Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].C[N+](C)(C)C.[CH3:7][C@@H:8]([C@@H:14]1[C@@:18]2([CH3:34])[CH2:19][CH2:20][C@@H:21]3[C@@:26]4([CH3:32])[CH2:27][CH2:28][C@@H:29]([OH:31])[CH2:30][C@H:25]4[CH2:24][C@@H:23]([OH:33])[C@H:22]3[C@@H:17]2[CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CO.CS(C)=O.[Ti]>[CH3:7][C@@H:8]([C@@H:14]1[C@@:18]2([CH3:34])[CH2:19][CH2:20][C@@H:21]3[C@@:26]4([CH3:32])[CH2:27][CH2:28][C@@H:29]([OH:31])[CH2:30][C@H:25]4[CH2:24][C@H:23]([OH:33])[C@H:22]3[C@@H:17]2[CH2:16][CH2:15]1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Ti]
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.08 h
Yield: 37.6 %

Procedure:
The cell was assembled with a lead-plated monel electrode as cathode and a ruthenized titanium anode. The cell was undivided and contained just one Telfon gasket. A stock solution of electrolyte was made up from 25 mL of 1.94 M tetramethylammonium hydroxide in methanol and 475 mL of dimethylsulfoxide dried over 3A molecular sieves. The entire solution was stored over 3A molecular sieves and then 60 mL of electrolyte placed in the reservoir. 2.0 g of 7-ketolithocholic acid was dissolved therein, the flow was adjusted to a steady stream, and a constant current of 200 ma was established. 3960 coulombs were accumulated. When the cell was opened it could be seen that the monel sub-surface of the electrode was exposed. There were fine flakes of lead in the reservoir and pump. The filtrate was evaporated under high vacuum. The crude product was dissolved in 30 mL of methanol and 30 mL of 2N sodium hydroxide added. The solution was left at room temperature for five minutes and then the methanol evaporated. The product was precipitated with hydrochloric acid at pH 4.0 yielding 1.79 g after drying. The HPLC analysis indicated 45% reduction with a 37.6% yield of UDCA and 7.4% CDCA. The UDCA/CDCA ratio is 5.08. Analysis by C13 nmr was qualitatively consistent with this ratio.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH3:25])[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:22])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(=O)C2(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2 (3H)-one synthesized in Reference Example 2 (2.10 g, 7.13 mmol) in DMF (30 mL) was added sodium hydride (a 60% fluidized paraffin dispersion, 314 mg, 7.84 mmol) at 0° C., and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added methyl iodide (1.11 g, 7.84 mmol) and the mixture was stirred for at room temperature 30 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2.07 g (yield 94%) of the title compound as an oily matter.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:19]([C:20]#[N:21])([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium bis-(trimethylsilyl)amide (7910 mL, 1M, 7910 mmol) was cooled to 0° C. A solution of 3,4-dichlorophenylacetonitrile (700 g, 3763 mmol) in THF (2.50 L) was added maintaining the temperature of the reaction mixture between 0° and 20° C. After 1 hour, the above solution is added by candula to a solution of ethyl bromoacetate (910 mL) in THF (1.40 L) cooled to 0° C. The addition is carried out at such a rate that the temperature of the reaction mixture does not rise above 20° C. After 15 minutes, the reaction was quenched by the addition of t-butyl methyl ether (7.0 L) and water (3.5 L). The organic layer was separated and was extracted with water, 5% NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was recrystallized from diethyl ether to give the title compound: mp=69°-71° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)(=[O:4])=[O:3]
Reactant: O=C(NCCO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCNC(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.6 ml of methanesulfonyl chloride in 3 ml of methylene chloride is added dropwise at 0° to a solution of 1.5 g (0.0075 mol) of N-(2-hydroxyethyl)-4-chlorobenzamide and 1 ml of triethylamine in 15 ml of methylene chloride. After 15 minutes, the mixture is poured on to ice/water and extracted. There are obtained 2.1 g of N-(2-methylsulfonyloxyethyl)-4-chlorobenzamide in crystalline form which is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][SH:13]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:12]([C:11]([O:15][CH2:16][CH3:17])=[O:14])[S:13][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCOC(=O)CS
Product: CCOC(=O)c1cc2ccc(Br)cc2s1

