Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:6][S:7][CH2:8][CH:9]([CH3:24])[C:10](=[O:23])[CH2:11][CH2:12]/[C:13](/[CH3:22])=[CH:14]\[CH2:15][CH2:16]/[C:17](/[CH3:21])=[CH:18]\[CH2:19][OH:20])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[C:1]([NH:4][C@H:5]([C:25]([O:27][CH3:28])=[O:26])[CH2:6][S:7][CH2:8][CH:9]([CH3:24])[C:10](=[O:23])[CH2:11][CH2:12]/[C:13](/[CH3:22])=[CH:14]\[CH2:15][CH2:16]/[C:17](/[CH3:21])=[CH:18]\[CH2:19][O:20][C:35](=[O:37])[CH3:36])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](CSCC(C)C(=O)CC/C(C)=C\CC/C(C)=C\CO)NC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CSCC(C)C(=O)CC/C(C)=C\CC/C(C)=C\COC(C)=O)NC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.5 g of methyl N-acetyl-3-[[(6Z,10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]alaninate dissolved in 15 mil of methylene chloride is treated at 0° with 39 ml of pyridine and 30 ml of acetic anhydride. The solution is stirred at room temperature for 20 hours. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The crude product is chromatographed on silica gel with ether-methanol 50:1. There is obtained methyl N-acetyl-3-[[(6Z,10Z)-12-acetoxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]alaninate which exhibits the following absorption bands in the IR spectrum: 1738 cm-1, 1713 cm-1, 1664 cm-1, 1438 cm-1, 1412 cm-1, 1236 cm-1, 1117 cm-1.
Reaction SMILES: [CH:1]([N:4]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6](=[O:25])[NH:5]1)([CH3:3])[CH3:2].CC([O:29][CH2:30][C@H:31]1[O:36][C@H:35](Br)[C@H:34]([O:38]C(C)=O)[C@@H:33]([O:42]C(C)=O)[C@@H:32]1[O:46]C(C)=O)=O.[OH-].[Na+]>ClCCl>[CH:1]([N:4]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:6]([O:25][C@@H:35]2[O:36][C@H:31]([CH2:30][OH:29])[C@@H:32]([OH:46])[C@H:33]([OH:42])[C@H:34]2[OH:38])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(Cc2c(Oc3ccccc3)n(C(C)C)[nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)C)c2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a suspension of 1-isopropyl-4-(4-methoxybenzyl)-5-phenoxy-1,2-dihydro-3H-pyrazol-3-one (10 mg), acetobromo-α-D-glucose (40 mg) and benzyl(n-tributyl)ammonium chloride (30 mg) in dichloromethane (3 mL) was added sodium hydroxide aqueous solution (2 mol/L, 0.1 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi-purified 1-isopropyl-4-(4-methoxybenzyl)-5-phenoxy-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy-1H-pyrazole was dissolved in methanol (5 mL) and sodium methoxide (28% methanol solution, 0.2 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added 10% citric acid aqueous solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18 UG80, 5 μm, 20×50 mm, flowrate 30 mL/min linear gradient, water/methanol=70/30-10/90) to give 10 mg of the title compound.
Reaction SMILES: C(O)=O.C(N(CC)CC)C.[F:11][C:12]([F:24])([F:23])[C:13]1[C:21]2[O:20][CH2:19][C:18](=[O:22])[C:17]=2[CH:16]=[CH:15][CH:14]=1>ClCCl>[F:24][C:12]([F:11])([F:23])[C:13]1[C:21]2[O:20][CH2:19][C@H:18]([OH:22])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COc2c1cccc2C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=CO
Product: O[C@H]1COc2c1cccc2C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of formic acid (60 μL, 1.56 mmol) and triethylamine (186 μL, 1.33 mmol), a dichloromethane (2.0 mL) solution of 7-(trifluoromethyl)-1-benzofuran-3-one (90 mg, 0.445 mmol) produced in Example 47 (47E) was added, and chloro[(1S,2S)—N-(p-toluenesulfonyl)-1,2-diphenylethanediamine](mesitylene)ruthenium(II) (8.4 mg, 0.013 mmol) was added thereto at room temperature, and then, the resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:23])[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([OH:21])[CH:12]=1)[OH:10].[C:24]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:22][C:6]1[CH:5]=[N+:4]([O-:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH3:24])[CH:12]=1)[OH:10]
Reactant: O=C([O-])[O-]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(O)c2)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(O)Cc2c(Cl)c[n+]([O-])cc2Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
