Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11](=[O:18])[NH:10][C:9]1=[O:19])(O)=[O:2].[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([C:1]([C:4]2[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=2)[CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:18])[NH:10][C:9]2=[O:19])=[O:2])[CH2:31][CH2:30]1
Reactant: O=C(O)c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
A mixture of 1-(3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (0.2 mmol), 1-(pyrimidin-2-yl)piperazine (0.2 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.26 mmol) and N,N-diisopropylethylamine (DIPEA, 0.4 mmol) in DMF (5 mL) was stirred at room temperature overnight. To the mixture was added 50 mL of water and it was extracted with EA (50 mL×3). The organic layer was washed by 1 N hydrochloric acid (50 mL×1) and saturated NaCl aquenous solution (50 mL×1), dried with anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by flash chromatography (DCM: MeOH=20:1) to give the title compound (20.43 mg, 23.3% yield) as white solid. 1H NMR (DMSO-d6): 11.35 (s, 1H), 8.39 (d, J=4.5 Hz, 2H), 7.48-7.41 (m, 1H), 7.36-7.24 (m, 3H), 6.67 (t, J=4.8 Hz, 1H), 5.10 (s, 2H), 3.88-3.20 (m, 8H), 2.46-2.42 (m, 2H), 2.25-2.21 (m, 2H), 1.69-1.43 (m, 4H). MS: m/z 447.4 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](N)=[O:4].N12CCCCC1C=NCCC2.[CH3:17][O:18][C:19]([C:21]#[C:22]C(OC)=O)=[O:20].Cl>CO>[CH3:17][O:18][C:19]([C:21]1[O:1][NH:2][C:3](=[O:4])[CH:22]=1)=[O:20]
Reactant: NC(=O)NO
Reactant: COC(=O)C#CC(=O)OC
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(=O)[nH]o1
Yield: 40.4 %

Procedure:
Prepared according to Synthesis 1985, 1100. To a stirred solution of N-hydroxyurea (3.80 g, 50 mmol) and 1,5-diazabicyclo[5.4.0]undec-5-ene (8.37 g, 55 mmol) in methanol (50 mL) with cooling (ice bath) was added dimethyl ethyne dicarboxylate (7.11 g, 50 mmol) dropwise over 20 min. A dark red colour appeared then dissipated with each drop added, until finally a deep orange/red clear solution had formed. After an additional 20 min the mixture was concentrated to give a red oil which was then acidified with cooling in an ice/water bath to pH 1 with HCl (conc.). The resulting yellow mixture was extracted with diethyl ether (3×40 mL) then the aqueous phase was saturated with brine and extracted with ether (2×50 mL). The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated to afford the title compound (2.89 g, 40%) as white crystals after recrystallisation from chloroform. MS: m/e=143.8 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:22][CH2:23]O>>[CH2:22]([O:16][C:15](=[O:17])[CH2:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1c(C)noc1-c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid (0.405 g, 1.37 mmol) in EtOH (4 mL) was treated with thionyl chloride (0.2 mL, 2.73 mmol) and the reaction was stirred at room temperature until no starting material was seen by analytical TLC. After basic workup the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH3:17])=[CH:10][C:11]([CH2:14][OH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH3:17])=[CH:10][C:11]([CH:14]=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(CO)ncc1OCc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: COc1cc(C=O)ncc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
[5-(4-Chloro-benzyloxy)-4-methoxy-pyridin-2-yl]methanol (640, 480 mg, 1.7 mmol) was dissolved in dimethyl sulfoxide (26 mL) and Dess-Martin periodinane (909 mg, 2.1 mmol) was added. The reaction was allowed to stir at room temperature for 2 hours. The reaction was concentrated under high vacuum and then poured into a solution of NaHCO3 and Na2S2O3. The mixture was extracted with ethyl acetate. The organic portions were dried with anhydrous sodium sulfate and filtered. The filtrate was adsorbed onto silica and purified by silica gel chromatography, ethyl acetate:hexanes, to provide the desired compound as a white powder (641, 343 mg, 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[N:15][CH:14]=[CH:13]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[N:15][CH:14]=[CH:13]3)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Brc1ccc2cnccc2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnn(-c2ccc3cnccc3c2)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 4-nitro-1H-pyrazole (510 mg, 4.51 mmol), 6-bromoisoquinoline (375 mg, 1.80 mmol) (commercially available from Gateway Chemical Technology, Inc.), tris(dibenzylideneacetone)dipalladium (0) (165 mg, 180 μmol), 2-ditert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (153 mg, 360 μmol), and cesium carbonate (1.76 g, 5.41 mmol) in dioxane (4 mL) was heated in a sealed vial at 105° C. for 6 hours. The mixture was cooled to ambient temperature and partitioned between DCM (30 mL) and H2O (30 mL). The layers were separated, and the aqueous layer was extracted with DCM (2×20 mL) and 10% MeOH/DCM (30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in DCM, evaporated onto silica gel, and purified by flash chromatography (Biotage Si 40+M, 20% to 50% acetone/hexanes) to provide 6-(4-nitro-1H-pyrazol-1-yl)isoquinoline (374 mg, 86% yield) as a white solid. LCMS (API-ES) m/z (%): 241.1 (100%, M++H); 1H NMR (300 MHz, CDCl3) δ ppm 7.76 (d, J=5.8 Hz, 1H), 8.01 (dd, J=8.8, 2.2 Hz, 1H), 8.14-8.23 (m, 2H), 8.36 (s, 1H), 8.65 (d, J=5.8 Hz, 1H), 8.83 (s, 1H), 9.34 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:16])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:16][C:6]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:8][N:7]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)(C)c1c(O)noc1-c1ccccc1
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(C)(C)C
Yield: 64.3 %

Procedure:
4-(tert-Butyl)-3-hydroxy-5-phenylisoxazole (0.15 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.12 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.16 g, 64%) as a colorless powder.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]1[CH2:15][O:14][C:9]([CH2:11][CH2:12][OH:13])([CH3:10])[O:8]1>ClCCl>[CH2:7]1[CH2:15][O:14][C:9]([CH3:10])([CH2:11][CH:12]=[O:13])[O:8]1
Reactant: CC1(CCO)OCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(CC=O)OCCO1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
Pyridine (7.2 g) and chromic oxide (CrO3) (4.6 g) are added in small fractions to dichloromethane (150 cc) over 10 minutes. After 15 minutes' stirring at a temperature in the region of 20° C., 2,2-ethylenedioxy-4-hydroxybutane (0.85 g, 6.4 mmol) is added quickly as a solution in dichloromethane (2 cc). After 15 minutes' stirring at 20° C., the black, viscous precipitate is separated off by filtration through silica and is washed with ether. After evaporation of the solvents, 3,3-ethylenedioxybutanal (0.59 g) is obtained (B.P.0.4 =35° C.).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2ccnc(C=O)c2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(c2ccnc(CO)c2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 4-(2-methyl-[1,3]dioxolan-2-yl)-pyridine-2-carbaldehyde (1100 mg, 5.69 mmol) was dissolved in MeOH (15 mL). NaBH4 (278 mg, 7.05 mmol) was added portionwise at 0° C. and the reaction mixture was stirred at rt for 1 h. Water was added and the mixture extracted with EA (3×30 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.41 min; [M+H]+=196.51.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:46])[C:15]([O:38]CC2C=CC=CC=2)=[C:16]2[C:35](=[O:36])[N:20]3[CH:21]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:25][CH:22]4[CH2:23][O:24][CH:19]3[CH2:18][N:17]2[CH:37]=1)=[O:12]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:46])[C:15]([OH:38])=[C:16]2[C:35](=[O:36])[N:20]3[CH:21]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:25][CH:22]4[CH2:23][O:24][CH:19]3[CH2:18][N:17]2[CH:37]=1)=[O:12]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C(C2)OCC2CC(c3ccccc3)CCC21
Agent: [Pd]
Solvent: CO
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C(C2)OCC2CC(c3ccccc3)CCC21
Yield: 56.2 %

Procedure:
racemic-(3S,4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-3-phenyl-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide (27 mg, 0.0432 mmol) was suspended in methanol, 10 w.t, % Pd/C (3 mg) was added and hydrogen was bubbled through the system several times until the reaction was determined complete by TLC (5% methanol/dichloromethane). The suspension was filtered through Celite eluting with methanol/chloroform and the filtrate was concentrated under reduced pressure and purified by HPLC to give the title compound (13 mg, 57%) as a white solid, 1H NMR (CDCl3) δ 12.40 (br s, 1H), 10.37 (m, 1H), 8.32 (s, 1H), 7.37-7.28 (m, 3H), 7.24-7.15 (m, 4H), 6.79 (m, 2H), 5.78 (br s, 1H), 4.85 (m, 1H), 4.62 (m, 2H), 4.29 (m, 1H), 4.16-4.09 (m, 2H), 3.92 (dd, J=11.6, 4.8 Hz, 1H), 2.58 (m, 1H), 2.46 (m, 1H), 2.07-1.64 (m, 7H); ES+ MS: 536 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([NH:7][C:8]2[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(NC3CCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(cyclohexylamino)-2-phenylquinoxaline-6-carboxylate (80 mg, 0.22 mmol, 1.00 equiv) in methanol (15 mL), a solution of sodium hydroxide (44.32 mg, 1.11 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was diluted in 20 mL of water. The pH value of the solution was adjusted to 4-5 with aq hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 60 mg (76%) of 3-(cyclohexylamino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH:21]3[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]3=[O:28])[CH:16]=1)=[C:8]([CH2:29][O:30]C(=O)C)[C:7]([CH2:34][O:35]C(=O)C)=[CH:6]2.C[O-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH:21]3[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][C:26]3=[O:27])[CH:16]=1)=[C:8]([CH2:29][OH:30])[C:7]([CH2:34][OH:35])=[CH:6]2
Reactant: COc1cc2cc(COC(C)=O)c(COC(C)=O)c(-c3ccnc(C4C(=O)CCCC4=O)c3)c2cc1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(C4C(=O)CCCC4=O)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
The compound obtained in Example 18 (440 mg) is suspended in methanol (3 ml), and thereto is added sodium methoxide (28% methanol solution, 0.495 ml) under ice-cooling. The mixture is stirred at room temperature for 30 minutes, during which the mixture is dissolved into a solution but then the crystals precipitate. The reaction solution is cooled with ice, and the pH value thereof is adjusted to pH 4 with a 1M hydrochloric acid. The precipitated crystals are collected by filtration, and washed with water to give 6,7-dimethoxy-1-[2-(1,3-dioxocyclohexan-2-yl)pyridin-4-yl]-2,3-bis(hydroxymethyl)naphthalene (320 mg).
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[CH3:14][C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([NH2:32])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:14][C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([NH:32][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[O:3])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccncn2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(C(=O)Nc2nc(-c3cccc(C)c3)c(-c3ccncn3)s2)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 65 %

Procedure:
Methyl 4-chloroformylbenzoate (1.1 g, 5.6 mmol) was added to a solution of [4-(3-methylphenyl)-5-(4-pyrimidinyl)-1,3-thiazol-2-yl]amine and 4-dimethylaminopyridine (0.14 g, 1.1 mmol) in N,N-dimethylacetamide (10 mL), and the mixture was stirred at 70° C. for 14 hrs. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the precipitated solids were collected by filtration. Crude crystals were washed with water, dried and recrystallized from pyridine to give the title compound (1.0 g, yield 65%).
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([Cl:21])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:22])[CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].N#N>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:20]=[C:19]([Cl:21])[C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH:9]([N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:8]3=[O:18])=[C:4]([Cl:22])[CH:3]=2)=[CH:29][CH:28]=1)=[O:26]
Reactant: O=C1C(N2CCCCC2)CCN1Cc1c(Cl)cc(Br)cc1Cl
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC(N4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 38.8 %

