Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([Br:16])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C1C=CC=CC=1.[Li+].[OH-].Cl>O1CCCC1.O>[CH2:26]([O:25][C:11]1[CH:12]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([Br:16])=[CH:15][C:10]=1[C:9]([OH:33])=[O:8])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,4-Bis-benzyloxy-5-bromo-benzoic acid benzyl ester (47.8 g, 95 mmol) was then dissolved in mixture of tetrahydrofuran (150 ml) and water (150 ml). LiOH (7.2 g, 0.3 mol) was added, and the resulting mixture was stirred at 80° C. overnight. After the reaction was complete, the reaction was cooled to r.t., acidified with 1M HCl to pH=1. After extraction with Et2O (500 ml×3), the combined organics were washed with water (250 ml) and saturated brine (250 ml) and dried over Na2SO4. After filtration and concentration, 2,4-bis-benzyloxy-5-bromobenzoic acid was obtained as a white solid (37.7 g, 96%). M.p.: 116-119° C.; 400 MHz 1H NMR (CDCl3) δ: 8.36 (s, 1H), 7.45-7.33 (m, 10H), 6.59 (s, 1H); 5.19 (s, 2H), 5.17 (s, 2H); LCMS: 413, 415 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O>O.NN>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: NN
Solvent: O
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 0 °C

Procedure:
5-Fluoroisatin (8.2 g) was dissolved in 50 mL of hydrazine hydrate and refluxed for 1.0 hr. The reaction mixtures were then poured in ice water. The precipitate was then filtered, washed with water and dried in a vacuum oven to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:3]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:11]=[CH:10][CH:9]=1)#[N:8]
Reactant: N#CCOc1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cccc(OCC#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
(3-Aminophenoxy)-acetonitrile (3.0 g) was dissolved in 12 ml of pyridine, cooled in an ice bath, treated with 3.47 g of methanesulfonyl chloride, and stirred at room temperature for 3 hours. The mixture was poured into ethyl acetate, washed with hydrochloric acid, then with water, dried, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (3:7) giving 3.0 g of N-(3-cyanomethoxyphenyl )-methanesulfonamide. An aliquot of this product was crystallized from ethyl acetate:hexane (3:7) to give a solid, mp 91-92° C. ##STR56##
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([O:4][CH:1]([OH:5])[C:2]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: O=CC(=O)O
Reactant: CCCCO
Product: CCCCOC(=O)C(O)OCCCC
Yield: 2 %

Procedure:
Aqueous glyoxylic acid (50%) in the amount of 1,980 parts (13.3 moles) and butanol in the amount of 1,210 parts (16.4 moles) are heated at 55°-60° C. and stripped under vacuum. Butanol in the amount of 1,210 parts (16.4 moles) is added and the reaction is heated at 80°-85° C. under reflux at reduced pressure for two hours. Volatiles are removed at 55°-60° C. under vacuum. Butanol in the amount of 807 parts (10.9 moles) is added and the reaction mixture is refluxed at 80°-85° C. under reduced pressure for six hours. Volatiles are again removed at 55°-60° C. under vacuum to yield 2,850 parts of butyl glyoxylate butyl hemiacetal containing about 2% butyl glyoxylate dibutyl acetal. To the crude hemiacetal (765 parts 3.0 moles) are added monomethyl ether of hydroquinone (0.65 parts and acrylamide (213 parts 3.0 moles). The reaction mixture is heated at 70°-75° C. for three hours. Three intermediate strippings under vacuum removes byproduct butanol (164 parts 2.2 moles). Methanol (870 parts, 25.5 moles) containing sulfuric acid (5.5 parts, 0.056 mole) is added. The reaction mixture is refluxed for 30 minutes and then wet methanol and butane were allowed to distill while fresh methanol (475 parts, 14.0 moles) is added in proportions approximately equal to the amount removed. The reaction mixture is then heated under reflux for an additional two hours. Treatment as described in Example 1 and neutralization of sulfuric acid catalyst with lithium oxide yielded 741 parts of orange colored liquid. Analysis of proton magnetic resonance shows the product contains approximately 90-95% methyl ether and methyl ester groups.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:8])[NH:4][C:5](=[O:7])[CH:6]=1.[Br:9]Br.N>O>[Br:9][C:6]1[C:5](=[O:7])[NH:4][C:3](=[O:8])[NH:2][N:1]=1
Reactant: BrBr
Reactant: O=c1cn[nH]c(=O)[nH]1
Agent: N
Solvent: O
Product: O=c1[nH]nc(Br)c(=O)[nH]1