(S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide (2 g, 5.46 mmol) was dissolved in DMF (16 mL) then K2CO3 (2 g, 14.47 mmol) and iodomethane (1.72 g, 12.12 mmol) were added and the mixture was stirred at r.t. for 4 hours. The mixture was poured into 200 mL of water, filtered, washed with water and dried under vacuum at 40° C. 1.98 g of whitish solid was obtained.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:17]=1[C:18]#[N:19].[OH-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:16]2[C:17]=1[C:18]([NH2:19])=[C:2]1[C:1]([CH2:6][CH2:5][CH2:4][CH2:3]1)=[N:15]2
Reactant: O=C1CCCCC1
Reactant: N#Cc1c(N)cccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c2c(nc3cccc(F)c13)CCCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
To a stirred solution of cyclohexanone (1.0 g, 10.0 mmole) in methylene chloride (10 ml) at -20° C., a 1M solution of titanium (IV) chloride in methylene chloride (20 ml) was added. The reaction mixture became yellow in color and to it a mixture of triethylamine (2.0 g, 20 mmole) and 2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmole) in methylene chloride (30 ml) were added. The reaction mixture immediately became dark in color and was allowed to warm to room temperature (about 25° C.) and stirred further for 15 hours. At the end of this period, the reaction mixture was treated with 12% aqueous NaOH (100 ml), and methylene chloride (100 ml). The reaction mixture was then filtered through a 2 inch diatomaceous earth pad (Celite (trademark)) which was washed with methylene chloride (50 ml) and water (100 ml). The organic layer was separated, washed with water (1×30 ml) and dried (anhydrous MgSO 4). The methylene chloride was removed under vacuum to afford an oil which was triturated with ether to give the title compound as a white solid (218 mg, 10%, m.p. 175° C.). 1H-NMR (CDCl3, 300 MHz,δ): 4H, m, 2.0 ppm; 2H, t, 2.59 ppm (J=7.0 Hz); 2H, t, 3.06 ppm (J=7.0 Hz); 2H, bs, 5.37 ppm; 1H, dd, 7.0 ppm (J=7.5, 14 Hz); 1H, dd, 7.46 ppm (J=8, 16 Hz); 1H d, 7.72 ppm (J=8.5 Hz). HRMS: Calculated--216.1053; Found--216.1039.
Reaction SMILES: C(OC1O[C@H](COC(=O)C2C=CC(Cl)=CC=2)[C@@H](OC(=O)C2C=CC(Cl)=CC=2)C1)(=O)C.C[Si](NC1N=C(O[Si](C)(C)C)N=CN=1)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CN.[NH2:61][C:62]1[N:67]=[CH:66][N:65]([C@H:68]2[O:82][C@H:81]([CH2:83][O:84][C:85](=[O:93])[C:86]3[CH:91]=[CH:90][C:89]([Cl:92])=[CH:88][CH:87]=3)[C@@H:70]([O:71][C:72](=[O:80])[C:73]3[CH:78]=[CH:77][C:76]([Cl:79])=[CH:75][CH:74]=3)[CH2:69]2)[C:64](=[O:94])[N:63]=1>CO.ClCCl>[NH2:61][C:62]1[N:67]=[CH:66][N:65]([C@@H:68]2[O:82][C@H:81]([CH2:83][O:84][C:85](=[O:93])[C:86]3[CH:91]=[CH:90][C:89]([Cl:92])=[CH:88][CH:87]=3)[C@@H:70]([O:71][C:72](=[O:80])[C:73]3[CH:78]=[CH:77][C:76]([Cl:79])=[CH:75][CH:74]=3)[CH2:69]2)[C:64](=[O:94])[N:63]=1
Reactant: Nc1ncn([C@@H]2C[C@H](OC(=O)c3ccc(Cl)cc3)[C@@H](COC(=O)c3ccc(Cl)cc3)O2)c(=O)n1
Agent: CC(=O)OC1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: CN
Agent: C[Si](C)(C)Nc1ncnc(O[Si](C)(C)C)n1
Solvent: ClCCl
Solvent: CO
Product: Nc1ncn([C@H]2C[C@H](OC(=O)c3ccc(Cl)cc3)[C@@H](COC(=O)c3ccc(Cl)cc3)O2)c(=O)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
1-O-Acetyl-3,5-di-O-(4-chloro-benzoyl)-2-deoxy-D-ribofuranose (3.603 Kg, 7.68 mol), 2-[(trimethylsilyl)amino]-4-[(trimethylsilyl)oxy]-s-triazine (1.970 Kg, 7.68 mol) and dichloromethane (71.6 Kg) were charged to a suitable reactor. The mixture was cooled to 0° C. TMSOTf (1.791 Kg, 8.06 mol) was added to the solution at 0° C. and stirred for 5 hours. 2M methyl amine in methanol solution (about 3.95 Kg) was then added to the mixture at 0° C. and stirred for 45 mins. The mixture was diluted with dichloromethane (71.6 Kg) and washed with saturated sodium bicarbonate solution (39.8 Kg) at 25° C. The organic layer was dried using molecule sieves (36 Kg). The molecule sieves were filtered and rinsed with dichloromethane (60.1 Kg). The organic layer was evaporated to dryness at 35° C. The solid was milled and vacuum dried at 45° C. to obtain 2.99 Kg (5.92 mol) of 4-amino-1-[3,5-di-O-(4-chloro-benzoyl)-2-deoxy-β-D-ribofuranosyl]-1H-[1,3,5]triazin-2-one (compound Ib) in 52% HPLC purity (40% yield based on 1-O-acetyl-3,5-di-O-(4-chloro-benzoyl)-2-deoxy-D-ribofuranose) and 4-amino-1-[3,5-di-O-(4-chloro-benzoyl)-2-deoxy-α-D-ribofuranosyl]-1H-[1,3,5]triazin-2-one (compound IVa) mixture in 27% HPLC purity. That α-anomer to β-anomer ratio was 1.0:1.91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.F[P-](F)(F)(F)(F)F.