Procedure:
4-Bromo-2-fluorobenzaldehyde and ethyl thioglycolate were treated in a manner similar to Reference Example 31-(1) to give 6-bromo-2-ethoxycarbonylbenzo[b]thiophene as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:6]=[CH:5]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1c(Br)ccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(Br)ccc2c1cnn2COCC[Si](C)(C)C
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
To a stirred solution of 5-bromo-4-methoxy-1H-indazole (1.33 g, 5.9 mmol) in THF (20 mL) at 0° C., under a nitrogen atmosphere, was added sodium hydride (280 mg, 7 mmol) portionwise. After 5 min, (2-chloromethoxy-ethyl)-trimethylsilane (1.36 mL, 7.7 mmol) was added dropwise. After 3 hours, the reaction mixture was quenched with water (20 mL). The resulting biphasic mixture was separated, extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 10-20% ethyl acetate in cyclohexane) to give the title compound as a yellow oil (1.19 g, 56%). LCMS (Method B): RT=4.91 min, [M+H]+=357.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:22])[CH2:19][CH2:20][NH2:21])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:17][C:18](=[O:22])[CH2:19][CH2:20][NH:21][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)=[O:13])[CH3:16]
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
1.98 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 25 ml of N,N-dimethylformamide; 1.78 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 1 hour. To this mixture, 1.69 g of β-alanine ethyl ester hydrochloride and 1.53 ml of triethylamine were added, followed by further stirring for 3 hours. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 2.57 g of the title compound.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:24])[CH:4]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]#[C:22][CH3:23])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:25]1([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:26]([C:31](O)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([CH:4]([C:3](=[O:24])[NH:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:31](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:11])=[O:12])=[CH:18][CH:17]=1)[C:21]#[C:22][CH3:23]
Reactant: CC#CCOc1ccc(S(=O)(=O)C(CCCCN)C(=O)NO)cc1
Reactant: O=C(O)c1ccccc1CCc1ccccc1
Product: CC#CCOc1ccc(S(=O)(=O)C(CCCCNC(=O)c2ccccc2CCc2ccccc2)C(=O)NO)cc1

Procedure:
6-Amino-2-(4-but-2-ynoxy-benzenesulfonyl)-hexanoic acid hydroxyamide resin (0.33 g, 1.1 meq/g) prepared in step B was acylated with 2-bibenzylcarboxylic acid (1.6 g, 4.0 eq) according to the procedure in Example 13, Step E to give N-[5-(4-but-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl-benzamide resin.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([O-])(=O)C.[K+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][CH2:28][C:29]2[NH:38][C:32]3=[N:33][CH:34]=[C:35](I)[CH:36]=[C:31]3[N:30]=2)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:35]2[CH:36]=[C:31]3[N:30]=[C:29]([CH2:28][CH2:27][C:23]4[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=[CH:25][N:24]=4)[NH:38][C:32]3=[N:33][CH:34]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CCNS(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCNS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCc4cc(OC)ccn4)nc3c2)cc1
Temperature: 90 °C
Yield: 58.1 %

