Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:6].C1C[O:21][CH2:20]C1.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CCOC(C)=O>[CH3:20][O:21][N:4]([CH3:3])[C:5]([C:7]1[N:8]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)=[O:6]
Reactant: COCNC(=O)c1ccc(-c2ccccc2)[nH]1
Reactant: Fc1ccc(CBr)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(-c2ccccc2)n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 100 mL round bottomed flask containing 5-phenyl-1H-pyrrole-2-carboxylic acid methoxymethylamide AV-6-1 (0.692 g, 3.01 mmol) was added a stirring bar and an argon inlet was attached. THF (15 mL) was added and, when all of the solids had dissolved, NaH-oil suspension (0.132 g of a 60% w/w suspension, 3.31 mmol) was added. This mixture was stirred 15 min at ambient temperature then 4-fluorobenzylbromide (0.41 mL, 3.31 mmol) was added. The resulting mixture was stirred 24 h at ambient temperature. The mixture was diluted with EtOAc and the solution was washed with 1N HCl, water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 25% EtOAc in hexanes a eluant to give 1-(4-fluorobenzyl)-5-phenyl-1H-pyrrole-2-carboxylic acid methoxy-methyl-amide AV-7-1. 1H NMR (CDCl3) δ 3.21 (3H, s), 3.47 (3H, s), 5.52 (2H, s), 6.24 (1H, d, j=3.9 Hz), 6.75 to 6.90 (5H, m), 6.94 (1H, d, j=3.9 Hz), 7.38 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OC)=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.N#N.Cl[P:21]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1C[O:37][CH2:36]C1>>[CH:22]1([P:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:4]2[C:5]([O:9][CH3:10])=[CH:6][C:7]([O:37][CH3:36])=[CH:8][C:3]=2[O:2][CH3:1])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cccc(OC)c1OC
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: C1CCOC1
Agent: N#N
Agent: [Li]CCCC
Product: COc1cc(OC)c(P(C2CCCCC2)C2CCCCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 25 %

Procedure:
To a solution of trimethoxybenzene (1.0062 g, 6 mmol) in 20 mL of dry THF was added n-butyl lithium (2.6 mL, 2.5 M in hexane, 6.6 mmol) dropwise under N2. The mixture was stirred for 4.5 hours at room temperature, at which time the reaction system was then cooled to −78° C. Chlorodicyclohexyl phosphine was added dropwise. After the mixture is stirred for 30 minutes, the reaction system was warmed up to room temperature and stirred for another 18 hours. Extraction with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether/ethyl acetate=10/1˜5/1) afforded 0.5514 g of product. The yield is 25%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][CH:49]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:59][C:57]2[S:56][C:46]3[C:47]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=3[N:58]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a stirred solution of 44 mg (0.31 mmol) 4-fluoro-benzoic acid in 4 ml THF were added 130 mg (0.34 mmol) HATU and 0.068 ml (0.62 mmol) N-methylmorpholine and stirring continued at 50° C. for 16 h. 40 mg (0.16 mmol) 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 7 mg (12%) 4-fluoro-N-(7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-yl)-benzamide as a white crystalline solid. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH:16]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH2:32][CH2:33][O:34][CH3:35])[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH:17]([CH3:19])[CH3:18])[C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].CO>O1CCCC1>[OH:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:15][CH:16]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH2:32][CH2:33][O:34][CH3:35])[CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(CC(Cc1ccc2cccc(OCCOC)c2c1)C(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cccc2ccc(CC(CC(CO)NC(=O)OC(C)(C)C)C(C)C)cc12
Reaction time: 23 h

Procedure:
A solution of 2.44 g of ethyl 2-tert-butoxycarbonylamino-4-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-5-methylhexanoate in 35 ml of tetrahydrofuran is admixed at room temperature with 0.25 g of lithium borohydride in portions. After 23 hours, 35 ml of methanol are added dropwise and the resulting mixture is concentrated by evaporation at 40° C. The residue is once more admixed with 35 ml of methanol and again concentrated by evaporation to dryness. The residue is admixed with ice/1N HCl and extracted with dichloromethane (3×)—the combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: C([Li])CCC.[CH:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCC.[CH2:19]([Si:21]([CH2:33][CH3:34])([CH2:31][CH3:32])[C:22]1[O:23][CH:24]=[C:25]([CH:27]([CH3:30])C=O)[CH:26]=1)[CH3:20].[O:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[OH:35][CH:36]([C:37]#[C:38][CH2:39][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:30][CH2:27][C:25]1[CH:26]=[C:22]([Si:21]([CH2:19][CH3:20])([CH2:31][CH3:32])[CH2:33][CH3:34])[O:23][CH:24]=1
Reactant: C1CCOC1
Reactant: C#CCCCCCCCCCCC
Reactant: CC[Si](CC)(CC)c1cc(C(C)C=O)co1
Agent: [Li]CCCC
Product: CCCCCCCCCCCC#CC(O)CCc1coc([Si](CC)(CC)CC)c1
Reaction time: 1 h

Procedure:
n-Butyl lithium (a 2.5M solution in tetrahydrofuran; 0.58 ml, 1.44 mmol) was added dropwise to a solution of 1-tridecyne (259 mg, 1.44 mmol) in tetrahydrofuran (6 ml) at 0°. After 1 hour, a solution of (2-triethylsilyl-4-furyl)-1-propanal (312 mg, 1.31 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued for 14 hours, while the cooling bath attained room temperature. The mixture was quenched with water and was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by a silica column using 15% ethyl ether/hexane to give the titled alcohol.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:2]1([C:1]2[CH:16]=[CH:15][CH:14]=[C:10]3[C:9]=2[CH:17]2[NH:21][CH2:18][CH2:19][N:20]2[C:11]3=[O:13])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: NCCN
Product: O=C1c2cccc(-c3ccccc3)c2C2NCCN12
Temperature: 0 °C

Procedure:
Reflux 45 g. of o-benzoylbenzoic acid and 120 ml. of ethylenediamine for 3 hours. Pour the mixture into ice water, allow to stand until the mixture is at room temperature and separate the product by filtration. Recrystallize from ethanol to obtain 9-phenyl-1,2,3,9b-tetrahydro-5H-imidazo-[2,1-a]isoindol-5-one, m.p. 155°-7° C. Elemental analysis confirms the empirical formula C16H14N2O.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[N:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:37]([NH:39][NH2:40])=O>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][N:31]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1cnccn1
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2cnccn2)C1
Temperature: 25 °C

Procedure:
To a solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (0.146 g, 0.5 mmol) in Dichloromethane (DCM) (3 mL) was added triethyloxonium tetrafluoroborate (0.100 g, 0.525 mmol). The solution was then stirred, under argon, for 10 minutes before 2-pyrazinecarbohydrazide (commercially available from e.g. TimTec, J& W PharmLab and Akos Consulting, 0.083 g, 0.600 mmol) was added. The solution was then stirred for a further hour before the solvent was concentrated and n-butanol (3.00 mL) was added. The solution was then stirred, under argon and reflux, for 3 hours before being cooled to room temperature. The solvent was then evaporated in vacuo and the remaining residue was purified by flash chromatography (Biotage SP4, 25M cartridge) with a gradient of 0-10% 2M NH3/MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo. The remaining residue was then further purified by mass-direct automated HPLC, before the solvent was again evaporated in vacuo. The remaining solid was then triturated in ether before being dried in a vac-oven to yield the product in 0.056 g.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: COc1cccc(COCCBr)c1
Solvent: CC#N
Product: COc1cccc(COCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)CC3)c1
Product: [Br-]
Temperature: 60 °C
Yield: 14 %

