Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.[H-].[Na+].[CH2:13]([OH:15])C.C(OCC)=O>CCOCC.O>[OH:15][CH:13]=[C:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC=O
Solvent: O
Product: CC1(C)OC(C)(C)C(=CO)C1=O
Temperature: 0 °C
Yield: 79 %

Procedure:
Mercuric oxide (600 mg) was dissolved in 200 mL of water containing 2 mL of concentrated H2SO4. Solid 2,5-dimethyl-3-hexyne-2,5-diol (50.0g, 352 mmol) was added and the solution was heated until the homogeneous solution turned cloudy. Heating was stopped and the flask was stirred in a room temperature water bath for 30 min. The solution was distilled and 250 mL of distillate was collected (more H2O was added). The biphasic material was taken up into ether, separated, washed with brine, dried over MgSO4, filtered, evaporated and distilled (150° C.) to give 44.5 g (89%) of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone as a water-white oil. Dihydro-2,2,5,5-tetramethyl-3(2H)furanone (32.1 g, 226 mmol) in 50 mL of ether was added dropwise to a suspension of sodium hydride (18.1 g of 60%, 453 mmol) in 400 mL of ether containing two drops of ethanol and 36.5 mL (453 mmol) of ethyl formate stirred at 0° C. After stirring overnight at room temperature, the reaction mixture was taken up into water, washed with additional ether, acidified with 6N HCl and extracted into ether. The combined ether layers were washed with water and brine, dried over MgSO4, decolorized with charcoal, filtered through celite and evaporated. The solid residue was recrystallized from a small volume of ether and a large quantity of hexanes. The solid was isolated by filtration and dried to give 30.4 g (79%) of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)-furanone as an off-white solid. Ethylenediamine (1.15 mL, 17.4 mmol) was added to a solution of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)furanone (5.9 g, 34.7 mmol) in 40 mL of THF. This solution was refluxed for one hour. The solvents were evaporated under high vacuum with moderate heating. The solid residue was slurried in 50 mL of cold ether and filtered to give 5.3 g (76%) of off-white solid. Recrystallization from 50 mL of THF followed by drying at 70° C. (1 Torr) for 6 hours gave 4.0 g of 1,2-bis[dihydro-2,2,5,5-tetramethyl3(2H)furanone-4-methyleneamino]ethane as a white solid: Anal. Calc'd for C20H32N2O4 : C, 65.93; H, 8.79; N, 7.69. Found: C, 65.68; H, 8.90; N, 7.65.
Reaction SMILES: [OH-:1].[Na+].OO.CS(C)=O.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]#[N:22])=[C:19]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[N:18]=1>O.C(O)C>[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17]1[C:24]([F:25])=[CH:23][C:20]([C:21]([NH2:22])=[O:1])=[C:19]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[N:18]=1
Reactant: N#Cc1cc(F)c(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc2ncccc12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5M sodium hydroxide aqueous solution (0.1 ml) and a 30% hydrogen peroxide solution (0.1 ml) were added to a solution of dimethyl sulfoxide (1 ml) and ethanol (0.5 ml) containing 6-(((1R,2S)-2-aminocyclohexyl)amino)-5-fluoro-2-(quinolin-5-ylamino)nicotinonitrile (20 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. 4M hydrogen chloride/1,4-dioxane (0.5 ml) was added to the obtained residue, the resulting precipitate was collected by filtration, and a red solid of 6-(((1R,2S)-2-aminocyclohexyl)amino)-5-fluoro-2-(quinolin-5-ylamino)nicotinamide (12 mg) was thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:21])=O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:21][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 3-[(3-nitroquinolin-4-yl)amino]propan-1-ol (20.75 g, 83.93 mmol), thionyl chloride (15.0 g, 125.89 mmol), and dichloromethane (420 mL). The bright yellow, homogeneous solution was stirred at ambient temperature for 2 hours at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and