Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:18])=[C:7]([CH2:16][CH3:17])[C:8]=2[N+:13]([O-])=O)[N:3]=1.[Cl:19][C:20]1[C:29]([Cl:30])=[N:28][C:27]2[C:22](=[CH:23][C:24]([CH2:35][CH3:36])=[C:25]([Cl:34])[C:26]=2[N+:31]([O-])=O)[N:21]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:13][C:8]1[C:7]([CH2:16][CH3:17])=[C:6]([Cl:18])[CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([Cl:12])[C:2]([Cl:1])=[N:3]2.[NH2:31][C:26]1[C:25]([Cl:34])=[C:24]([CH2:35][CH3:36])[CH:23]=[C:22]2[C:27]=1[N:28]=[C:29]([Cl:30])[C:20]([Cl:19])=[N:21]2
Reactant: CCc1c(Cl)cc2nc(Cl)c(Cl)nc2c1[N+](=O)[O-]
Reactant: CCc1cc2nc(Cl)c(Cl)nc2c([N+](=O)[O-])c1Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1c(Cl)cc2nc(Cl)c(Cl)nc2c1N
Product: CCc1cc2nc(Cl)c(Cl)nc2c(N)c1Cl
Yield: 91 %

Procedure:
A mixture of 2,3,7-trichloro-6-ethyl-5-nitroquinoxaline and 2,3,6-trichloro-7-ethyl-5-nitroquinoxaline (200 mg, 0.652 mmol), tin (II) chloride dihydrate (1.03 g, 4.57 mmol) and ethyl acetate (6.5 ml) was heated under reflux for 4h, cooled and diluted with ethyl acetate. The solution was washed with 10% aqueous sodium carbonate (25 ml). The aqueous layer was extracted with ethyl acetate (2×25 ml), and the combined organic solutions were washed with 10% aqueous sodium carbonate (2×25 ml), saturated aqueous sodium chloride (25 ml), dried (MgSO4) and concentrated under reduced pressure to give 5-amino-2,3,7-trichloro-6-ethylquinoxaline and 5-amino-2,3,6-trichloro-7-ethylquinoxaline as an orange solid (174 mg, 91%), ratio 1:1.
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>C(#N)C>[CH:1]([O:14][CH2:15][CH2:16][C:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH:22]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(OCCc2ccncc2)c2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: C1=C(CCOC(c2ccccc2)c2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 4 h
Yield: 94.3 %

Procedure:
With reference to FIG. 7, 4-(2-(benzhydryloxy)ethyl)pyridine 3 (4.0 g, 13.82 mmol) and benzyl bromide (2.86 g, 16.73 mmol) were dissolved in 20 ml of dry acetonitrile and refluxed for 6 hrs. The solvent was removed in vacuo. After drying the residue for 2 hrs under high vacuum, it was dissolved in 30 ml of dry methanol and cooled in an ice-bath. Sodium borohydride (0.76 g, 20.05 mmol) was then added very slowly portionwise over a period of 1.5 hrs, and the solution was gradually brought to room temperature. The reaction was quenched with water after stirring for 4 h, and methanol was removed in vacuo. The residual product was dissolved in ethyl acetate, washed with water, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography over silica gel (hexane:ethyl acetate 5:1) to produce 4 (5.0 g, 94%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): 2.086 (brs, 2H, H-3), 2.32-2.35 (t, 2H, J=6.8 Hz, OCH2CH2), 2.52-2.54 (t, 2H, J=5.6 Hz, H-2), 2.94-2.94 (brm, 2H, H-6) 3.52-3.55 (m, 4H, NCH2Ph, OCH2CH2), 5.34 (s, 1H, PhCH(O)Ph), 5.41-5.42 (brs, 1H, CH═C), 7.12-7.37 (m, 15H, ArH).
Reaction SMILES: CO[C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=O.[CH3:11][CH:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:13]([C:15]1[CH:16]=[C:17]([OH:22])C=[C:19]([CH:21]=1)[OH:20])[CH3:14].Cl.[CH2:29]([OH:31])C>>[OH:22][C:17]1[C:3]2[C:5]3[CH2:9][CH2:8][S:7][C:6]=3[C:29](=[O:31])[O:20][C:19]=2[CH:21]=[C:15]([CH:13]([CH:12]([CH3:11])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:14])[CH:16]=1
Reactant: CCO
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: COC(=O)C1CSCC1=O
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Reaction time: 72 h