[N:37]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O.O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:37])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (211 mg, 0.50 mmol) obtained in Example 12 in N,N-dimethylformamide (5 ml), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (390 mg, 0.75 mmol), 1-hydroxybenzotriazole (101 mg, 0.75 mmol), ammonium chloride (54 mg, 1.00 mmol), and N-ethyldiisopropylamine (0.348 ml, 2.00 mmol) were added in an argon atmosphere at room temperature. After stirring for 5 hours at room temperature, ethyl acetate and water were added to the reaction mixture, and the resulting mixture was washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=7:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane, and was collected by filtration, to obtain the title compound (154 mg, 0.37 mmol, 73%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][CH2:6][N:7]([CH3:26])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[F:25])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)C.CCCCCC>O1CCCC1.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1N=CN=C(NC(N2CCCC2)=O)C=1.C(OCC)(=O)C>[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:26])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:40])=[CH:20][C:19]=2[F:25])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:28]
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)CCCN(C)C(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-1-methylurea (100 mg) in tetrahydrofuran (2.0 ml) was added a solution of phenylacetyl isocyanate in hexane (3.4 ml, Production Example 1), followed by stirring under a nitrogen atmosphere at room temperature for 30 min. A solution of phenylacetyl isocyanate in hexane (1.0 ml, Production Example 1) was further added thereto, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between a mixed solvent of ethyl acetate-tetrahydrofuran (1:1, 200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (15 ml). The organic layer was washed with a 1 N aqueous solution of sodium hydroxide, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing a crude product were concentrated to give a residue, which was then dissolved in ethyl acetate and washed with a 1 N aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which diethyl ether (3 ml) and hexane (3 ml) were then added to precipitate a solid. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (8.3 mg, 5.9%) as colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]#[CH:10].C(NCC)C>C(=O)(O)[O-].[Na+]>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:10]#[C:9][CH2:8][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C#CCOCCCCCCNCc1ccccc1
Reactant: Brc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCNCC
Product: C(#Cc1ccccn1)COCCCCCCNCc1ccccc1
Reaction time: 18 h
Yield: 73.5 %

Procedure:
A mixture of 2-bromopyridine (2.0 g), N-[6-[(2-propynyl)oxy]hexyl]benzenemethanamine (3.2 g), BTPC (0.07 g), cuprous iodide (0.007 g), and diethylamine (20 ml) was stirred under nitrogen for 18 h, treated with aqueous sodium bicarbonate (1M, 50 ml), and extracted with diethyl ether (2×100 ml). The dried extract was evaporated and the residue was purified by FCC eluting with diethyl ether to give the title compound as a yellow oil (3.0 g), t.l.c. (diethyl ether) Rf 0.05.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.[ClH:21].[H][H].[Cl-].[Na+].N>[Fe].CO>[ClH:21].[ClH:21].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CO
Product: Nc1ccc(C=Cc2ccc(N)cc2)cc1
Temperature: 25 °C

Procedure:
A portion (40.5 grams, 0.15 mole) of 4,4'-dinitrostilbene from A above, concentrated hydrochloric acid (250 milliliters) and methanol (200 millileters) are added to a flask and maintained therein as stirred mixture. Over the next three hour period, 325 mesh powdered iron is added to the reaction mixture in one grams aliquots until a total of 22.0 grams (0.40 mole) has been added. With each added aliquot of iron, heating with vigorous hydrogen evolution occurs causing frothing of the reaction mixture. Frothing is moderated as needed by cooling of the flask on a sodium chloride and ice bath between iron additions. After completion of the iron addition, the mixture is heated for 16 hours at reflux then cooled to room temperature (25° C.) and filtered. The dark brown liquid filtrate is concentrated by rotary evaporation under vacuum at 85° C. to one half original volume then decolorized by the addition of activated charcoal. After filtration, the filtrate is desalted by passing through a column of Sephadex G-50. The eluate is rotary evaporated under vacuum to provide a pale tan colored solid. Recovery of this solid followed by drying in a vacuum oven at 110° C. and 5 mm Hg provides a constant product weight of 29.4 grams. Fourier transform infrared spectrophotometric analysis of a nujol mull of the product on a sodium chloride plate confirms the product structure (disappearance of the absorbances observed for the conjugated nitro group, appearance of --NH3 + stretching absorbances at 3040, 2603 and 2550 cm-1 and appearance of a --NH3 + bending absorbance at 1497 cm-1). Proton nuclear magnetic resonance spectroscopy further confirms the product structure. Differential scanning calorimetry of a portion (3.62 milligrams) of the product under a stream of nitrogen flowing at 35 cubic centimeters per minute and using a heating rate of 10° C. per minute with a range of 200° C. to 450° C. reveals a endotherm at 263° C. (enthalpy=162.85 J/g) followed by second endotherm at 291° C. (enthalpy=337.82 J/g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=1[F:25].[BH4-].[Na+].[OH-].[Na+]>[Pd](Cl)Cl.C1COCC1.O>[OH:1][C@@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:25]
Reactant: O=C(N[C@@H]1CCC[C@@H](O)[C@H]1O)c1ccncc1Nc1ccc(I)cc1F
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H]1CCC[C@@H](O)[C@H]1O)c1ccncc1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A sealed tube was charged with (N-[(1R,2S,3R)-2,3-dihydroxycyclohexyl]-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide) (8) (42 mg, 0.09 mmol), Sodium borohydride (34 mg, 0.89 mmol), palladium dichloride (7.9 mg, 0.04 mmol), sodium hydroxide (17.8 mg, 0.45 mmol), THF-Water (1:1, 3 ml). The mixture was stirred at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated. The resulting residue was subjected to flash chromatography to obtain the product. LC/MS [Method A: rt: 0.43 min; m/z: 346 (M+1)].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.C([O:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])[CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(c1cc(Br)ccc1F)C(F)(F)F
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Diisopropylamine (4.40 mL, 31.4 mmol) was dissolved in THF (28 mL) and cooled to −40° C. Then n-butyllithium (12.6 mL, 2.5 M in hexanes, 31.4 mmol) was added dropwise, and the reaction was stirred at −40° C. for 1 h, then cooled to −78° C. A solution of 1-bromo-4-fluorobenzene (5 g, 28.6 mmol) in THF (6.0 mL) was added, and the reaction was stirred at −78° C. for 1 h. Trifluoroacetic acid ethyl ester (3.73 mL, 31.4 mmol) in THF (6.0 mL) was then added, and the reaction was slowly warmed to 0° C. over an hour. The reaction was quenched with NH4Cl (aq. sat), and extracted with EtOAc, washed with brine, and dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]1[S:21][C:14]2[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=2[C:12]=1[C:22]([O:24]C(C)(C)C)=[O:23])=[O:7]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]1[S:21][C:14]2[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=2[C:12]=1[C:22]([OH:24])=[O:23])=[O:7]
Reactant: COc1cccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)O)CC(C)(C)OC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of 40% v/v TFA/DCM (20 mL) was added to tert-butyl 2-(3-(3-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.32 g, 0.67 mmol) and the mixture was stirred at room temperature for 1 h. The volatiles were removed at 30° C. and the material was purified by reverse-phase chromatography (10-100% MeCN/water). 2-(3-(3-Methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (0.114 g, 0.26 mmol, 39% yield) was isolated as a pale, yellow solid. 1H NMR (500 MHz, DMSO) δ 14.84 (s, 1H), 13.39 (s, 1H), 11.78 (s, 1H), 7.58-7.54 (m, 1H), 7.54-7.51 (m, 1H), 7.45 (apparent t, J=7.9 Hz, 1H), 7.22 (apparent ddd, J=8.3, 2.6, 0.9 Hz, 1H), 4.66 (s, 2H), 3.85 (s, 3H), 2.74 (s, 2H), 1.23 (s, 6H). 13C NMR (126 MHz, DMSO) δ 174.24, 166.41, 165.25, 158.88, 146.70, 133.23, 129.51, 128.99, 123.98, 120.94, 119.29, 116.40, 113.19, 70.04, 58.71, 55.33, 37.16, 26.08. LCMS retention time: 3.199 min; LCMS purity at 214 nm=97%. HRMS m/z calculated for C19H21N2O5S2 [M++1]: 421.0886. found 421.0889. Melting point 199.3° C., decomposition.