Procedure:
2H-[1,2,4]triazin-3,5-dione (50 g, 442 mmol) is placed in the presence of 60 ml of bromine in 800 ml of water at 60° C. for 10 h. The reaction medium is then slowly added to an ammonia solution until pH=5. It is then extracted in ethyl acetate and the organic phases are dried on MgSO4. After filtration and dry concentration, 1a is isolated in the form of a white solid (79.2 g, yield=93%). TLC silica gel 60 F 254 Merck, CH2Cl2:MeOH 90:10, Rf=0.32.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]>ClCCl.Cl>[O:26]=[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][CH:12]=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1CCCCO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 87.2 %

Procedure:
To a 250-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was added a solution of oxalic dichloride (2.52 g, 19.85 mmol, 1.98 equiv) in 40 mL of anhydrous dichloromethane. This solution was cooled to −78° C. under nitrogen. A solution of DMSO (1.56 g, 19.97 mmol, 1.99 equiv) in dichloromethane (10 mL) was added dropwise with stirring at −78° C. and the resulting solution was stirred for 20 min at −78° C. A solution of 2-(4-hydroxybutyl)-2,3-dihydro-1H-isoindole-1,3-dione (2.2 g, 10.03 mmol, 1.00 equiv) in 20 mL of dichloromethane was added dropwise with stirring. Stirring was continued for 20 min at −78° C., and then TEA (8.1 g, 80.20 mmol, 7.99 equiv) was added via syringe at the same temperature. The resulting solution was allowed to react, with stirring, for an additional 60 min at 0° C. After completion, the resulting mixture was diluted with 1 M aqueous hydrochloric acid, extracted with DCM, washed with 3×100 mL of brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:1) to provide the desired 4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)butanal (1.9 g, 87%) as a white solid. MS (ES): m/z 218 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:5]1([CH2:11][CH2:12][C:13]([Cl:3])=[O:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCc1ccccc1
Reaction time: 8 h

Procedure:
Thionyl chloride (21.8 mL, 300 mmol) was added to a solution of 3-phenylpropionic acid (15 g, 99.9 mol) in DCM (40 mL) and was stirred overnight. The mixture was concentrated in vacuo to yield intermediate (7a), which was used in the next step without further purification.
Reaction SMILES: NN.O=C1C2C(=CC=CC=2)C(=O)[N:5]1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C(O)C>[NH2:5][O:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(ON)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Hydrazine solution (1.40 g, 29.0 mmol) was added to a solution of tert-butyl 4-(1,3-dioxoisoindolin-2-yloxy)piperidine-1-carboxylate (5.00 g, 14.5 mmol) in ethanol (50 ml) and stirred at room temperature for 30 minutes. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was triturated with diethyl ether (30 ml), and the resulting solid was filtered off again and concentrated in vacuo to give tert-butyl 4-(aminooxy)piperidine-1-carboxylate (2.75 g, 88%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.[H-].[Na+].[CH2:13]([O:15][C:16](=[O:27])[C:17](P(OCC)(OCC)=O)=[CH2:18])[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16]([C:17]1[CH2:18][O:10][C:4]2[C:5]([CH:6]=1)=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:27])[CH3:14]
Reactant: C=C(C(=O)OCC)P(=O)(OCC)OCC
Reactant: O=Cc1ccc(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccc(Cl)cc2OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
4-Chloro-2-hydroxybenzaldehyde (Acta. Chem. Scand., vol. 53, p. 258 (1999)) (510 mg) was dissolved in tetrahydrofuran (40 mL), and sodium hydride (60% in oil, 157 mg) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture was added a solution of 2-diethylphosphonoacrylic acid ethyl ester (J. Org. Chem., vol. 43, p. 1256 (1978)) (769 mg) in tetrahydrofuran (10 mL), and the thus-obtained mixture was stirred at room temperature for 2 hours, followed by heating under reflux overnight. After the reaction mixture was cooled to room temperature, the mixture was partitioned between water and diethyl ether. The organic layer was dried over sodium sulfate anhydrate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to thereby give the title compound (247 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])=[CH:17][CH:16]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:45][C:46]1[CH:47]=[C:48]([O:56][CH3:57])[C:49]2[C:54]([CH:55]=1)=[CH:53][CH:52]=[CH:51][CH:50]=2.[N+](C1C=CC=CC=1O)([O-])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:45][C:46]2[CH:47]=[C:48]([O:56][CH3:57])[C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:55]=2)[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])=[CH:17][CH:16]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)[C@H](OC[C@H]2COC(C)(C)O2)C1
Reactant: COc1cc(CCl)cc2ccccc12
Agent: O=[N+]([O-])c1ccccc1O
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 3-chloromethyl-1-methoxy-naphthalene [example 1) (a)] to yield the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 773 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].CCOCC>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of the indole of Step 1 (8.9 g, 45 mmol) in DMF (150 mL) at 0° C. was added portionwise NaH (2.2 g, 55 mmol, 60% in oil). The reaction mixture was stirred for 30 minutes at 0° C. and triisopropylsilyl chloride (10.5 g, 55 mmol) was added. The reaction mixture was stirred for 30 minutes and 400 mL of Et2O was added. The reaction was quenched with saturated aqueous NH4Cl and extracted with Et2O. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 100% Hexanes to provide 16 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)ccc2c1
Product: COc1ccc2nc(Cl)ccc2c1

