Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[N:29]1([CH2:35][B-](F)(F)F)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:32]1[CH2:33][CH2:34][N:29]([CH2:35][C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([CH2:11][C:12]4[CH:28]=[CH:27][C:15]5[N:16]=[C:17]([NH:19][C@@H:20]6[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]6[OH:26])[S:18][C:14]=5[CH:13]=4)[C:5]3=[N:6][CH:7]=2)[CH2:30][CH2:31]1
Reactant: F[B-](F)(F)CN1CCOCC1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(CN5CCOCC5)cnc43)cc2s1
Temperature: 85 °C
Yield: 34.2 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.22 mmol) from Example 29, potassium (morpholin-4-yl)methyltrifluoroborate (59 mg, 0.28 mmol), Pd(OAc)2 (1.5 mg, 0.007 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.2 mg, 0.013 mmol) and Cs2CO3 (213 mg, 0.66 mmol) in THF/H2O (1.5 mL, 4:1, v/v) was purged with argon for 10 min. The mixture was then heated at 85° C. in a sealed reaction vessel overnight. LCMS showed the reaction complete. After cooling to rt, the reaction mixture was filtered through a Celite plug and the filtrate was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((6-(morpholinomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a white powder (36 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.31 (d, J=1.5 Hz, 1H), 7.88-8.04 (m, 2H), 7.67 (d, J=0.9 Hz, 1H), 7.26-7.33 (m, 1H), 7.17-7.26 (m, 1H), 5.46 (s, 2H), 4.75 (br s, 1H), 3.60 (s, 2H), 3.45-3.58 (m, 5H), 2.36 (br s, 4H), 2.03 (d, J=10.4 Hz, 1H), 1.79-1.89 (m, 1H), 1.62 (d, J=5.1 Hz, 2H), 1.05-1.37 (m, 4H). LCMS (ESI) m/z 479 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[C:14]1([CH:24]=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:24]\[C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)/[C:10](=[O:11])/[C:12](=[CH:24]/[C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: O=Cc1cccc2ccccc12
Product: Cc1ccc2c(c1)O/C(=C\c1cccc3ccccc13)C(=O)/C(=C/c1cccc3ccccc13)O2

Procedure:
Calone is reacted with naphthalene-1-carbaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-naphthalen-1-yl-meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[OH:19])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([C:14]2[CH:15]=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[O:19][S:36]([C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCn1ncc(C(=O)c2ccc(Cl)c3ncccc23)c1O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2ccc(Cl)c3ncccc23)c1OS(=O)(=O)c1ccc(Cl)cc1

Procedure:
1.00 g of 4-[(8-chloroquinolin-5-yl)carbonyl]-1-ethyl-5-hydroxy-pyrazole, 0.70 g of triethylamine and 0.70 g of 4-chlorobenzenesulfonyl chloride in 15 ml of methylene chloride were stirred at room temperature for 12 hours. The reaction mixture was then poured into aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated and the residue was purified by chromatograpy over silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C(Cl)Cl>[C:2]1([NH:1][C:14](=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Aniline (2.03 g, 25.0 mmol) was dissolved in CH2Cl2 (30 mL). To the solution were added pyridine (2.22 mL, 27.5 mmol) and decanoyl chloride (5.25 g, 27.5 mmol) in an ice bath. After stirring for 3 h at room temperature, the reaction mixture was poured into 1M HCl (30 mL) and the mixture extracted with CH2Cl2 (3×100 mL). The organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated to give 5.62 g (22.8 mmol, 91%) of N-phenyldecanamide as a white solid, mp 65-66° C. (lit5 mp 65-66° C.); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=6.9 Hz), 1.26 (m, 12H), 1.72 (m, 2H), 2.35 (t, 2H, J=7.8 Hz), 7.10 (t, 2H, J=7.8 Hz), 7.31 (t, 1H, J=7.8 Hz) 7.50 (t, 2H, J=7.9 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 22.5, 25.7, 29.2, 29.2, 29.3, 29.3, 31.7, 37.5, 120.1, 124.0, 128.7, 138.1, 172.3.
Reaction SMILES: BrC[CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:24]([I:25])=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:26].[Br:27]CCCBr.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:27][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:24]([I:25])=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:26]
Reactant: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCCO3)n2CCCBr
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1I)OCCO3)n2CCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9-(3-Bromopropyl)-8-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-6-amine (S9-5). A mixture of S9-3 (0.213 g, 0.5 mmol), 1,3-dibromopropane (0.512 g, 2.5 mmol) and Cs2CO3 (0.184 g, 0.75 mmol) in anhydrous DMF (6 mL) was stirred at room temperature for 3 h. Solids were filtered and the filtrate was condensed under reduced pressure to give a residue that was purified by preparative thin layer chromatography (CHCl3:MeOH—NH3 (7N), 20:1) to give S9-5 (0.104 g, 38%). 1H NMR (CDCl3, 500 MHz) δ 8.26 (s, 1H), 7.32 (s, 1H), 6.94 (s, 1H), 5.6 (br s, 2H), 4.27 (t, J=7.0 Hz, 2H), 4.10-4.17 (m, 4H), 3.32 (t, J=7.0 Hz, 2H), 2.26 (m, 2H); MS (ESI) m/z 547.9/549.8 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:29][CH2:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH2:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCCc1ccccc1N
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCc1ccccc1N
Yield: 91 %

