Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].CNCCNC.CC(O)(C)C.[Na+].[I-:38]>C(Cl)Cl.[Cu]I>[I:38][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23]
Reactant: [I-]
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: FC(F)(F)c1nc2ccc(I)cc2c(C(F)(F)F)c1-c1ccccc1

Procedure:
A mixture of 6-bromo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (273 mg, 0.650 mmol, Intermediate 8, step c), CuI (14 mg, 0.074 mmol), N,N′-dimethylethylenediamine (0.0158 mL, 0.147 mmol), t-BuOH (0.65 mL), and NaI (200 mg, 1.33 mmol) was microwaved at 150° C. for 30 min (Biotage). The reaction was diluted with DCM (10 mL), filtered through Celite® and a 0.45 um filter, and concentrated. The residue was flash chromatographed with a heptane to 20% EtOAc/heptane gradient to afford the title compound as a light yellow oil that crystallized upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: BrC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCCCC1

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2CO3 (1.5 equiv.) and bromocyclohexane (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=O>P(Cl)(Cl)(Cl)=O>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][C:15]([C:16]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)=[C:14]([O:13][CH2:12][CH2:11][CH2:10][Cl:9])[CH:22]=1
Reactant: COc1ccc(C(=O)O)c(OCCCCl)c1
Reactant: Nc1ccncc1N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cnccc3[nH]2)c(OCCCCl)c1

Procedure:
A mixture of 3,4-diaminopyridine and 2-(3-chloropropoxy)-4-methoxybenzoic acid in phosphorus oxychloride was stirred at reflux for 4 hours. The excess phosphorus oxychloride was then removed in vacuo and the residue carefully treated with water before basifying with dilute ammonia hydroxide and extracting with chloroform. The crude product was then dissolved in ethyl acetate, decolourised with charcoal and triturated with ethereal HCl to give the title compound m.p. 174°-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([CH3:68])=[C:53]([C:55]2[C:56](=[O:67])[N:57]([CH3:66])[C:58]3[C:63]([CH:64]=2)=[CH:62][N:61]=[C:60]([CH3:65])[CH:59]=3)[CH:54]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:48][C:49]1[CH:50]=[CH:51][C:52]([CH3:68])=[C:53]([C:55]2[C:56](=[O:67])[N:57]([CH3:66])[C:58]3[C:63]([CH:64]=2)=[CH:62][N:61]=[C:60]([CH3:65])[CH:59]=3)[CH:54]=1)=[O:7]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(NC(=O)c3cc(Br)cc(C(F)(F)F)c3)ccc1C)c(=O)n2C
Reaction time: 0.03 h

Procedure:
To a solution of 3-bromo-5-trifluoromethyl-benzoic acid 21 (193 mg, 0.716 mmol) in DMF (5 mL) is added HATU (272 mg, 0.716 mmol) and di-isopropylethylamine (278 mg, 2.15 mmol) at rt. The resulting mixture is stirred for 2 min. A solution of 3-(5-amino-2-methyl-phenyl)-1,7-dimethyl-1H-[1,6]naphthyridin-2-one 15 (200 mg, 0.716 mmol) in DMF (5 mL) is added. The reaction mixture is stirred at rt overnight, diluted with EtOAc, and washed with brine three times. The organic layer is dried (MgSO4) and concentrated. The residue is purified by automated chromatography to give the desired product 22 as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.99 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.66 (d, J=2.1 Hz, 1H), 7.62 (dd, J=8.3, 2.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 3.63 (s, 3H), 2.65 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([NH2:8])=[NH:7])[N:3]=[CH:2]1.[Cl:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=O.C([O-])(=O)C.[Na+]>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[NH:8][C:21]([CH3:23])=[C:20]([C:19]([O:25][CH2:26][CH3:27])=[O:24])[CH:12]([C:11]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:10]=3[Cl:9])[N:7]=2)[N:3]=[CH:2]1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: N=C(N)c1cscn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(c2cscn2)=NC1c1ccc(F)cc1Cl
Yield: 36.9 %

