Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:18]C)[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].C[Si](Cl)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([OH:18])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CC(C)(C)C(=O)Oc1ccc(O)cc1C(C)(C)C
Yield: 95 %

Procedure:
5.00 g of 3-t-butyl-4-trimethylacetoxyanisole was dissolved in 45 ml of acetonitrile and 4.54 g of sodium iodide was added at room temperature under a nitrogen stream and 3.84 ml of trimethylsilyl chloride was further added dropwise. This solution was refluxed for 6 hours, then poured into a saturated aqueous sodium bicarbonate solution and extracted with diethyl ether. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 17% ethyl acetate) to give 4.50 g of 3-t-butyl-4-trimethylacetoxyphenol as a white solid (yield 95%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[C:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:30])[CH2:22][N:23]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24]2)[CH2:19][CH:20]=1)=[O:6]>C(O)C.[Pd]>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:30])[CH2:22][N:23]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24]3)[CH2:19][CH2:20]2)=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:31]=[CH:32][CH:33]=[CH:2][CH:3]=2)[CH:13]=1
Reactant: Cc1cc(C)n(CC(=O)N2CC=C(c3ccc(Cl)cc3NC(=O)c3cccc(Cl)c3)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)n(CC(=O)N2CCC(c3ccc(Cl)cc3NC(=O)c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 10.7 %

Procedure:
To a solution of 3-chloro-N-(5-chloro-2-{1-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-phenyl)-benzamide (0.100 g, 0.207 mmol) in ethanol (5 mL) is added Pd on 5% activated carbon (10 mg) in a round bottom flask and the mixture is purged three times and back filled with H2 using a H2 filled balloon. The reaction is allowed to stir at room temperature for 20 h. The reaction is filtered through a pad of diatomaceous earth and washed with MeOH. The filtrate is concentrated and purified via preparative HPLC. Removal of the solvent gives 0.010 g of N-(5-chloro-2-{1-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-benzamide in 10% yield. MS MH+=450.2 and 0.030 g of N-(2-{1-[2-(3,5-Dimethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-benzamide in 35% yield. MS MH+=417.3.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[C:14]4[CH:22]=[CH:21][CH:20]=[CH:19][C:15]4=[CH:16][CH:17]=3)[NH:12][C:11](=[O:23])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[C:14]4[CH:22]=[CH:21][CH:20]=[CH:19][C:15]4=[CH:16][CH:17]=3)[NH:12][C:11](=[O:23])[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc(=O)[nH]c3c2ccc2ccccc23)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1nc(-c2cccc(O)c2)c2ccc3ccccc3c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
To an ice-cold suspension of 4-(3-methoxyphenyl)-1H-benzo[h]quinazolin-2-one (120 mg, 0.397 mmol) in dichloromethane (2 mL) was added 1M boron tribromide in dichloromethane (400 μL, 0.400 mmol). The mixture was stirred at room temperature for 18 hours. The resultant mixture was poured into a saturated aqueous sodium bicarbonate solution. The precipitated solid was collected by filtration, purified by silica gel column chromatography (chloroform/methanol=97/3), and recrystallized from DMF/methanol to give the titled compound as a yellow crystal (41 mg, yield 36%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:11])[CH2:7]1
Reactant: C=CCN
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2cccc(C)c2)C1
Reaction time: 18 h