Procedure:
The compound prepared in Example 3 was reacted with 2-(2-amino-phenyl)-ethylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:14](=[O:16])[CH3:15])[CH2:6][CH2:7][C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2].[H-].[Na+].Cl([F:24])(=O)(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:14](=[O:16])[CH3:15])([F:24])[CH2:6][CH2:7][C:8]#[C:9][Si:10]([CH3:11])([CH3:13])[CH3:12])[CH3:2]
Reactant: CCOC(=O)C(CCC#C[Si](C)(C)C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)(CCC#C[Si](C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-acetyl-6-(trimethylsilyl)-5-hexynoic acid ethyl ester (7.1 g) was added to a suspension of sodium hydride (1.0 g) in toluene under a positive argon atmosphere. After stirring for 1 hour, the reaction mixture was cooled to -10° and a mixture of perchloryl fluoride and argon gases was bubbled through the reaction mixture at such a rate that the internal temperature never exceeded 0° C. The perchloryl fluoride addition was discontinued when it ceased to be exothermic. Argon was bubbled through the mixture as it was allowed to warm to room temperature. The reaction mixture was partitioned between hexane and water and the organic phase was dried (MgSO4) and condensed by rotary evaporation to give an oil. The components of the oil were separated by silica gel chromatography using 30% ethyl acetate/hexane as the eluant to give 5.9 g of 2-acetyl-2-fluoro-6-(trimethylsilyl)-5-hexynoic acid ethyl ester. There was also obtained 0.25 g of 2-fluoro-6-(trimethylsilyl)-5-hexynoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](N)[CH:5]=[C:4]([Br:12])[N:3]=1.N([O-])=O.[Na+].O.[ClH:18]>>[Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:18])[CH:5]=[C:4]([Br:12])[N:3]=1
Reactant: Cl
Reactant: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(Cl)cc(Br)nc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,6-dibromo-3-nitro-pyridin-4-ylamine (6.5 g, 21.9 mmol) was suspended in concentrated HCl (100 mL) and cooled to 0° C., then sodium nitrite (7.5 g, 109 mmol) was added. There mixture was stirred for 30 minutes then warmed to room temperature. 100 mL of cooled water were added and the mixture was extracted with 100 mL of ethyl acetate. The organic layer was washed with 100 mL of water, dried over magnesium sulphate and the solvent was removed in vacuo to give 5.8 g of 2,6-dibromo-3-nitro-4-chloro pyridine as an orange oil. The oil was dissolved in 80 mL of THF and cooled to 0° C. Benzylamine (94.9 mL, 44.9 mmol) was dissolved in 20 mL of THF and added dropwise to the reaction followed by potassium carbonate (6.6 g, 48.2 mmol). The mixture was warmed to room temperature then heated at 50° C. overnight. Once the reaction was complete, the mixture was partitioned in water (150 mL) and ethyl acetate (100 mL). The organic layer was washed with 200 mL of water and 200 mL of brine, dried over magnesium sulphate and the solvent was removed in vacuo. 100 mL of ethanol was added and the mixture was sonicated for five minutes and let in the fume hood overnight. The precipitate was filtered off and washed with 30 mL of ethanol to give 4.56 g of the title compound as a yellow solid.
Reaction SMILES: [CH:1]([N:3]1C(=O)C2=CC=CC=C2C1=O)=[CH2:2].[CH:14]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH2:15].O1CCCC1.O.NN>C(O)C>[CH:1]([NH2:3])=[CH2:2].[CH:14]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH2:15]
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: C=Cn1c2ccccc2c2ccccc21
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C=CN
Temperature: 25 °C

Procedure:
3.6 grams of a random copolymer of N-vinylphthalimide/N-vinylcarbazole (9.2/90.8 mole percent) are dissolved in a solution containing 100 milliliters of tetrahydrofuran and 10 milliliters of ethanol. After the copolymer has been dissolved, 0.13 grams hydrazine hydrate (85%) were added and the solution thereafter heated to boiling under refluxing conditions overnight. At the end of this interval, the solution apparently remains unchanged, it retaining its characteristic yellow color. An additional 2.6 grams of hydrazine hydrate are then added and the solution refluxed for an additional two days. At the end of this time, the characteristic yellow color of the solution has disappeared and a white precipitate formed. The solution is now allowed to cool to room temperature and the precipitate removed by filtration. This precipitate is believed to be phthalhydrazide. The polymer is separated from the solution by precipitation with hexane in a Waring blender. The number average molecular weight of the polymeric product is about 78,000.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[OH:14])=[O:4].[C:15]([O:19][C:20](=[O:28])[CH2:21][NH:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:28])[CH2:21][N:22]([C:8](=[O:10])[C:7]1[C:6](=[C:5]([C:3](=[O:4])[CH2:2][Cl:1])[CH:13]=[CH:12][CH:11]=1)[OH:14])[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1cccc(C(=O)CCl)c1O
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(C(=O)c1cccc(C(=O)CCl)c1O)C1CCCC1

Procedure:
3-Chloroacetylsalicylic acid was combined with N-cyclopentylglycine t-butyl ester and N,N1 -dicyclohexylcarbodiimide at 0° C. in methylene chloride as described in Example I. Similar workup gave crude N-(3-chloroacetylsalicyloyl)-N-cyclopentylglycine t-butyl ester, which was cleaved to N-(3-chloroacetylsalicyloyl)-N-cyclopentylglycine using iodotrimethylsilane prepared in situ as described in Example I. Hydrolysis with aqueous sodium hydroxide (Example IV) provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:23]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]2[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:23]=2)[CH2:10][CH:9]1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1c1ccc(Cl)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(C(=O)OC(C)(C)C)C(c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 94.3 %

Procedure:
A solution of 4-(tert-butoxycarbonyl)-3-(4-chlorophenyl)piperazine (330 mg, 1.1 mmol), 2-chloro-3-methyl-6-(4-pyridyl)pyrimidin-4-one (246 mg, 1.1 mmol) and triethylamine (170 μl, 1.22 mmol) in tetrahydrofuran were refluxed. Usual workup and purification by silica gel column chromatography gave 2-(1-(tert-butoxy-carbonyl)-2-(4-chlorophenyl)-piperazine-4-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (500 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.C(Cl)Cl.O=S(Cl)Cl.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].C(N(CC)CC)C>CCOC(C)=O.C(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1)[CH3:22]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCNCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
3-Fluoro-4-nitrobenzoic acid (5.0 g, 27.0 mmol) was refluxed in a mixture of 2:1 CH2Cl2/SOCl2 (150 mL) overnight. The solvent was concentrated and the residue dissolved in CH2Cl2 (50 mL). Another CH2Cl2 solution (50 mL) of diethylamine (3.35 mL, 1.2 eq) and triethylamine (7.5 mL, 2 eq) was then added dropwise to the cold stirring solution (0° C.) of the acid chloride. The solution was stirred at rt for 1 h. The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 2:1/hex:EtOAc on silica gel to afford the title compound (5.10 g, 79% yield); 1H NMR (400 MHz, CDCl3) δ 8.12 (m, 1H), 7.29 (m, 2H), 3.56 (br d, 2H), 3.23 (br d, 2H), 1.27 (br s, 3H), 1.15 (br s, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.CN([CH:35]=[O:36])C>C1COCC1.C(OCC)(=O)C>[CH3:9][C:10]1[CH:15]=[C:14]([C:16]2[S:20][C:19]([CH:35]=[O:36])=[N:18][CH:17]=2)[CH:13]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=2)[CH:11]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a flask was added tetrahydrofuran (60 mL) and the solution was cooled to −78° C. Lithium diisopropylamide (19.8 mL, 35.7 mmol) was added and the mixture was allowed to cool to −78° C. INTERMEDIATE 4 (4.0 g, 11.90 mmol) was dissolved in THF (60 mL) and added in portion. The solution was stirred for 30 minutes. DMF (1.30 g, 17.84 mmol) was dissolved in THF (60 mL) and added over a period of five minutes. The solution was then allowed to warm to room temperature. The reaction mixture was then diluted with ethyl acetate, washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel column chromatography to yield 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carbaldehyde (3.5 g, 81%). MS ESI: [M+H]+ m/z 364.8. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.91 (s, 1H), 8.86 (d, J=5.3, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.31 (d, J=5.2, 1H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN1CCN(C)CC1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: Cc1cc2c(cc1C)-n1c(nn(CCCN(C)C)c1=O)-c1cccnc1N2C(=O)CN1CCN(C)CC1
Reaction time: 22 h

Procedure:
In the manner given in Example 21, to 6,7-dimethyl-2,9-dihydro-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling [3-(dimethylamino)propyl]chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)propyl]-9-[(4-methylpiperazino)-acetyl]-3-H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[C:14]([CH:18]=C)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:20])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].CSC.C[OH:25]>ClCCl>[NH2:20][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[C:14]([CH:18]=[O:25])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: C=Cc1ccc2nc(N)c3ncn(CC(C)C)c3c2c1
Reactant: CO
Solvent: ClCCl
Solvent: CSC
Product: CC(C)Cn1cnc2c(N)nc3ccc(C=O)cc3c21
Temperature: 25 °C

Procedure:
A solution of 1-isobutyl-8-vinyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.9 mmol) in dichloromethane (30 mL) and methanol (5 mL) was cooled to −78° C. Ozone was bubbled through the solution for 10 minutes. While still cold, the reaction was purged with oxygen for 15 minutes and dimethyl sulfide (0.7 mL, 9.4 mmol) was added. The reaction was warmed to ambient temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and washed with 1% aqueous sodium carbonate (2×15 mL). The combined aqueous fractions were extracted with chloroform (3×20 mL) and sequentially dried (MgSO4), filtered, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a gradient of 0-6% methanol in dichloromethane) to provide 237 mg of 4-amino-1-isobutyl-1H-imidazo[4,5-c]quinoline-8-carbaldehyde as an off-white solid. MS (ESI) m/z 269 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2
Reactant: [H][H]
Reactant: O=c1ccc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cccc2[nH]c(=O)ccc12
Yield: 100.3 %

Procedure:
4.5 g of 5-nitroquinolin-2(1H)-one (Chem. Pharm. Bull. (1981), 29, pp. 651-56) is hydrogenated in 200 ml of ethyl acetate and 500 ml of methanol in the presence of 45 mg of palladium on activated carbon as a catalyst under normal pressure with hydrogen until the reaction is completed. The catalyst is removed by filtration through diatomaceous earth, and the reaction solution is concentrated by evaporation in a vacuum. 3.8 g of the title compound is obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:23]2)=[CH:19][CH:18]=1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4ccc(Cl)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-chloro-benzyl)-1H-pyrazol-3-yl amine. The title compound was obtained as a light yellow solid (Yield=28%). MS ISP (m/e): 389.2 (100) [(M+H)+].
Reaction SMILES: Br[CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[OH:5][CH2:4][C:3]1([CH2:7][OH:8])[CH2:6][N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1
Reactant: OCC1(CBr)COC1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Product: OCC1(CO)CN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
18.1 g of 1A and 11.7 g of benzylamine were mixed with 5 ml of water and the resulting mixture was stirred at 100° C. After 4 hours the solution was allowed to cool to ambient temperature and 13.8 ml of 36% (w/w) hydrochloric acid was added. The resulting mixture was stirred at 60° C. After 2 hours the solution was again allowed to cool to room temperature and then washed with dichloromethane to remove by-products. The aqueous layer was made alkaline by the addition of a solution of 5.5 g of sodium hydroxide in 10 ml of water and stirred at 100° C. for 1 hour. After cooling to ambient temperature the pH of the mixture was raised by addition of another solution of 5.5 g of sodium hydroxide in 10 ml of water and washed with hexane to remove benzylamine. The water was evaporated under reduced pressure, and the solid residue was taken up in dichloromethane. Inorganic salts, which remained undissolved, were removed by filtration, and the dichloromethane was evaporated in vacuo, leaving 1, as a white crystalline solid.