Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[C:10]([O:20][N:21]=C(C)C)=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][CH3:19])[C:12]2=[N:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:18]([N:15]1[C:12]2=[N:13][CH:14]=[C:9]3[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:21][O:20][C:10]3=[C:11]2[CH:17]=[N:16]1)[CH3:19]
Reactant: CCn1ncc2c(ON=C(C)C)c(C(=O)c3ccccc3)cnc21
Agent: Cl
Solvent: CCO
Product: CCn1ncc2c3onc(-c4ccccc4)c3cnc21
Yield: 80.5 %

Procedure:
5-Benzoyl-1-ethyl-4-isopropylideneaminooxy-1H-pyrazolo[3,4-b]pyridine (2.50 g) was refluxed for 2 hours in a mixture prepared from 100 ml of 5% hydrochloric acid and 15 ml of ethanol. The reaction mixture was then extracted into ether and washed consecutively with 5% sodium hydroxide solution and water. Evaporation of the organic phase gave 1.65 g of product. An analytical sample recrystallized from ethyl acetate/methanol had mp 151°-153° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:7])([CH3:6])[CH3:5])#[N:2].N1C=CC=CC=1.[C:14](Cl)([Cl:16])=[O:15]>ClCCl>[C:1]([CH2:3][C:4]([O:7][C:14]([Cl:16])=[O:15])([CH3:6])[CH3:5])#[N:2]
Reactant: CC(C)(O)CC#N
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(CC#N)OC(=O)Cl
Temperature: 25 °C

Procedure:
Chloroformic cyanotert. butyl ester is prepared by reacting cyanotert butanol (10 g, 100 mMole) and pyridine (10 g, 125 mmole) in dichloromethane (150 ml) at about -40° C. together with liquid phosgene (-70° C., 40 ml, 600 mMole). The mixture is allowed to warm to room temperature and stirred over night. It is then extracted with ice cold aqueous hydrochloric acid (1N) washed twice with ice water immediately dried by shaking several times with fresh anhydrous sodium sulfate, the aqueous phases and the sodium sulfate are twice reextracted with a small amount of dichloromethane, and the combined organic phases are evaporated under reduced pressure (20° C. bath) to yield the product (17 g, 100% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:12]([C:18](OCC)=[O:19])[C:13](OCC)=[O:14])[CH2:8][CH2:9][CH2:10][CH3:11].Cl>O1CCCC1.O>[CH2:7]([CH:12]([CH2:18][OH:19])[CH2:13][OH:14])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(CO)CO
Yield: 67.9 %

Procedure:
35 g (0.92 mol) of lithium aluminum hydride was dispersed in 420 cm2 of anhydrous tetrahydrofuran (THF) and 193 g (0.84 mol) of diethyl pentylmalonate was added drop-wise to the dispersion while stirring at a speed to gently reflux the THF. The solution was refluxed and stirred for 3 hours. The product of the reaction was cooled with water and THF containing 10% water was added until the mixture ceased to foam. 500 cm2 of concentrated hydrochloric acid was added. The oily layer was separated and the water layer was extracted three times with 200 cm3 of ether. The oily layer and the ether layers were combined and washed with a saturated aqueous solution of sodium chloride. The ether layer was dried with anhydrous sodium sulfate and boiled to distil off the ether. The residue of the distillation was subjected to vacuum distillation (b.p. 120° C./2 Torrs) to yield 83 g (0.57 mol) of 2-pentylpropane-1,3-diol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([C@H:22]3[CH2:23][CH2:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]3)=[O:21])[CH2:18][CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)[C@H]3CC[C@H](C(=O)O)CC3)CC2)CC1

Procedure:
Prepared from ethyl trans-4-[[-4-[1-(tert-butyloxycarbonyl)-piperidin-4-yl]-piperazin-1-yl]-carbonyl]-cyclohexane-carboxylate by hydrolysis with lithium hydroxide analogously to Example 24. Mass spectrum: (M+H)+ =424; Rf value: 0.24 (silica gel; methylene chloride/methanol/concentrated ammonia=4:1:0.2)
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:40](Cl)(=[O:42])[CH3:41].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:40](=[O:42])[CH3:41])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCCc1cccc2ccccc12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 3-[4-amino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (300 mg, 0.54 mmol) and acetyl chloride (45 mg, 0.57 mg) in methylene chloride (10 mL) was added triethylamine (58 mg, 0.57 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in ethyl acetate (50 mL). The resulting solution was extracted with 0.1N HCl (50 mL) and brine (50 mL), dried (MgSO4), and evaporated to give 3-(4-acetylamino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (300 mg) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12].C1(NN=CC2C=CC=CC=2O)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>CN(C)C=O.O.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH3:12])[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C[C@@H](N)C(=O)O
Agent: [Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 80 °C
Reaction time: 16 h
Yield: 60.4 %