he resulting solid stirred in water (400 mL) made basic (pH 10) with solid sodium carbonate. A bright yellow solid was collected by filtration to afford N-(3-chloropropyl)-3-nitroquinolin-4-amine (21.63 g, 81.41 mmol) which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[C:13]([C:15]1[CH:42]=[CH:41][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25](/[CH:29]=C4/C(=O)N(CC(O)=O)C(=O)S/4)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[C:17]([C:43]([F:46])([F:45])[F:44])[CH:16]=1)#[N:14]>>[C:13]([C:15]1[CH:42]=[CH:41][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25](/[CH:29]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:26][CH:27]=3)[CH:22]=[N:21]2)=[C:17]([C:43]([F:46])([F:45])[F:44])[CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CC(=O)O)C4=O)ccc32)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C#N)cc3C(F)(F)F)c2)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Cyano-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-cyano-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 346) following General Procedure E.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13](OCC)=[O:14])[C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>O1CCCC1>[OH:14][CH2:13][C:12]1[C:7]2[CH2:6][CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[CH:2]([OH:1])[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cccc2c1CCc1ccccc1C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1CCc1ccccc1C2O
Reaction time: 2 h
Yield: 104.2 %

Procedure:
560 mg of ethyl 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-1-carboxylate prepared in Example 1-b was dissolved in 20 ml dry tetrahydrofuran, and 120 mg of lithium aluminum hydride was added under ice-cooling, followed by stirring for 2 hours. To the reaction mixture were successively added 0.1 ml of water, 0.1 ml of 15% potassium hydroxide solution and 0.3 ml of water, followed by stirring at room temperature for 0.5 hour. The reaction mixture was filtered through Celite, washed with ethyl acetate, and the solvent was evaporated, to give 500 mg of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Li+].F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[N+:17]([C:16]1[C:11]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:12][CH:13]=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: CC(O)C(F)(F)F
Reactant: O=[N+]([O-])c1cccnc1F
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(Oc1ncccc1[N+](=O)[O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1,1,1-Trifluoro-2-propanol (3.2 g) was dissolved in THF (4.0 ml) and cooled to 0° C. Then LiH MDS (1M in THF; 28.3 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 20 minutes. A solution of 2-fluoro-3-nitro-pyridine (4.0 g) in THF (1 ml) was added and the mixture was stirred overnight. It was quenched by addition of saturated NH4Cl solution and extracted with dichloromethane. The organic layer was dried and concentrated in vacuo.
Reaction SMILES: Cl.[NH2:2][C:3](=[O:30])[CH2:4][CH2:5][N:6]([C:23](OC(C)(C)C)=[O:24])[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1>C(OCC)(=O)C>[O:24]=[C:23]1[NH:2][C:3](=[O:30])[CH2:4][CH2:5][N:6]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N(CCC(N)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.8 %

Procedure:
4N Hydrogen chloride in ethyl acetate (4 mL) was added to a solution of benzyl 4-[(3-amino-3-oxopropyl)(tert-butoxycarbonyl)amino]piperidin-1-carboxylate (3.38 g) obtained in Example 45c) in ethyl acetate (16 mL), and the mixture was stirred at room temperature for 15 hours. The white solid (2.73 g) formed was collected by filtration. A solution of the resulting white solid (1.0 g), CDI (0.47 g) and DBU (0.89 g) in dichloroethane (30 mL) was refluxed for 15 hours. The reaction mixture was washed with an aqueous 5% citric acid solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (0.21 g, 21%) as a white powder.
