Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C.O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:14][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:21]=4[N:20]=3)=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cccc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
To a solution of 2.0 g of 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride in 50 ml of acetonitrile, 0.98 g of 2-amino-3-methylbenzoic acid was added. The mixture was stirred at room temperature for 10 minutes and then, 0.9 ml of triethylamine was added thereto. The mixture was stirred at room temperature for 20 minutes and then, 1.8 ml of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 0.56 ml of methanesulfonyl chloride was added and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 1.17 g of 2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:10](=[O:20])[NH:9][C:8](=[O:21])[CH:7]=1>C(O)(=O)C>[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:10](=[O:20])[NH:9][C:8](=[O:21])[C:7]=1[N:1]=[O:3]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1cccc(Cl)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1cccc(Cl)c1

Procedure:
6.4 ml of 4N sodium nitrite was added at 65-70° C. to a suspension of 6.29 g (25 mM) of 6-amino-1-(3-chlorobenzyl)-uracil in 92 ml of acetic acid. After 30 minutes the mixture was cooled, the solid collected and washed with the acetic acid and water to give the title compound (5.21 g) as a pink solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: COCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
6-Amino-9-benzyl-2-(2-methoxyethyl)aminopurine (70 mg, 0.24 mmol) and bromine (0.5 ml) were dissolved in methylene chloride (50 ml). The solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (71 mg, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:29][C@H:28]([CH2:30][O:31]C(=O)C4C=CC=CC=4)[C@@:23]([CH3:40])([O:24]C(=O)C)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:29][C@H:28]([CH2:30][OH:31])[C@@:23]([CH3:40])([OH:24])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)O[C@]1(C)[C@@H](COC(=O)c2ccccc2)O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@]1(O)[C@@H](CO)O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@@H]1O
Reaction time: 16 h
Yield: 73.9 %

Procedure:
Nucleoside triester 116 (100 mg, 0.172 mmol) was dissolved in methanol (5 mL) and K2CO3 (28.6 mg, 0.207 mmol) was added. The reaction progressed for 16 h. The reaction was neutralized with acetic acid (24.8 mg, 0.412 mmol). Then the solvent removed by rotary vacuum and the solid submitted to HPLC purification (MeCN—H2O) yielding 42 mg (74%) of white solid: 1H NMR (400 Mz, d6-DMSO) δ 11.20 (s, 1H), 6.89 (br s, 2H), 5.80 (d, J=8.0, 1H), 5.36 (d, J=6.0, 1H), 4.77 (t, J=8.0, 1H), 4.62 (s, 1H), 4.48 (m, 1H), 3.75 (m, 1H), 3.58-3.44 (m, 2H), 1.19 (s, 3H); Analysis calc'd for C14H14N4O6S.0.125H2O.0.125HCO2H: C, 39.33; H, 4.34; N, 16.43; S, 9.40. Found: C, 39.77; H, 4.81; N, 15.02; S, 9.69; [M+H]+ m/z 331.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CC(C)=O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClCC1CO1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OCC1CO1
Yield: 12 %

Procedure:
A mixture of 15.2 g (0.10 mole) of methyl 2-hydroxybenzoate, 27.6 g (0.20 mole) of potassium carbonate and 31 ml (0.40 mole) of epichlorohydrin in 250 ml of acetone was heated to reflux for 24 hours. The reaction medium was then filtered and evaporated under reduced pressure. The resulting oil was dissolved in 100 ml of toluene and washed consecutively with 100 ml of water, 2×100 ml of 1.0N sodium hydroxide and 2×100 ml of water. The organic phase was then dried over magnesium sulfate and evaporated under reduced pressure to provide the crude product as an oil. Purification was effected by vacuum distillation to provide an oil in 12% yield: boiling point 148° C. (75μ). The NMR and IR spectra and elemental analysis were consistent with the assigned structure.
Reaction SMILES: CN(OC)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:6][C:5]=1[NH2:15].[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([Li])CCC.O>O1CCCC1.C(OCC)(=O)C>[NH2:15][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:9][C:4]=1[C:3]([C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:27][NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH:33]=1)=[O:16]
Reactant: CON(C)C(=O)c1cc(OCC(C)C)ccc1N
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(N)c(C(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)c1
Temperature: -78 °C

Procedure:
N-Methyl-N-methyloxy-2-amino-5-isobutyloxybenzamide (0.6 g) and N-tert-butoxycarbonyl 3-bromobenzylamine (0.76 g) were dissolved in tetrahydrofuran (18 ml). The solution was cooled to −78° C., to which was added dropwise, while stirring, 9 ml of a hexanoic solution of n-butyl lithium (1.6 mol./L) over 20 minutes. To the reaction mixture were added water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by means of a silica gel column chromatography to give 2-amino-3′-tert-butoxycarbonylaminomethyl-5-isobutyloxy-benzophenone as a yellow oily product (0.38 g).
Reaction SMILES: C(=[N:14][CH:15]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]2[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]2)=[CH:23][CH:22]=1)[C:16]#[N:17])(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[NH2:14][CH:15]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C@@H:29]2[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]2)=[CH:23][CH:22]=1)[C:16]#[N:17]
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCC(C#N)N=C(c3ccccc3)c3ccccc3)cc2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2ccc(CCCC(N)C#N)cc2)O1
Temperature: 40 °C

Procedure:
To a solution of 2-(benzhydrylidene-amino)-5-[4-((R)-2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-phenyl]pentanenitrile (7.2 g, 15.5 mmol) in THF (50 mL) is added aqueous HCl (5 mL of a 2 M solution). The solution is heated at 40° C. for 4 h and then allowed to cool to RT. The pH is adjusted to 9-10 using saturated aqueous sodium hydrogen carbonate solution and the organic solvent is removed in vacuo. The crude residue is dissolved in EtOAc (100 mL) and washed with water, brine then dried (MgSO4), filtered and concentrated in vacuo. The resulting residue is purified by chromatography (SiO2, iso-hexane:EtOAc with 1% triethylamine) to yield the title compound as colourless oil that solidifies upon standing as a mixture of diastereoisomers. [M+H]+ 305.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12]/[C:13](=[N:16]/[H])/[NH:14][OH:15])[C:7]([CH2:18][CH2:19][CH3:20])=[CH:6]2)#[N:2].[F:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:21]([F:24])([F:23])[F:22])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:18][CH2:19][CH3:20])[N:16]=1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(C(F)(F)F)c(C#N)ccc21)NO
Reactant: O=C(Cl)c1cc(F)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)ccc2F)n1
Temperature: 150 °C
Yield: 42.2 %

Procedure:
To a solution of (1Z)-2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.050 g, 0.154 mmol) in anhydrous acetonitrile (2.0 mL) under N2, was added 2,5-difluorobenzoyl chloride (0.121 g, 0.177 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.029 g (42% yield) of pure product: MS (ES) m/z 446 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N+:4]([O-:18])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)c(Cl)n1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)c(Cl)[n+]1[O-]
Temperature: 50 °C
Yield: 1230.1 %

Procedure:
step a—To a solution of 3-bromo-2-chloro-6-methyl-pyridine (2.0 g, 0.687 mmol) in CHCl3 was added MCPBA (3.3 g, 19.1 mmol) and the resulting solution was heated at 50° C. overnight. The resulted solution was cooled and partitioned between DCM and sat'd. aq. NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (30 to 80% EtOAc) to afford 1.88 g (87%) of 3-bromo-2-chloro-6-methyl-pyridine 1-oxide (357a) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O.C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:15])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: c1ccccc1
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reaction time: 16 h
Yield: 93.9 %

Procedure:
A solution of 4-nitro-3-trifluoromethylphenol (27 g, 130 mmol) in acetone (250 mL) was treated with K2CO3 (18 g, 130 mmol) and methyl iodide (16 mL, 260 mmol) and the mixture was heated at reflux under nitrogen. After 16 h, the cooled mixture was filtered to remove K2CO3 and the filtrate was concentrated in vacuo to give the crude product (32 g), which was taken up in benzene (250 mL). The organic solution was washed with water and brine (125 mL each), dried (MgSO4) and concentrated in vacuo to give the title compound (27 g, 94%) as a yellow oil which was pure enough for further use.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[O:14]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16][CH2:15]1.[Cl-].[NH4+]>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2([OH:21])[CH2:18][CH2:19][CH2:20][O:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: O=C1CCCOCC1
Reactant: Ic1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCCOCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
Under an argon atmosphere, a solution of n-butyllithium (1.50 M, in hexane) (0.5 ml) was added dropwise to a solution of 1,4-diiodobenzene (250 mg) in anhydrous THF (3 ml) at −78° C., and the resulting mixture was stirred at −78° C. for 30 minutes. Oxepan-4-one (151 mg) was added to the reaction solution, and the resulting mixture was stirred at −78° C. for 1 hour. Saturated aqueous ammonium chloride solution was added thereto, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=5/1) to obtain 4-(4-iodophenyl)oxepan-4-ol (89 mg). (2) Under an argon atmosphere, a solution of 4-(4-iodophenyl)oxepan-4-ol (86 mg) obtained in (1) in anhydrous DMF (1.0 mL) was added to a suspension of sodium hydride (60 wt %) (16 mg) in anhydrous DMF (1.0 ml) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes. Methyl iodide (0.025 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 10 hours. Saturated brine was added thereto, and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=6/1) to obtain 4-(4-iodophenyl)-4-methoxyoxepane (63 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][C:15]([C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1.CC[O:25]C(C)=O.[ClH:29]>CO>[OH2:25].[ClH:29].[CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[NH:13][C:12]3=[CH:14][C:15]([C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]=4)=[N:16][C:11]3=[CH:10][N:9]=2)[CH2:5][CH2:4][NH:3]1
Reactant: CCOC(C)=O
Agent: CC1CC(c2ncc3nc(-c4cnccn4)cc-3[nH]2)CCN1
Agent: Cl
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing 2-(1-pyrrolidinylvinyl)pyrazine (freshly prepared before use) (2.15 g, 12.3 mmol), 2-methyl-4,6-dichloro-5-nitropyrimidine (Example 76(b)) (2.50 g, 12.3 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (2.1 mL, 12.3 mmol), piperidine (Aldrich Chemical Company) (1.9 mL, 19.7 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (37 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 116 mg (4%) of the free base as a brown colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.66 (br s, 6), 2.44 (s, 3), 3.30 (s, 2, under H2O), 3.77 (br s, 2), 6.80-7.15 (m, 1), 8.91 (br s, 2), 9.33 (s, 1), 11.42 (s, 1). MS m/z: 295 (M+1). To a hot solution of 2-methyl-4-piperidyl-6-pyrazin-2-ylpyrrolo[3,2-d]pyrimidine (0.12 g, 0.39 mmol) in 10:1 EtOAc:MeOH (30 mL) was added 1N etheral HCl (Aldrich Chemical Company) (0.40 mL, 0.39 mmol). Cyrstallization occurred as the mixture cooled and the precipitate was collected by filtration, washed with Et2O (3×10 mL), and dried under vacuum to give 68 mg (53%) of the title compound as a brown colored solid. Mp: 280-283.5° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.72 (s, 6), 2.59 (s, 3), 4.08 (br s, 4), 7.29 (s, 1), 8.74 (d, 1, J=2.4), 8.82 (br s, 1), 9.49 (s, 1), 12.41 (s, 1), 14.41 (s, 1). MS m/z: 295 (M+1 for free base). Anal. Calcd for C16H16N6.HCl.1.4H2O: C, 54.07; H, 5.64; N, 23.65; Cl, 10.19. Found C, 54.32; H, 5.69; N, 23.26; Cl, 10.18.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[S:23][CH:24]=[C:25]([CH2:27]O)[N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:25]4[N:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[S:23][CH:24]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 12.5 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (63 mg), [2-(trifluoromethyl)-1,3-thiazol-4-yl]methanol (90 mg) and triphenylphosphine (193 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (173 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (13 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:35]5[CH2:34][CH2:33][NH:32][CH:31]([C:27]6[S:26][CH:30]=[CH:29][CH:28]=6)[CH2:36]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1csc(C2CNCCN2)c1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCNC(c5cccs5)C4)c(F)cc3cc2c1=O
Yield: 90.5 %

Procedure:
(RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 1-cyclopropyl-7,8-difluoro-3-ethoxycarbonyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.7 g) and (RS)-2-(2-thienyl)piperazine (1 g). (RS)-1-Cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-8-[3-(2-thienyl)-1-piperazinyl]-1,4-dihydrobenzo[b][1,8]naphthyridine (2.2 g) is obtained in the form of a yellow solid, m.p. 210°-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Temperature: 25 °C

Procedure:
The preparation of ethyl 4-[(3-amino[1,5]naphthyridine-4-yl)amino]butyrate is described in Parts A-B of Example 4. Trimethyl orthobutyrate (9.1 mL, 57.2 mmol) and pyridine hydrochloride (110 mg, 0.95 mmol) were added to a solution of ethyl 4-[(3-amino-[1,5]naphthyridine-4-yl)amino]butyrate (13.08 g, 47.7 mmol) in toluene (190 mL) and heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 14.9 g of ethyl 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-butyrate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([NH:16]C(=O)OC(C)(C)C)[CH3:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:24]>O1CCOCC1.CO>[ClH:24].[ClH:24].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N2CCN(C)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(N2CCN(C)CC2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 1,1-dimethylethyl {(1S)-1-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}carbamate (2 g, 6.3 mmol) and 4N hydrogen chloride in dioxane (5 mL) in methanol (5 mL) was refluxed for 2 min. After cooling to room temperature the mixture was concentrated and rotary evaporated from benzene, and further dried in vacuo to afford 1.7 g, 5.9 mmol (95%) of (S)-1-[4-(4-methylpiperazin-1-yl)phenyl]ethylamine dihydrochloride. MS (EI) for C13H21N3: 220 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([NH2:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([C:24]#[C:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C>CN(C)C=O.CO.CS(C)=O>[NH2:19][C:17]1[C:18]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[C:12]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][N:40]3[CH2:39][CH2:38][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:42][CH2:41]3)[C:13]=2[N:14]=[C:15]([CH2:20][CH2:21][CH2:22][CH3:23])[N:16]=1
Reactant: CCCCc1nc(N)c2c(n1)c(C#CCCCCl)cn2COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCc1nc(N)c2c(n1)c(C#CCCCN1CCN(C(=O)OC(C)(C)C)CC1)cn2COCc1ccccc1
Temperature: 70 °C
Reaction time: 22 h
Yield: 58.7 %

Procedure:
To a solution of 5-((benzyloxy)methyl)-2-butyl-7-(5-chloropent-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (100 mg, 0.243 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added 1-BOC-piperazine (50 mg, 0.268 mmol) and triethylamine (51 νL, 0.366 mmol). The reaction was stirred at 70° C. for 22 hours. A further 100 mg (0.537 mmol) of 1-BOC-piperazine and 0.1 mL (0.717 mmol) of triethylamine was added to the reaction. The reaction was stirred at 70° C. for a further 24 hours. The cooled reaction was evaporated in vacuo and partitioned between dichloromethane and water. The organic layer was passed through a hydrophobic frit and evaporated in vacuo to yield a yellow oil. The oil was dissolved in MeOH:DMSO (1:1) (2×1 mL) and purified by MDAP (Method B). Appropriate fractions were combined and evaporated in vacuo to yield the title compound as a colourless oil (80 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:23]=[C:22]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:21]=[CH:20][C:12]=3[C:13]([O:15]C(C)(C)C)=[O:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1>FC(F)(F)C(O)=O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[CH:23]=[C:22]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:21]=[CH:20][C:12]=3[C:13]([OH:15])=[O:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(Nc3ccc4sccc4c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(CCc2ccc(C(=O)O)c(Nc3ccc4sccc4c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-((benzothiophen-5-yl)amino)-4-(2-(3-methoxyphenyl)ethyl)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-((benzothiophen-5-yl)amino)-4-(2-(3-methoxyphenyl)ethyl)benzoic acid 61 mg of a brown solid.