Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].C.C1C(Br)=C(Br)[NH:15]C=1C(O)=O.[N+]([O-])(O)=O.N([O-])=O.[Na+]>O>[OH-:2].[S:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]#[N:15])=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2]
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: N#[N+]c1ccc(S(=O)(=O)O)cc1
Product: [OH-]
Temperature: 25 °C

Procedure:
A solution of 43 g of sulfanilic acid in 2 L of water at about 75° C. was added to 202 g of a carbon black having a surface area of 230 m2 /g and a DBPA of 70 ml/100 g with stirring. The stirring mixture was allowed to cool to room temperature, and 26.2 g of concentrated nitric acid was added. A solution of 20.5 g of NaNO2 in water was added. 4-Sulfobenzenediazonium hydroxide inner salt is formed, which reacts with the carbon black. The dispersion was stirred until the resulting bubbling stopped. After drying at 70° C., the product was washed with methanol and dried in an oven at 90° C. The product has attached p-C6H4SO3- groups.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:15])[CH2:13][CH3:14].[CH2:16]=O.[OH-].[Na+]>C(O)(=O)C.O>[N:1]1([CH2:16][CH:10]2[CH:11]=[N:7][C:8]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: C1COCCN1
Reactant: CCC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)C1=CC(CN2CCOCC2)C=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of morpholine (89.3 mmoles) in acetic acid (50 ml) at 0° C. there are added 1-(1H-pyrrol-2-yl)-propan-1-one (81.2 mmoles) and formaldehyde (89.3 mmoles) 37% in water. The reaction mixture is stirred overnight at ambient temperature. After concentration of the mixture, the solution is brought to alkaline pH (10-12) using 20% aqueous NaOH solution at 0° C. and is then extracted with DCM. The organic phase is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness and purified by flash chromatography on silica gel (SiO2; gradient 100% AcOEt to AcOEt/MeOH 9/1) to yield the title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)=[O:4].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1
Temperature: 40 °C
Yield: 91.7 %

Procedure:
To a mixture of methyl-m-toluate (180 g, 1.2 mol) and N-bromosuccimide (235 g, 1.32 mol) in CCl4 (2 L) was added in portion benzoyl peroxide (18 g, 0.1 times) at 50° C. The mixture was refluxed for 5 h. Then the mixture was allowed to cool down to 40° C. and the solid was filtered off. The filtrate was concentrated to give methyl 3-(bromomethyl)benzoate (252 g, 91%) as light yellow liquid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:26])=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)[N:13]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:12]=1>O1CCCC1>[Cl:26][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])=[N:12][N:13]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:18][C:17]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(Cl)cc21
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(NC(=O)Nc2ccccc2)c2cc(-c3ccccc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Stage 1: 39 □l of phenyl isocyanate are added to a solution of 102.2 mg of 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilylethoxy)methyl]indazole in 2.5 cm3 of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 24 hours and is then evaporated. Purification of the crude product by chromatography on silica (eluant: methylene chloride/acetone (98/2, v/v)) makes it possible to obtain 122.5 mg of 1-[6-chloro-5-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-3-yl]-3-phenylurea (colorless solid).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:19])=[N:8][N:9]2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[C:28]1([C:34]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:35]2[CH:39]=[C:38]([C:40](=[O:42])[CH3:41])[N:37]=[CH:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[NH2:18][C:14]1[N:13]=[C:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[C:2][C:40]([C:38]4[N:37]=[CH:36][N:35]([C:34]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[CH:39]=4)([OH:42])[CH3:41])[CH:11]=3)[C:7]([CH3:19])=[N:8]2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (180 mg at 90% purity, 0.65 mmol) in THF (2.5 mL) at −78° C. under nitrogen was added 2M LDA in THF (0.81 mL, 1.63 mmol). After 5 minutes 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (458.08 mg, 1.3 mmol) in THF (1.5 mL) was added. After 20 minutes, the mixture was allowed to warm up to RT and stirred for a further 1 hr. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (1 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 2-12% methanol gradient in DCM) to give the title intermediate as a yellow oil: 1H NMR (500 MHz, CDCl3) delta 1.96 (3H, s), 2.58 (3H, s), 4.41 (1H, s), 5.36 (2H, s), 6.96 (1H, d, J=1.0), 7.19-7.09 (6H, m), 7.24 (1H, d, J=5.7 Hz), 7.35-7.30 (10H, m), 7.44 (1H, d, J=1.0 Hz), 7.53 (1H, d, J=8.2), 8.24 (1H, d, J=5.7), 8.83 (1H, s); LC-MS: m/z=+360.35 (M-C(C6H5)3)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OC(=O)[NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([Br:29])=[CH:27][N:26]=[C:25]([Cl:30])[N:24]=1)(C)C>C(#N)C.Cl.O>[ClH:30].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]1[C:28]([Br:29])=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1Br
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: NCCCNc1nc(Nc2ccc(S(N)(=O)=O)cc2)ncc1Br
Yield: 74.3 %

Procedure:
To a solution of 4-aminobenzenesulfonamide (190 mg) in acetonitrile (20 mL), hydrochloric acid solution (4M in dioxane, 0.3 mL) and water (0.3 mL) was added (3-((5-bromo-2-chloro-4-pyrimidinyl)amino)propyl)-carbamic acid-1,1-dimethylethyl ester (360 mg). The resulting mixture was refluxed overnight. The precipitate was collected and washed with acetonitrile and methanol to afford the title compound (320 mg).
Reaction SMILES: [C:1](#[N:3])C.[F:4][C:5]([F:23])([F:22])[CH:6]([C:15]1[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=1)[O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10].C[Si](C#N)(C)C>C(N(CC)CC)C>[F:4][C:5]([F:23])([F:22])[CH:6]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:1]#[N:3])[CH:16]=1)[O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CC#N
Reactant: CC[Si](CC)(CC)OC(c1cc[n+]([O-])cc1)C(F)(F)F
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OC(c1ccnc(C#N)c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To 40 ml of acetonitrile were added 5 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine N-oxide, 5.26 ml of triethylamine, and 5.62 g of trimethylsilyl cyanide, and the mixture was stirred at 90° C. for 20 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 3 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine-2-carbonitrile.
Reaction SMILES: [CH3:1][S:2]([CH2:5]P(=O)(OCC)OCC)(=[O:4])=[O:3].[Li+].[Cl-].C1CCN2C(=NCCC2)CC1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:41]2[C:49]3[C:44](=[C:45]([CH:50]=O)[CH:46]=[CH:47][CH:48]=3)[CH:43]=[CH:42]2)([CH2:39][CH3:40])[C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=1>CC#N.C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:41]2[C:49]3[C:44](=[C:45](/[CH:50]=[CH:5]/[S:2]([CH3:1])(=[O:3])=[O:4])[CH:46]=[CH:47][CH:48]=3)[CH:43]=[CH:42]2)([CH2:39][CH3:40])[C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(C=O)cccc21
Reactant: CCOP(=O)(CS(C)(=O)=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(/C=C/S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl methylsulfonylmethylphosphonate (1.05 g, 4.56 mmol) in CH3CN (30 mL) at RT was added LiCl (0.16 g, 3.80 mmol) and DBU (2.40 g, 9.56 mmol). After 5 min, a solution of methyl 2-(4-chlorophenyl)-2-(4-formyl-1H-indol-1-yl)butanoate (1.35 g, 3.80 mmol) in CH3CN (10 mL) was added dropwise. The resulting mixture was stirred for 4 hours at RT. Then it was diluted with DCM (50 mL) and the organic layer was washed with water (30 mL), dried over Na2SO4, filtered. After removal of the solvent, the residue was purified via column chromatography (0-30% EtOAc/hexanes) to provide the title compound. LC/MS m/z=432.0[M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(=S)=S.[CH2:8]([N:10]([CH2:17][CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9].[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21]>C(Cl)(Cl)Cl.O>[CH2:17]([N:10]([CH2:8][CH3:9])[C:11]1[CH:16]=[CH:15][C:14]([C:19](=[O:23])[C:20]([C:14]2[CH:15]=[CH:16][C:11]([N:10]([CH2:17][CH3:18])[CH2:8][CH3:9])=[CH:12][CH:13]=2)=[O:21])=[CH:13][CH:12]=1)[CH3:18]
Reactant: CCN(CC)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc(C(=O)C(=O)c2ccc(N(CC)CC)cc2)cc1

Procedure:
To 11.6 g of anhydrous aluminum chloride, 60 ml of carbon disulfide was added, followed by dropwise addition of 30 g of N,N-diethylaniline under ice-cooling. Then, 10 g of oxalyl chloride was added dropwise thereto at 5° C. or lower, followed by the reaction for 1 hour with stirring. After the reaction, the reaction solution was poured into 100 ml of water and 200 ml of chloroform. The chloroform layer obtained by separation was washed with 2N hydrochloric acid, dried and concentrated. The residue was recrystallized from ethyl acetate to give yellow 1,2-bis(4-diethylaminophenyl)ethane-1,2-dione in an amount of 7.0 g.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:15][N:16]=1.Cl>O.CO>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[NH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])=[N:16][CH:15]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2ccccc2OC)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccccc1-c1cnc(CCCCCCC(=O)O)[nH]1
Temperature: 40 °C
Yield: 76.3 %

Procedure:
Add a solution of sodium hydroxide (1.85 g, 46 mmol) in water (40 mL) to a solution of 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid methyl ester (5.84 g, 18.5 mmol) in methanol (30 mL) at room temperature under nitrogen and heat the mixture at 40° C. for 4.5 hours. Cool the mixture and treat with 1 N HCl (46 mL) and heat at reflux for 30 minutes. Collect the precipitate, wash with water (3×30 mL), and dry under reduced pressure for 12 hours. Triturate the solid with methylene chloride (50 mL) at reflux for 40 min and collect by filtration to provide 7-[5-(2-methoxyphenyl)-1H-imidazol-2-yl]heptanoic acid (4.27 g, 77%). APCI mass spectrum m/z 301 [C17H22N2O3−H]−.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>ClCCl>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:9]2[S:10][CH:11]=[CH:12][C:8]=2[O:7][CH3:6])=[O:20])=[CH:17][CH:16]=1
Reactant: COc1ccsc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2sccc2OC)cc1
Reaction time: 8 h

Procedure:
2.7 ml of tin tetrachloride were added to a solution of 2.3 g of 3-methoxy-thiophene and 3.4 g of 4-methoxybenzoyl chloride in 50 ml of dichloromethane while cooling in ice. The mixture was stirred at room temp. overnight. For workup, 75 ml of 2 hydrochloric acid were added and the mixture was extracted three times with dichloromethane. The combined organic phases were washed twice with each of 2 N sodium carbonate solution and water, and then the solvent was removed in vacuo, and the crude product was purified by column filtration (SiO2, ethyl acetate/n-heptane=1:2). The product with the molecular weight of 248.3 (C13H12O3S), MS (Cl): 249 (M+H+) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OCC1CC1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Yield: 59.4 %

Procedure:
A mixture of 3.0 g (13 mmol) 5-Bromo-6-chloro-nicotinic acid, 1.4 g (19 mmol) (hydroxymethyl)cyclopropane and 2.85 g (51 mmol) potassium hydroxide in DMSO (12 mL) was heated under microwave radiation for 6 min to 100° C. 50 mL water and 150 mL citric acid (10%) was added. A solid precipitated, was filtered off, re-dissolved in ethyl acetate and dried with Na2SO4. The product crystallized upon evaporation of the solvent from ethyl acetate/heptane 1:1 to yield 2.1 g (71%) of the title compound as white solid, MS (ISP): 270.3 (M−H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1OCc1ccccc1
Yield: 85.7 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (0.55 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was heated under reflux for 1 hr. The reaction mixture was neutralized by adding 1N hydrochloric acid and water, and the precipitated crystals were collected by filtration to give 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.45 g, yield 85%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 184-185° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13])=[O:5])[CH3:2].[Cl-].[CH3:15][NH2+]C.C=O>>[CH:12]([C:11](=[CH2:15])[CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:13]
Reactant: CCOC(=O)COCCCCC=O
Reactant: C[NH2+]C
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCCOCC(=O)OCC

Procedure:
16 g (85 mmol) of 5-ethoxycarbonylmethoxypentanal, 7.8 g (95.2 mmol) of dimethylammonium chloride and 7.4 ml (99.4 mmol) of a 37% solution of formaldehyde are stirred for 1 hour at a bath temperature of 110° C. The reaction mixture is allowed to cool and extracted three times with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and concentrated by evaporation giving ethyl 7-formyl-3-oxaoct-7-enoate as a colourless oil which is further reacted without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH2:19][CH3:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH2:32][C:23]2[CH:22]=[C:21]([CH2:18][CH2:19][CH3:20])[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:24]=2)[CH2:11][CH2:10]1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Product: CCCc1cc(CNCCN2CCN(c3ccc(C)cc3C)CC2)nn1-c1ccccc1
Yield: 73.6 %

Procedure:
Compound 27 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][NH2:16]>>[CH3:15][NH:16][S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1

Procedure:
10.5 g (45 mmol) of 4-acetylaminobenzenesulfonyl chloride are stirred at 50° C. for 3 hours in 100 ml of 40% strength methylamine solution. The solution is then extracted three times with ethyl acetate. The organic phases are dried using Na2SO4 and concentrated. The residue is stirred with dichloromethane and the insoluble constituents are filtered off. Concentration of the filtrate gives the desired sulfonamide in adequate purity and almost quantitative yield. (MS-CI+: 229.1; LCMS Rt=3.249 min)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:3]=1.[CH2:15]([NH2:17])[CH3:16]>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:17][CH2:15][CH3:16])[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1
Reactant: CCN
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CC(C)=O
Product: CCNc1nc(NC(C)C)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3.5 grams of 4,6-dichloro-2-isopropylamino-5-pyrimidinecarbonitrile in 100 ml of acetone was cooled to between 0° and -5°; a solution of 2.1 grams of aqueous 70% ethylamine in 25 ml of acetone was added dropwise. Upon complete addition, the reaction mixture was warmed to room temperature and stirred for 18 hours. The acetone was removed under reduced pressure, and the residue was extracted with a mixture of diethyl ether and water. The organic layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was recrystallized from methylcyclohexane to give 3.1 grams of 4-chloro-6-ethylamino-2-isopropylamino-5-pyrimidinecarbonitrile; mp, 144°-146°.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]3[C:8](I)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[N:13][C:14]=3[NH2:15])[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)[CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2c1c(I)nn2C1CCCC1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)nn2C1CCCC1
Temperature: 85 °C
Yield: 12.3 %

Procedure:
To a mixture of 1-cyclopentyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.631 mmol, 1 equiv) and 3-(benzyloxy)phenylboronic acid (0.110 g, 0.487 mmol, 1.0 equiv) in DME (6 mL) was added tetrakis(triphenylphosphine)palladium (0.044 g, 0.038 mmol, 0.07 equiv) and a solution of sodium carbonate monohydrate (0.187 g, 1.51 mmol, 2.4 equiv) in water (2 mL). The mixture was heated at 85° C. for 16 h, then allowed to cool to ambient temperature. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to afford an oily red-orange solid. Recrystallization from hot EtOAc afforded a red-orange solid which was purified by preparative RP-HPLC (Rainin C18, 8μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to afford 3-[3-(benzyloxy)phenyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.023 g, 0.060 mmol): 1H NMR (d6 CDCl3, 400 MHz): δ H 8.34 (1H, s), 7.27-7.46 (8H, m), 7.07-7.10 (1H, m), 5.63 (2H, bs), 5.31 (1H, quint, J=7.6 Hz), 5.16 (2H, s), 2.15-2.20 (4H, m), 1.96-2.01 (2H, m), 1.72-1.75 (2H, m); RP-HPLC (Hypercil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 15 min, 1 mL/min) Rt 14.00 min. MS: MH+ 386.