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:15]=1.C(N(C(C)C)C(C)C)C>C(OCC)(=O)C.O.CN(C=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][N:22]([CH2:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH2:4][CH2:5][CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:15]=1
Reactant: BrCCCOC1CCCCO1
Reactant: c1cncc(CCNCc2ccncc2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: c1cncc(CCN(CCCOC2CCCCO2)Cc2ccncc2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 13.3 %

Procedure:
Sodium iodide (1.5 g, 10 mmol) was added to a DMF solution (20 ml) of 2-(3-bromopropoxy)tetrahydropyran (0.85 ml, 5 mmol), and stirred at 70° C. for 7 hours. The reaction mixture was cooled to room temperature. (2-Pyridin-3-ylethyl)pyridin-4-ylmethylamine (1.28 g, 6 mmol) and N-ethyl diisopropylamine (1.3 ml, 7.5 mmol) were then added to the reaction mixture and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water, and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was concentrated under reduced pressure to thereby obtain 236 mg (yield: 13%) of (2-pyridin-3-ylethyl)pyridin-4-ylmethyl-[3-(tetrahydropyran-2-yloxy)propyl]amine as a colorless oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11].Cl[C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([CH3:22])=[CH:15][N+:14]=1[O-:23]>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([CH3:22])=[CH:15][N+:14]=1[O-:23]
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c[n+]([O-])c(Oc2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a suspension of sodium hydride (0.47 g, 60% in oil) in 50 mL of THF was added dropwise a solution of 1 mL of 2,4-difluorophenol in 10 mL of THF. The reaction mixture was stirred for one hour, and 2-chloro-5-methyl-4-nitropyridine-1-oxide (2.0 g) was added slowly. The resulting mixture was stirred at reflux for 8 hours and at room temperature overnight. The solvent was removed and the light yellow solid isolated by extraction with methylene chloride. Purification via chromatography (silica gel, ethyl acetate/hexane, 1:1) gave 1.65 g of 2-(2,4-difluorophenoxy)-5-methyl-4-nitropyridine-1-oxide (55% yield). Mass Spec. M+H=283.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH:16]=[CH:17][CH2:18][NH:19][OH:20])=[CH:4][CH:3]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C.Cl>O1CCOCC1>[OH:20][N:19]([CH2:18][CH:17]=[CH:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:26]([NH2:25])=[O:27]
Reactant: ONCC=Cc1c(F)cccc1Sc1ccc(F)cc1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)N(O)CC=Cc1c(F)cccc1Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[3-[2-(4-fluorophenylthio)-6-fluorophenyl]prop-2-enyl]hydroxylamine (0.91 g, 3.1 mmol) is dissolved in 16 ml of dry dioxane. Trimethylsilyl isocyanate (0.36 g, 3.1 mmol) is then added dropwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is poured into 1N HCl solution and then extracted twice with diethyl ether. The extracts are washed with water and then with brine and dried over K2CO3 to afford the crude product. Recrystallization from ethyl acetate afforded the subtitle compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:17]1([C:23]([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:27]=[CH:26][C:25]([C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:24])=[CH:30][CH:29]=2)=[CH:3][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3ccc(C(=O)N4CCOCC4)cc3)cnc2N)nn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (4-(morpholine-4-carbonyl)phenyl)boronic acid (183 mg, 0.77 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (690 mg, 2.12 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (40 mg, 0.03 mmol) was added and allowed to stir at 110° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5% MeOH in DCM to afford 100 mg (yield: 35.97%) of the title compound as pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[CH3:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>>[CH3:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:1]1[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CNc1ccccc1N
Product: Cn1c(-c2cccc(C(=O)O)c2)nc2ccccc21
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield (428 g, a slight brown solid) from 3-formylbenzoic acid (500 mg, 3.33 mmol) and N1-methylbenzene-1,2-diamine (407 mg, 3.33 mmol) by the similar manner in Intermediate-7.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[CH:7][CH:6]=2)[C:3]([OH:34])=[O:2])(=[O:21])=[O:22])=[CH:24][CH:25]=1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)O)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A mixture of methyl({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate (2.52 g, 5.19 mmol) and 5N NaOH (5.18 mL) in THF (32 mL) and methanol (32 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in water and neutralized with HCl to pH˜6. The precipitated solid was filtered to provide 1.61 g of ({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetic acid as a white solid. Yield 66%. mp 245-247° C. Electrospray Mass Spec 473.2 (M+H)+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=2)=[C:16]([F:45])[CH:15]=1>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=[C:22]([C:17]3[C:16]([F:45])=[CH:15][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:19]([O:20][CH3:21])[CH:18]=3)[C:30]=12
