Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].CC(C)([O-])C.[CH3:12][CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:22]([O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH3:23]>C(O)(C)(C)C>[C:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:13]([CH3:12])([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O:24][CH2:22][CH3:23])=[O:32]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CCOC(=O)CCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)CCCCCC(C)(C(C)=O)C(=O)OCC
Temperature: 50 °C
Yield: 485 %

Procedure:
A mixture of 1.34 g (12 mmol) potassium t-butoxide and 10 g t-butanol was stirred and heated until the t-butoxide had been dissolved. The solution was cooled to about 50° C. and 1.7 g (1 1.8 mmol) of ethyl 2-methylacetoacetate (I) was added dropwise. Ethyl-6-bromohexanoate (3 g, 13.5 mmol) was then added dropwise and the reaction mixture was stirred and refluxed for 5 hours. The mixture was filtered and the solvent was removed under reduced pressure. The residue was partitioned between 1 M HCl and chloroform. The organic layer Was dried over magnesium sulfate and purified on silica gel using 1:10 ethyl acetate/hexane as the eluent to yield 2.5 g (75%) of ethyl 2-(5-carboethoxypentyl)-2-methylacetoacetate (IIa) as yellow liquid.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:19][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([NH2:17])[C:7]3[N:6]=[CH:5][N:4]([CH2:3][CH:2]([CH3:18])[CH3:1])[C:16]=3[C:15]=2[CH:14]=1
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
A solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (30.0 g, 125 mmol) in chloroform (620 mL) was heated to 50° C., and N-bromosuccinimide (28.8 g, 162 mmol) was added in five portions over a period of five minutes. The resulting dark red solution was heated at reflux for 45 minutes, allowed to cool to ambient temperature, and stirred for one hour. A precipitate formed, was isolated by filtration, and was washed with water and diethyl ether to provide 9.0 g of 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([F:48])[CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[C:46]([F:48])[CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cc(F)cc(F)c3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (250 mg, 0.56 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (226 mg, 0.68 mmol, 1.20 equiv), tetrakis(triphenylphosphane)palladium (39 mg, 0.03 mmol, 0.06 equiv), dioxane (50 mL), sodium carbonate (149 mg, 1.41 mmol, 2.50 equiv), and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath and then concentrated under vacuum. The resulting solution was extracted with dichloromethane and the organic layers combined, dried and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.237 g (81%) of tert-butyl (2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[C:8]([CH3:15])[CH:7]=1.[CH3:16][N:17]=[C:18]=[S:19]>C(#N)C>[CH3:13][N:12]([CH2:11][C:9]1[O:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:18]([NH:17][CH3:16])=[S:19])=[CH:7][C:8]=1[CH3:15])[CH3:14]
Reactant: Cc1cc(CSCCN)oc1CN(C)C
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)NCCSCc1cc(C)c(CN(C)C)o1

Procedure:
A solution of 5-[[2-(amino)ethyl]thio]methyl-N,N,3-trimethyl-2-furanmethanamine (0.5 g) and methylisothiocyanate (0.15 ml) in dry acetonitrile was stirred for 24 hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:5][S:6]([CH2:9][C:10](O)=O)(=[O:8])=[O:7].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:21]=1C=O.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[CH:21]=[C:20]([O:19][CH3:18])[C:27]=1/[CH:10]=[CH:9]/[S:6]([CH2:5][C:4]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:2]([OH:1])[CH:3]=1)(=[O:8])=[O:7]
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1O
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(O)c2)c(OC)c1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A mixture of the 2-((3-hydroxy-4-methoxybenzyl)sulfonyl)acetic acid (1.9 g, 7.3 mmol, 1 eq), 2,4,6-trimethoxybenzaldehyde (1.58 g, 8.0 mmol, 1.1 eq.), benzoic acid (134 mg, 0.15 eq.) and piperidine (81 mg, 0.13 eq.) in toluene (50 mL) was heated at reflux temperature for 2-3 h with continuous removal of water using a Dean-Stark trap. When the reaction was complete by TLC analysis, the reaction mixture was cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extract was washed with saturated aqueous sodium bicarbonate solution (50 mL), dilute hydrochloric acid (50 mL), and water (50 mL) and dried (sodium sulfate). Volatile components were removed in vacuo to yield the crude product, which was purified by recrystallization from isopropanol to yield 1.8 g (62.5%) of the desired (E)-5-((2,4,6-trimethoxystyryl-sulfonyl)methyl)-2-methoxyphenol.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=O)=[CH:24][CH:23]=1>>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(N)cc3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.88 g (11.4 mmol) of 4-aminophenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].Cl.Cl.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:1].[ClH:32].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:10]([NH:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[O:11])[CH2:24][CH2:23]2)=[CH:27][CH:28]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1c(Cl)cccc1Cl
Yield: 104 %

Procedure:
The procedure described in Example 29 was followed, using 2,6-dichlorophenyl isocyanate (1.88 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), methylene chloride (50 ml) and triethylamine (4.3 ml; 31 mmole). Recrystallization from methanol provided the title compound (2.75 g; 52% yield) as colorless crystals, m.p. 246°-248° C.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+].CN(C)C=O>O>[C:17]1([S:23][C:2]2[CH:15]=[CH:14][C:13]3[S:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2sc2ccc(Sc3ccccc3)cc12
Temperature: 25 °C
Yield: 45 %

Procedure:
After mixing 11.0 parts of 2-chlorothioxanthone, 4.9 parts of thiophenol, 2.5 parts of potassium hydroxide, and 162 parts of N,N-dimethylformamide uniformly and then making them react at 130° C. for 9 hours, the reaction solution was cooled to room temperature (about 25° C.) and then was poured into 200 parts of distilled water, so that the product was precipitated. This was filtered and the residue was washed with water until the pH of the filtrate became neutral. Then the residue was dried under reduced pressure, affording a yellow powdery product. The product was purified by column chromatography (eluate:toluene/hexane=1/1:volume ratio) to afford 2-(phenylthio)thioxanthone in a yield of 45%. The product was identified by 1H-NMR {d6-dimethyl sulfoxide, δ (ppm) 8.43 (1H, d), 8.25 (1H, s), 7.75-7.90 (3H, m), 7.66 (1H, d), 7.60 (1H, t), 7.42-7.46 (5H, m)}.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: BrCC1CC1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCC4CC4)nc3N21
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of 1.2 g (37.6 mmol) (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 30 ml N,N-dimethylformamide was added 0.18 g (41.4 mmol) sodium hydride. After 30 min 0.72 ml (1.01 g, 75.2 mmol) (bromomethyl)cyclopropane was added and the reaction was stirred for 3 h. The reaction mixture was poured into 10% aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with a gradient of ethyl acetate:n-hexane (1:1 to 100:0) as eluant to afford the compound as a light yellow oil (67.1%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=12.[C:15]([O-])(=[O:17])C.[Na+].C=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[OH:17][CH2:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2=[N:1][CH:2]=1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cccn2ccnc12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cccn2c(CO)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
A mixture of ethyl imidazo[1,2-a]pyridine-8-carboxylate (1 g, 5.26 mmol), sodium acetate (1.725 g, 21.03 mmol), formaldehyde (36.5% wt. in water, 2.5 mL, 33.1 mmol) and acetic acid (1.145 mL, 20 mmol) was stirred at room temperature for 3 hours. The reaction mixture was then heated at reflux for a further 4 hours and then cooled and diluted with water (50 mL). The pH was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution (ca. 10 mL) and the solution was extracted successively with ethyl acetate (3×50 mL) and 3:1 chloroform:isopropanol (100 mL). The organic extracts were combined, washed successively with saturated sodium bicarbonate (50 mL) and brine (50 mL) and dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane and purified on a silica cartridge (100 g) using a 0-30% methanol (+1% Et3N)-DCM gradient over 60 mins. The product containing fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (1.007 g)
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[CH3:32][S:33]([CH2:36][C:37](O)=[O:38])(=[O:35])=[O:34]>>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:9]2[N:10]=[C:11]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:6]3[S:5][C:4]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:28][CH2:27]4)=[C:3]([CH3:2])[C:7]=3[N:8]=2)=[CH:23][N:22]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)CS(C)(=O)=O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 57.6 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 50 mg 2-(methylsulfonyl)acetic acid via General Procedure B to give 54.6 mg of 350 after reverse phase HPLC purification. MS (Q1) 547.2 (M)+.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[N:6]([CH2:24][C:25]2[N:34]=[C:33]([CH3:35])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[C:7](=[O:23])[C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:10]=[N:11][C:12]=2[N:13]=1.CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:9]2[C:8]3[C:7](=[O:23])[N:6]([CH2:24][C:25]4[N:34]=[C:33]([CH3:35])[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:5]4=[N:4][CH2:3][CH2:2][N:13]4[C:12]=3[N:11]=[CH:10]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2cnc3nc(NCCO)n(Cc4nc(C)c5ccccc5n4)c(=O)c32)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2cnc3c2C(=O)N(Cc2nc(C)c4ccccc4n2)C2=NCCN23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2-(2-hydroxyethylamino)-7-(4-methoxybenzyl)-1-((4-methylquinazolin-2-yl)methyl)-1H-purin-6(7H)-one 12 (1.68 g, 3.56 mmol) in DCM (66 ml) was added Et3N (1.50 ml, 10.7 mmol) and MsCl (0.55 ml, 7.1 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with DCM, washed with water, NaHCO3 and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (MeOH/DCM) to afford 3-(4-methoxybenzyl)-5-((4-methylquinazolin-2-yl)methyl)-7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 13. 