Procedure:
A solution of 1.7 g of 6-methoxy-2(1H)-quinolone (10 mmoles) in 25 mL POCl3 was refluxed for 2 hours. The reagent was removed under reduced pressure and the resulting gum dissolved in CH2Cl2. The solution was washed with aqueous NaHCO3 to remove remaining acid, dried over MgSO4, and then evaporated to afford 2-chloro-6-methoxy-quinoline as a solid.
Reaction SMILES: [OH-].[Na+].P(=O)(O)(O)O.[C@@H:8]1([O:39][P:40]([OH:43])([OH:42])=[O:41])[C@@H:13]([O:14][P:15]([OH:18])([OH:17])=[O:16])[C@H:12]([O:19][P:20]([OH:23])([OH:22])=[O:21])[C@@H:11]([O:24][P:25]([OH:28])([OH:27])=[O:26])[C@@H:10]([O:29][P:30]([OH:33])([OH:32])=[O:31])[C@H:9]1[O:34][P:35]([OH:38])([OH:37])=[O:36]>O>[CH:10]1([O:29][P:30]([OH:33])([OH:32])=[O:31])[CH:11]([O:24][P:25]([OH:27])([OH:28])=[O:26])[CH:12]([O:19][P:20]([OH:22])([OH:23])=[O:21])[CH:13]([O:14][P:15]([OH:18])([OH:17])=[O:16])[CH:8]([O:39][P:40]([OH:43])([OH:42])=[O:41])[CH:9]1[O:34][P:35]([OH:37])([OH:38])=[O:36]
Reactant: O=P(O)(O)O[C@H]1[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H]1OP(=O)(O)O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=P(O)(O)OC1C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C1OP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Soybeans were pressurized, and then oil therein was extracted, separated, and removed using n-hexane as an extraction solvent to obtain low denatured defatted soybeans. To 5 kg of the obtained low denatured defatted soybeans (nitrogen solubility index (NSI) 91) was added 35 kg of water, and the pH was adjusted to 7 using diluted sodium hydroxide solution. Next, it was extracted while stirring for one hour at room temperature, and then centrifuged at 4000 G to separate bean curd refuse and insolubles, to obtain defatted soybean milk. The pH of this defatted soybean milk was adjusted to 4.5 using phosphoric acid, and then centrifuged using a continuous centrifugal separator (decanter) at 2000 G, to obtain an insoluble fraction (acid precipitated curd) and a soluble fraction (whey). Water was added so that the acid precipitated curd became 10% by mass of solid content, to obtain an acid precipitated curd slurry. After the pH of this was adjusted to 4.0 using phosphoric acid, it was heated to 40° C. To this solution (phytic acid content 1.96% by mass; solid content, TCA solubilization ratio 4.6%) was added phytase (manufactured by NOVO, Inc.) of equivalent to 8 units per solid content, allowing the enzymes to act for 30 minutes. After the reaction, the pH of this enzyme-applied product (phytic acid content 0.04% by mass; solid content, TCA solubilization ratio substantially unchanged) was adjusted to 3.5, and heat treatment was performed at 120° C. for 15 seconds, using a continuous direct heat treatment sterilizer. This was then spray dried, to obtain 1.5 kg of low phytate soybean protein powder. The dissolution ratio of this protein (pH 3.5) was 95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Li][CH2:13]CCC.CI.O>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:13])[S:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2ccsc2c1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2cc(C)sc2c1
Temperature: -50 °C
Yield: 97 %