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
trans-2-phenyl-1-cyclopropanecarbonyl chloride (32 mg, 0.176 mmol) in dichloromethane (0.3 mL) was added to a solution of trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.176 mmol) in pyridine (1.5 mL) at 0° C. After 5 minutes the ice-water bath was removed and the reaction mixture was stirred at room temperature for 3 hours. More trans-2-phenyl-1-cyclopropanecarbonyl chloride (32 mg, 0.176 mmol) was added to ensure the reaction went to completion. Solvent was evaporated and the residue was purified by flash column chromatography to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2-phenyl-1-cyclopropanecarboxamide (93 mg, 88%). 1H NMR (DMSO-d6) δ 1.35 (m, 1H), 1.50 (m, 3H), 1.98 (m, 6H), 2.19 (s, 3H), 2.37-2.68 (m, 11H), 3.87 (s, 3H), 4.64 (m, 1H), 7.09 (m, 1H), 7.21 (m, 3H), 7.31 (m, 2H), 8.21 (m, 2H), 9.82 (m, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=599.3, Rt=1.97 min.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[C:4]([F:21])[CH:3]=1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:28]>O>[Br:28][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([F:21])[CH:3]=1
Reactant: Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cc(Br)ccc1N1CCNCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (885 mg, 3 mmol) in 8 mL of aq HBr was added a solution of NaNO2 (228 mg, 3.3 mmol) in 2 mL of H2O at 0° C., then the mixture was stirred at 0° C. for 40 minutes. After that, the mixture was poured into a solution of CuBr (905 mg, 6.3 mmol) in 8 mL aq HBr at 0° C. The reaction was heated to 60° C. and stirred for 2 hours. After cooling, the mixture was based with 2M NaOH to pH=8-9 and extracted with EA, washed with H2O and brine, dried and concentrated to give black solid. MS (m/z): 261 (M+H)+
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[CH2:8]([N:15]([CH2:17][CH2:18]Cl)[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1(C)C=CC=CC=1.O.CO>[CH3:3][CH:2]([CH3:4])[CH2:1][O:5][CH2:18][CH2:17][N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:16]
Reactant: CC(C)CO
Reactant: CN(CCCl)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)COCCN(C)Cc1ccccc1
Yield: 71.7 %

Procedure:
A solution of 5.0 g of isobutanol in 50 ml of toluene was added at a temperature of 0° C. to a solution of 3.25 g of sodium hydride in 100 ml of toluene, and the reaction mixture was heated under reflux for 3 hours. 12.4 g of N-benzyl-N-methyl-2-chloroethylamine were then added to the reaction mixture, and the solution was heated under reflux for a further 8 hours. The reaction solution was worked up by cautiously adding 5 ml of methanol and then 100 ml of water, and the pH was then adjusted to pH 2 by adding dilute aqueous hydrochloric acid solution. After shaking, the organic phase was separated and discarded. The aqueous phase was adjusted to pH 13 by addition of aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, filtered and concentrated. The remaining residue was purified by chromatography on silica gel using n-hexane/ethyl acetate as the eluent. 10.7 g of N-[2-(2,2-dimethylethoxy)ethyl]-N-benzyl-N-methylamine were obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([CH2:25][CH2:26][C:27]1([CH2:33][CH2:34][O:35][C:36]2[CH:37]=[C:38]([C:45]([O-])=[O:46])[CH:39]=[C:40]([CH:44]=2)[C:41]([O-])=[O:42])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O1CCCC1.O.C(OCC)C>[O:7]([CH2:25][CH2:26][C:27]1([CH2:33][CH2:34][O:35][C:36]2[CH:44]=[C:40]([CH2:41][OH:42])[CH:39]=[C:38]([CH2:45][OH:46])[CH:37]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](OCCC1(CCOc2cc(C(=O)[O-])cc(C(=O)[O-])c2)CCCCC1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCC1(CCOc2cc(CO)cc(CO)c2)CCCCC1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Lithium aluminum hydride (172 mg) was suspended in tetrahydrofuran (10 mL). To this was added a solution of dimethyl 5-[2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethoxy]isophthalate (synthesized in Example 24) (1.30 g) in tetrahydrofuran (15 mL) dropwise at room temperature. The suspension was stirred for 3 hours. Water (0.16 mL) was added to the suspension and it was stirred for 10 minutes. A 15% aqueous sodium hydroxide solution (0.16 mL) was added to the suspension and it was stirred for 15 minutes. Diethyl ether was added to the mixture, followed by addition of water (0.48 mL). The solution was stirred for 30 minutes. The solution was dried over anhydrous magnesium sulfate, filtered and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, ethyl acetate] to give the title compound (1.04 g).