Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN4CCOCC4)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (21.9 μl, 0.13 mmol) was added morpholine (11.0 μl, 0.13 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 20% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 87% conversion to product. A further portion of morpholine (11.0 μl, 0.13 mmol) was added and the reaction mixture stirred at 40° C. for 5 hr. LC-MS indicated 94% conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with MeOH (5.0 mL). The solid was collected by filtration to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-morpholinoacetamide (Example 7) as a light yellow solid (11 mg, 20%): m/z 648 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.54 (4H, m), 3.20 (2H, s), 3.63 (4H, m), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.28 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.63-7.56 (3H, m), 7.92 (1H, d), 8.37-8.29 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 10.01 (1H, s).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21].C(=O)(O)[O-].[Na+]>CN(C=O)C.CC(N(C)C)=O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: Nc1ccc(F)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: Fc1cc2c(Nc3ccc(F)c(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.7 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (93) (4.0 g, 24.2 mmol), thionyl chloride (100 mL) and a catalytic amount of DMF (3 drops) was stirred under reflux for 1 h. The resulting solution was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a mixture of 3-bromo-4-fluoroaniline (5.1 g, 26.8 mmol) and dry DMA (25 mL). The reaction mixture was stirred at room temperature for 40 min, then a 5% solution of sodium bicarbonate (250 mL) was added and the mixture was stirred at room temperature for 15 min. The precipitated solid was collected by filtration and washed successively with water and hexane several times, before being dried under vacuum over silica gel to give N-(3-bromo-4-fluorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (162) (8.13 g, 99%), mp 275-277° C. (literature mp 269-270° C.; Smaill et al. J Med Chem, 1999, 42, 1803-1815); 1H NMR δ [(CD3)2SO] 10.12 (s, 1H), 8.97 (s, 1H), 8.74 (s, 1H), 8.32 (dd, J=6.4, 2.6 Hz, 1H), 8.23 (poorly resolved d, J=0.8 Hz, 1H), 7.93-7.87 (m, 1H), 7.46 (t, J=8.8 Hz, 1H). Anal. Calcd for C13H7BrF2N4: C, 46.32; H, 2.09; N, 16.62%. Found C, 46.54; H, 3.33; N, 16.42%.
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13]Cl)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][N:21]3[C:20](=[O:22])[C:19]4=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]4[C:17]3=[O:27])[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CCl)O2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC2(CC1)OCC(CN1C(=O)c3ccccc3C1=O)O2
Reaction time: 6 h
Yield: 101.4 %

Procedure:
A mixture of 8-t-butyl-2-chloromethyl-1,4-dioxaspiro(4,5)decane (10 g, 40 mmol) (prepared as described in EP 281842; see also the references cited in this document for related compounds), potassium phthalimide (8.9 g, 48 mmol) and a catalytic amount of tetra-n-butyl ammonium iodide in DMF (80 ml) were heated to 120° C. for 3 hours. Additional potassium phthalimide (2.8 g, 16 mmol) was then added and heating was continued for 6 hours. The solvent was then evaporated in vacuo and toluene (150 ml) was added. After filtration from insoluble material the organic phase was washed two times with brine (100 ml), dried (MgSO4) and evaporated in vacuo. The resulting residue (22 g) was purified by flash chromatography on silica (toluene/ethylacetate 3:1) yielding the title compound as light yellow crystals (14.5 g, Fp. 97°-115° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH:29]1[CH3:41])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:38][CH:39]=2)[CH2:30][CH:29]1[CH3:41])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Product: CC1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1C(=O)OC(C)(C)C
Yield: 97.7 %

Procedure:
Using Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethyl amide (0.142 g, 0.485 mmol) and (+/−)-4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.156 g, 0.533 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino) pyridin-3-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (260 mg, 97%) (following SiO2 chromatography, eluting with 0-3% MeOH/dichloromethane). MS (ESI) m/z 549.3 (M+H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[C:9](Cl)(=[O:13])C(Cl)=O.Cl.[N:16]1C=CC=C[CH:17]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:17][N:16]([O:13][CH3:9])[C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: c1ccncc1
Reactant: O=C(O)c1ccoc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
To a solution of furan-3-carboxylic acid (26 g, 0.23 mol) in 250 mL of toluene was added 24.15 mL (0.276 mol) of oxalyl chloride and 1 drop of pyridine and the mixture was heated on a steam-bath for 2 h. The mixture was cooled to room temperature, and N,O-dimethylhydroxamine hydrochloride (24.66 g, 0.253 mol), 4-dimethylaminopyridine (DMAP, 1.2 g, 0.01 mol), and 600 mL of methylene chloride were added. The mixture was cooled to 0° C., 50.1 mL of pyridine in 50 mL of methylene chloride was added slowly, the mixture was heated to warm to room temperature (3 h), and 2 g of N,O-dimethyl-hydroxamine hydrochloride and 1 g of 4-dimethylaminopyridine (DMAP) were added. The resulting mixture was stirred for 12 h. The above mixture was cooled to 0° C., filtered, and the filtrate was washed with 3N HCl, brine, dried over sodium sulfate, and concentrated in vacuo to yield 14 g (39%) of 3-(N-methyl-N-methoxycarbamoyl)furan.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][CH2:32]OS(C)(=O)=O)=[O:17])[CH:13]=[CH2:14].O>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:20][C@H:19]1[CH2:31][CH2:32][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOS(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1ccnc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of imidazole (1.52 in N,N-dimethylformamide (70 ml) were added potassium t-butoxide (2.51 g) and a solution of (2R,4R)-1-allyloxycarbonyl-2-(2-methanesulfonyloxyethyl)-4-(t-butyldimethylsilyloxy)pyrrolidine (8.3 g) in N,N-dimethylformamide (13 ml) at ambient temperature with stirring, and the mixture was stirred at about 60° C. for 1 hour. The reaction mixture was cooled with ice-cooling, and water and ethyl acetate were added thereto. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a mixture of chloroform and methanol (10:0.3, V/V) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(imidazol-1-yl)ethyl]-4-(t-butyldimethylsilyloxy)pyrrolidine (11.11 g).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([OH:9])=O.Cl.[OH:20][C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(#N)C.C(N(CC)CC)C>[F:18][CH:2]([F:1])[O:3][C:4]1[C:5]([CH3:17])=[C:6]([C:7]([C:22]2[CH:23]=[N:24][N:25]([CH3:26])[C:21]=2[OH:20])=[O:9])[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: Cn1nccc1O
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1OC(F)F
Reaction time: 12 h

Procedure:
To a stirred mixture of 3-(difluoromethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (500 mg, 1.78 mmol) and 5-hydroxy-1-methylpyrazole hydrochloride (288 mg) in anhydrous acetonitrile (10 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (443 mg), triethylamine (360 mg) and dimethylaminopyridine (217 mg) at room temperature. After being stirred for 12 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of methylene chloride. This solution was washed with 100 mL of water, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 10 mL of anhydrous acetonitrile, and triethylamine (260 mg) and acetone cyanohydrin in a catalytic amount were added, followed by stirring overnight at room temperature. 150 mL of methylene chloride was added to the reaction mixture, followed by extraction with a 1N potassium carbonate aqueous solution, and the aqueous layer was acidified by 2N hydrochloric acid. The obtained acidic aqueous solution was extracted twice with methylene chloride (100 mL), the combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1 to 9:1) to obtain 5-hydroxy-1-methylpyrazol-4-yl 3-(difluoromethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone as an oil.
Reaction SMILES: [Cl:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O.O>[Cl:1][CH2:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(CCl)c1ccc(F)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(Oc2ccc(S(=O)(=O)CCl)cc2)cc1
Temperature: 95 °C

Procedure:
A mixture of 1-chloromethanesulfonyl-4-fluoro-benzene (0.5 g, 2.4 mmol) from Step A, 4-methyl-phenol (0.21 mL, 2.0 mmol) and K2CO3 (0.55 g, 4.0 mmol) in dry DMA (10 mL) was heated at 95° C. overnight. The reaction mixture was diluted with EtOAc and water. After the usual work-up, crude product was purified by chromatography (silica gel, 25% EtOAc/hexanes). MS 319 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][C:25]#[CH:26])[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C=O.[C:29](O)(=O)[CH3:30].[CH2:33]([NH:35][CH2:36]C)[CH3:34]>O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH2:24][C:25]#[C:26][CH2:36][N:35]([CH2:29][CH3:30])[CH2:33][CH3:34])[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: C#CCN(C(C(=O)OC)C(C)C)S(=O)(=O)c1ccc(OCC#CC)cc1
Reactant: CCNCC
Reactant: CC(=O)O
Agent: C=O
Solvent: C1COCCO1
Product: CC#CCOc1ccc(S(=O)(=O)N(CC#CCN(CC)CC)C(C(=O)OC)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.00 g (2.653 mmol) of methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-3-methylbutanoate in 8.0 mL of dioxane was added 0.198 g (6.632 mmol) of paraformaldehyde, 10 mg of cuprous chloride, 1.0 mL of acetic acid and 0.55 ml (5.305 mmol) diethylamine. The resulting mixture was stirred at room temperature for 15 minutes after which the reaction had turned green. The reaction was then heated to reflux for 2 h, after which the reaction had turned brown. The reaction mixture was cooled to room temperature and extracted with ether. The combined organics were washed with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo to give 1.23 g of methyl 2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(diethylamino)-2-butynyl]amino}-3-methylbutanoate as a brown oil.
Reaction SMILES: C([C:3]1[N:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=[C:7](Br)[CH:6]=2)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[CH2:29][C:30]1[C:31]([NH2:37])=[N:32][C:33]([NH2:36])=[N:34][CH:35]=1)#[CH:25].C(=O)([O-])[O-].[Na+].[Na+].[CH2:51](N(CC)CC)[CH3:52]>CN(C)C=O.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>[CH:18]1([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:25]#[C:24][C:26]4[CH:27]=[C:28]([CH2:29][C:30]5[C:31]([NH2:37])=[N:32][C:33]([NH2:36])=[N:34][CH:35]=5)[CH:38]=[C:39]([O:43][CH3:44])[C:40]=4[O:41][CH3:42])[CH:6]=3)[C:11](=[O:16])[C:12]([C:13]([O:15][CH2:51][CH3:52])=[O:14])=[CH:3]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C#Cc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reactant: CCN(CC)CC
Reactant: CCc1c(C(=O)O)c(=O)c2ccc(Br)cc2n1C1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2cc(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)ccc2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3 g of ethyl 7-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (Example 13ad)) are dissolved in 35 ml of N,N-dimethylformamide to 90° C. under argon with 200 mg of bis(triphenylphosphine)palladium(II) dichloride and treated dropwise within one hour with a solution of 5-[3-ethynyl-4,5-dimethoxy-benzyl]-pyrimidine-2,4-diamine (Example 11b)) in 35 ml of N,N-dimethylformamide and 35 ml of triethylamine. The dark red solution is stirred at 90° C. for a further 1 hr. The reaction mixture is left to cool to room temperature and is poured into 150 ml of 10% aqueous sodium carbonate solution while stirring. After 15 min. the suspension is suction filtered and the residue is washed with 100 ml of water and then with 100 ml of diethyl ether and dried at room temperature in a high vacuum. The crude product is triturated with 50 ml of diethyl ether for one hour, filtered off under suction and dried in a high vacuum at room temperature. 3.83 g (83%) of ethyl 1-cyclohexyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained as a light yellow solid. M.p. 228°-230° C.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:18]=[C:19]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]#[N:26])[CH2:20]2.C(N(CC)CC)C.O>ClCCl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:18]=[C:19]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]#[N:26])[CH2:20]2)(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: N#CC1Cc2cc(O)ccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: N#CC1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reaction time: 72 h

