rt=2.55.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH2:12]([O:15][C:16]1[CH:29]=[CH:28][C:27]2[C:18](=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=1)[C:13]#[CH:14]>O>[CH:12]([O:15][C:16]1[CH:29]=[CH:28][C:27]2[C:18](=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=1)=[C:13]=[CH2:14]
Reactant: C#CCOc1ccc2cc3ccccc3cc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C=COc1ccc2cc3ccccc3cc2c1
Yield: 56.5 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 1.203 parts of t-BuOK and 6.816 parts of THF and to this, a mixture of 10.000 parts of 2-propargyloxyanthracene and 23.333 parts of THF was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. THF layer and water layer were removed off by using an evaporator, and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 2-allenyloxy anthracene as colorless crystals (M.P. 90.3°-95.6° C).
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH3:45])[CH2:3][O:4][C:5](=[O:44])[N:6]=[C:7]([NH2:43])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:29]2[N:33]=[C:32]([O:34][CH2:35]Cl)[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])=[CH:10][CH:9]=1.C(=O)([O-])O.[K+].[I-].[Na+].[CH2:54]([O:56][C:57](=[O:64])[C:58]([CH3:63])([CH3:62])[C:59]([OH:61])=[O:60])[CH3:55]>CN(C=O)C>[CH2:54]([O:56][C:57](=[O:64])[C:58]([CH3:63])([CH3:62])[C:59]([O:61][CH2:35][O:34][C:32]1[N:31]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:30]=[C:29]([C@H:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH2:43])=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:46])([CH3:45])[CH3:1])=[O:44])=[CH:9][CH:10]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])[N:33]=1)=[O:60])[CH3:55]
Reactant: CCOC(=O)C(C)(C)C(=O)O
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)C(=O)OCOc1nc([C@H](Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2cc(OC)cc(OCCO)c2F)nn1-c1ncccn1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of [1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester (Example 2b, 100 mg), potassium hydrogen carbonate (107 mg), and DMF (8 mL), sodium iodide (113 mg) and 2,2-dimethylmalonic acid monoethyl ester [CAS No. 5471-77-2] (121 mg) were added, and the resulting mixture was stirred at 45° C. overnight. The reaction mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain a racemate of the captioned compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+:30]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.P([O-])([O-])([O-])=O.N[C@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[OH-].[Na+].COC1C=C2C(CCC(N)C2)=CC=1>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@H:9]([NH2:30])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: COc1ccc2c(c1)CC(N)CC2
Agent: C[C@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: O
Product: COc1ccc2c(c1)C[C@@H](N)CC2

Procedure:
Into a flask containing 300 mg of a substrate 7-methoxy-2-tetralone, 460 mg of D-glucose, 3 mg of NAD+, 3 ml of 1 M phosphate buffer solution (with a pH of 7), 910 mg of L-alanine, and 4.0 mg of pyridoxal phosphate, 6 ml of the bacterial suspension were poured, and then deionized water was added so that total volume was 30 ml. The resultant product was stirred at 30° C. for 25 hours while being adjusted to a pH of 6.8 by drippage of 5 N aqueous solution of sodium hydroxide. After the reaction, 7-methoxy-2-aminotetraline produced in the reaction liquid was analyzed under the following HPLC conditions, whereby the rate of conversion and optical purity were measured. In the result, it was found that 7-methoxy-2-aminotetraline was produced, but in such a small amount that the rate of conversion into 7-methoxy-2-aminotetraline was 1.5%. The absolute configuration of 7-methoxy-2-aminotetraline was (S), and the optical purity was 74.1% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH2:26]([N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH3:27]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCNc1ccccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccn1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (150 mg, 0.36 mmol), ethyl-pyridin-2-yl-amine (131 mg, 1.08 mmol), BOP (207 mg, 0.47 mmol), DIEA (400 μL, 2.16 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid ethyl-pyridin-2-yl-amide: MS m/z: (M+H) 519.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH2:13]([NH2:15])[CH3:14]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:15][CH2:13][CH3:14])=[O:8]
Reactant: CCN
Reactant: O=C(Cl)/C=C/c1cccc(Br)c1
Solvent: CCOCC
Product: CCNC(=O)/C=C/c1cccc(Br)c1

Procedure:
A solution of trans 3-bromocinnamoyl chloride (12.3 g) in anhydrous toulene (150 ml) was added slowly with stirring to a solution of ethylamine (10 g) in dry ether (100 ml) at room temperature. The reaction mixture was heated at reflux for 1 hour, and the solvent and excess amine were then removed under reduced pressure. The residue was triturated with water, filtered, and recrystallized from ethanol-water to give trans 3-bromo-N-ethylcinnamamide, m.p. 89°-90° C., as a white crystalline material. NMR and IR spectra as well as elemental analysis were consistent with the assigned structure.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[N+:19]([C:22]1[C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[O:30][C:31](=O)[C:26]=2[CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20].[Li+].CC([N-]C(C)C)C.CCOC(C)=O.[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O>[N+:19]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:27]=1[NH:28][C:29]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=1)=[C:14]([C:13]([O:16][CH2:17][CH3:18])=[O:15])[C:31]2=[O:30])([O-:21])=[O:20]
Reactant: CCOC(C)=O
Reactant: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2c([N+](=O)[O-])cccc12
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2cccc(C(F)(F)F)c2)[nH]c2c([N+](=O)[O-])cccc2c1=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
A solution of diisopropylamine (7.00 mL, 50.0 mmol) in THF (100 mL) was cooled to −78° C., and n-BuLi (20.0 mL, 2.5 M in hexanes, 50.0 mmol) was added. After stirring for 20 min at −78° C., ethyl acetate (5.72 mL, 58.6 mmol) was added. The solution was stirred at −78° C. for 10 min, warmed to 0° C. and stirred for 10 min, then cooled back to −78° C. A solution of 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazin-4-one 3 (9.85 g, 29.3 mmol) in THF (100 mL) was added over 5 min to the LDA/EtOAc mixture. The reaction was stirred at −78° C. for 1 h, then warmed to room temperature over 2 h. 1N NaOH (50 mL) was then added, and the reaction stirred vigorously overnight. Brine (50 mL) was added, and the organic layer separated. The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layers dried with MgSO4 and concentrated under reduced pressure. The remaining material was purified by MPLC (using a gradient of 20% to 50% EtOAc in pentane) to give 36 (5.00 g, 42% yield).
Reaction SMILES: C(OC([N:8]1[N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.O=S(Cl)Cl>CO>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CN1C(=O)OC(C)(C)C
Solvent: O=S(Cl)Cl
Solvent: CO
Product: c1ccc2c(c1)CNNC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1,4-dihydrophthalazine-2,3-dicarboxylic acid di-tert-butyl ester, 4, (1.0 g, 3 mmol) is dissolved in MeOH (20 mL) and SOCl2 (0.5 mL) added dropwise. After stirring at room temp for 72 hours, the solvent is removed in vacuo to afford 0.6 g of the desired product as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]([CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[C:6]1[N:7]=[N:8][NH:9][N:10]=1.[C:35](=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.S(OC)(OC)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([C:31]([F:34])([F:32])[F:33])=[CH:26][C:3]=1[CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([C:22]([F:23])([F:24])[F:25])[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1)[C:6]1[N:7]=[N:8][N:9]([CH3:35])[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)cc1C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cc1cc(Br)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 97.7 %

Procedure:
To a solution of N-(2-bromo-4-methyl-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine (76 mg, 0.135 mmol) in anhydrous THF (5 mL) was added sodium carbonate (28 mg, 0.270 mmol) and N,N-dimethylformamide (1 mL) followed by dimethyl sulfate (34 mg. 0.270 mmol). The solution was heated to 70° C. for 18 hours then the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL) and the combined organics were washed with water (3×20 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (76 mg, 97.5%). 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H) 7.62 (s, 2H) 7.44(s, 1H) 7.40(s, 1H) 4.79(s, 2H) 4.76(s, 2H) 4.20(s, 3H) 2.39(s, 3H). LC-MS calc. 576 found 577 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:16]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:39].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:17][CH2:18][C:19]([OH:39])=[O:20])[S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(OCc1ccccc1)C1(N(CCCO)S(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)CCCC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of the crude 1-[(4'-fluorobiphenyl-4-sulfonyl)-(3-hydroxypropyl)amino]cyclopentanecarboxylic acid benzyl ester (22.1 grams) in acetone (400 mL) was cooled in an ice bath and treated with Jones reagent (about 20 mL) until an orange color persisted. The mixture was stirred from 0° C. to room temperature over 2 hours. After quenching excess oxidant with isopropanol (1 mL), Celite™ was added and the mixture was filtered. The filtrate was concentrated under vacuum. The residue was taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated to afford crude 1-[(2-carboxyethyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]-cyclopentanecarboxylic acid benzyl ester as an oil (21.4 grams).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[CH:14]=[C:15]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Cl:29])[CH:25]=3)[C:20]2=[O:30])[CH:16]=[N:17][CH:18]=1)(C)(C)C.Cl.O1CCOCC1>CO>[Cl:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:30])[N:19]([C:15]1[CH:16]=[N:17][CH:18]=[C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[CH2:7][OH:6])[CH:14]=1)[CH2:28][CH2:27]2
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(N2CCC[C@H]2CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 2-{5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (0.110 g, 0.233 mmol) in MeOH (2 mL) was added 4M HCl in dioxane (0.233 ml, 0.932 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness, the residue was diluted with DCM (20 mL) and washed with NaHCO3 (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH (1% NH4OH)-DCM gradient to give the title compound (0.06 g, 72%) as a light yellow solid. MS: 358.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2cccnc2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cccnc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-3-yl-pyrimidine-5-carbonitrile, 2-pyridylethylmercaptan and DBU in DME. EI-MS m/e (%): 334 (M+, 35), 333 ([M—H]+, 100), 138 (52), 106 (33).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11]>C(OCC)C>[CH2:1]([NH:5][C:10]([NH:9][CH2:8][CH2:7][Cl:6])=[O:11])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: CC(C)CNC(=O)NCCCl
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Isobutylamine (7.3 g, 0.1 mol) was dissolved in 20 ml of diethyl ether and cooled to less than 5° C. Chloroethyl isocyanate (10.5 g, 0.1 mol) dissolved in 15 ml of ether was added maintaining a temperature between 0° and 5° C. with vigorous stirring. Stirring continued an additional 2 hrs. the mixture was cooled to -5° C., and the product (4.1 g, 46%) was filtered and dried in vacuo for 18 hrs. over KOH, MP 79.5° C. (decomposes). IR analysis showed peaks at 1630/cm (C=O) and 1585/cm (N--C=O). NMR: Doublet at 0.9 ppm (J=6.4 Hz), multiplet (1H) at 2.1 ppm, quartet (2H) at 2.9 ppm (J=6.4 Hz), multiplet (4H) at 3.5 ppm.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH:11]1([CH2:15][N:16]2[CH2:33][CH2:32][C@@:23]34[C:24]5[CH:25]=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=5[CH2:30][C@@H:17]2[C@@H:18]3[C@@H:19]([CH3:35])[CH2:20][C:21](=[O:34])[CH2:22]4)[CH2:14][CH2:13][CH2:12]1>C(O)C>[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[CH:11]1([CH2:15][N:16]2[CH2:33][CH2:32][C@@:23]34[C:24]5[CH:25]=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=5[CH2:30][C@@H:17]2[C@@H:18]3[C@@H:19]([CH3:35])[CH2:20][C:21](=[O:34])[CH2:22]4)[CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: C[C@H]1CC(=O)C[C@]23CCN(CC4CCC4)[C@H](Cc4ccc(O)cc42)[C@H]13
Solvent: CCO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
To a stirred solution of d-tartaric acid (16.09, 106 mmole) in ethanol (100 ml) was added dropwise a solution of 17-cyclobutylmethyl-3-hydroxy-8β-methylmorphinan-6-one (TR-5130-free base, 32.0 g, 94 mmole) in ethanol (100 ml). After several minutes of stirring, a white solid began to precipitate. The slurry was stirred at room temperature for several hours and then kept in the cold overnight. The solid was collected, washed with cold ethanol followed by ether and dried at atmospheric pressure and 115° C. for one hour to give 32.0 g (69%) of TR-5257 as a white powder, mp. 210°-213° dec.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[NH:22][C:21]2=[O:45])=[CH:17][CH:16]=1
Reactant: Cn1c(CCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(CCCOc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 240 mg of 5-[4-{3-(3-methylimidazo[5,4-b]pyridin-2-yl)propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 35) and 10 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:3 to 0:1 by volume as the eluent, to give 93 mg of the title compound, melting at 185-186° C.