Procedure:
A stirred solution of 3.92 g (0.01 mole) of crude (57.59%) 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated with 2.25 g (0.03 mole) of 2-propenylamine. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and a reddish oil separated. A sample of this oil crystallized at -70° C. and was used to seed the oil residue. The resulting solid was collected by filtration to yield 3.6 g which was recrystallized from benzene-ligroin yielding, after charcoal treatment, 1.53 g (62.2%) of pale beige crystals, m.p. 95°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([NH2:18])=[S:17])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.Br.CS(C)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: COc1cnc(N2CCOCC2)cc1NC(N)=S
Agent: Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cnc(N2CCOCC2)c2sc(N)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a stirred suspension of 3.51 g (13.1 mmol) (5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea in 75 ml ethyl acetate heated to reflux was added dropwise over 5 min 4.59 ml (26.2 mmol) hydrobromic acid (5.7 M solution in acetic acid) and stirring continued for a further 15 min. 1.12 ml (15.7 mmol) DMSO was then added dropwise and the reaction mixture stirred for a further 30 min at reflux. The mixture was then cooled to room temperature and partitioned between tetrahydrofuran and saturated brine. 5 N sodium hydroxide solution was added until the aqueous phase was pH 14, then 10% aq. citric acid solution was added until the aqueous phase was pH 6. The mixture was stirred for 20 min and then the phases were separated. The organic phase was dried over sodium sulfate and concentrated in vacuo. Trituration of the residue in ether afforded 2.23 g (64%) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine as an off-white crystalline solid. ES-MS m/e (%): 267 (M+H+, 100).
Reaction SMILES: O([C:3](C)(C)C)[K].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])[CH:9]=1>CN1C(=O)CCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[N:14]([CH3:3])[C:16]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH3:24])=[CH:15]2
Reactant: CC(C)(C)O[K]
Reactant: C[C@@H]1CCCN1CCC#Cc1cc(Br)ccc1N
Solvent: CN1CCCC1=O
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a cooled (0° C.) suspension of KO-tBu (95%, 6.2 g, 52 mmol) in NMP (120 mL) was added a solution of 4-bromo-2-[4-(2-(R)-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine (8.0 g, 26 mmol) in NMP (50 mL) dropwise keeping the temperature below 5° C. The resulting mixture was then stirred at room temperature for 3 hours under nitrogen. HPLC indicated that all the starting material was consumed. Mel (1.95 mL, 31.3 mmol) was then added. The resulting mixture was stirred at room temperature for 2 hours. HPLC indicated that all the indole intermediate was methylated. H2O (300 mL) was added slowly to the reaction mixture followed by addition of IPAc (400 mL). The resulting mixture was stirred for 5 minutes and the organic layer was separated. The organic layer was washed with 20% brine (3×150 mL), dried over Na2SO4 and treated with activated carbon. After filtration, the filtrate was concentrated under vacuum to give the title compound as a thick oil (7.5 g), which was used in the next coupling reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=1.8 Hz, 1H), 7.36 (dd, J=1.8, 8.7 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 6.37 (s, 1H), 3.81 (s, 1H), 3.40-3.45 (m, 1H), 3.26-3.34 (m, 1H), 3.04-3.16 (m, 2H), 2.51-2.61 (m, 2H), 2.39 (q, J=8.78 Hz, 1H), 2.09-2.14 (m, 1H), 1.87-1.99 (m, 2H), 1.61-1.68 (m, 1H), 1.30 (d, J=6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 140.30, 135.60, 129.18, 123.08, 121.92, 112.29, 109.95, 98035, 60.16, 54.22, 53.19, 32091, 29.86, 26.85, 22.00, 19.34. [M+H]+ at m/z 322.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH2:9]([N:11]([CH2:22][CH3:23])[C:12](=[O:21])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH3:10].[I:24]I>O1CCCC1>[CH2:22]([N:11]([CH2:9][CH3:10])[C:12](=[O:21])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[I:24])[CH3:23]
Reactant: CCN(CC)C(=O)Oc1cccc(Cl)c1
Reactant: II
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1cccc(Cl)c1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of lithium diisopropylamine (2M in THF) (21.40 ml; 42.8 mmol) in dry tetrahydrofuran (117 ml) under nitrogen atmosphere at −78° C. was added 3-chlorophenyl diethylcarbamate (8.86 g; 38.91 mmol). The reaction mixture was stirred for 30 min at −78° C., and iodine (0.669 g; 46.7 mmol) was added. The solution was stirred for 30 min. at 0° C. and was then allowed to warm up to room temperature for 2 h. The reaction mixture was quenched by adding water and the organics were removed under reduced pressure. The aqueous phase was extracted with ethyl acetate, washed with a solution of hydrochloric acid 1 N, dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford 8.32 g (55%) of 3-chloro-2-iodophenyl diethylcarbamate as brown solid.
Reaction SMILES: O(C)[Na].C(OC)(=O)CC(OC)=O.BrCC(C)C.[OH-].[Na+].[CH2:20]([CH:24]([C:28](O)=O)[C:25]([OH:27])=[O:26])[CH:21]([CH3:23])[CH3:22].CNC.C=O.C(=O)=O.OS(O)(=O)=O>CO.O.C(OCC)(=O)C>[CH2:20]([C:24](=[CH2:28])[C:25]([OH:27])=[O:26])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CC(C(=O)O)C(=O)O
Agent: C=O
Agent: CNC
Agent: CO[Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)CBr
Product: C=C(CC(C)C)C(=O)O