Procedure:
A solution of 20 g. (0.125 mole) of methyl-4-oxo-2,3,4,5-tetrahydrothiophene-3-carboxylate and 32 g. (0.135 mole of 5-(3-methyl-2-octyl)resorcinol in 200 ml. of absolute ethanol was cooled in an ice-salt bath and saturated with anhydrous hydrogen chloride. The reaction mixture was allowed to stand at room temperature for 72 hours and the solid which formed was removed by filtration. Recrystallization from ethanol gave 16 g. (37%) m.p. 165°-166°C. The structure was confirmed by infrared and nuclear magnetic resonance spectra.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:11])[C:6]([Cl:10])=[C:7]([Cl:9])[Cl:8])#[N:2].[Cl:12][C:13]([Cl:19])([S:17]Cl)[CH:14]([Cl:16])[Cl:15].N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:17][C:13]([Cl:19])([Cl:12])[CH:14]([Cl:16])[Cl:15])[C:5](=[O:11])[C:6]([Cl:10])=[C:7]([Cl:8])[Cl:9])#[N:2]
Reactant: N#CCNC(=O)C(Cl)=C(Cl)Cl
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#CCN(SC(Cl)(Cl)C(Cl)Cl)C(=O)C(Cl)=C(Cl)Cl
Reaction time: 23 h
Yield: 57.1 %

Procedure:
A mixture of 5.0 g. (0.023 moles) N-cyanomethyl trichloroacrylamide (the product of Example 21) and 5.5 g (0.023 moles) 1,1,2,2-tetrachloroethyl-sulfenyl chloride in 75 ml methylene chloride were stirred together to give a clear solution. The resulting mixture was cooled in an ice bath; then 2.2 g (0.028 moles) pyridine in 25 ml methylene chloride were added over twenty minutes. The ice bath was removed; stirring was continued for 23 hours. (TLC monitored the course of the reaction). The reaction mixture was cooled again in an ice bath. Triethylamine, 2.4 g (0.024 moles) in 25 ml methylene chloride was added over fifteen minutes; the mixture was stirred for one hour. The solvent was stripped to give an oil. The oil was chromatographed on a column of 165 g silica gel and eluted with benzene to give 5.4 g of the above-identified product which slowly solidified on standing to give a solid which liquified at 70°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[NH:9][C:10]3[C:16]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44]Br)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:44][CH2:43][CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:37][CH2:38]3)[C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:10]=3[N:9]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Reactant: Clc1ccc(OCc2nc3cccc(OCc4ccccc4)c3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCc4ccccc4)cccc32)CC1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-benzimidazole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride (60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for thirty minutes and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (7.24 mg, 2.36 mmol, 1.2 eq) was added to the reaction mixture. The resulting mixture was stirred at 70° C. for three hours. The reaction was quenched by the addition of water (1×30 ml). The aqueous fraction was extracted with diethyl ether (1×30 ml). The organic fractions were combined, washed with water (1×30 ml), then brine (1×30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by flash chromatography to provide a white foam in 38% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27]1>CN(C)C=O>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:39][CH2:40]2)=[N:27]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2noc3ccccc23)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.6 g), triethylamine (1.8 cc) and 4(1,2-benzisoxazol-3-yl)piperazine (2.69) in dimethylformamide (200 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-{3-[4-(1,2-benzisoxazol-3-yl) -1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained, m.p. 263° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([OH:7])=O.[NH2:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][O:24][C:25](=[O:33])[NH:26]C(=O)C(Cl)(Cl)Cl)[CH2:21][S:22][C@H:17]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:5]([NH:15][CH:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][O:24][C:25](=[O:33])[NH2:26])[CH2:21][S:22][C@H:17]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1cccc(O)c1
Yield: 19.8 %

Procedure:
2-Methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (1.1 g.) and 7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (2.35 g.) were reacted and post-treated according to a similar manner to that of Example 3 to give 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g.). This compound is identified with the compound obtained in Example 2 by I.R. and N.M.R. spectra.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:29]1
Reactant: OB(O)c1ccoc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccoc2)c1