Procedure:
Purge a mixture of 1-(4-bromo-2,6-dichloro-benzyl)-3-piperidin-1-yl-pyrrolidin-2-one (0.429 g, 1.06 mmol) and 4-methoxycarbonyl phenylboronic acid (0.57 g, 3.16 mmol) in toluene (15 mL) and 2M sodium carbonate (3.7 mL) with N2. Treat the reaction with Pd(PPh3)4 (0.061 g, 0.053 mmol) and heat to 90° C. for 7 hours under N2. Cool the reaction, dilute with ethyl acetate, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo afford crude product, and purify with a 0 to 10% methanol in CH2Cl2 gradient to afford 0.19 g (39%) of the titled product. Rf=0.40 (9/1 CH2Cl2/methanol). ES MS (m/z): 461 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CCOCC.C1COCC1>[ClH:1].[CH2:13]([O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Reactant: COc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate (17.95 g), 4-methoxyaniline (8.29 g), anhydrous potassium carbonate (18.6 g) and THF (250 ml) was stirred at ambient temperature for 48 hours. The mixture was evaporated to dryness and water was added to the residue. The mixture was extracted with dichloromethane to give a solid which was dissolved in IMS (50 ml). The solution was saturated with hydrogen chloride gas whilst cooling the mixture in ice. Ether was added to induce precipitation. The solid was collected by filtration to give ethyl 6-ethoxy-4-(4-methoxyanilino)-1,5-naphthyridine-3-carboxylate hydrochloride, m.p. 160°-162° C. Active (3/3) at 30 mg/kg.
Reaction SMILES: Br[C:2]1[C:3]([O:21]C)=[CH:4][C:5]([O:19]C)=[C:6]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=3[O:10][N:9]=2)[CH:7]=1.[Li][CH2:24]CCC.IC.B(Br)(Br)Br>C1COCC1>[OH:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([CH3:24])[C:3]([OH:21])=[CH:4][C:5]=3[OH:19])=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: [Li]CCCC
Reactant: COc1ccc2c(-c3cc(Br)c(OC)cc3OC)noc2c1
Agent: BrB(Br)Br
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(-c2noc3cc(O)ccc23)c(O)cc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 3-(5-bromo-2,4-dimethoxyphenyl)-6-methoxy-1,2-benzisoxazole (200 mg, 0.55 mmol) in THF (6 mL) at −78° C. was added n-BuLi (0.24 mL, 0.60 mmol, 2.5 M in hexanes) dropwise. The solution was stirred at −78° C. for 30 min and then iodomethane (60 μL, 0.96 mmol) was added dropwise. The cooling bath was switched to an ice bath and the solution was stirred at 0° C. for 2 h. The reaction was quenched with water, most of the solvent was removed in vacuo, and extraction was conducted in EtOAc (2×30 mL) with water (20 mL). Flash chromatography with silica gel (gradient to 25% EtOAc/hexanes) provided a mixture of the desired methylated product and the protonated side product (both compounds have the same Rf). The above mixture of compounds was treated with BBr3 according to Example 2, Step i, to produce the title compound as a light orange solid (114 mg, 81% yield for two steps): mp 195° C. (dec.); 1H NMR (300 MHz, acetone-d6) δ 2.25 (s, 3H), 6.59 (s, 1H), 7.04 (dd, 1H, J=8.5, 2.1 Hz), 7.09 (d, 1H, J=1.8 Hz), 7.80 (s, 1H), 8.12 (d, 1H, J=8.8 Hz), 8.88 (broad s, 1H), 9.42 (broad s, 1H), 9.52 (s, 1H); MS m/e 258 (M+H)+.
Reaction SMILES: CC([NH:9][CH:10]([CH3:23])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)C1C=CC=CC=1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>CO.[Ni]>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:23][C@H:10]([NH2:9])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: CC(CCc1ccc(S(N)(=O)=O)cc1)NC(C)c1ccccc1
Agent: [Ni]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: C[C@H](N)CCc1ccc(S(N)(=O)=O)cc1

Procedure:
4-(4-Aminosulphonylphenyl)butanone-2 was reacted with (S)-(-)-α-phenylethylamine and p-toluenesulphonic acid as the catalyst in toluene with separation of water to give the Schiff's base (S)-N-(α-methylbenzyl)-1-methyl-3-(4-aminosulphonylphenyl)propylimine. The imine was hydrogenated in methanol in the presence of Raney-nickel to give a mixture of the optical isomers of N-(α-methylbenzyl)-1-methyl-3-(4-aminosulphonylphenyl)propylamine. The amine was converted with oxalic acid into a mixture of the oxalates from which there was obtained by two-fold crystallization pure (S)-1-methyl-3-(4-aminosulphonylphenyl)propylamine oxalate of melting point 123°-127°, [α]D20 =-68° (c=1.0 in methanol). Hydrogenolysis of this substance in alcohol under 4 bar of hydrogen at 60° for 24 hours yielded pure (S)-1-methyl-3-(4-aminosulphonylphenyl)propylamine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: c1ccc(CN2CCNCC2)cc1
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCN(Cc2ccccc2)CC1
Yield: 89 %

Procedure:
The experimental protocol used is the same as that described for compound 6.1, 2-fluoro-5-nitrobenzonitrile replacing 2-fluoro-5-nitrotoluene and 1-benzylpiperazine replacing tert-butyl 1-piperazinecarboxylate. A light ochre-coloured solid is obtained (yield 89%). Melting point: 124.0° C.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][C:34](=[O:37])[C:33]2(O)[C:38]1[C:46]([OH:47])=[CH:45][C:41]2[O:42][CH2:43][O:44][C:40]=2[CH:39]=1>>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][C:34](=[O:37])[CH:33]2[C:38]1[C:46]([OH:47])=[CH:45][C:41]2[O:42][CH2:43][O:44][C:40]=2[CH:39]=1
Reactant: O=C1Nc2c(F)cccc2C1(O)c1cc2c(cc1O)OCO2
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1Nc2c(F)cccc2C1c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 7-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (100%): 1H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.22 (s, 1H), 7.01 (t, 1H), 6.87-6.78 (m, 1H), 6.71 (d, 1H), 6.62 (s, 1H), 6.35 (s, 1H), 5.90-5.85 (m, 2H), 4.67 (s, 1H); MS (ES+) m/z 288.5 (M+1).