Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.[CH3:17][C:18]([CH3:20])=[O:19].Cl>O1CCCC1.[OH-].[Na+]>[OH:19][C:18]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([CH3:20])[CH3:17]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CC(C)=O
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1C(C)(C)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
4-Bromo-3-methyl-benzoic acid (3.96 g, 18.4 mmol) was dissolved in tetrahydrofuran (100 mL) and the solution was cooled to −78° C. n-Butyllithium in hexanes (16.2 mL of 2.5 M, 41 mmol) was added dropwise over 20 minutes. The reaction mixture was allowed to stir for 30 minutes at −78° C. and then acetone (1.35 mL, 18.4 mmol) was added in a drop-wise manner. The reaction mixture was allowed to stir for 30 minutes at −78° C., and then it was allowed to warm to room temperature. The reaction mixture was then diluted with 100 mL of 1M aqueous sodium hydroxide. The organic layer was discarded and then the aqueous layer was made acidic with 4M aqueous hydrochloric acid. The aqueous layer was then extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate and then evaporated to dryness. The crude material was further purified on silica gel utilizing a gradient of 0-10% methanol in dichloromethane to give 4-(1-hydroxy-1-methyl-ethyl)-3-methyl-benzoic acid (1.51 g, 42%). 1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 7.68 (dd, J=3.9, 2.5 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 5.06 (s, 1H), 2.56 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (43 mg, 77%), MS (ISP) m/z=325.4 [(M+H)+], mp 258.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 11) (50 mg, 0.17 mmol) and commercially available 4-chloro-phenylboronic acid (34.7 mg, 0.22 mmol).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]>OS(O)(=O)=O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)Cc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
HNO3 (10.35 g, 98.6 mmol) was added drop-wise to a −10° C. solution of 2-(2-chloro-4-fluorophenyl)acetic acid (16.9 g, 89.6 mmol) in conc. H2SO4 (60 mL), stirred at 0° C. for 10 min, then carefully poured into ice water. The off-white solid was collected by filtration and dried to give 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 98% yield). 1H NMR (400 Hz, DMSO-d6): δ 12.71 (br s, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.92 (d, J=11.2 Hz, 1H), 3.85 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:3]=1.O.C([OH:19])C.[OH-].[Na+].OO>C1COCC1>[OH:19][CH:3]1[CH:2]([CH3:1])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1
Reactant: CC1=CCC(NC(=O)OC(C)(C)C)CC1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCC(NC(=O)OC(C)(C)C)CC1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a stirring solution of tert-butyl 4-methylcyclohex-3-enylcarbamate (1.5844 g, 7.50 mmol) in THF (94 mL) at 0° C. was added 1M borane THF complex (33.7 mL, 33.7 mmol). The solution was stirred at 0° C. for 1 h and then at room temperature for 2 h. The reaction was quenched very slowly with water (40.5 mL, 2249 mmol), diluted with ethanol (39.8 mL, 682 mmol) and basified with aqueous sodium hydroxide solution (5 N, 37.5 mL, 187 mmol). To the stirring biphasic mixture was slowly added hydrogen peroxide (38.3 mL, 375 mmol) and the resulting mixture was heated to 45° C. for 20 h. The crude reaction was quenched with saturated aqueous sodium sulfite solution (70 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexanes). The product fractions were combined and concentrated to afford a mixture of four isomers of tert-butyl 3-hydroxy-4-methylcyclohexylcarbamate (trans relationship between 3-hydroxy and 4-methyl moieties) (0.9608 g, 4.19 mmol, 55.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.60-6.85 (m, 1H), 4.29-4.58 (m, 1H), 3.35-3.80 (m, 1H), 2.81-3.28 (m, 1H), 1.20-1.96 (m, 14H), 0.79-1.14 (m, 5H; MS (ESI) m/z 230.5 [M+1]+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[CH3:2].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:8]([C:6]1[S:7][C:3]([CH2:1][CH3:2])=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.7 %

Procedure:
To a solution of 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (283 mg, 1.2 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (461 mg, 1.2 mmol) [prepared according to Preparation 6] and diisopropylethylamine (1.043 ml, 5.99 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (615 mg, 1.317 mmol) in one portion. The solution was stirred at 25° C. over 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol, 71.6% yield) as a clear oil: LCMS (ES) m/e 567 (M+H)+.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4](C(OCC)=O)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:26][CH2:25]C1>>[O:1]1[C:7]2=[CH:8][CH:9]=[CH:10][C:11]([CH2:25][OH:26])=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCOc2ccccc2C1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cccc2c1CCCCO2
Reaction time: 18 h

Procedure:
A solution of ethyl 2,3,4,5-tetrahydrobenzoxepin-4-carboxylate (2.85 g, 13 mmol) in THF (30 ml) was stirred as LAH (1 g, 26 mmol) was slowly added. The mixture was stirred for 18 hr, and then quenched by the sequential addition of water (1 ml), 15% sodium hydroxide (1 ml), and water (3 ml). The mixture was filtered and the filter cake washed with ethanol. The filtrate was concentrated in vacuo to an oil (2.3 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[O:40][CH2:41][CH:42]([CH2:44][OH:45])[OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:66](Cl)(=[O:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>N1C=CC=CC=1.ClCCl>[C:66]([O:43][CH:42]([CH2:41][O:40][C@H:10]1[O:11][C@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:44][OH:45])(=[O:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: OCC(O)CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC(CO)CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
Glycerol 8 (900 mg, 1.47 mmol) and trityl chloride (490 mg, 1.76 mmol) were dissolved in dry pyridine (60 mL) and heated at 100° C. The disappearance of 8 was monitored by TLC and after 90 min the reaction was cooled to 0° C. and a solution of benzoyl chloride (1.0 g, 7.0 mmol) in dry dichloromethane (10 mL) was added. The reaction was warmed to room temperature and stirring was continued for 2 h. The solvent was removed and the residue was dissolved in chloroform (50 mL), washed with 2M HCl (2×20 mL), saturated sodium bicarbonate solution (2×20 mL), water (25 mL) and dried over magnesium sulfate. The solvent was removed, the residue was dissolved in mixture of dichloromethane and methanol (7:3, 50 mL) and p-TSA (75 mg) was added. The reaction was stirred at room temperature overnight and solvent was removed. The residue was purified over silica [hexane/ether, 8:2 to 7:3 as eluent] to afford the title compound 9 (816 mg, 77%) as a pale syrup; Rf 0.4 (ether/hexane, 2:1); 1H NMR (500 MHz, CDCl3) δ 8.05 br (d, 3H, J 7.5 Hz), 7.51 (t, 2H, J.5 Hz), 7.41-7.12 and 7.18-7.10 (m, 20 Hs, Ar—H), 5.30-5.20 (m, 1H, H-2′), 4.94 and 4.89 (2×d, each 1H, J 2 Hz, H-1), 4.85 and 4.83 (2×d, each 1H, J 10.5 Hz, PhCH2), 4.77-4.46 (m, 7H), 4.05-3.62 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 166.1, 166.0 (CO), 138.3, 138.2, 138.1, 138.05 (ipso-C), 133.0, 132.96, 129.8, 129.7, 129.6, 129.5, 128.3, 128.2, 128.2, 128.13, 128.10, 128.07, 127.83, 127.80, 127.74, 127.65, 127.62, 127.59, 127.56, 127.41, 127.38, 127.36, 127.32 (CH—Ar), 98.0 and 97.5 (C-1), 79.7, 79.6, 74.8, 74.7, 74.6, 73.8, 73.4, 73.2, 73.1, 72.4, 72.0, 71.9, 69.0, 68.9, 65.6, 65.3, 65.25, 61.2, 57.9; νmax/cm−1 (CHCl3) 1716; LRMS-ESI (+ve) m/z 742 [MNa]+ (100); HRMS-ESI (+ve) (Found: m/z 719.3220 (MH+). C44H47O9 requires m/z 719.3220).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([O:10][CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])([CH3:12])[CH3:11])=[O:30])=[CH:27][CH:26]=1
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(C)(C)NC(=O)OC(C)(C)C)cc1
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (0.95 g, 5.0 mmol) and diisopropylethylamine (0.87 mL, 5.0 mmol) in DCM (25 mL) was added 4-methoxybenzoyl chloride (0.69 mL, 5.0 mmol) at room temperature and the mixture was stirred for 4 h. The reaction mixture was partitioned between DCM and 50% brine solution. The organic layer was separated, dried with Na2SO4, filtered and concentrated. The residue was dissolved in ethyl acetate and washed with 0.5 M hydrochloric acid. The organic layer was separated, dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate in heptane (0-25%) to give the title compound (0.55 g, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.09-7.90 (m, 2 H), 7.04-6.81 (m, 2 H), 4.65 (br s, 1 H), 4.35 (s, 2H), 3.88 (s, 3 H), 1.44 (s, 9 H), 1.40 (s, 6 H). m/z (APCI+) for C17H25NO5 224.1 (M-tBuCO2—+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][N:13]1[C:17]([C:18]#[N:19])=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Br-]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1COCC1>[F:11][C:4]1[CH:3]=[C:2]([C:14]2[N:13]([CH3:12])[C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]#[N:10]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: N#CNc1ccc(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1-c1ccc(NC#N)c(F)c1
Yield: 12.5 %

Procedure:
4-bromo-2-fluorophenylcyanamide (0.106 g, 0.5 mmol), tris(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL) was added with stirring. Tri-tert-butylphosphine (10 wt % in hexane) (0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stir until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate, filtered through a plug of silica gel, the solvent evaporated and the residue was flash chromatographed on silica gel using 4/1 Hexane/THF to give [2-fluoro-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]cyanamide (0.015 g, 12%).
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[N:27]=[N:28][NH:29][CH:30]=2)=[O:25])[CH2:9][C@@:10]([CH3:22])([CH2:14][O:15]C2CCCCO2)[C:11](O)=[O:12])=[CH:3][CH:2]=1.[CH2:37]([OH:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].Cl.O1CCOCC1>>[CH2:37]([O:44][C:11](=[O:12])[C@@:10]([CH2:14][OH:15])([CH3:22])[CH2:9][C@H:8]([NH:23][C:24]([C:26]1[N:27]=[N:28][NH:29][CH:30]=1)=[O:25])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:2][CH:3]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Reactant: CCCCCCCO
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-methyl-2-(tetrahydropyran-2-yloxymethyl)-4-[(1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (100 mg, 0.2 mmol) was combined with 1-heptanol (0.3 mL, 2 mmol) and 4 M HCl in 1,4-dioxane (0.3 mL, 1 mmol). The mixture was stirred for 2 hours at 60° C. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography to yield the title compound (60 mg). MS m/z [M+H]+ calc'd for C29H38N4O4, 507.29. found 507.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)c1cncnc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cncnc3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
0.1 g of pyrimidine-5-carboxylic acid (0.805 mmol) and 0.28 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (0.805 mmol) were dissolved in 10 ml of dichloromethane. 0.46 g of diisopropylethylamine (3.17 mmol), 0.054 g of hydroxybenzotriazole (HOBt, 0.4 mmol), and 0.17 g of N-ethyl-N′-(3-dimethylamino-propyl)-carbodiimide hydrochloride (EDCl, 0.88 mmol) were added at 0° C. The reaction mixture was stirred for 16 h at room temperature. Then, 0.085 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred for 4 h. The solvent was evaporated and the residue partitioned between and ethyl acetate and saturated aqueous sodium chloride. 4 ml of acetone were added to improve phase separation. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5-10%). Evaporation of the solvent yielded 0.16 g of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13]C)=[O:11])=[O:2].Cl.[C:19]([BH3-])#N.[Na+].O>CO>[CH3:19][O:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)CCCOc1cccc(C=O)c1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1cccc(OCCCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
A solution of 4-(3-formylphenoxy)butyric acid, ethyl ester (4.72 g) in methanol (25 ml) containing hydrogen chloride (0.35 g) was stirred for 12 hr. at room temperature, then cooled to 0°. Sodium cyanoborohydride (1.26 g) was added and after 30 min., iced water (200 ml) was added and the mixture extracted with ether (2×150 ml). Evaporation of the dried (MgSO4) ethereal extracts gave a pale yellow oil which was distilled (165°/0.8 mm) to give the title compound (3.8 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O
Yield: 56.4 %

Procedure:
The 1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine was prepared under the conditions of Example 35 but starting from 1.5 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 2.7 g of piperazine. After recrystallizing once from 40 cm3 of propan-2-ol, 1 g of 1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine is obtained in the form of a yellow solid melting at 256° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[N+:18]([C:17]1[C:12]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 69 %

Procedure:
5-Aminoindole and 2-chloro-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was stirred at room temperature for 4 days. The resulting reaction mixture was filtered to afford the title compound (69%) as an orange solid: mp, 162.0°-163.5° C.; 13C NMR (CDCl3) δ 155.6, 150.5, 135.5, 133.5, 129.7, 127.9, 127.6, 125.9, 118.5, 115.0, 113.4, 111.2, 101.2; Anal. calcd for C13H10N4O2 : C, 61.41; H, 3.96; N, 22.04. Found: C, 61.22; H, 3.80; N, 22.08.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[OH-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:15]1([S:21]([N:10]2[C:7]3=[N:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=[C:6]3[CH:12]=[CH:11]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COCc1cnc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COCc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
To a solution of tetrabutylammonium bromide (104 mg, 0.32 mmol) and 5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (1.74 g, 10.76 mmol) in dichloromethane (100 mL) was added sodium hydroxide powder (1.3 g, 32.4 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min and then treated with benzene sulfonyl chloride (1.7 mL, 14.0 mmol). The mixture was stirred at 0° C. for another 15 min before it was warmed to 25° C. and stirred for 12 h. The resulting mixture was filtered and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (1.54 g, 47.5%) as a white solid: LC/MS m/e calcd for C15H14N2O3S [M+H]+ 303.35, observed 302.9.
Reaction SMILES: FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)O)[CH:16]=[N:17][CH:18]=1.[SiH](CC)(CC)CC>O>[Br:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]([CH2:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[CH:14]=1
Reactant: CCOc1ccc(C(O)c2cncc(Br)c2)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Cc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Then, trifluoroacetic acid (12.5 mL, 0.162 mol) was added dropwise to a chloroform solution of (5-bromopyridine-3-yl)(4-ethoxyphenyl)methanol (2.5 g, 8.11 mmol) and Et3SiH (5.1 mL, 40.6 mmol) at 4° C. and stirred at room temperature for 2.5 hours. The reaction mixture was added with water and extracted with chloroform. After washed with brine, the organic phase was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound in a colorless needle form (1.83 g, 77%).