Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: Cn1cnc2ccccc21
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: Cn1c(-c2ccc(-c3ccccc3[N+](=O)[O-])cc2)nc2ccccc21
Temperature: 65 °C
Reaction time: 156 h

Procedure:
To a three-necked flask equipped with a magnetic stir bar was added 4′-iodo-2-nitrobiphenyl (3.90 g, 12.0 mmol, 1.2 equiv), 1-methyl-1H-benzo[d]imidazole (1.32 g, 10.0 mmol, 1.0 equiv), Ag2CO3 (5.52 g, 20.0 mmol, 2.0 eq), Pd(dppf)Cl2.CH2Cl2 (0.41 g, 0.5 mmol, 0.05 eq) and PPh3 (0.26 g, 1.0 mmol, 0.1 eq). The tube was evacuated and back-filled with nitrogen, and this evacuation/back-fill procedure was repeated twice. Then solvent CH3CN (60 mL) was added under the protection of nitrogen. The mixture was stirred in an oil bath at a temperature of 60-70° C. for 6.5 days and then cooled. The solid was filtered off through a pad of celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1-5:1-3:1-2:1) as an eluent to afford the desired product, 1-methyl-2-(2′-nitrobiphenyl-4-yl)-1H-benzo[d]imidazole, as a white solid (1.36 g in 41% yield). 1H NMR (DMSO-d6, 400 MHz): δ 3.95 (s, 3H), 7.25-7.29 (m, 1H), 7.31-7035 (m, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.65-7.72 (m, 4H), 7.84 (td, J=7.6, 1.2 Hz, 1H), 7.98 (d, J=7.6 Hz, 2H), 8.06-8.08 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH2:30](N)[CH2:31][NH2:32].[S]>CN(C=O)C>[NH:21]1[CH2:30][CH2:31][N:32]=[C:20]1[C:16]1[CH:15]=[C:14]([O:13][C:12]2[CH:22]=[CH:23][C:9]([NH:8][C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NCCN
Reactant: N#Cc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Agent: [S]
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccc(Oc3ccnc(C4=NCCN4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 80 °C

Procedure:
A mixture of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile (0.2 g, 0.53 mmol, prepared in Example 8), ethylene diamine (0.095 g, 1.58 mmol), and sulfur (0.05 g, 1.58 mmol) in DMF (3 mL) was heated at 80° C. for 3 days. The solvent was then removed by evaporation under reduced pressure. The residue was purified by preparative HPLC followed by preparative TLC (EtOAc:NH4OH=99:2) to afford pure product, 0.01 g (5%). 1H NMR (DMSO-d6) δ 9.39 (s, 1H), 8.41 (d, 1H), 7.84 (m, 4H), 7.42 (m, 3H), 7.37 (d, 1H), 7.09 (m, 3H), 6.95 (s, 1H), 6.46 (s, 1H), 6.37 (s, 2H); MS ES 424 (M+H)+calc 424.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2([CH2:24]O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]2=[O:23])=[C:4]([OH:26])[CH:3]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[O:26][CH2:24][C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]3=[O:23])[C:5]=2[CH:6]=1
Reactant: CCCCCN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc(F)c(F)cc32)c2ccccc21
Yield: 71 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(4,5-difluoro-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 71% yield: mp 48-50° C.; 1H NMR (300 MHz, CDCl3) δ 7.33 (td, 1H), 7.18-7.12 (m, 2H), 6.93 (d, 1H), 6.77 (dd, 1H), 6.51 (dd, 1H), 4.96 (d, 1H), 4.71 (d, 1H), 3.87-3.64 (m, 2H), 1.82-1.65 (m, 2H), 1.46-1.28 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.6, 156.8, 152.9, 149.8, 144.2, 142.6, 131.8, 129.4, 124.1, 123.5, 111.7, 109.0, 100.2, 80.9, 57.9, 40.6, 29.1, 27.2, 22.5, 14.1; MS (ES+) m/z 344 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH2:20][OH:21].[H-].[Na+].Br[CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH:2]=[C:3]([CH3:10])[CH3:4])=[O:17])=[CH:12][C:11]=1[CH2:20][O:21][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CO)c1
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(C(=O)OCC=C(C)C)cc2COCC=C(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a solution of 66.63A (0.322 mmol) in DMF (4 mL), was added NaH (0.0100 g, 0.419 mmol). The resulting mixture was stirred at room temperature for 10 minutes. 1-Bromo-3-methylbut-2-ene (0.240 g, 1.61 mmol) (commercially available from Aldrich) was added and the mixture was stirred at room temperature for 2 hours. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:6 EtOAc/hexane) and gave 67.27A as a colorless oil, in 77% yield. MS ESI (pos.) m/e: 430 (M+18)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2NCc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2NCc1ccc(Cl)cc1
Yield: 14 %

Procedure:
The title compound was synthesized from methyl 4-(4-chlorobenzylamino)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.023 g, 0.075 mmol) and lithium hydroxide (0.023 g, 0.55 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by reverse phase chromatography, eluting with MeOH in water (0.1% formic acid) a to afford a yellow solid: 3 mg, 14% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.47-2.58 (m, 1H), 2.71-2.83 (m, 1H), 2.87-3.06 (m, 2H), 4.23 (q, J=13.16 Hz, 2H), 4.54-4.67 (m, 1H), 6.81 (s, 1H), 7.38-7.56 (m, 4H), 8.49 (s, 1H); LCMS-MS (ESI−) 289.0 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N+]=[N-])[CH:5]=[CH:6][CH:7]=1.[O:18]=[CH:19][C:20](=[CH2:22])[CH3:21]>ClCCl.CCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[CH2:21][C:20]2([CH3:22])[CH:19]=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C=O
Reactant: [N-]=[N+]=C(c1cccc(F)c1)c1cccc(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1(C=O)CC1(c1cccc(F)c1)c1cccc(F)c1
Temperature: 43 °C

Procedure:
A solution of bis(3-fluorophenyl)diazomethane, prepared as in Example 84 by the action of activated manganese dioxide (33 g) on 3,3'-difluorobenzophenone hydrazone (21.76 g) in dichloro-methane (105 mL), was added to a solution of methacrolein (15 mL) in hexane (100 mL). The mixture was heated at 43° C. for 20 hours then the amber solution was evaporated in vacuo. The crude solid was triturated with hexane to yield 23.1 g of 2,2-bis(3-fluorophenyl)-1-methylcyclopropanecarboxaldehyde, mp 92°-93° C. Recrystallization of a sample from hexane furnished the analytical specimen, mp 92°-93.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[O:12]1[CH2:15][CH:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:13]1>CCO>[N+:8]([C:7]1[CH:6]=[CH:5][N+:4]([O-:11])=[CH:3][C:2]=1[N:19]1[CH2:20][CH2:21][N:16]([CH:14]2[CH2:15][O:12][CH2:13]2)[CH2:17][CH2:18]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Reactant: C1CN(C2COC2)CCN1
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])cc1N1CCN(C2COC2)CC1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A mixture of 3-bromo-4-nitro-1-oxido-pyridin-1-ium (500 mg, 2.283 mmol) and 1-(oxetan-3-yl)piperazine (649.3 mg, 4.566 mmol) in EtOH (10 mL) were heated at reflux for 17 hours. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residue was passed through a 25 g SCX-2 cartridge (pre-wetted with MeOH), eluting with 2M NH3 in MeOH/DCM. The solvents were removed in vacuo and the residue purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give 1-(4-nitro-1-oxido-pyridin-1-ium-3-yl)-4-(oxetan-3-yl)piperazine as an orange solid (553 mg, 86% Yield).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25]C[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CC(O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][C:26]([CH3:28])([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: OC1CNC1
Product: CC1(O)CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and azetidin-3-ol hydrochloride and isolated as white solid (10.3 mg, 56%). MS (m/e): 387.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2].[Br:17]N1C(=O)CCC1=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Br:17][C:5]1[CH:6]=[C:7]([CH:10]([CH:14]([CH3:15])[CH3:16])[C:11]([OH:13])=[O:12])[CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(C(C(=O)O)C(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(C(=O)O)C(C)C)cc1Br
Yield: 59 %