Procedure:
A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 60 mg, 0.134 mmol), furan-3-ylboronic acid (22.6 mg, 0.202 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol), Na2CO3 (42.8 mg, 0.403 mmol), DME (570 μL), water (163 μL) and EtOH (81 μL) in a MW vial was sealed, evacuated/purge with argon and subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 46.7 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 25% for 0.2 min then 25% to 55% in 14 min) to yield the title compound as a white solid. LC-MS (Condition 2) tR=1.92 min, m/z=434.1-435.2 [M+H]+, m/z=432 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.81 (m, 1H) 1.82-1.92 (m, 1H) 3.07 (d, J=11.49 Hz, 1H) 3.30-3.45 (m, 1H) 3.48-3.57 (m, 2H) 4.21-4.27 (m, 1H) 6.68 (s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.76 (t, J=1.59 Hz, 1H) 7.83 (s, 1H) 7.84-7.88 (m, 2H) 7.98 (d, J=2.45 Hz, 1H) 8.70 (d, J=2.45 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C([Si](C)(C)O[CH2:22][CH2:23][O:24][CH3:25])(C)(C)C.C([SiH](CC)CC)C>C(#N)C>[CH3:1][C:2]1([C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])[CH2:3][CH2:4][CH:5]([O:8][CH2:22][CH2:23][O:24][CH3:25])[CH2:6][CH2:7]1
Reactant: COCCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)COC(=O)C1(C)CCC(=O)CC1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: COCCOC1CCC(C)(C(=O)OCC(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A solution of isobutyl 1-methyl-4-oxocycylohexanecarboxylate (D67, 12.7 g, 59.8 mmol), t-butyl dimethyl 2-methoxyethoxy silane (11.4 g, 59.9 mmol), and anhydrous ferric chloride (250 mg, 1.541 mmol) in acetonitrile (150 mL) at 0° C. was treated with triethylsilane (12 mL, 75 mmol). The mixture was stirred for 1 h at room temperature, then partitioned between saturated sodium bicarbonate and dichloromethane, and the organic layer was dried and evaporated to give isobutyl 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate (27 g, 49.6 mmol, 83% yield) as a cis/trans mixture containing one equivalent of t-butyldimethyl triethyl siloxane.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:16][C:17]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[O:29][CH3:30])([CH3:21])[CH3:20])[N:6]=1)=O.[BH4-].[Na+].CCCCCC.C(OCC)(=O)C>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:20])([CH3:21])[CH2:18][C:17]([C:31]([F:32])([F:34])[F:33])([OH:35])[CH2:16][NH:15][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]=[CH:14][C:5]([CH2:3][OH:2])=[N:6]3)=[C:23]([O:29][CH3:30])[CH:24]=1
Reactant: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3ccc(Cl)cc3OC)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F

Procedure:
Analogously to Example 40, 200 mg (0.39 mmol) of 5-[4-(4-chloro-2-methoxy-phenyl) -2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylic acid methyl ester is dissolved in 5.0 ml of methanol and mixed with 60 mg (1.56 mmol) of sodium borohydride. After chromatography on silica gel with hexane-ethyl acetate (0–100%), 70 mg (37% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:34])([CH2:28]OS(C)(=O)=O)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:34])([CH2:28][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 50 °C
Yield: 34.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (200 mg) was dissolved in dimethylformamide (10 ml), to which 1H-1,2,4-triazole (83 mg) and potassium carbonate (168 mg) were added, and the mixture was heated at 50° C. for 20 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with water (15 ml), 1N-hydrochloric acid (15 ml×2) and a saturated aqueous solution of sodium chloride (15 ml). The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:ethyl acetate). The desired fraction was concentrated and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H) -imidazolone (Compound 44, 65 mg) as a colorless crystalline powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([CH2:23]O)[CH:14]=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([CH2:23][Cl:3])[CH:14]=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1cnn(Cc2ccccc2)c1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: ClCc1cnn(Cc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Thionyl chloride (4.35 g) was added to a solution of (1-benzyl-5-phenyl-1H-pyrazol-4-yl)methanol (8.06 g) in toluene (100 ml) dropwise at 0° C., and the mixture was stirred at room temperature for one hour and then refluxed for ten minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 1-benzyl-4-chloromethyl-5-phenyl-1H-pyrazole (8.31 g, yield: 96%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](C(OC(C)(C)C)=O)=[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[O:10][N:9]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].Cl>ClCCl.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([NH:20][S:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCCOc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)on1
Yield: 47.9 %