Procedure:
2.4 mL of triflic anhydride (1.2 equivalents) are poured at 0° C., over 1 hour, into a solution of 2 g (13.8 mmoles) of 3-hydroxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile in 40 mL of dichloromethane and 3.9 mL (2 equivalents) of triethylamine. Stirring is carried out for 3 days at 25° C. The reaction mixture is poured into water, extracted with dichloromethane, dried over MgSO4, filtered and evaporated to obtain 3.8 g of an oil. This residue is purified by flash chromatography over 150 g of silica; eluant=100% toluene. The expected product is obtained in the form of an oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.C(N(CC)CC)C.C([CH:28]([CH2:32][C:33](Cl)=[O:34])[C:29](Cl)=[O:30])C.[OH2:36]>C1COCC1>[O:34]=[C:33]1[C:32]([CH2:28][C:29]([OH:30])=[O:36])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]2[C:2](=[CH:10][C:9]3[CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=2)[O:1]1
Reactant: CCC(CC(=O)Cl)C(=O)Cl
Reactant: O
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)CCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)CCC3
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of (6-hydroxy-2,3-dihydro-1H-inden-5-yl)(phenyl)methanone (1.0 g) and triethylamine (0.98 ml) in THF (20 ml) was combined with ethyl succinyl chloride (0.55 ml) at 0° C., and stirred for 1 hour. The reaction solution was combined with water, and the product was extracted with ethyl acetate. The extract was washed with a 1 N solution of hydrochloric acid followed by a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was dissolved in toluene (10 ml), combined with DBU (0.25 ml), and heated under reflux for 2.5 hours. After cooling, the reaction solution was diluted with ethyl acetate (60 ml), and washed with water followed by a 1 N solution of hydrochloric acid and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by a column chromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:2). The resultant crude product of ethyl (2-oxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetate was dissolved in acetic acid (20 ml) and concentrated hydrochloric acid (10 ml), and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the resultant residue was dissolved in a solvent mixture of THF (5 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by recrystallization from ethyl acetate-isopropyl ether to obtain the title compound (0.95 g, yield: 70%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:38]([C:35]1[CH:36]=[C:37]3[C:32]([CH:31]=[CH:30][NH:29]3)=[CH:33][CH:34]=1)=[O:39])=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc3cc[nH]c3c2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
3-{[(1H-Indole-6-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-7-trifluoromethyl-1,4-di-hydro-[1,8]naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 1H-indole-6-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.35 (br. s., 1H) 8.90 (d, J=8.15 Hz, 1H) 8.36 (br. s., 1H) 7.96 (d, J=8.15 Hz, 1H) 7.89 (s, 1H) 7.37-7.59 (m, 8 H) 6.46 (br. s., 1H) 4.47 (d, J=4.83 Hz, 2H) 3.37 (s, 3H) MS calcd. for C27H19F3N4O4 [(M+H)+] 521.1 obsd. 521.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][OH:15]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][CH2:14][C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1ccco1
Product: Brc1ccc(OCc2ccco2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and 2-furanmethanol by the method of Example 10(b).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].C1(C)C=CC(S(O[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C.O>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]2)[C:9]([O:13][CH3:14])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 80.5 %

Procedure:
2-nitro-4-hydroxy-5-methoxybenzonitrile (388 mg, 2 mmol) in DMF (5 ml) and acetonitrile (5 ml) was reacted with 4-(4-tolylsulphonyloxymethyl)-1-tert-butyloxycarbonyl-piperidine (738 mg, 2 mmol) and K2CO3 (414 mg, 3 mmol) at 110° C. for 3.5 hours. The mixture was diluted with water, extracted with ethylacetate, washed HCl (2N), dried over MgSO4, evaporated to give title compound (630 mg, 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1
Reactant: CCOC(=O)C[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@H]1CCCNC1

Procedure:
290 mg (1.07 mmol) of ethyl (R)-(1-tert-butoxycarbonylpiperidin-3-yl)acetate (Example 17A) are stirred with 2 ml of dichloromethane and 2 ml of trifluoroacetic acid at RT for 1 h. The volatile components are removed on a rotary evaporator and the residue is dried under high vacuum. The resulting oil (301 mg, 99% of theory) is reacted further as it is.