Procedure:
2 mmol 4-Thiazolyl formamidine (Diana, G. D., Yarinsky, A., Zalay, E. S., et al. J. Med. Chem. 1969, 12(9):791-793), 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol ethyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.28 g of a yellow crystal (yield 37%) with mp 140-142° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.01-1.05 (3H, m); 2.49 (3H, s); 3.92-3.95 (2H, m); 5.99 (1H, s); 7.36-7.39 (3H, m); 8.15 (1H, d, J=1.96 Hz); 9.18 (1H, d, J=1.96 Hz); 9.47 (1H, s); MS (FAB) 380.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:33][CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37].O>ClCCl>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:13][CH2:12][N:11]([C:9]([C:5]2[C:6]([CH3:8])=[N:7][C:2]([N:1]3[CH2:33][CH2:34][CH2:35][S:36]3(=[O:38])=[O:37])=[CH:3][CH:4]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)nc3C)CC2)c(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Amino-2-methylpyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (180 mg) described in Preparation Example 136 and triethylamine (0.19 mL) were dissolved in dichloromethane (5 mL), 3-chloropropane-1-sulfonyl chloride (0.14 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, the mixture was extracted with dichloromethane, the extract was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (5 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.12 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (57 mg).
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[CH:7][CH:8]=2)[C:3]1=[O:25].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][N:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:29][CH:26]([CH3:28])[CH3:27])=[CH:16][CH:17]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[CH:7][CH:8]=2)[C:3]1=[O:25]
Reactant: CC(C)N
Reactant: COc1ccc2cc(-c3ccc(OCC4CO4)cc3)n(C)c(=O)c2c1
Product: COc1ccc2cc(-c3ccc(OCC(O)CNC(C)C)cc3)n(C)c(=O)c2c1
Yield: 63 %

Procedure:
2-Methyl-3-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example (1b) from 2-methyl-3-[4-(2,3-epoxypropoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one and isopropylamine at a reaction temperature of 50° C.
Reaction SMILES: N1CCCCC1.[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=O.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].C(=O)=O.Cl>N1C=CC=CC=1>[Cl:7][C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[CH:10]=[CH:20][C:21]([OH:23])=[O:22]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C