Procedure:
To a solution of tert-butyl 3-[2-(acetoxy)ethoxy]-5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-4-isoxazolecarboxylate (Preparation 2) (3.16 g) in dichloromethane (40 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was heated to reflux for 3 hours. After which time the reaction mixture was basified to pH8 using sodium hydrogen carbonate solution and then re-acidified to pH2 using aqueous hydrochloric acid (1.0 M). This aqueous layer was extracted into ethyl acetate (2×250 mL) and the organics combined, dried over magnesium sulfate and the solvent removed in vacuo to yield the crude material (2.6 g). This was dissolved up in toluene and refluxed for 2 hours. The solvent was removed in vacuo to yield the crude material as a light brown solid (2.3 g). The crude material was purified using the Biotage Flash 40i system (silica, 90 g) and eluted with hexane:ethyl acetate (5:2) to yield the product as a white solid (1.2 g).
Reaction SMILES: [OH-].[Na+].[C:3]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[S:18])[CH3:17])=[CH:11][CH:10]=1)(=[O:5])[CH3:4]>O.ClCCl>[CH3:17][C:16]1[S:18][C:13]2[CH:14]=[C:9]([CH2:8][CH2:7][O:6][C:3](=[O:5])[CH3:4])[CH:10]=[CH:11][C:12]=2[N:15]=1
Reactant: CC(=O)OCCc1ccc(NC(C)=S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCc1ccc2nc(C)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K3Fe(CN)6 (7.6 g, 23.1 mmol) was dissolved in water (18 ml) and then mixed with 50 ml 2% NaOH aqueous solution. 4-Thioacetamidophenethyl acetate (1.0 g, 4.1 mmol) was dissolved in dichloromethane (50 ml) and then added to the K3Fe(CN)6 solution. The reaction mixture was stirred at room temperature for 1 hr. The organic layer was separated by a separatory funnel, washed with water, and then dried over anhydrous sodium sulfate. The dried solution was concentrated and then purified by flash silica gel chromatography. Yield: 0.6 g (61%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:44]([NH2:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(Cl)Cl>[C:12]1([C:11]2[N:10]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:51][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:28])[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCNC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
Part A. To a solution of 8-(4,5-diphenyl-1H-imidazol-2ylthio)octanoic acid (8.44 g, 0.02 mol) in methylene chloride (100 mL) at 0° was added, portionwise as a solid, dicyclohexylcarbodiimide (4.12 g, 0.02 mol), and the reaction mixture was stirred at 0° for 30 minutes. To this reaction mixture was added, dropwise, heptylamine (2.96 mL, 2.3 g, 0.02 mol) and the reaction mixture was stirred at reflux for 72 hours. The reaction mixture was cooled, and the solids were filtered and washed with chloroform. The filtrate was concentrated under vacuum and the residue was chromatographed with a gradient of 7:3 to 1:1 hexane-ethyl acetate. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 8-(4,5-diphenyl-1H-imidazol-2-ylthio) -N-heptyloctanamide (3.28 g, 0.0067 mol) as a white solid, mp 119°-120°. 1H NMR (DMSO-d6) δ 12.5(s,1H), 7.8-7.1(m,10H), 3.2-2.9(m,4H), 2.0(t,2H,J=7 Hz), 1.75-1.0(m,21H),1.0-0.8 (m,3H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:13]=1[NH2:14])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][CH:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:12]([CH:9]([CH3:11])[CH3:10])[C:13]=1[NH:14][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH3:20]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OCC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To a solution of acetoxyacetyl chloride (13.5 g, 98.7 mmol) in toluene (70 mL) at 0° C. is added dropwise via a dropping funnel a solution of 2,6-diisopropylaniline (17.5 g, 98.7 mmol) and triethylamine (20.6 mL, 148.1 mmol) in toluene (20 mL). After completion of the addition, the mixture is allowed to warm to room temperature and stirred for 24 hours. The mixture is filtered through a small pad of silica gel. The filtrate is concentrated to afford 11 g of a brown solid. The precipitate is suspended in ethyl acetate and stirred overnight. After filtration, the filtrate is concentrated to give another 10 g of a brown solid. Recrystallization (ethyl acetate/hexane) of the combined material provided 12 g of the title compound as an off-white solid; mp 179°-182° C.