1H NMR S 8.03 (d, J=7.81, 1H), 7.87 (d, J=7.81, 1H), 7.78 (t, J=7.03, 1H), 7.55 (t, J=7.03, 1H), 7.46 (s, 1H), 7.28 (d, J=8.59, 2H), 6.85 (d, J=8.59, 2H), 5.60 (s, 2H), 5.38 (s, 2H), 4.20 (d, J=9.37, 2H), 3.78 (d, J=9.37, 2H), 3.78 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[C:8]([NH2:34])=[N:9][C:10]=2[CH:11]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (51.1 g, 0.148 mol) in dichloromethane (1 L) was slowly added 3-chloroperoxybenzoic acid (1.0 equivalent of 50% pure material) in small portions. The reaction was maintained at room temperature for one hour. Concentrated ammonium hydroxide (600 mL) was added with stirring. After 15 minutes, p-toluenesulfonyl chloride (1.1 equivalents.) was added in small portions. The reaction was stirred at room temperature overnight. The reaction was quenched by adding water (1 L) and stirred for an additional hour. A solid was present and was isolated by filtration to provide 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([CH:19]([CH3:21])[CH3:20])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[N:4]=1.[H-].[Na+].[CH3:24][O:25][CH2:26]Cl>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([CH:19]([CH3:21])[CH3:20])[C:12]([N:14]([CH2:24][O:25][CH3:26])[S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[N:6]=1
Reactant: COCCl
Reactant: COc1cc(OC)nc(C(C(=O)NS(C)(=O)=O)C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN(C(=O)C(c1nc(OC)cc(OC)n1)C(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
2.0 g of 2-(4,6-dimethoxypyrimidin-2-yl)-3-methyl-N-methylsulfonylbutyric acid amide was placed in a round bottomed flask, and was dissolved in 50 ml of DMF. To the resultant solution, was gradually added 0.28 g of 60% sodium hydride, and the mixture was stirred at room temperature for one hour. Thereafter, 1.0 g of chloromethyl methyl ether was added dropwise to the resultant mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water, and was extracted with 200 ml of diethyl ether, followed by drying with anhydrous sodium sulfate. After filtrating the inorganic salt, the solvent was distilled off under reduced pressure. An oily product thus obtained was purified by silica gel column chromatography (developing solvent: N-hexane/ethyl acetate=10/l ) to obtain 1.8 g of the aimed product of colorless transparent viscous liquid (yield=78.3%) having a refractive index (nD20) of 1.4976.
Reaction SMILES: CC(C)(OC([NH:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]1)=O)C.[ClH:33]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[ClH:33].[CH:30]1[C:31]2[CH:19]([CH2:18][O:17][C:15]([N:12]3[CH2:13][CH2:14][CH:9]([NH:8][NH2:7])[CH2:10][CH2:11]3)=[O:16])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NNC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.8 g (0.0498 mol) of N-(1,1-dimethylethoxycarbonyl)-N′-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine were dissolved in 100 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The excess trifluoroacetic acid was removed in vacuo, the residue was dissolved in 50 ml of water and made alkaline with 10% aqueous sodium carbonate solution. The solution was extracted thoroughly with dichloromethane, the combined extracts were dried over magnesium sulphate and evaporated down in vacuo. The residue thus obtained was taken up in ethyl acetate and converted into the hydrochloride by the addition of ethereal hydrogen chloride solution. After recrystallisation from anhydrous ethanol 6.2 g (33.3% of theory) of colourless crystals of melting point 160-162° C. were obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]>C1COCC1>[CH2:10]([O:9][C:3]([CH:4]([C:5](=[O:6])[CH3:7])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25])=[O:8])[CH3:11]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)OC)cc1OC)C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in mineral oil; 1.45 g) was added portionwise over 10 min to a solution of ethyl acetoacetate (4.4 mL) in THF (60 mL) at 0° C. The resulting suspension was stirred at 0° C. for 10 min and a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (7.5 g) in THF (40 mL) added portionwise over 10 min. The mixture was warmed to 70° C. and stirred for 15 h. The mixture was allowed to cool and then poured cautiously into ice/water (300 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc and the combined organic phase was dried filtered and evaporated to afford crude product. The reaction was repeated on an identical scale and the two batches of crude product were combined and purified by chromatography eluting with 20-30% EtOAc in isohexane to give the subtitle compound as a colorless oil 14.70 g.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: CCN1CCNCC1
Product: CCN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(Cl)c4)c23)CC1
Yield: 70 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and N-ethylpiperazine to give the title compound in 70% yield; NMR Spectrum: 0.95 (t, 3H), 2.25 (q, 2H), 2.32 (br s, 4H), 2.45 (s, 3H), 2.50 (hidden by DMSO, 4H), 2.80 (t, 2H), 4.45 (t, 2H), 7.20 (d, 1H), 7.26 (br s, 2H), 7.73 (d, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 509 (MH+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:8]2[C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=3)=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:3].O.O.[Sn](Cl)Cl>C(O)C>[CH3:3][CH:2]([C:4]1[C:8]2[C:9]([O:13][C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc2cccc(Oc3ccc([N+](=O)[O-])cn3)c12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)c1noc2cccc(Oc3ccc(N)cn3)c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3-(1-methylethyl)-4-[(5-nitro-2-pyridinyl)oxy]-1,2-benzisoxazole (Intermediate 41, 8.7 mg) was dissolved in 3.0 ml of ethanol. Tin(II) chloride dihydrate (19.7 mg, 0.087 mmol) was added and the reaction mixture was stirred at 80° C. for 3 hours. After quenching with water and extraction with ethyl acetate, the gathered organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound.