Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N+:10]=2[O-:16])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N+:17]([O-])([O-:19])=[O:18].[K+].C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]([CH3:15])=[CH:11][N+:10]=2[O-:16])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(-c2nc(C)ccc2F)[n+]([O-])c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc(F)c(-c2cc([N+](=O)[O-])c(C)c[n+]2[O-])n1
Temperature: 80 °C

Procedure:
To a solution of cold H2SO4 (0-10° C.) (170 mL) was added 2-(3-fluoro-6-methylpyridin-2-yl)-5-methylpyridine 1-oxide (4. g, 19. mmol) followed by portionwise addition of KNO3 (4 g, 39 mmol) and the reaction was heated overnight at 80° C. The reaction mixture was then cooled to room temperature, and poured into ice-water and the pH adjusted to about 8 with a saturated solution of Na2CO3. The mixture was extracted with dichloromethane, the organic layer dried, and purified by flash silica chromatography eluted with petroleum ether/ethyl acetate (4:1) to give 2-(3-fluoro-6-methylpyridin-2-yl)-5-methyl-4-nitropyridine 1-oxide. (2.9 g; 57.8%). 1HNMR (CDCL3): δ ppm 8.37 (s, 1H), 8.27 (s, 1H), 7.50-7.47 (m, 1H), 7.38-7.37 (m, 1H), 2.70 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=1)([OH:13])=[O:12].C[OH:39]>C1(C)C=CC=CC=1>[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:39])=[CH:32][CH:31]=1)([OH:13])=[O:12]
Reactant: CO
Reactant: N#Cc1ccc(NCCCCCCCCCCCCCCCC(=O)O)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(NCCCCCCCCCCCCCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-iso-butylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 5.1 g. of 4-(15-carboxypentadecylamino)benzonitrile under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. Recrystallization from hexane affords 4-(15-carboxypentadecylamino)benzaldehyde as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=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.O>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([C:21]3[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC(C)C(C)n1cc(Br)c2[nH]nc(N)c2c1=O
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: CN(C)C=O
Solvent: O
Product: CC(C)C(C)n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 120 °C
Yield: 10.8 %

Procedure:
A mixture of 3-amino-7-bromo-5-(3-methylbutan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G (332 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (347 mg), tetrakis(triphenylphosphine)palladium(0) (128 mg), aqueous sodium carbonate solution (2 M, 1.11 ml) and N,N-dimethylformamide (6.0 mL) was heated with microwave irradiation at 120° C. for 1 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). To the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (36.0 mg).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29](O)=[O:30].[NH2:50][CH2:51][C@@H:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[OH:53]>>[OH:53][C@H:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:51][NH:50][C:29]([C:28]1[S:27][C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:46])[F:48])=[CH:40][CH:39]=3)[C:33]2=[O:49])=[N:25][C:24]=1[CH3:23])=[O:30]
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NC[C@H](O)c1ccccc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NC[C@H](O)c1ccccc1
Yield: 67 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with (R)-(−)-2-amino-1-phenylethanol, the title compound was obtained as a white powder in 67% yield: mp 149-151° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.38-7.16 (m, 9H), 6.24 (br s, 1H), 4.92-4.89 (m, 1H), 4.44 (s, 2H), 4.28-4.02 (m, 2H), 3.85-3.41 (m, 2H), 3.57-3.38 (m, 3H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 157.5, 155.4, 152.8, 148.9, 141.7, 134.3, 129.7, 128.5, 127.8, 125.8, 121.4, 117.6, 73.5, 47.8, 47.2, 42.0, 41.7, 17.1; MS (ES+) m/z 521.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)CC2C=CC(OC)=CC=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.Br[C:42]([CH3:47])([CH3:46])[C:43]([NH2:45])=[O:44].[I-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CC#N.C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH:33]3[CH2:35][CH2:34]3)[C:20]3=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]3[N:18]=2)=[CH:4][C:5]([C:14]#[N:15])=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:42]([CH3:47])([CH3:46])[C:43]([NH2:45])=[O:44])[CH2:10][CH2:9]1
Reactant: CC(C)(Br)C(N)=O
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C(N)=O)N1CCC(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, (Example 208D) (25 mg, 0.045 mmol), 2-bromo-2-methylpropanamide (37.5 mg, 0.226 mmol), sodium iodide (33.8 mg, 0.226 mmol) and Cs2CO3 (58.8 mg, 0.180 mmol) in CH3CN (1.2 mL) was heated at 120° C. for 2 h using microwave irradiation. The reaction mixture was diluted with DCM, filtered to remove insoluble material. The filtrate was concentrated. The residue was dissolved in DCE (1 mL). To this was added TFA (0.5 ml), anisole (0.1 ml, 0.918 mmol), and then heated at 50° C. for 3 h. Solvent was removed. The residue was applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with large amount (3 CV) of mixture of 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left 23 mg material which was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammonium acetate; Gradient: 50-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-1-yl)-2-methylpropanamide (3.6 mg).
Reaction SMILES: CC(S([NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH2:19])=[O:18])[CH:12]=1)[CH2:9][CH3:10])=O)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH2:19])=[O:18])[CH:12]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C(N)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1ccnc(C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of 85% 4-[(S)-1-(2-methyl-propane-2-sulfinylamino)-propyl]pyridine-2-carboxylic acid amide (5.5 g, 16.5 mmol) in methanol (50 mL) was added a 4 N solution of HCl in dioxane (4.33 mL, 17.32 mmol). After 2 hour, additional 4 N HCl in dioxane (0.5 mL) was added. The reaction was monitored by TLC (eluting with EtOAc). After 1.5 hours, the mixture was concentrated in vacuo to remove MeOH and EtOAc (400 mL) was added. The mixture was washed with saturated sodium carbonate solution (100 mL) and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 4-((S)-1-amino-propyl)-pyridine-2-carboxylic acid amide.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=2)[O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=2)[O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([NH:50][CH2:49][CH2:48][C:47]([OH:51])=[O:46])=[O:37])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCCC(=O)O)c2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCCC(=O)NCCC(=O)O)c2)cc1

Procedure:
The product from Example 117B and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.97 (s, 1 H), 7.86 (t, 1 H), 7.23 (m, 8 H), 6.88-7.08 (m, 5 H), 6.67 (m, 1 H), 6.48 (m, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.91 (t, 2 H), 3.35 (br.s, 1 H), 3.22 (dd, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.35 (t, 2 H), 2.09 (t, 2 H), 1.50-1.74 (m, 4 H); MS (APCI) m/z 658 (M−H−).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:47]2[CH:48]=[CH:49][C:44]([C:42]([NH:41][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:43])=[CH:45][CH:46]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)(C)NC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 56.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (522 mg, 1 mmol), [4-(tert-butylaminocarbonyl)phenyl]boronic acid (442 mg, 2 mmol), and dichlorobis(triphenylphosphine)palladium (II) (70.2 mg, 0.1 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.25 mL, 2.5 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) to afford 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (300 mg, 56.9%) as a light yellow solid: LC/MS m/e calcd for C31H33N3O3S [M+H]+ 528.69, observed 528.0.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)/[C:6](=[C:16](/[NH:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[CH:26][CH:25]=2)\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:5]1=[O:40])(=O)C.[CH3:41][N:42]([CH3:47])[C:43](=[O:46])[CH2:44]Br.CC(C)([O-])C.[K+].[OH-].[Na+]>CS(C)=O.CO>[CH3:41][N:42]([CH3:47])[C:43]([CH2:44][N:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:23]/[C:16](=[C:6]2\[C:5](=[O:40])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:29][CH:28]=1)[S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])=[O:46]
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(NS(=O)(=O)c3ccccc3)cc2)c2ccccc2)c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CN(C)C(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1)S(=O)(=O)c1ccccc1

Procedure:
Prepared analogously to Examples 82 and 187 from (Z)-1-acetyl-3-[1-(4-phenylsulphonylamino-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone, bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSO and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:5][CH:4]=1)#[N:2]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=Cc2ccc(C#N)cn2)Cn2cncn2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(Cc2ccc(C#N)cn2)Cn2cncn2)cc1
Reaction time: 1 h

Procedure:
A mixture of 6-[-2-(4-cyanophenyl)-3-(1,2,4-triazol- 1-yl)prop-1-enyl]nicotinonitrile (0.2 g) and 10% by weight palladium-on-carbon (0.1 g) in ethyl acetate (20 ml) was stirred rapidly under an atmosphere of hydrogen at atmospheric pressure for 1 h. The mixture was filtered and the filtrate was evaporated to dryness. The residue was triturated with diethyl ether to give a white solid, which was filtered off, washed with more ether (10 ml) and dried to give 6-[-2-(4-cyanophenyl)-3-(1,2,4-triazol-1-yl)propyl]nicotinonitrile, m.p. 98°.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].COC1C=CC(C[N:12]2[C:17]3=[N:18][N:19]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)=[CH:31][CH:30]=4)[C:20]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]3[C:15](=[O:41])[N:14]([CH3:42])[C:13]2=[O:43])=CC=1.C1(OC)C=CC=CC=1>ClCCCl>[CH3:42][N:14]1[C:15](=[O:41])[C:16]2=[C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:19]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:33][CH:34]=3)[N:18]=[C:17]2[NH:12][C:13]1=[O:43]
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n(Cc4ccc(-c5ccccn5)cc4)nc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccn4)cc3)c(Nc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
AlCl3 (0.733 g, 5.50 mmol) is added to a solution of 7-(4-methoxybenzyl)-5-methyl-3-(phenylamino)-2-(4-(pyridin-2-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.08 g, 1.98 mmol) and anisole (mL) in 1,2-dichloroethane (15 mL) under argon. The reaction mixture is stirred at room temperature overnight, and then quenched with water with cooling. The resulting suspension is treated with 20% NaOH (70 mL), and then extract with methylene chloride 5 times. The organic phase is combined and evaporated to dryness. The residue is further purified by chromatography to give 751 mg of pure product (Yield: 89%). MS (FAB) m/z 425.3 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])C1C=CC=CC=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(Cl)Cl>[F:22][C:17]([F:23])([C:18]([F:19])([F:20])[F:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: FC(F)(F)C(F)(F)CCCCCCCCOCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: OCCCCCCCCC(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 40.9 %

Procedure:
26 g of 1-benzyloxy-9,9,10,10,10-pentafluorodecane are dissolved in 1000 ml of abs. methylene chloride, treated at 0° C. with 28.9 ml of N,N-dimethylaniline and stirred for 5 minutes. 41.1 g of aluminium trichloride are then added in portions and the reaction mixture is warmed to 50° C. for 45 minutes. For work-up, the mixture is allowed to come to room temperature, stirred into 2N hydrochloric acid, extracted 3 times with methylene chloride, and the organic phase is washed with sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The crude product is chromato-graphed on silica gel using a hexane-ethyl acetate radient. 7.8 g of 9,9,10,10,10-pentafluorodecan-1-ol are obtained as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][O:34][NH2:35])[N:27]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1>CN(C=O)C>[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][O:34][NH:35][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])[N:27]([CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c(CONC(=O)C2CC2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
Triethylamine (0.634 mL, 4.55 mmol) and cyclopropanecarbonyl chloride (0.248 mL, 2.73 mmol) were added to a solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). The cloudy mixture was stirred for 2 hours at room temperature, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration, washed with dichloromethane and acetonitrile, and dried in a vacuum oven to provide 442 mg of N-{[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}cyclopropanecarboxamide as a hydrate, white crystals, mp 209-210° C.
Reaction SMILES: NC1N=C(C)C2C(=NO)CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1.Cl.ClCC[CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1.[H-].[Na+].CN(C)C[CH2:42][CH2:43][O:44][N:45]=[C:46]1[CH2:55][CH:54]([C:56]2[CH:61]=[C:60](F)[CH:59]=[CH:58][C:57]=2[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:53][C:52]2[N:51]=[C:50]([NH2:69])[N:49]=[C:48]([CH3:70])[C:47]1=2>>[N:33]1([CH2:42][CH2:43][O:44][N:45]=[C:46]2[CH2:55][CH:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:53][C:52]3[N:51]=[C:50]([NH2:69])[N:49]=[C:48]([CH3:70])[C:47]2=3)[CH2:32][CH2:31][O:36][CH2:35][CH2:34]1
Reactant: ClCCC1CNCCO1
Reactant: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Agent: Cl
Agent: [H-]
Product: Cc1nc(N)nc2c1C(=NOCCN1CCOCC1)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (30 mg, 0.087 mmol), 2-(chloro-ethyl)-morpholine hydrochloride (32 mg, 0.214 mmol) and sodium hydride (60% dispersion in oil) (18 mg, 0.470 mmol), following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.Cl.[CH2:25]([NH:29][C:30]([CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1)=[O:31])[CH:26]([CH3:28])[CH3:27].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C=O)C>[CH2:25]([NH:29][C:30]([CH:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:33]1)=[O:31])[CH:26]([CH3:28])[CH3:27]
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CC(C)CNC(=O)C1CCCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(C(=O)NCC(C)C)C2)nc1-c1ccc(C)cc1
Temperature: 110 °C

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.100 g; 0.300 mmol), N-isobutylpiperidine-3-carboxamide hydrochloride (0.198 g; 0.901 mmol) and triethylamine (0.211 mL; 1.50 mmol) in a mixture of tetrahydrofuran (2 mL) and DMF (0.4 mL) was heated at 110° C. in a sealed tube for 18 h. After cooling, the reaction mixture was diluted in a saturated solution of sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane (with 0.5% of triethyl amine) furnished 0.150 g (quantitative) of the title compound as a yellow oil.