Procedure:
A solution of 860 ml (3.74 mole) of 25% of NaOCH3 in CH3OH and an equal volume of CH3OH is warmed to near reflux. Dimethyl malonate (425 ml, 3.74 mole) is added, followed by 410 ml (3.74 mole) of 1-bromo-2-methyl propane. Heating back to reflux gives a clear yellow solution. Refluxing under N2 for 18 hours gives a slurry. While at reflux a total of 425 ml of 50% NaOH is added plus enough water to dissolve the precipitated salts, for a total reaction volume of 5 liters. The basic (pH=14) mixture is refluxed until little cloudiness is observed on dilution of a sample with water. Distillation until T≅90°, cooling in ice, acidification with 25% H2 SO4 to pH=1, and extraction with 4 liters of ethyl acetate gives on drying and evaporation, a slurry. Benzene is added and the slurry evaporated to a solid. Trituration with hexane, filtering and drying in air gives 402 g, m.p. 101°-105° (67%). An additional 25 g, m.p. 92°-101°, were obtained on further extraction with ethyl acetate and rework of the mother liquors, for a total of 427 g (71%). A 410 g (2.56 mole) sample of isobutyl malonic acid is dissolved in 3.5 liters of water. This yellow solution is cooled in ice and treated with 288 g (2.56 mole) of 40% aqueous dimethylamine. Stirring with cooling is continued, and when the internal temperature equals 10° C., 210 g (2.56 mole) of 37% formalin is added. The resulting clear yellow solution is stored at 5° C. for 21/2 days, whereupon it is a solid mass of white solid. This mixture is carefully brought to near reflux (foaming) with stirring, and held there until the solution is clear and CO2 is no longer evolved to a significant extent (heated 2 hours after complete solution). The mixture is cooled in ice and acidified strongly with 350 ml of 7.2 M H2SO4 (pH=1). Extraction with 2 liters of hexane and drying (Na2SO4) gives 206 g of isobutyl acrylic acid. Extraction with another 2 liters of hexane gives 6 g, for a total of 212 g (65%) of the unsaturated acid.
Reaction SMILES: [NH2:1][CH:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].N[C@H](C([O-])=O)CCC([O-])=O.[Na+].[Na+].[C:25](O)(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].S(=O)(=O)(O)O>O.CC(C)=O>[C:25]([NH:1][CH:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: NC(CCC(=O)O)C(=O)O
Agent: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)NC(CCC(=O)O)C(=O)O
Temperature: 0 °C

Procedure:
DL-Glutamic acid 14.7 g was suspended in 75 ml water and 45 ml acetone and then added 8 g of sodium hydroxide. To the solution of the sodium glutamate was added lauric acid-sulfuric acid mixed anhydride with 10 N sodium hydroxide at pH 12 - 13 on the ice bath with stirring. The reaction mixture was stirred for an additional 1 hour, then treated by the same manner as in Example 1. N-Lauroyl-DL-glutamic acid was obtained 19.7 g (59.7 %) M.P. 116° - 119°C.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[N:8]=1)=O.O.[NH2:23][NH2:24]>C(O)C>[CH3:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:5]3[C:4]([CH2:17][CH2:18][CH3:19])=[C:3]([S:2][CH3:1])[NH:24][N:23]=3)=[N:8][C:9]=2[CH:15]=1
Reactant: NN
Reactant: CCCC(C(=O)c1nc2cc(C)ccc2[nH]1)=C(SC)SC
Solvent: O
Solvent: CCO
Product: CCCc1c(-c2nc3cc(C)ccc3[nH]2)n[nH]c1SC

Procedure:
A mixture of 2-(bis-methylsulfanyl-methylene)-1-(5-methyl-1H-benzoimidazol-2-yl)-pentan-1-one [˜0.49 mmole, Reference Example 2(l)] and hydrazine hydrate (200 μL) in ethanol (6 mL) was heated at reflux temperature for 2 days, then evaporated. The mixture was then treated with hydrochloric acid (4 mL, 4N) and heating was continued at reflux temperature for a further 24 hours. The reaction mixture was cooled, then neutralised by addition of sodium hydroxide solution (4N) and then extracted with dichloromethane. The extract was evaporated to give 5-methyl-2-(5-methylsulfanyl-4-propyl-1H-pyrazol-3-yl)-1H-benzoimidazole. MS: 287 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:6]([CH:8]([C:11](=O)[CH3:12])[C:9]#[N:10])[CH:7]=1.Cl.Cl.[NH2:26][NH2:27].C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C:5]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:6]([C:8]2[C:11]([CH3:12])=[N:26][NH:27][C:9]=2[NH2:10])[CH:7]=1
Reactant: COCCOc1cc(F)cc(C(C#N)C(C)=O)c1OCCOC
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCCOc1cc(F)cc(-c2c(C)n[nH]c2N)c1OCCOC
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of 2-(5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.26 mg, 0.80 mmol) in ethanol (5 mL) was added hydrazine dihydrochloride (105 mg, 0.9 mmol). The resulting mixture was heated at reflux for 1 hour. It was cooled to room temperature then poured into a saturated sodium bicarbonate solution (10 mL) and the mixture was extracted with ethyl acetate (3×10 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 5% methanol-dichloromethane) to provide 4-(5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-methyl-1H-pyrazol-5-amine (0.15 g, 0.45 mmol, 56%) yield 1H NMR (400 MHz, d6-DMSO): 7.06-7.02 (m, 1H), 6.72-6.69 (m, 1H), 4.18-4.16 (m, 2H), 3.83-3.81 (m, 2H), 3.71-3.69 (m. 2H), 3.36-3.64 (m, 2H), 3.32 (s, 3H), 3.10 (s, 3H), 2.16 (s, 3H); MS (EI) for C16H22FN3O4: 340 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[C:11]([C:12]([C:14]2[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(OC)c1C(O)c1cc2ccccc2nc1Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1Cl
Temperature: 25 °C

Procedure:
(2-Chloroquinolin-3-yl)(2,6-dimethoxyphenyl)methanol (0.5 g, 1.5 mmol) and triethylamine (0.84 mL, 6.1 mmol) were dissolved in dimethyl sulfoxide (20 mL) and mixed with a solution of sulfur trioxide-pyridine complex (0.72 g, 4.55 mol) in dimethyl sulfoxide (5 mL) under nitrogen. The batch was stirred at room temperature until the reaction was complete (TLC monitoring). After adding water, the mixture was stirred for 1 hour at room temperature. The precipitated product was filtered with suction, washed with water and dried in a vacuum drying cabinet (20 mbar, 50° C.). Yield: 0.45 g (1.37 mmol, 91%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:35][NH:36][S:37](CC(C)C)(=[O:39])=[O:38])=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-:44].[K+:45]>C(O)(C)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:35][N:36]([CH2:21][CH:22]([CH3:29])[CH3:23])[S:37]([O-:38])(=[O:44])=[O:39])=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[K+:45]
Reactant: [OH-]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)CC(C)C)nc32)[C@H](O)[C@@H]1O
Agent: [K+]
Solvent: CC(C)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN(CC(C)C)S(=O)(=O)[O-])nc32)[C@H](O)[C@@H]1O
Yield: 145.1 %

Procedure:
N-({9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-2-methyl-1-propanesulfonamide (example 15) (1.9 g, 3.11 mmol) was dissolved into isopropyl alcohol (20 ml) and a 4 molar solution of potassium hydroxide (0.9 ml, 3.11 mmol) added. The isopropyl alcohol was removed by evaporation under reduced pressure and more isopropyl alcohol (20 ml) added to the residue, then the solvent removed under reduced pressure again. The residue was suspended in isopropyl alcohol (160 ml) and then the suspension heated under reflux for 1 hr. The resulting suspension was allowed to cool and then filtered. The white solid was washed with a little isopropyl alcohol and then dried. This gave the title compound (1.5 g) as a white crystalline solid m.p. 231° C.
Reaction SMILES: C(=O)([O-])O.[Na+:5].CC1(C)CC(=O)CC(=O)C1.P(OCC)(OCC)OCC.C([O:29][C:30]([C:32]1[N:36]2[C:37](=[O:42])[C@H:38]([C@H:39]([OH:41])[CH3:40])[C@H:35]2[C@@H:34]([CH3:43])[C:33]=1[S:44][C@H:45]1[CH2:49][NH:48][C:47](=[S:50])[CH2:46]1)=[O:31])C=C>O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O1CCCC1>[Na+:5].[NH:48]1[CH2:49][C@H:45]([S:44][C:33]2[C@H:34]([CH3:43])[C@@H:35]3[C@@H:38]([C@H:39]([OH:41])[CH3:40])[C:37](=[O:42])[N:36]3[C:32]=2[C:30]([O-:31])=[O:29])[CH2:46][C:47]1=[S:50]
Reactant: C=CCOC(=O)C1=C(S[C@H]2CNC(=S)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@H]3CNC(=S)C3)[C@H](C)[C@H]12
Reaction time: 0.05 h
Yield: 90 %

Procedure:
A mixture of sodium hydrogen carbonate (0.84 g) in water (10 ml), dimedone (0.84 g) and tetrahydrofuran (80 ml) is treated with ultrasonics, and thereto is added palladium diacetate (0.11 g) and triethyl phosphite (0.58 g) under nitrogen atmosphere, and the mixture is stirred for three minutes. To the mixture is added (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (3.83 g), and the mixture is stirred at 35°-37° C. for 45 minutes. The mixture is stirred at 5° C. for 30 minutes, and the precipitated crystals are collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylic acid sodium salt (3.28 g).
Reaction SMILES: [CH:1](Br)([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.[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:22])[NH:17]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]([N:20]1[CH2:19][C@H:18]([CH3:22])[NH:17][C@H:16]([CH3:15])[CH2:21]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
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1
Reaction time: 8 h

Procedure:
Benzhydryl bromide (4.33 g, 17.5 mmol) is added to s stirred solution of 2,6-cis-dimethylpiperazine (2.00 g, 17.5 mmol) and diisopropylethylamine (2.94 g, 22.8 mmol) in anhydrous dichloromethane (50 mL) at 0° C. The resultant mixture is allowed to stir overnight. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 1-3%, benzhydryl-3,5-cis-dimethyl-piperazine is obtained as a white solid (3.0 g, 61% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([O:26][C:27]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37])(=[O:25])=[O:24])=[CH:18]2.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O.C(Cl)Cl.ClCCCl>[CH2:38]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([O:26][C:27]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37])(=[O:25])=[O:24])=[CH:18]2)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=Cc1ccccc1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)cccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A 10-mL round-bottom flask was charged with perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate (from STEP 2 of INTERMEDIATE KK) (56.79 mg, 0.102 mmol), DCE (509 μl), and benzaldehyde (31.0 μl, 0.306 mmol) to give a suspension. Sodium triacetoxyborohydride (43.2 mg, 0.204 mmol) was added, followed by an additional portion of DCE (509 μl) to thin the mixture. After 1 h, a saturated aq. Rochelle's salt solution (3 mL) and DCM (2 mL) were added, and the resulting mixture was stirred vigorously for 3 h. The mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on a 12-g with 0 to 40% EtOAc/Heptane to give perfluorophenyl 5-(1-benzylpyrrolidin-2-yl)naphthalene-2-sulfonate (52.93 mg, 0.099 mmol, 97% yield) as a clear oil: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.86-8.70 (m, 2H), 8.22-8.10 (m, 2H), 8.00 (dd, J=2.2, 9.1 Hz, 1H), 7.81-7.73 (m, 1H), 7.33-7.26 (m, 4H), 7.25-7.17 (m, 1H), 4.20 (t, J=8.2 Hz, 1H), 3.77 (d, J=13.2 Hz, 1H), 3.20 (d, J=13.2 Hz, 1H), 3.13-3.02 (m, 1H), 2.48-2.40 (m, 1H), 2.33 (q, J=9.2 Hz, 1H), 1.93-1.82 (m, 2H), 1.78-1.60 (m, 1H); m/z (ESI) 534.4 (M+H)+.