Procedure:
Into a solution of 0.15 g (0.67 mM) of 2-(4-ethoxyphenyl)isovaleric acid in 3 ml of chloroform, 0.24 g (1.35 mM) of N-bromosuccinimide was added, and the mixture was heated for 3 hours in the presence of a catalytic amount of anhydrous aluminum chloride under a reflux condition. The oily substance obtained by condensing the reaction mixture was subjected to silica gel column chromatography while using a 1:3 mixture of ethyl acetate and n-hexane as an eluent, thereby 0.12 g of 2-(3-bromo-4-ethoxyphenyl)isovaleric acid was obtained as a colourless and oily substance (yield: 60%).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:25][CH3:26])[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[O:16][C:15]3([CH3:24])[CH3:23])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH2:25]([N:11]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[O:16][C:15]2([CH3:23])[CH3:24])[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:27])=[O:3])=[CH:10][CH:9]=1)[CH3:26]
Reactant: CCOC(=O)c1ccc(N(CC)c2ccc3c(c2)C(C)(C)OC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)OC2(C)C
Temperature: 55 °C
Yield: 98.2 %

Procedure:
A solution of 4-[ethyl-(1,1,3,3-tetramethyl-1,3-dihydro-isobenzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 80, 0.224 g, 0.6 mmol) in 20 mL of ethanol was treated with 2 mL of 5M sodium hydroxide solution and the resulting solution was heated at 55° C. for 2 hours. The volatiles were removed by distillation in vacuo and the residue was acidified using hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to a residue which was recrystallized from hot ethyl acetate to afford the title compound (0.2 g, 88%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.20 (s, 1H), 7.71 (d, 2H, J=8.8 Hz), 7.25 (d, 1H, J=8.4 Hz), 7.09 (m, 2H), 6.67 (d, 2H, J=8.9 Hz), 3.76 (t, 2H, J=6.9 Hz), 1.44 (s, 6H), 1.41 (s, 6H), 1.14 (t, 3H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([N:18](S(C)(=O)=O)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:28])([CH3:27])[C:9]2=[O:29])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl.O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:12]=3[O:11][C:10]([CH3:27])([CH3:28])[C:9]2=[O:29])=[CH:6][CH:7]=1
Reactant: CC1(C)Oc2cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 91.4 %

