Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=[N:8]/[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])/[NH:6][CH:7]=1.CCN(C(C)C)C(C)C.Br[CH2:29][C:30]([NH2:32])=[O:31].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=[N:8]/[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])/[N:6]([CH2:29][C:30]([NH2:32])=[O:31])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)/N=c2/ccc(Br)c[nH]2)cc1
Reactant: NC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)/N=c2/ccc(Br)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-[5-Bromo-1H-pyridin-(2Z)-ylidene]-4-methyl-benzenesulfonamide (80 g, 244.5 mmol) is suspended in anhydrous DMF (350 ml). Hunigs base (46.8 ml, 268.9 mmol) is added followed by 2-bromoacetamide (37.12 g, 268.9 mmol) and the mixture is stirred at room temperature for 72 hours. The reaction is poured into water (1000 ml) and the mixture is stirred for 1 hour. The product is collected by filtration, washed with more water (300 ml) and dried in a vacuum oven at 50° C. to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][C@:9]3([CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[C:8]2=[O:17])[CH2:3][CH2:2]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:13]2[CH2:14][CH2:15][CH2:16][C@@:9]3([C:8](=[O:17])[N:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:11][CH2:10]3)[CH2:12]2)=[N:20][CH:21]=1
Reactant: O=C1N(C2CCOCC2)CC[C@]12CCCNC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCC[C@]3(CCN(C4CCOCC4)C3=O)C2)nc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of (5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one [90 mg, 0.0004 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 92, steps 1-3], 2-chloro-5-nitropyridine (69 mg, 0.00044 mol), and potassium carbonate (160 mg, 0.0012 mol) in N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at 120° C. for 1.5 hours. After cooling the reaction mixture to ambient temperature, the solid was filtered off and the filtrate was concentrated in-vacuo to afford the desired product. LC-MS: 361.2 (M+H)+. The resulting residue was dissolved in methanol and to this solution was added 10% Pd on carbon and the reaction vessel was placed under a H2 (g) atmosphere and stirred at rt for 1.5 h. The catalyst was filtered off from the mixture and the filtrate was concentrated to afford the desired product in quantitative yield and was used in the next step without further purification. LC-MS: 331.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])[N:7](C(=O)C)[CH2:6][C:5]2([CH3:23])[CH3:22].Cl>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:12])=[O:13])[NH:7][CH2:6][C:5]2([CH3:23])[CH3:22]
Reactant: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)N3CCCC3)cc21
Agent: Cl
Product: CC1(C)CNc2cc(S(=O)(=O)N3CCCC3)c(F)cc21
Yield: 57.9 %

Procedure:
The title compound was prepared by treating 1-[5-Fluoro-3,3-dimethyl-6-(pyrrolidine-1-sulfonyl)-2,3-dihydro-indol-1-yl]-ethanone (287 mg, 0.84 mmol) with hydrochloric acid (5 M, 1.7 mL) following similar methods to those described in Preparation 66 to give the title compound (145 mg) as a light brown oil. 1H NMR (DMSO-d6): 7.13 (1H, d), 6.79 (1H, d), 5.79 (1H, d), 3.25 (2H, s), 3.23-3.11 (4H, m), 1.83-1.68 (4H, m), 1.25 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:16]([O:17][CH2:18][CH:19]3[O:21][CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:16]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:26][CH:23]([CH3:25])[CH3:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: O=C1c2ccccc2C(OCC2CO2)N1c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: CC(C)NCC(O)COC1c2ccccc2C(=O)N1c1cccc(Cl)c1

Procedure:
A solution of 2-(3-chlorophenyl)-3-(2,3-epoxypropoxy)-isoindolin-1-one (12 g.) and isopropyl-amine (120 cc.) in anhydrous toluene (200 cc.) is heated under reflux for 5 days. The reaction mixture is then evaporated to dryness under reduced pressure and the residue obtained is recrystallised from ethyl acetate (65 cc.). After drying, 2-(3-chlorophenyl)-3-(2-hydroxy-3-isopropylamino-propoxy)-isoindolin-1-one (11.6 g.), melting at 128° C., is obtained.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:17]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]1[CH3:32].[OH-].[Na+].Cl>O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:17]2[C:16]([CH2:15][C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[N:5]([CH2:4][C:3]([OH:33])=[O:2])[C:6]=3[CH3:32])=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccnc2S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 21.1 %

Procedure:
A mixture of {3-[2-(4-chlorobenzenesulfonyl)pyridin-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}acetic acid methyl ester (0.19 g) and tetrahydrofuran (1.5 mL) was treated with 5.0 M aqueous sodium hydroxide solution (2.0 mL), and the resulting mixture was stirred at 40° C. for 3 hours. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (3.5:6.5 to 9:1 by volume) to afford the title compound as a white solid (0.039 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:10]([F:43])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[N:20]([Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[C:10]([F:43])=[C:11]([C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[N:20]([Si:33]([CH:37]([CH3:39])[CH3:38])([CH:40]([CH3:42])[CH3:41])[CH:34]([CH3:35])[CH3:36])[CH:19]=2)=[O:17])[C:12]([F:15])=[CH:13][CH:14]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)c2c(F)ccc(N(Cc3ccccc3)Cc3ccccc3)c2F)c2cc(-c3cccnc3)cnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(=O)c2c(F)ccc(N)c2F)c2cc(-c3cccnc3)cnc21
Reaction time: 8 h

Procedure:
To (3-dibenzylamino-2,6-difluoro-phenyl)-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (56, 55.0 mg, 0.080 mmol) in methanol (15 mL) was added 20% palladium hydroxide on carbon (20 mg). The reaction was stirred under an atmosphere of hydrogen overnight. The reaction was filtered to remove the catalyst, and then concentrated to give the crude compound that was used in the next step.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Br)nc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(Br)nc1)C(=O)OCC

Procedure:
6-bromopyridin-3-amine (74 g, 0.43 mol) and diethyl ethoxymethylenemalonate (100 mL) were added to 680 mL of ethanol and heated under reflux for 5 h. The reaction mixture was cooled to precipitate a solid, suction filtrated, and the resulting solid was washed with petroleum ether to give 125.4 g of a pale yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:26][C@@H:27]([CH3:43])[CH2:28][N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([Cl:42])[CH:35]=2)=[N:30]1>C(Cl)Cl>[Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:26][C@@H:27]([CH3:43])[CH2:28][N:29]2[CH:33]=[CH:32][C:31]([C:34]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([Cl:42])[CH:35]=3)=[N:30]2)=[O:10])[CH:4]=1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(CBr)on1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
5-(Bromomethyl)isoxazole-3-carboxylic acid (1.027 g, 4.99 mmol) and DCC (1.029 g, 4.99 mmol) were dissolved in dry DCM under nitrogen atmosphere and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.0 g, 3.84 mmol) was added. The mixture was stirred overnight at RT and a precipitate was filtered. The filtrate was washed with water, dried and evaporated to dryness. The evaporation residue was purified by Flash-chromatography to give the title compound. Yield 83%. 1H-NMR (400 MHz; DMSO): δ 1.17 (d, 3H), 4.32 (d, 2H), 4.40-4.50 (m, 1H), 4.86 (s, 2H), 6.81 (s, 1H), 6.94 (d, 1H), 7.82 (d, 1H), 7.91 (dd, 1H), 7.97 (dd, 1H), 8.08 (dd, 1H). 8.85 (d, 1H)
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=1)C.[OH-].[K+]>C(O)C>[I:22][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:23])=[O:3])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCCCCCCCCCCc1cccc(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCCCCCc1cccc(I)c1
Yield: 88 %

Procedure:
Ethyl-12-(m-iodophenyl)-dodecanoate (7.17 g, 16.67 mmol), 95% ethanol (100 ml) and KOH (2.0 g) were placed into a 250 ml round-bottomed flask fitted with a reflux condenser. The reaction mixture was refluxed overnight. The ethanol was removed in vacuo and H2O was added. The aqueous solution was acidified and then extracted with ether. The ether layer was dried (MgSO4), and the solvent was evaporated to yield a yellow solid. The crude product was recrystallized with 95% ethanol to provide a white flaky solid, compound 7, 12-m-iodophenyldodecanoic acid (5.9 g, 88.0% yield).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1)(=[O:10])[CH3:9].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(=O)Nc1ccc(Sc2cccnc2)cc1
Yield: 82.7 %

Procedure:
The general procedure in example 39 was followed. 3-Iodopyridine (205 mg, 1.0 mmol), 4-acetamidothiophenol (167 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-(4-acetamidophenyl)sulfanylpyridine (202 mg, 83% yield) as white solid. Column chromatographic solvent (ethyl acetate). Rf=0.4 (ethyl acetate). Melting point; 138-140° C. 1H NMR (CDCl3, 300 MHz) δ 8.42 (d, 1 H, J=1.8 Hz), 8.38 (dd, 1 H, J=0.9 Hz, 4.5 Hz), 8.29 (s, 1 H), 7.52 (d, 2 H, J=8.7 Hz), 7.35 (d, 2 H, J=8.4 Hz), 7.18 (dd, 1 H, J=3.0 Hz, 7.8 Hz), 2.17 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 169.0, 149.5, 147.1, 138.9, 136.8, 135.3, 134.0, 127.3, 124.2, 120.9, 24.9. IR (neat, cm−1) 3286, 3245, 3176, 3105, 2360, 2342, 1650. MS (EI) m/z (relative intensity) 244 (100), 202 (100). Anal. Cald. for C13H12N2OS, Cald. C, 63.91; H, 4.95. Found C, 63.80; H, 4.93.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]([CH3:17])=[O:16]>>[O:7]([CH2:14][C@@H:15]1[CH2:17][O:16]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)glycidyl 3-nitrobenzesulfonate(25.9 g, 100 mmol) in 500 mL of acetone was treated with 3 equivalents of potassium carbonate (41.5 g, 300 mmol) and stirred at reflux for 1 day. The suspension was cooled to ambient temperature; the solid was filtered; and the filtrate concentrated to dryness. The residue was partitioned between methylene chloride and water and the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over magnesium sulfate and concentrated to give the title compound (15.0 g, 99%) as an orange oil; 1H NMR (300 MHz, CDCl3) δ 6 2.76 (dd, J=4.9, 2.6 Hz, 1 H), 2.90 (dd, J=4.9, 4.9 Hz, 1 H), 3.30-3.40 (m, 1 H), 3.95 (dd, J=11.0, 5.4 Hz, 1 H), 4.18 (dd, J=11.0, 3.0 Hz, 1 H), 6.85-7.00 (m, 3 H), 7.25-7.35 (m, 2 H); MS (ES) m/z: 151.0 (MH+).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][C@H:9]([OH:14])[C:10]([CH3:13])([OH:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1>COC(OC)(C)C>[C:1]([Si:5]([CH3:15])([CH3:16])[O:6][CH2:7][CH2:8][C@H:9]1[C:10]([CH3:11])([CH3:13])[O:12][C:18]([CH3:23])([CH3:19])[O:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1503.3 %

Procedure:
Step E To a suspension of (S)-5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-diol (6.8 g, 27 mmol) in 2,2-dimethoxypropane (35 mL) was added p-toluenesulfonic acid monohydrate (0.2 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20) to give tert-butyl-dimethyl-[2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethoxy]-silane as a yellow oil (4.56 g, 58%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1.C(=O)(O)[O-].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[C:33]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1)(=[O:35])[CH3:34]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 62.1 %

Procedure:
3-(4-((3S)-3-Amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one hydrochloride salt (170 mg, 0.43 mmol) was stirred in a mixture of saturated sodium bicarbonate solution (5 ml) and dichloromethane (5 ml) in an ice-bath. Acetic anhydride (2 mmol) was added dropwise, and the mixture stirred 18 hours, allowing the temperature to rise to ambient. Dichloromethane (10 ml) was added, and the mixture filtered through phase separating paper, the organic layer evaporated, and crystallised from ethanol to give the desired product (108 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[N:22][CH:23]=3)[NH:20][CH2:19][CH2:18][CH:17]4[OH:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=1O>CO.C(Cl)Cl>[Cl:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=1[O:24][CH:17]1[C:16]2[C:21](=[N:22][CH:23]=[C:14]([C:11]3[CH:12]=[N:13][C:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][CH:10]=3)[CH:15]=2)[NH:20][CH2:19][CH2:18]1
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: CN1CCN(c2ccc(-c3cnc4c(c3)C(O)CCN4)cn2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Oc3c(F)ccc(F)c3Cl)CCN4)cn2)CC1
Yield: 54 %

Procedure:
6-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (85 mg) was reacted with 2-chloro-3,6-difluorophenol (50 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-10% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (54% yield). LCMS: m/z=472 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.89 (m, 1H), 2.21 (s, 3H), 2.24 (m, 1H), 2.39 (t, J=4.8 Hz, 4H), 3.40 (m, 1H), 3.47 (t, J=4.8 Hz, 4H), 3.63 (m, 1H), 6.82 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H) 7.25 (m, 1H), 7.39 (m, 1H), 7.52 (dd, J=2.5, 8.8 Hz, 1H), 8.08 (d, J=2.5 Hz, 1H), 8.19 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[NH2:24][CH:19]([CH:21]1[CH2:23][CH2:22]1)[C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=1
Reactant: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 3-benzyl-7-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 17 G, 0.10 g, 0.29 mmol) and sodium azide (30 mg, 0.46 mmol) in DMF (2 mL) was stirred at rt under nitrogen overnight. The reaction mixture was diluted with EtOAc to 40 mL, washed with water and brine, dried over MgSO2 and concentrated to a pale oil. The oil was dissolved in THF (6 mL) and water (0.2 mL), flushed with nitrogen and treated with triphenylphosphine (0.15 g, 0.58 mmol). The reaction mixture was heated at 66° C. for 5 h. The solvents were removed under reduced pressure. Purification of the residue by flash column chromatography (SiO2, EtOAc/hexane/MeOH/NH4OH 500:500:50:5) gave the title compound as a colorless oil (69 mg, 73%): 1H NMR (CDCl3) δ 7.35 (m, 4H), 7.22 (d, 1H, J=7.7 Hz), 7.11 (m, 1H), 6.54 (m, 1H), 5.65 (m, 1H), 5.37 (m, 1H), 3.73 (m 1H), 2.00 (m, 1H),1.60 (m, 1H), 1.33 (m, 1H), 0.58 (m, 1H), 0.29 (m, 2H); MS (ESI+) 329.09, 331.07 (M++H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(Cl)cc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(Cl)cc4)CC3)cnc12
Yield: 46.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(4-chlorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.19 mmol) obtained in step 2 and methanesulfonamide (0.090 g, 0.950 mmol), the title compound (0.05 g, 47%) was obtained.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([NH:25][C@@H:26]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]2)=[O:24])=[CH:21][C:20]=1[O:34][CH2:35][CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH2:35]([O:34][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:19]=1[NH:18][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1)[C:23]([NH:25][C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27]1)=[O:24])[CH3:36]
Reactant: CC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: CCOc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: CCOc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1Nc1ncc2c(n1)N(C(C)C)CCC(=O)N2C
Yield: 60.7 %

Procedure:
10-Chloro-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 10; 100 mg, 0.39 mmol), 4-amino-3-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 166; 104 mg, 0.39 mmol) and 4-toluenesulphonic acid monohydrate (187 mg, 0.98 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The cooled reaction mixture was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified preparative reverse phase HPLC to yield the title compound as a white solid (114 mg, 61%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.O.[NH2:32][NH2:33].O>CN(C=O)C>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: NN
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (304 mg, 0.76 mmol, prepared in Synthetic Example 18) in DMF (7.5 ml) was added hydrazine monohydrate (80%, 108 μl, 2.70 mmol, 3.6 eq.), and the mixture was then stirred at 100 to 110° C. for 5 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (260 mg, 86%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:19])[CH:10]=1.[OH:20][C:21]1[CH:41]=[CH:40][C:24]([C:25]([NH:27][CH2:28][C@H:29]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[CH:23][CH:22]=1>CC(=O)CC.[I-].[K+]>[CH3:19][C:11]1[CH:10]=[C:9]([CH2:8][O:20][C:21]2[CH:41]=[CH:40][C:24]([C:25]([NH:27][CH2:28][C@H:29]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCCCC1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCCCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
270 mg (1.9 mmol) of potassium carbonate then 380 mg (1.9 mmol) of 4-chloromethyl-2-methylquinoline and 15 mg of potassium iodide are added to a solution of 500 mg (1.6 mmol) of methyl (S)-3-(4-hydroxybenzoyl-amino)-2-piperidin-1-ylpropanoate in 15 ml of 2-butanone. The reaction medium is stirred at 80° C. for 18 h. After filtration, the filtrate is concentrated under vacuum. The crude product is purified by chromatography over silica gel eluted with a 50/50 heptane/ethyl acetate mixture. 620 mg (83%) of methyl (S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzoylamino]-2-piperidin-1-ylpropanoate are obtained in the form of a yellow solid.