Procedure:
A mixture of 0.348 g of N-ethyl4-bromobenzenesulfonamide, 0.42 g of bis-pinacolato)diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed-tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphos-phine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-15:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.248 g of the title compound as a solid of m.p. 214-216° C. The mass spectrum shows the molecular peak MH+ at 438.4 Da.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[N:4][CH:5]=[CH:6][C:7]=1I.C([Mg]Cl)(C)C.C(OCC)C.[CH:20]1([NH:25][C:26]2[C:31](I)=[CH:30][N:29]=[C:28]([NH2:33])[N:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>CC(O)C.C(=O)=O.C(Cl)Cl.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[Br:1][C:2]1[C:3]([F:9])=[N:4][CH:5]=[CH:6][C:7]=1[C:31]1[C:26]([NH:25][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:27][C:28]([NH2:33])=[N:29][CH:30]=1
Reactant: Fc1nccc(I)c1Br
Reactant: Nc1ncc(I)c(NC2CCCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1ncc(-c2ccnc(F)c2Br)c(NC2CCCC2)n1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
In a dry 3 neck 2 L flask equipped with a dry addition funnel, thermometer and stir bar was added 3-bromo-2-fluoro-4-iodopyridine (83.4 g, 276 mmol) followed by 300 mL of anhydrous THF under an atmosphere of nitrogen. The solution was cooled to −70° C. in 2-propanol/dry ice bath. A solution of isopropylmagnesium chloride 2.0 M in diethyl ether (145 mL, 290 mmol) was added drop wise over a period of 30 minutes. The solution was then stirred for 30 minutes before zinc (II) chloride 0.5 M in THF (276 mL, 138 mmol) was cannulated in. The solution was warmed to room temperature and stirred for 1 hour. The addition funnel was replaced with a reflux condenser and N4-cyclopentyl-5-iodopyrimidine-2,4-diamine (243, see example 200) (28.00 g, 92.1 mmol) was added, followed by Pd(PPh3)4 (5.32 g, 4.60 mmol). The solution was heated over night at a gentle reflux. After concentrating the solution to 1/10th of the volume under vacuum, it was cooled in an ice bath. To this was added 100 mL of cold saturated NH4Cl, followed by 500 mL of water. 500 mL of 12% isopropanol/DCM was then added and the solution was stirred at room temperature for 1 hour before being filtered through filter paper. The filter cake was washed in succession with water, DCM and 12% 2-propanol/DCM. The filtrate was partitioned in a separation funnel and the aqueous layer was washed with 12% 2-propanol /DCM. The organics were dried over MgSO4 and then concentrated under vacuum. The residue obtained was partially dissolved in DCM with sonication and filtered off to give compound 244 (26.45 g, 81.6%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.18 (1 H, d, J=4.9 Hz), 7.52 (1 H, s), 7.26 (1 H, dd, J=4.9, 0.7 Hz), 6.34 (2 H, s), 6.12 (1 H, d, J=7.6 Hz), 4.42 (1 H, sxt, J=7.4 Hz), 1.76-1.96 (2 H, m), 1.55-1.68 (2 H, m), 1.31-1.53 (4 H, m)) ppm; LCMS-ESI (POS), M/Z, M+1: Found 352.0.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[C:12]([Cl:19])[C:11]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:20][C:11]1[C:12]([Cl:19])=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=1[Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 75 °C
Yield: 99 %

Procedure:
Benzyl bromide (17.25 mL, 144 mmol) was added to a stirring solution of 2,6-dichloro-4-nitrophenol (5 g, 24 mmol) and potassium carbonate (13.3 g, 96 mmol) in acetone (30 mL). The mixture was heated to 75° C. for 12 h before being cooled to room temperature and poured into ice-water (100 mL). The mixture was extracted with chloroform (200 mL), washed with brine (100 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (9:1, hexane/dichloromethane) to afford 2-(benzyloxy)-1,3-dichloro-5-nitrobenzene as a white solid (99% yield).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[OH:10][CH2:9][C:2]1[O:3][CH:4]=[C:5]([O:8][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:6](=[O:7])[CH:1]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2coc(CO)cc2=O)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a stirred slurry of kojic acid (500 g, 3.518 mol) in dry DMF (5 L) was added dry potassium carbonate (972 g, 7.036 mol) followed by 4-methoxy benzyl chloride (661 g, 4.221 mol) at 0° C. The reaction mixture was warmed to room temperature and then heated at 80° C. for 3 hours. After cooling to room temperature the reaction mixture was poured into ice cold water (15 L) and stirred vigorously. The precipitate was collected by filtration and dried under vacuum to afford the title compound as a pale brown solid (687 g, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6](C)[C:7](C1C=CC(OCCCCl)=CC=1)=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CCC=O
Temperature: 80 °C
Yield: 293 %