Procedure:
1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) was added to a solution of 1-{[(2-bromoethyl)oxy]methyl}-3-(methyloxy)benzene (35 mg, 0.143 mmol) in 2 CH3CN/3 CHCl3 (3 mL). The reaction was heated at 60° C. for 96 h. The reaction was concentrated, and the crude product washed with EtOAc (3×1 mL) and then MeOH (1×1 mL). The product was dried under high vacuum to give the title compound (7.7 mg, 14%). LC/MS ESI RT 1.97 min M+458
Reaction SMILES: C([Mg]Br)C.[C:5]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:10]=1[OH:21])([CH3:8])([CH3:7])[CH3:6].[CH2:22]=[O:23].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1>[C:5]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:11]([CH:22]=[O:23])[C:10]=1[OH:21])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)c1cc(-c2ccccc2)ccc1O
Reactant: C=O
Agent: CC[Mg]Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2ccccc2)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
Into a 1 liter reactor thoroughly purged with nitrogen, 66.80 ml of an ether solution containing 200.4 mmol of ethylmagnesium bromide and 100 ml of THF were introduced. To the reactor, a solution containing 43.16 g (190.7 mmol) of 2-t-butyl-4-phenylphenol diluted with 90 ml of a THF was dropwise added at 0° C. over a period of 40 minutes, then the temperature of the system was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Then, 700 ml of toluene was added, and the system was heated to 100° C. to distill off 52 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to −20° C., 13.84 g (460.9 mmol) of paraformaldehyde and 38.1 ml (273.4 mmol) of triethylamine were added, followed by stirring at 90° C. for 30 minutes. After ice cooling, the reaction solution was quenched with 133 ml of 18% hydrochloric acid. The organic layer was washed with 300 ml of water, 300 ml of a sodium hydrogencarbonate aqueous solution and 300 ml of a sodium chloride aqueous solution, and then concentrated. The resulting liquid was purified by silica gel column chromatography to obtain 37.73 g (yield: 78%) of 3-t-butyl-5-phenylsalicylaldehyde.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[O:15]1[CH2:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:18]2[CH2:19][CH2:20][O:15][CH2:16][CH:17]=2)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Br
Temperature: 100 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a microwave vial containing a suspension of ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (300.0 mg, 0.8849 mmol, prepared as in MPI10-008P1M) and 3,6-dihydro-2 h-pyran-4-boronic acid pinacol ester (204 mg, 0.973 mmol) in 1,4-dioxane (8.98 mL, 115 mmol) and water (0.925 mL, 51.3 mmol) were added tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.0885 mmol) and cesium carbonate (865 mg, 2.65 mmol). The vial was sealed, degassed by bubbling argon through for 10 minutes, and then heated at 100° C. with stirring for 24 h. The reaction was then cooled to room temperature and partitioned between EtOAc and water. Layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Residue was subjected to column chromatography as a solution in DCM (40 g column, gradient elution 0 to 25% EtOAc/hexanes) to afford ethyl 3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate as a white solid (183 mg, yield 63%). LCMS: (FA) ES+ 342, 344; 1H NMR (400 MHz, DMSO) δ 6.86-6.79 (m, 1H), 4.36-4.27 (m, 4H), 3.82 (dd, J=5.4, 5.4, 2H), 2.53 (ddd, J=2.1, 4.9, 10.0, 2H), 1.30 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH2:12][CH:13]=[CH2:14])[C:8]1=[O:23].C12BC(CCC1)CCC2.[OH-:40].[Na+].OO>O1CCCC1.CO.ClCCl>[CH3:30][O:29][C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:26]=1[O:27][CH3:28])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH2:12][CH2:13][CH2:14][OH:40])[C:8]1=[O:23]
Reactant: [OH-]
Reactant: C=CCC1(Cc2ccc(F)cc2)CCN(Cc2cc(OC)c(OC)c(OC)c2)C1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(CN2CCC(CCCO)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(allyl)-2-oxopyrrolidine (0.677 g, 1.64 mmol) and tetrahydrofuran (10 mL). Add dropwise a solution of 9-BBN (9-borabicyclo[3.3.1]nonane) (5.56 mL, 0.5 M, 2.78 mmol) in tetrahydrofuran. After 1.5 hours, add dropwise an aqueous sodium hydroxide solution (10 mL, 1 M) and 30% aqueous hydrogen peroxide (1.5 mL, about 14.7 mmol). After 15 minutes heat the reaction mixture to reflux. After 1 hour, cool to ambient temperature, saturate the aqueous mixture with potassium carbonate and separate the layers. Extract the aqueous layer five times with diethyl ether. Combine the organic layers and dry over potassium carbonate, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane to give the title compound.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][C:16]1[C:17]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=2[S:19][CH:20]=1>O1CCOCC1>[Cl:25][C:23]1[CH:22]=[CH:21][C:18]2[S:19][CH:20]=[C:16]([CH2:15][N:1]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[C:2]3=[O:3])[C:17]=2[CH:24]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1C(=O)N(Cc2csc3ccc(Cl)cc23)c2ccccc21
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 25 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0° C. under argon. The mixture was allowed to stir for 5 minutes and then a solution of 3-(bromomethyl)-5-chlorobenzo[b]thiophene (267 mg, 1.02 mmol) in dioxane (10 mL) was added dropwise to the reaction mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified by preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (125 mg, 0.38 mmol, 45%). 1H NMR (400 MHz): δ 7.89 (s, 1H), 7.79 (d, J=8.5, 1H), 7.65 (d, J=7.5, 1H), 7.54 (t, J=8.0, 1H), 7.42 (s, 1H), 7.38. (d, J=8.5, 1H), 7.14 (t, J=7.5, 1H), 6.88 (d, J=7.8, 1H), 5.13 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[CH3:14][C:15]1[CH:16]=CC(S(N)(=O)=O)=CC=1.[OH-:25].[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([OH:25])[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Reactant: [OH-]
Agent: [Na+]
Product: Cc1cccc(C)c1N(CC(C)O)S(C)(=O)=O
Reaction time: 8 h
Yield: 75.5 %