Procedure:
A mixture of 6.00 g (22.00 mmol) 3,4-dichloroiodobenzene, 2.94 g (33.00 mmol) D-alanine, 0.42 g (2.20 mmol) copper(I) iodide, 0.96 g (4.40 mmol) 2-hydroxybenzaldehyde phenylhydrazone, 14.00 g (66.00 mmol) tri-potassium phosphate in 32 ml of N,N-dimethylformamide was stirred at 80° C. for 16 h under argon, then after cooling diluted with water and acidified to pH 3 by addition of 25% aq. HCl solution. The mixture was extracted with EtOAc (3×), the organic phases were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2; dichloromethane/MeOH 95:5 to 4:1) afforded 3.11 g (60%) of the title compound (as 81:19 mixture of the (R) and (S) stereoisomers, BGB-175*0.25 column) as light brown solid. MS: 231.9 (M−H−, 2Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>[Pd].CO>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc[n+]([O-])cc1C
Agent: [Pd]
Solvent: CO
Product: COc1ccncc1C
Yield: 90.2 %

Procedure:
A mixture of 4 g (28.8 mmol) 3-methyl-4-methoxy pyridine N-oxide (prepared according to the method described in Kohl, Bernhard et al; J. Med. Chem.; 1992; 1049-1057) and 1.1 mg of 5% palladium on charcoal in 50 ml of methanol is hydrogenated at 20 atms at room temperature for 12 hours (2*6 hours). Filtration through celite, and evaporation gave 3.2 g (90%) of a light green oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](=[O:25])(=[O:24])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:23][O:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][S:11]([CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)(=[O:25])=[O:24]
Reactant: COC(=O)c1ccc(CS(=O)(=O)NCc2ccc(OC)cc2OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(CO)cc2)c(OC)c1
Yield: 108 %

Procedure:
To a solution of 4-[(2,4-dimethoxybenzylsulfamoyl)methyl]benzoic acid methyl ester (6 g) in THF (300 ml) was added, at 0° C., lithium aluminum hydride (1.5 g) in portions, and the mixture was stirred at room temperature for 1 h. Then water (9 ml), 6 M NaOH (7 ml) and water again (27 ml) were added successively. The solids were filtered off and dichloromethane was added to the filtrate. The organic phase was removed, dried over magnesium sulfate and concentrated. This gave the product (6 g) with a molecular weight of 351.4 g/mol (C17H21NO5S).
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[CH:39][C:40](Br)=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].CN(C)[CH:45]=[O:46].[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.CO>[C:35]([N:19]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[C:40]([CH2:45][OH:46])[CH:39]=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CN(C)C=O
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
Add butyl lithium (0.157 mL, 0.252 mmol, 1.6 M in hexanes) dropwise to a solution of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.100 g, 0.168 mmol) in tetrahydrofuran (2 mL) under nitrogen at −78° C. and stir for 1 h. Add N,N-dimethylformamide (0.052 mL, 0.672 mmol) dropwise to the cold solution and stir for 40 min at −78° C. then warm to room temperature. Quench the reaction with saturated aqueous ammonium chloride (10 mL) and dilute with ethyl acetate (20 mL). Separate the layers and wash the organic layer with water (2×30 mL) and brine (30 mL), then dry over sodium sulfate, filter and remove solvent under reduced pressure to provide the crude aldehyde. Dissolve the crude aldehyde (0.091 g, 0.167 mmol) in methanol (3 mL) and add sodium borohydride (0.019 g, 0.501 mmol) in one portion at room temperature. After stirring for 3 h, dilute the reaction with ethyl acetate (25 mL) and wash with brine (40 mL), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the crude material by chromatography on silica gel, eluting with acetonitrile to provide the title compound as an off-white solid (0.008 g, 8%): ESI MS 547 (M+H).
Reaction SMILES: B.C1COCC1.[N+:7]([C:10]1[CH:18]=[C:14]([C:15](O)=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl.C(OC)(C)(C)C>C1COCC1>[OH:16][CH2:15][C:14]1[CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[CH:12][C:13]=1[OH:19]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=[N+]([O-])c1ccc(O)c(CO)c1
Temperature: 15 °C
Reaction time: 7 h
Yield: 76.2 %