Procedure:
A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-3-methyl-4-oxo-butyric acid ethyl ester (7 g, 22 mmol), K2CO3 (9.3 g, 67 mmol), Nat (330 mg, 2.2 mmol), and (R)-methyl-pyrrolidinium benzenesulfonate (11 g, 47 mmol) in CH3CN (160 mL) was heated under argon at 80° C. for 36 h. The reaction mixture was concentrated at reduced pressure and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material. The crude material was purified by ISCO (80 g siliga gel column) chromatography using 2% to 9% methanol in methylene chloride to 10% methanol containing 2.5 mL ammonium hydroxide in methylene chloride to afford a pure product. The pure product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated to give 3-methyl-4-{4-R-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-butyric acid ethyl ester (8.39 g, quantitative yield), MS m/z 362 (M+H).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=P(Cl)(Cl)Oc1ccc(Br)cc1

Procedure:
Another embodiment of the invention provides a method of preparing d4T-5′-(para-bromophenyl methoxyalaninyl phosphate) in a single reaction vessel without purification of the intermediates formed. Phosphorous oxychloride is reacted with a para-bromophenol moiety to form para-bromophenyl phosphorodichloridate. Without purification, the para-bromophenyl phosphorodichloridate is contacted with alanine methyl ester to produce para-bromophenyl methoxyalaninyl phosphorochloridate. Without purification, the para-bromophenyl methoxyalaninyl phosphorodichloridate is reacted with d4T.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.Cl>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:28][CH:25]2[CH2:27][CH2:26]2)[S:7]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(CCCCBr)Cc2ccccc2N1c1ccccc1F
Reactant: NC1CC1
Agent: Cl
Product: O=S1(=O)N(CCCCNC2CC2)Cc2ccccc2N1c1ccccc1F
Yield: 92 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(4-bromobutyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.11 g, 0.26 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]butyl}cyclopropanamine (0.099 g, 92%) as a white solid:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([OH:10])=[O:9])[N:6]=1.[C:19](OC(=O)C)(=[O:21])C.C(=O)(O)[O-].[Na+].Cl>C(O)=O>[CH:19]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([OH:10])=[O:9])[N:6]=1)=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: O=CNc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Yield: 60.4 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.5 g.), acetic anhydride (2.27 g.) and formic acid (1.03 g.) were treated in a similar manner to that of Example F-(5), and the oil obtained was suspended in an aqueous solution of sodium bicarbonate. The suspension was adjusted to pH 3.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.0 g.), mp. above 230° C.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([C:18]1([C:21]2[CH:22]=[CH:23][C:24]([O:29][CH3:30])=[C:25]([CH:28]=2)[CH:26]=O)[CH2:20][CH2:19]1)#[N:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl>[C:16]([C:18]1([C:21]2[CH:22]=[CH:23][C:24]([O:29][CH3:30])=[C:25]([CH:28]=2)[CH2:26][NH:15][C@H:14]2[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:20][CH2:19]1)#[N:17]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41 %

Procedure:
To a stirred suspension of Compound 3 (150 mg, 0.60 mmol) and Compound 2 (145 mg, 0.72 mmol) in dry CH2Cl2 (5 ml) was added NaBH(OAc)3 (358 mg, 1.68 mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature for 6 h. The mixture was basified to pH10-11 with 10% NaOH aq. with ice-cooling. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product. The crude product (300 mg) was purified by column chromatography on silica gel with CH2Cl2 -MeOH (20:1-10:1) to give Compound 4 (89 mg, 41%) as a yellow viscous oil.