Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=CC=2)C=C1C(N)=O.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.NN>O.C(O)C>[C:21]1([NH:27][N:28]=[C:18]2[C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCCC(=O)C1
Agent: NC(=O)c1cc2ccccc2[nH]1
Agent: NN
Solvent: O
Solvent: CCO
Product: O=C1CCCCC1=NNc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83386.8 %

Procedure:
The title compound was prepared by a modification of published procedures (M. S. Berridge et al., Nucl. Med. Biol. 19 (5) 563-569 (1992); Brueckner R. et al., EP 1 424 337 A1 (2004)). To a stirred suspension of cyclohexane-1,3-dione (10 g, 0.089 mol) in water (64 mL) under nitrogen was added via dropping funnel 10-15 drops of a solution of phenylhydrazine (8.8 mL, 0.089 mmol) in water (124 mL). The mixture was stirred for 15 minutes at room temperature and then the remainder of the phenylhydrazine solution was added dropwise over a 4 hour period. Ethanol (21 mL) was added to facilitate stirring after about 30 mL of the hydrazine solution had been added. Stirring was continued for an additional 30 minutes. The orange solid was collected by filtration, washed with water and a small amount of 3:1 (v/v) water-ethanol, and dried in vacuo overnight to provide the title compound (15.01 g, 83.3%). MS (ES): [M+H]+ @m/z 203.1
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][CH:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C:14](Cl)=[O:15]>O>[CH3:11][CH:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C:14]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:15]
Reactant: c1ccccc1
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(CC(=O)c1ccccc1)CC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 143.4 grams of aluminum chloride and 351.6 grams of benzene was stirred at room temperature while 100 grams of 3,5,5-trimethylhexanoyl chloride was added to the reaction keeping the reaction temperature at approximately 35° C. over a period of 1.5 hours. The mixture was then stirred for 3hours. The reaction mixture was poured into 500 grams of ice and stirred until all the ice dissolved. Water was added with cooling to give a homogenous mixture followed by extraction with 400 mL of ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate and stripped to dryness to give 3,5,5-Trimethylhexanoylbenzene.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1.O.[N+:12]([CH:15]([CH:18]=O)[CH:16]=O)([O-:14])=[O:13].[Na].O>CC(O)=O>[CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[C:9]2[C:8](=[N:10][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:18]=2)[NH:7][N:6]=1
Reactant: C[C@H]1C[C@H]1c1cc(N)[nH]n1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H]1C[C@H]1c1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 35.6 %

Procedure:
3-(cis-2-Methylcyclopropyl)-1H-pyrazol-5-amine (0.0742 g, 0.541 mmol) and sodium nitromalonaldehyde hydrate (0.0892 g, 0.568 mmol) were heated in AcOH at 90° C. overnight. Water was added, and the precipitate was collected by filtration. This solid was taken up in water as a slurry and heated to reflux for two days. The solution was cooled to room temperature, and the resulting crystals were collected by filtration. The mother liquor was extracted with DCM (3×), dried over Na2SO4 and concentrated to a solid, which was combined with the crystals to provide 3-(cis-2-methylcyclopropyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (42 mg, 65%) as a solid.
Reaction SMILES: C(C1C=CC=CC=1)C.[F:9][C:10]1[C:17]([F:18])=[C:16](C#N)[C:15]([F:21])=[C:14]([F:22])[C:11]=1[C:12]#[N:13].[H][H]>[Pd]>[F:9][C:10]1[C:17]([F:18])=[CH:16][C:15]([F:21])=[C:14]([F:22])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCc1ccccc1
Product: N#Cc1c(F)c(F)cc(F)c1F
Temperature: 190 °C

Procedure:
200 g of ethylbenzene, 0.30 g of 5% palladium/activated carbon, and 6.0 g of 2,3,5,6-tetrafluoroterephthalonitrile were added to a 1000 cc stainless steel autoclave in a nitrogen atmosphere. The gas phase was sufficiently replaced with a mixed gas of 41 vol % hydrogen and 59 vol % nitrogen, then the mixed gas was used to keep the pressure at 0.23 MPa and the temperature was maintained at 190° C. After 2, 4, and 6 hours, the reaction solution was analyzed by gas chromatography, whereupon the conversions of 2,3,5,6-tetrafluoroterephthalonitrile were found to be 23, 62, and 99% and the yields of 2,3,5,6-tetrafluorobenzonitrile (based on 2,3,5,6-tetrafluoroterephthalonitrile) were 22, 56, and 87%, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]([O-:16])(C)[CH3:14].[K+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[C:3]([O:16][CH:13]([CH3:14])[CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ncc(C(=O)O)cc1Cl
Temperature: 80 °C

Procedure:
5,6-Dichloronicotinic acid (1.95 g, 10 mmol) is added to a solution of KOtBu (2.28 g, 20 mmol) in isopropanol (20 mL). The mixture is heated at 80° C. for 15 h. The mixture is diluted with water (60 mL) and acidified with 1M aq. HCl. The aq. solution is extracted with ether (5×50 mL) and the combined org. extracts are dried (Na2SO4), filtered and evaporated to provide 5-chloro-6-isopropoxy-nicotinic acid; 1H NMR (d6-DMSO) δ 1.38 (d, J=6.2 Hz, 7H), 5.44 (hept, J=6.2 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.[OH-].[Na+]>>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][S:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)(=[O:11])=[O:10])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(S(=O)(=O)Oc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 48.7 %

Procedure:
By a method similar to Example 31, using 4-methoxybenzenesulfonyl chloride (248 mg, 1.2 mmol) and 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (230 mg, 1.0 mmol), 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) gave 225 mg of crude product. The crude product was recrystallized from ethyl acetate to give 195 mg (49%) of the title compound as a white powder: mp=186-187° C.; MS(m/e): 400 (M+); Calculated for C21H24N2O4S: Calcd: C, 62.98; H, 6.04; N, 6.99. Found: C, 63.10; H, 6.18; N, 7.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]([OH:14])[CH:5]2[CH2:15][S:16]([NH:19][CH2:20][C:21](O)=[O:22])(=[O:18])=[O:17].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:36]([NH2:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.CC(=O)OCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[CH:6]([OH:14])[CH:5]2[CH2:15][S:16]([NH:19][CH2:20][C:21]([NH:44][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:22])(=[O:18])=[O:17]
Reactant: CC1(C)Oc2ccc(Cl)cc2C(CS(=O)(=O)NCC(=O)O)C1O
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(Cl)cc2C(CS(=O)(=O)NCC(=O)NCCc2ccccc2)C1O
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of 0.5 g (1.37 mmol) of [(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)methanesulfonylamino]acetic acid and 0.27 g (1.65 mmol) of CDI in 7 ml of THF was stirred at RT for 3 h. 0.33 g (2.75 mmol) of phenethylamine was then added and the reaction mixture was stirred overnight. After stripping off the solvent, the residue was taken up in EA and washed with dil. hydrochloric acid and water. After purification through a short chromatography column, 0.56 g of 2-[(6-chloro-3-hydroxy-2,2-dimethylchroman-4-yl)methanesulfonylamino]-N-phenethylacetamide was obtained; m.p. 168-170° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2C(=C(OS(C(F)(F)F)(=O)=O)N(C3C=CC=C(Cl)C=3)N=2)CC1)=O)(C)(C)C.ClC1C=C(NN)C=CC=1.C1(B(O)O)C=CC=CC=1>>[Cl:24][C:20]1[CH:19]=[C:18]([N:13]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(Cl)c3)c(-c3ccccc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(Cl)c3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Agent: NNc1cccc(Cl)c1
Agent: OB(O)c1ccccc1
Product: Clc1cccc(-n2nc3c(c2-c2ccccc2)CCNCC3)c1

Procedure:
2-(3-Chloro-phenyl)-3-phenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The desired compound (53.9 mg) was prepared from 142.7 mg of 2-(3-chloro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made as in Example 176, Steps A and B) replacing phenylhydrazine with (3-chloro-phenyl)-hydrazine, as described in Example 43, Step D, using 102.1 mg of phenylboronic acid. MS (ESI): exact mass calculated for C24H26ClN3O2, 423.17; found, m/z 424.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[S:8][C:7]=2[CH:27]=1.CS(C)=[O:30]>>[F:24][C:23]([F:26])([F:25])[C:13]1[CH:12]=[C:11]([C:9]2[S:8][C:7]3[CH:27]=[C:3]([CH:2]=[O:30])[CH:4]=[CH:5][C:6]=3[CH:10]=2)[CH:16]=[CH:15][C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1cc(-c2cc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Reactant: CS(C)=O
Product: O=Cc1ccc2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 100 °C

Procedure:
To a solution of 6-bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (180 mg, 0.4 mmol) in 5 mL DMSO, Ag2CO3 (330 mg, 1.2 mmol) is added. The suspension is heated to 100° C. for 3 hours. After work up, the organic layer is dried and concentrated. The residue is applied in column (hexane:EtOAc 9:1) to afford 100 mg of 2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene-6-carbaldehyde as a off white solid. MS m/z 383[M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH3:26])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([C:17]1[C:18]([CH3:26])=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:16]=1[O:15][CH3:14])=[O:9]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COc1ccc(Br)c(C)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2C)c(OC)c1OC

Procedure:
50B (240 g, 1.0 mol) is reacted with 3,4,5-trimethoxytoluene (182 g; 1.0 mol) in the presence of P2O5 (1.0 kg) and dichloromethane as described in Example 6 yielding white crystals, 220 g (54% ), mp 89-91° C.
Reaction SMILES: [CH:1]1([CH3:30])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11](=[O:29])[CH:12]([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23](=[O:28])C(Cl)(Cl)Cl)[C:13](OCC)=[O:14])[CH2:2]1.Cl.[Br:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[C:35]([F:41])[CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[CH:1]1([CH3:30])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([O:10][C:11]([CH:12]2[N:18]3[CH:22]=[CH:21][CH:20]=[C:19]3[C:23](=[O:28])[N:38]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([Br:32])=[CH:34][C:35]=3[F:41])[C:13]2=[O:14])=[O:29])[CH2:2]1
Reactant: NCc1ccc(Br)cc1F
Reactant: CCOC(=O)C(C(=O)OC1CC(C)CCC1C(C)C)n1cccc1C(=O)C(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3cccn32)C1
Temperature: 75 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid ethyl (-)-menthyl ester (87.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (53.0 g) and triethylamine (66.4 g, 91.0 ml) in anhydrous dimethylformamide (200 ml) was stirred under the stream of nitrogen at 75° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with 5% cold hydrochloric acid and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from methanol to give the title compound (74.0 g, 78.7%) as colorless crystals, mp 98°-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([Si:14](Cl)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
5-Bromoindole (2.5 g, 12.75 mmol) was dissolved in tetrahydrofuran (THF; 50 mL) and cooled to 0° C. and Sodium Hydride NaH (920 mg, 23 mmol, 60%) was added in portions. The mixture was allowed to warm to RT with stirring for 1 hour. The reaction mixture was again cooled to 0° C. and triisopropylsilyl chloride (TIPSCl; 2.78 mL, 13.1 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was washed with 2.0 N H3PO4, and the organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography (100% Hexanes) to give compound 8 as an oil (4.3 g; 96% yield; M+1=353.4)
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCOCC1>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(F)c(=O)[nH]c2=O)cc1
Yield: 62.3 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil and 1.28 g (0.01 mole) of anhydrous potassium carbonate were suspended in 50 ml. of dioxane and reacted with 3.82 g (0.02 mole) of p-toluenesulfonyl chloride in the same manner as in Example 10. There was obtained 3.54 g (62.3% yield) of 5-fluoro-1-(p-toluenesulfonyl)uracil. Recrystallization of the product from methanol-chloroform gave leaflets melting at 241°-242°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[O:41][C:42]4[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[CH:45][C:43]=4[N:44]=3)=[CH:35][CH:34]=2)O1.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:38]=[CH:37][C:36]([NH:39][C:40]4[O:41][C:42]5[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[CH:45][C:43]=5[N:44]=4)=[CH:35][CH:34]=3)[C:10]=12
Reactant: CN1CCN(C2CCC(n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CCc1ccc2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
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: CCc1ccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.06 g, 0.00014 mol), N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-ethyl-1,3-benzoxazol-2-amine (0.062 g, 0.00017 mol), tetrakis(triphenylphosphine)palladium (0.011 g, 0.00001 mol) and sodium carbonate (0.037, 0.00035 mol) in ethylene glycol dimethyl ether (3 mL) and water (1 mL) was heated at 80° C. for 16 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure, and the residue was purified by flash column chromatography on silica using 2% aqueous ammonium hydroxide solution/5%-25% methanol/dichloromethane as a mobile phase. The solvent was removed under reduced pressure to give cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-ethyl-1,3-benzoxazol-2-amine (0.065 g, 0.00012 mol). 1H NMR (DMSO-d6, 400 MHz) δ 11.25 (s, 1H), 8.65 (s, 1H), 8.37 (d, 2H), 8.09 (d, 2H), 7.84 (d, 1H), 7.76 (s, 1H), 7.42 (d, 1H), 5.22 (br, 1H), 3.13 (q, 2H), 2.52 (br, 7H), 2.69 (br, 4H), 2.64 (s, 3H), 2.49 (br, 2H), 2.11 (br, 2H), 2.01 (br, 2H), 1.63 (t, 3H). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.3 min. MS: MH+ 552
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH4+:10].[OH-]>>[NH2:10][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: [NH4+]
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [OH-]
Product: Cc1nc(N)cc(Cl)n1
Temperature: 90 °C
Yield: 81.5 %

Procedure:
Part A: A mixture of 4,6-dichloro-2-methylpyrimidine (1.63 g, 10.0 mmol) in NH4OH (35%, 8 mL, 200 mmol) was heated, in a Parr bomb, in an oven at 90° C. overnight. The vessel was cooled to room temperature, the mixture was filtered and the solids were washed with water (3×10 mL). Excess solvent was removed in vacuo to give 4-amino-6-chloro-2-methylpyrimidine (1.17 g, 81%) as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)cc1
Temperature: 25 °C

Procedure:
After 2-[(4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 200.5 mg.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:23][OH:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C=O)C.CCOCC>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:23][O:24][CH3:25])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
Sodium hydride (0.857 g, 21.42 mmol) was added portionwise to stirred Et2O (23.0 ml) at 25° C. under nitrogen. A solution of (1,4-dibenzylpiperazin-2-yl)methanol (1.411 g, 4.76 mmol) in DMF (8.0 ml) was added portionwise under nitrogen. The resulting suspension was stirred at room temperature for 1 h. A solution of methyl iodide (0.454 ml, 7.28 mmol) in Et2O (7.0 ml) was added dropwise to the reaction mixture at 10° C., under nitrogen. The resulting mixture was stirred at room temperature for 21 h. The reaction mixture was quenched with water (35 mL and extracted with Et2O (3×50 mL). The organic layers were combined and washed with water (50 mL), dried over MgSO4, filtered and evaporated to afford 1,4-dibenzyl-2-(methoxymethyl)piperazine (1.580 g, 107%) as a yellow oil. This was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl-:9].[Cl-].[Cl-].[Al+3].ClCl>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:9]
Reactant: Clc1ccc(Cl)nn1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Product: Clc1cc(Cl)c(Cl)nn1
Yield: 145.7 %

Procedure:
44 g 3,6-dichloropyridazine and 22 g aluminium trichloride are heated to 140° C. At this temperature 10.6 l chlorine are piped into the reaction mixture over a period of 4 hours. After cooling the product is extracted with toluene, washed with a 10% sodium chloride solution and distilled (bp=127-129° C.). 44.1 g of product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Cc3cccc([N+](=O)[O-])c3)c3cc(-c4cccnc4)cnc32)cc1
Reaction time: 3 h

Procedure:
To 3-(3-nitro-benzyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (P-1402, 141 mg, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 21 mg, 0.512 mmol) under an atmosphere of nitrogen. After thirty minutes, p-toluenesulfonyl chloride (114 mg, 0.60 mmol) in N,N-dimethyl-formamide was added and the reaction was stirred for three hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. All solids were filtered and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give the compound (552, 120 mg, 58%). MS(ESI)[M+H+]+=485.25.
Reaction SMILES: [CH2:1]([C:3]1OCC[N:7]=1)[CH3:2].[NH2:8][NH2:9]>O1CCCC1>[CH2:1]([C:3]1[NH:8][NH:9][C:3]([CH2:1][CH3:2])=[N:7][N:7]=1)[CH3:2]
Reactant: CCC1=NCCO1
Reactant: NN
Solvent: C1CCOC1
Product: CCC1=NN=C(CC)NN1
Temperature: 60 °C

Procedure:
In a nitrogen flushed flask were mixed 2-ethyl-2-oxazoline (99 g, 1 mole) and anhydrous hydrazine (32 g, 1 mole) in 150 ml of tetrahydrofuran. The mixture was heated 2 hours at 60° C. to obtain a yellow solution. The solvent was stripped to give a pale yellow oil. On standing, white crystals formed. They were recrystallized from 2-propanol to give 3,6-diethyl-1,2-dihydro-1,2,4,5-tetrazine as identified by mass spectroscopy, 13C NMR, and infrared analyses, mp 118.5°-119.5° C.