Procedure:
To a BH3.THF solution (110 mL, 1M, 110 mmoles) was added dropwise a solution of 5-nitro-salicylic acid (10.0 g, 54.6 mmoles) in 930 mL THF. After a few milliliters, the reaction mixture was cooled with ice to maintain a temperature of about 15° C. The clear brown solution was warmed to room temperature and stirred for an additional 7 hours. During this time a precipitate formed. BH3.THF (20 ml, 20 mmoles) was added and stirring was continued overnight. The mixture was cooled to 5° C. and carefully hydrolyzed with 1 M HCl (100 mL). Methyl tert-butyl ether (MTBE) (100 mL) was added, the phases were separated and the aqueous layer was extracted with MTBE (2×70 mL). The combined organic layers were dried over MgSO4 (10 g), filtered and evaporated to give 10.5 g of a pale ochre solid. This solid was recrystallized from 65 mL toluene to give 7.033 g (76%) of 2-hydroxymethyl-4-nitrophenol as a pale ochre solid.
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4](=[O:13])[CH2:3]1.Br[CH2:15][CH2:16][Cl:17]>CO.C(Cl)Cl.O>[Cl:17][CH2:16][CH2:15][N:5]1[C:4](=[O:13])[CH2:3][CH:2]([CH3:1])[N:6]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCCBr
Reactant: CC1CC(=O)NN1c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC1CC(=O)N(CCCl)N1c1ccccc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A sodium methylate solution, obtained from 3.9 g sodium and 80 ml methanol is added to a suspension of 26.1 g 5-methyl-1-phenylpyrazolin-3-one in 200 ml methanol. After stirring for 30 minutes, 43.02 g 1-bromo-2-chloroethane are added to the clear solution at ambient temperature. The reaction mixture is heated for 15 hours under reflux. Then the solvent is drawn off under reduced pressure. The residue which remains is dissolved in 250 ml methylene chloride and 100 ml water. The organic phase is separated off, dried over sodium sulphate, filtered, and the solvent is evaporated off under reduced pressure. The residue is dissolved in ethyl ether, and the solution is filtered to remove the remaining initial material. Then the solvent is evaporated and the residue (27 g) is boiled in 100 ml butanol or 8 hours under reflux. Finally, the solvent is evaporated in a vacuum and the residue is purified by column chromatography over silica gel. 20 g 2-(2-chloroethyl)-5-methyl-1-phenylpyrazolin-3-one are obtained as an oil.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10](=[O:16])[N:11]([CH3:15])[CH2:12][CH2:13][CH3:14])[CH:7]=[N:6][C:5]=1[Cl:17].[OH-].[Na+]>CO.O>[Cl:17][C:5]1[N:6]=[CH:7][C:8]([C:10](=[O:16])[N:11]([CH3:15])[CH2:12][CH2:13][CH3:14])=[CH:9][C:4]=1[C:3]([OH:18])=[O:2]
Reactant: CCCN(C)C(=O)c1cnc(Cl)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(C)C(=O)c1cnc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 2-chloro-5-(methyl-propylcarbamoyl)-nicotinic acid methyl ester (96 mg, 0.35 mmol) in 1 N sodium hydroxide (0.71 mL, 0.71 mmol) and methanol (2 mL). Stir at room temperature for 2 h. Concentrate organic and redissolve the residue in water (15 mL). Wash with dichloromethane (3×10 mL), acidify the aqueous layer with 1 N HCl to about pH=2. Extract with dichloromethane, dry (sodium sulfate) and concentrate to give the crude title product which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]=O)[CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:19]=1[CH3:20])=[O:13]
Reactant: C1COCCN1
Reactant: CCN(c1cc(-c2cccc(C=O)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCN(c1cc(-c2cccc(CN3CCOCC3)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (270 mg, 0.53 mmol) and morpholine (94 mg, 1.07 mmol) in dichloroethane (5 mL), acetic acid (194 mg, 3.23 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (343 mg, 1.61 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (200 mg, 65%). LCMS: 573.25 (M+1)+; HPLC: 90.21% (@ 254 nm) (Rt; 4.048; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.20 (t, 1H), 7.52 (s, 1H), 7.49 (d, 2H, J=7.6 Hz), 7.39 (d, 1H, J=5.6 Hz), 7.29 (d, 1H, J=7.2 Hz), 7.20 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.82-3.84 (m, 2H), 3.56 (m, 4H), 3.52 (s, 2H), 3.22-3.30 (m, 2H), 3.08-3.10 (m, 2H), 3.01 (m, 1H), 2.37 (s, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.54 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[CH:14]=[C:12]([CH3:13])[C:11]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[SH:25][CH2:26][CH2:27][OH:28]>CN(C)C=O.C(OCC)(=O)C>[OH:28][CH2:27][CH2:26][S:25][C:12]1([CH3:13])[CH2:14][C:15](=[O:16])[N:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:11]1=[O:17]
Reactant: OCCS
Reactant: CCCCCCCCCN1C(=O)C=C(C)C1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCN1C(=O)CC(C)(SCCO)C1=O