Procedure:
20.20 g (0.12 mol) of 6-Methoxybenzo[b]thiophene diluted in 450 mL of anhydrous THF are introduced into a 3-necked round-bottomed flask under nitrogen. The mixture is cooled to −50° C. 64 mL (0.14 mol) of a 2.5M solution of nBuLi in hexane are added dropwise. The resulting mixture is stirred for 1 h30 at −40° C. and then cooled to −78° C. 52 g (0.36 mol) of MeI are added. The mixture is allowed to return to room temperature, then hydrolysed with 250 mL of water. The water-THF mixture is extracted three times with 300 mL of Et2O. The resulting organic phase is washed several times with saturated aqueous NaCl solution, dried over magnesium sulfate and then concentrated under reduced pressure. The solid collected is recrystallised from methanol to give a white solid (21.25 g, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.Cl[Si:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][Si:18](Cl)([CH3:20])[CH3:19]>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[Si:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][Si:15]2([CH3:23])[CH3:22])=[N:3][CH:4]=1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: Nc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 2-amino-5-bromopyridine (5.00 g, 28.90 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to −78° C., and then treated with a 2.5M solution of n-butyllithium in hexanes (11.68 mL, 29.20 mmol). The resulting reaction mixture was stirred for 1 h, at which time, a solution of 1,2-bis(chlorodimethylsilyl)ethane (6.22 g, 28.90 mmol) in tetrahydrofuran (15 mL) was added dropwise to the reaction. The reaction mixture was stirred for another 90 min at −78° C. and then was treated with another portion of a 2.5M solution of n-butyllithium in hexanes (11.68 mL, 29.20 mmol). The reaction was slowly warmed to 25° C. where it was stirred for 2 h. The reaction was then quenched by the addition of a saturated aqueous sodium chloride solution (50 mL) and then extracted with diethyl ether (2×200 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Kugelrohr distillation at 125–135° C. at 0.5 mmHg afforded 5-bromo-2-(2,2,5,5-tetramethyl-[1,2,5]azadisilolidin-1-yl)-pyridine (5.38 g, 59%) as a white solid: mp 50.4–55.8° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][C:4]1[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([I:1])[CH:3]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Reaction time: 2 h

Procedure:
To a flask containing the product of Step 2 (2.79 g, 7.06 mmol) in DMF (71 mL) were added tert-butyldimethylsilyl chloride (1.60 g, 10.59 mmol), imidazole (0.96 g, 14.12 mmol) and DMAP (86 mg, 0.71 mmol). After two hours, the reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography on silica gel afforded N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-iodophenyl]-4-(trifluoromethyl)pyrimidin-2-amine. MS ESI calc'd. for C18H24F31N3OSi: [M+H]+ 510. found 510.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Li])CCC.IC>C1COCC1.CCCCCC>[C:1]([SiH2:5][O:6][C:7]([CH3:21])([CH3:20])[C:8]1[N:9]=[C:10]([CH3:22])[N:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn(-c2ccc(F)cc2)cn1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(C(C)(C)O[SiH2]C(C)(C)C)cn1-c1ccc(F)cc1
Temperature: -25 °C
Reaction time: 0.17 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-1H-imidazole is dissolved in THF and cooled to −78° C. n-Butyl lithium in hexane is added dropwise. The reaction mixture is warmed up to −25° C., kept at −25° C. for 10 min and then cooled again to −78° C. Iodomethane is added dropwise. The reaction mixture is slowly warmed up to room temperature and stirred at room temperature overnight. The desired compound 4-(tert-butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole is obtained.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:26]([F:29])([F:28])[F:27])[C:6]=1[CH3:30].COC(=O)CC1C2C(=NC=CC=2)NC=1C.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.BrCC1C=CC(S(CC)(=O)=O)=CC=1C(F)(F)F>CN(C=O)C>[CH2:24]([S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:6]2[CH3:30])=[C:16]([C:26]([F:28])([F:29])[F:27])[CH:17]=1)(=[O:23])=[O:22])[CH3:25]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(C(F)(F)F)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: COC(=O)Cc1c(C)[nH]c2ncccc12
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[1-(4-Ethanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.77 g, 3.78 mmol) in dry DMF (12 ml) under an inert atmosphere of Argon is added dropwise, BEMP (1.75 ml, 6.04 mmol). The mixture was allowed to stir at room temperature for 1 hour and then treated with 1-bromomethyl-4-ethanesulfonyl-2-trifluoromethyl-benzene (2 g, 6.04 mmol). Stirring continues for a further 2 hours after which time, the reaction mixture is partitioned between ethyl acetate/diethyl ether (80 ml of a 1:1 mixture) and water (100 ml). The organic portion is separated and washed with brine and concentrated in vacuo. Purification of the crude by chromatography on silica eluting with iso-hexane/ethyl acetate (3:1 increasing to 2:1) yields the titled product. (MH+455)