Procedure:
20 g (0.1 moles) of N-(2,6-dimethylphenyl)-methane-sulfonamide, prepared as described by M. A. Bambenek [Rec. Trav. Chim. 82, 97 (1963)] for the corresponding p-toluenesulfonamide derivative, m.p.: 128°-129° C., are dissolved in 200 ml of 0.5 n aqueous sodium hydroxide solution under stirring. 12.7 ml (10.6 g, 0.18 moles) of 1,2-propylene-oxide are added dropwise to the solution at 80°-85° C. within 3 hours, and then the mixture is allowed to stand overnight. The separated crystalline substance is filtered off, washed with water and dried. 19.4 g (75.5%) of 1-[N-(2,6-dimethylphenyl)-methane-sulfonamido]-2-propanol are obtained; m.p.: 81°-84° C. When recrystallized from diisopropyl ether, the product melts at 85°-87° C.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:19][C:20]1[C:21]([OH:30])=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24].[N:31]1([C:37]2[N:38]=[C:39]([CH2:44][C:45]([O-])=[O:46])[NH:40][C:41](=[O:43])[CH:42]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Na+]>CN(C)C=O>[OH:30][C:21]1[C:20]([NH:19][C:45](=[O:46])[CH2:44][C:39]2[NH:40][C:41](=[O:43])[CH:42]=[C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:38]=2)=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.4 %

Procedure:
6 ml of pyridine, 1g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 1 g of methyl 3-amino-2-hydroxybenzoate are added to a solution of 1 g of [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 6 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 1.27 g of methyl 2-hydroxy-3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a grey solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2[NH2:33])[N:26]([C@H:34]2[CH2:39][CH2:38][C@@H:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)[CH2:36][CH2:35]2)[N:25]=1.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>[NH:7]([C:8]1[CH:9]=[CH:10][C:11]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[N:30][C:31]=3[NH2:33])[N:26]([CH:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]4)[CH2:38][CH2:39]3)[N:25]=2)=[CH:12][CH:13]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)OB(c2ccc(Nc3ccccc3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: COCCOC
Solvent: O
Product: CN1CCN(C2CCC(n3nc(-c4ccc(Nc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of N-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (Intermediate AE) (0.33 g, 0.0011 mol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.43 g, 0.00097 mol), tetrakis(triphenylphosphine)palladium (0.0067 g, 0.000058 mol) and sodium carbonate (0.26 g, 0.0024 mol) was heated in a mixture of ethylene glycol dimethyl ether (16 mL) and water (8 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (92:7:1) as a mobile phase to give 3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.400 g, 0.00074 mol). It was dissolved at reflux in ethanol (17 mL) and a preheated solution of maleic acid (0.342 g, 0.003 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine trimaleate (0.44 g, 0.00053 mol) 1H NMR (DMSO-d6, 400 MHz) 8.45 (s, 1H), 8.23 (s, 1H) 7.52 (d, 2H), 7.28 (m, 2H), 7.20 (m, 4H), 6.89 (t, 1H), 6.19 (s, 6H), 4.83 (m, 1H), 3.1 (br, 9H), 2.72 (s, 3H), 2.28 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H);