Procedure:
A solution of N-nonyl citraconimide (0.5 mM) prepared as described in Example 5 above in dimethylformamide (10 ml) was treated with triethylamine (0.5 mM) and then 2-mercaptoethanol (0.5 mM) was added dropwise. The progress of the reaction was monitored by thin layer chromatography and when the starting material could no longer be detected the reaction mixture was concentrated in vacuo. The residue obtained was dissolved in ethyl acetate, washed with water and dried over sodium sulfate. Purification by chromatography yielded the desired product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11].[I:12][C:13]1[C:21]2[C:16](=[N:17][C:18](S(C)(=O)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:14]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:18]1[N:17]=[C:16]2[N:15]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:14]=[C:13]([I:12])[C:21]2=[CH:20][N:19]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cnc(S(C)(=O)=O)nc21
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cnc(Oc3ccc(F)cc3F)nc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
Sodium hydride (3.88 g of 60% dispersion in mineral oil, 0.097 mol) was added to 150 mL of dry DMF under nitrogen, and the reaction mixture was cooled in an ice bath. 2,4-Difluorophenol (8.85 mL, 0.092 mol) was added dropwise over 10 minutes (maintaining temperature between 5 and 10° C.), after which the reaction mixture was stirred for 15 minutes at 0° C., followed by 15 minutes of stirring at room temperature. A solution of 3-Iodo-6-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (11.91 g, 0.026 mol) in 100 mL dry DMF was added, and the reaction mixture was heated to 140° C. for four hours while stirring under nitrogen. The reaction mixture was cooled to room temperature, and volatiles were removed under reduced pressure. The was added to 200 mL of 10% aqueous ammonium chloride, 50 mL water, and 250 mL EtOAc. The aqueous phase was partitioned off and extracted once with 250 mL EtOAc. The combined organic phases were washed with saturated aqueous brine, dried over MgSO4, filtered, and evaporated under reduced pressure to yield an oil. The oil was eluted through silica gel with hexanes EtOAc (20:1 to 10:1) to afford 6.23 g of 6-(2,4-Difluoro-phenoxy)-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2>CO.O=[Pt]=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][CH2:13][CH2:12][CH2:11]2
Reactant: COCCOc1cccc2cccnc12
Agent: O=[Pt]=O
Solvent: CO
Product: COCCOc1cccc2c1NCCC2

Procedure:
8-Methoxyethoxyquinoline (6.48 g, 31.9 mmol) was dissolved in methanol (50 ml) and reduced on a Parr hydrogenation apparatus using PtO2 catalyst. The catalyst was removed, and the solution was taken to dryness. The dark brown oil which remained was purified on a short silica gel column using 4:1 heptane:ethyl acetate for elution. The isolated oil (1,2,3,4-tetrahydro-8-methoxyethoxyquinoline) had the following NMR spectrum: (CDCl3) δ 1.93 (quintet, 2, CH2 (beta-H)), 2.76 (tr, 2, CH2), 3.32 (tr, 2, CH2), 3.43 (s, 3, OMe), 3.72 (tr, 2, OCH2), 4.11 (tr, 2, CH2O), 4.31 (br, 1, NH), 6.57 (s, +sh, 3, Ar-3H). Anal. Calcd. for C12H17NO2 : C, 69.54; H, 8.27; N, 6.76. Found: C, 69.42; H, 8.26; N, 6.70.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22].Cl>O1CCOCC1.CO.O1CCOCC1.CCOC(C)=O>[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][C:16]=1[CH3:22]
Reactant: COC(=O)Cc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1C
Temperature: 100 °C
Reaction time: 54 h

Procedure:
A mixture of 1.5 g of 2-chloro-3-nitro-pyridine, 3.39 g of (4-amino-2-methyl-phenyl)-acetic acid methyl ester and 6.9 ml of an 4 N solution of HCl in dioxane in 30 ml of MeOH/dioxane (1:1, v/v) is stirred for 54 hours at 100° C. The mixture obtained is allowed to cool to rt and concentrated in vacuo. The concentrate obtained is dissolved in EtOAc, the mixture obtained is washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The concentrate obtained is subjected to silica gel column chromatography. [2-Methyl-4-(3-nitro-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester is obtained. ES-MS: 302.1 [M+H]+; tR=4.79 min (System 1); Rf=0.43 (CH2Cl2).