Procedure:
8.5 g of piperidine were added to 185.5 g (1 mole) of 2-chloro-5-nitrobenzaldehyde and 125 g (1.2 moles) of malonic acid in 400 ml of pyridine, and the mixture was stirred at 110° C. until the evolution of CO2 was complete (about 3 hours). The reaction mixture was then poured on to a mixture of 1 l of ice and 350 ml of concentrated HCl, a yellow solid being precipitated. The product was filtered off under suction, washed with water and dried to give 220 g (97% of theory) of the above compound of melting point 193°-196° C.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[CH2:15][C:16]([NH:18][C:19]1[CH:20]=[N:21][N:22]([CH3:44])[C:23]=1[NH:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17]>C(O)C.O1CCCC1>[NH2:6][CH2:15][C:16]([NH:18][C:19]1[CH:20]=[N:21][N:22]([CH3:44])[C:23]=1[NH:24][C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:17]
Reactant: Cn1ncc(NC(=O)CN2C(=O)c3ccccc3C2=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cn1ncc(NC(=O)CN)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Hydrazine monohydrate (1.46 ml) was added to a solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]acetamide (5.42 g) in ethanol (108 ml) and tetrahydrofuran (54 ml) at room temperature, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to 0° C., and the insoluble materials were removed by filtration. The filtrate was concentrated in vacuo. The residue was triturated with diisopropyl ether, collected by filtration and dried in vacuo to give 2-amino-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]acetamide (3.37 g) as a solid. This product was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:12][O:11][C:9]([CH2:8][CH2:7][C:6]1[CH:13]=[CH:14][C:3]([CH:1]=[CH:16][C:17]([OH:19])=[O:18])=[CH:4][CH:5]=1)=[O:10]
Reactant: COC(=O)CCc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(C=CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of methyl 4-formylhydrocinnamate (2.30 g), malonic acid (2.50 g) and piperidine (0.1 ml) in 12 ml pyridine was stirred at 100° C. for 2 hours, and subsequently at 140° C. for 2 hours. After addition of 100 ml ice-cold water, 210 ml of 0.5 mol/l hydrochloric acid was added dropwise to the reaction mixture to precipitate a solid, which was then filtered, washed with water, and dried by heating under reduced pressure to give 4-[2-(methoxycarbonyl)ethyl]cinnamic acid (2.38 g, 84%) as a colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.[C:38](Cl)(=O)[O:39]C1C=CC([N+]([O-])=O)=CC=1.[CH2:51]([NH2:53])[CH3:52]>CN(C)C1C=CN=CC=1.ClCCCl.C(=O)([O-])O.[Na+]>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([NH:1][C:38](=[O:39])[NH:53][CH2:51][CH3:52])[CH2:3][N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Reactant: CCN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCNC(=O)N[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCCCSC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R,5S)-3-amino-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (97 mg) and N,N-dimethylpyridin-4-amine (33 mg) in 1,2-dichloroethane (4 ml) was added a solution of 4-nitrophenyl chlorocarbonate (55 mg) in 1,2-dichloroethane (1 ml) under ice-cooling and the mixture was stirred at room temperature for 1 hr. Ethylamine (2 M solution in THF, 450 μl) was added, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (95.9 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].C(O[CH2:21][CH:22]=[CH2:23])(=O)C.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC>CN(C)C=O>[CH2:23]([C:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14])[CH:22]=[CH2:21]
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1Br
Reactant: C=CCOC(C)=O
Agent: CCCC[Sn](CCCC)CCCC
Solvent: CN(C)C=O
Product: C=CCc1c(C(=O)OC)[nH]c2c(C)ccc(C)c12
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
Under nitrogen atmosphere, 1.00 g (3.54 mmol) of methyl 3-bromo-4,7-dimethylindole-2-carboxylate and 0.31 g (5.23 mmol) of dichloro [1,1-bis(diphenylphos-phino)ferrocene]palladium (PdCl2 (dppf)) were suspended in 4 ml of anhydrous dimethylformamide (DMF). Thereto were added 0.57 ml (5.32 mmol) of allyl acetate and 2.7 ml (5.32 mmol) of hexabutylditin. The reaction mixture was stirred at 120° C. for 90 minutes and then subjected to Celite filtration. The filtrate was extracted with chloroform. The extract was purified by silica gel column chromatography (chloroform:n-hexane=1:1 to 3:1) to provide 0.75 g of white crystals. Yield: 87%
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[CH2:57][CH:58]([NH:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH:59]([CH3:61])[CH3:60])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][N:62]2[CH:58]([CH:59]([CH3:60])[CH3:61])[CH2:57][C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])=[CH:69][CH:68]=1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)CC(NCc1ccc(F)cc1)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)C1CC(O)=C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 13.4 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.095 g, 0.269 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.113 g, 0.297 mmol) and 4-methylmorpholine (0.059 mL, 0.537 mmol) were added sequentially to a solution of) rac-3-(4-fluoro-benzylamino)-4-methyl-pentanoic acid ethyl ester (0.072 g, 0.269 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 20 h, then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (5 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.349 mL, 1.08 mmol) was added and the reaction mixture was heated to 60° C. for 4 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-6-isopropyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.020 g, 0.036 mmol, 13%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.86 (3H, d, J=7.0 Hz), 0.94 (3H, d, J=7.2 Hz), 2.04-2.09 (1H, m), 2.56 (1H, d, J=17.3 Hz), 2.95 (3H, s), 3.04-3.10 (1H, m), 3.38-3.41 (1H, m), 4.14 (1H, d, J=15.4 Hz), 4.23 (2H, d, J=5.7 Hz), 5.15 (1H, d, J=14.7 Hz), 7.11-7.16 (2H, m), 7.22 (1H, s), 7.35-7.38 (2H, m), 7.63 (1H, t, J=5.8 Hz). LC-MS (ESI) calculated for C22H25FN4O6S3 556.09. found 557.2 [M+H+].
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[CH:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[F:31])[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].BrC1C=CC2N(N=CC=2C(NC2C=C(C(=O)NCC3C=CC=CC=3N3CCN(C)CC3)C=CC=2C)=O)C=1>>[CH2:21]([NH:20][C:18]([C:17]1[CH:28]=[CH:29][C:30]([F:31])=[C:15]([NH:14][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[O:13])[CH:16]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccc1F
Reactant: O=C(O)c1cnc2ccc(I)cn12
Agent: Cc1ccc(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnn2cc(Br)ccc12
Product: O=C(NCc1ccccc1)c1ccc(F)c(NC(=O)c2cnc3ccc(I)cn23)c1

Procedure:
The title compound was prepared from 6-iodoimidazo[1,2-a]pyridine-3-carboxylic acid (step 1) and 3-amino-N-benzyl-4-fluorobenzamide (step 2) analogously 6-bromo-N-(2-methyl-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide (Intermediate 4A);
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:31][CH:32]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Product: COC(=O)c1c(CNC(=O)c2ccc(C(C)(C)C)cc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
3-[(4-tert-Butyl-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester was prepared starting from intermediate K and 4-tert-butyl-benzoyl chloride. MS calcd. for C30H30N2O5 [(M+H)+] 499.2, obsd. 499.2.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=1>C(Cl)Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:3](=[O:4])[CH:2]([F:6])[F:1])=[CH:25][N:24]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)C(F)F
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Difluoracetic acid was added to a mixture of carbonyl diimidazole (8.4 g, 0.052 mol) and methylene chloride (100 ml) under a nitrogen atmosphere. Gas was evolved and a new solid formed in the reaction. After stirring at room temperature for 30 minutes, 5-amino-2-methoxypyridine (5.7 ml, 0.052 mol) was added over a two-minute period. The reacion was slightly exothermic and was stirred further for another 30 minutes when it was washed with water (100 ml), 5% aqueous acetic acid (2×50 ml), 5% sodium bicarbonate (25 ml); dried over anhydrous magnesium sulfate; filtered; and evaporated in vacuo to give an oil. The oil was extracted with ether and the ether extract on dilution with pentane gave 3.7 g of crude product. This was extracted with ether and diluted with pentane to give 2.0 g of the title compound, m.p. 75°-78° C. The title product was identified by IR, NMR and MS analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(N(CC)CC)C.[S:18]1[C:22]2[C:23]([C:27](Cl)=[O:28])=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1>C(OCC)(=O)C>[S:18]1[C:22]2[C:23]([C:27]([O:8][C:6]3[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=3)=[O:28])=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C=C(OC(=O)c2cccc3nnsc23)C1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
5.6 g (0.04 mol) of 5,5-dimethyl-1,3-cyclohexanedione are dissolved in a mixture of 4.4 g (0.044 mol) of triethylamine and 120 ml of ethyl acetate. 8.7 g (0.044 mol) of benzothiadiazole-7-carboxylic acid chloride are added dropwise at 15° to 20° C., and the mixture is subsequently stirred overnight at room temperature. The ethyl acetate solution is washed with H2O, dried and concentrated. Purification by column chromatography using ethyl acetate/hexane gives 10.5 g (87.5%) of the title compound, melting point 131°-133° C.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20]C3C=CC=CC=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](OCC)=O)=[CH:32][CH:31]=1.FC(F)(F)C1C=CC(CC(OCC)=O)=CC=1.C(N)CC1C=CC=CC=1.NC1C=CC=CC=1>>[C:3]1([CH3:2])[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20][CH2:37][CH2:36][C:33]3[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=c1c(-c2ccc(C(F)(F)F)cc2)c[nH]c2ccnc(Nc3ccccc3)c12
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: NCCc1ccccc1
Solvent: Nc1ccccc1
Product: Cc1ccc(-c2c[nH]c3ccnc(NCCc4ccccc4)c3c2=O)cc1

Procedure:
3-(4-Trifluoromethylphenyl)-1,4-dihydro-4-oxo-5-phenylamino-1,6-naphthyridine The title compound was prepared as described in Example 1 above except that ethyl (4-chlorophenyl)acetate was replaced with ethyl (4-trifluoromethyl-phenyl)acetate and phenethylamine was replaced with aniline. MS 382 (M+1)+.