Procedure:
N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-N-(methylsulfonyl)methanesulfonamide (8.5 g) was dissolved in dimethylsulfoxide (51 mL), a solution of potassium carbonate/water (7.98 g/8.5 mL) was added dropwise thereto at 25° C., and the mixture was stirred at the same temperature for 23 hours. To the reaction mixture was added dropwise concentrated hydrochloric acid/water (4.0 g/76.5 mL) at 30° C. or lower, then cooled to 20° C., and the mixture was stirred for 90 minutes. The precipitated crystals were collected by filtration, washed with water (76.5 mL), and then dried to obtain the title compound (6.40 g) as white crystals (Form B crystals). Subsequently, said crystals (6 g) were added to dimethylsulfoxide (21 mL), dissolved at about 50° C., then activated carbon (120 mg) and dimethylsulfoxide (3 mL) were added thereto, and stirred for 1 hour. After the mixture was filtered, to the filtrate at about 50° C. was added dropwise purified water (9 mL), and then stirred at the same temperature for 30 minutes. The mixture was cooled to 20° C., stirred for 1 hour, then the precipitated crystals were collected by filtration, and successively washed with purified water (54 mL) and ethanol (12 mL). The obtained crystals (6.57 g) were suspended in ethanol (30 mL), the suspension was heated under reflux for 2 hours, then cooled to 20° C., and stirred for 1 hour. The precipitated crystals were collected by filtration, and dried under reduced pressure at 50° C. to obtain the title compound (5.48 g) as crystals (Form A crystals) (yield: 83%, purity: 100%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10]C)=[C:8]([F:12])[C:7]([Br:13])=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5].B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:12])[C:7]([Br:13])=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5]
Reactant: COc1c(N)c(C#N)c(C)c(Br)c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(F)c(O)c(N)c1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
2-Amino-5-bromo-4-fluoro-3-methoxy-6-methylbenzonitrile (I-45) (8.63 g, 33.30 mmol) was dissolved in methylene chloride (270 ml), and at −20° C., boron tribromide (1 M methylene chloride solution, 100 ml, 100.00 mmol) was gradually dropwise added. With gradually heating, this was stirred at room temperature for 15 hours. After the reaction, water with ice was added, followed by neutralization to pH of 7 with an aqueous saturated sodium hydrogencarbonate solution. Adding methylene chloride for fractionation was tried, but resulted in suspension, and therefore, this was dissolved in ethyl acetate, washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/methylene chloride to obtain the entitled compound (7.86 g, 96%) as a pale brown solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][C:25]=2[N:26]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:28]2[CH:29]=[CH:30][C:24]3[S:23][C:22]([CH3:21])=[N:26][C:25]=3[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc2cc(C=O)ccc2s1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2sc(C)nc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-methylbenzo[d]thiazole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.23 min.; [M+H]+: 411.11 g/mol.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].Cl.[NH2:31][CH2:32][CH2:33][N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36].C[O-].[Na+]>CCO>[CH3:38][S:35]([N:34]([CH3:39])[CH2:33][CH2:32][NH:31][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4])(=[O:37])=[O:36]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 34.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.065 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (49 mg, 0.26 mmol), and NaOMe (14 mg, 0.26 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and dried over MgSO4. After evaporating the solvent, the residue was purified by silica gel chromatography (0-3% MeOH/CH2Cl2) to give 11.4 mg of the title compound as a light yellow solid. MS: (+) m/z 507.36 (M+1).
Reaction SMILES: [P:1]([O:19][C:20]([C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=1[F:56])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[CH2:21][N:22]1[CH:26]=[N:25][C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])=[CH:31][CH:30]=2)=[N:23]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].Br[Si](C)(C)C.N1C=CC=CC=1.[OH-].[Na+].S(=O)(=O)(O)O>C(Cl)Cl>[P:1]([OH:11])([OH:3])([O:19][C:20]([C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][C:50]=1[F:56])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[CH2:21][N:22]1[CH:26]=[N:25][C:24](/[CH:27]=[CH:28]/[C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]([F:41])([F:42])[CH:38]([F:40])[F:39])=[CH:33][CH:34]=2)=[N:23]1)=[O:2]
Reactant: O=P(OCc1ccccc1)(OCc1ccccc1)OC(Cn1cncn1)(Cn1cnc(/C=C/c2ccc(OCC(F)(F)C(F)F)cc2)n1)c1ccc(F)cc1F
Agent: C[Si](C)(C)Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=P(O)(O)OC(Cn1cncn1)(Cn1cnc(/C=C/c2ccc(OCC(F)(F)C(F)F)cc2)n1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A solution of the compound of step (a) (298 mg, 0.37 mmol) in methylene chloride (5 ml) was cooled to 0° C. and then treated with bromotrimethylsilane (254 mg, 1.66 mmol) and pyridine (180 mg, 3.10 mmol). The resulting mixture was stirred at 0° C. for 3 hours and then quenched with water (1 ml) containing sodium hydroxide (96 mg, 2.41 mmol). The mixture was then acidified with dilute sulphuric acid and the product extracted into ethyl acetate. After washing with brine, the ethyl acetate phase was dried (MgSO4) and the solvent evaporated to give the title compound as a pale yellow foam (202 mg, 88%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH:17]([CH2:26][C:27]([O-:29])=O)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:6][O:7][C:8]=2[CH:9]2[CH2:12][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10]2)[CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH2:38].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:27]([CH2:26][CH:17]([C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:8]([CH:9]2[CH2:10][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:12]2)[O:7][N:6]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:29]
Reactant: Cc1ccc(N)c(Cl)c1
Reactant: CC(C)CC1CC(c2onc(C(CC(=O)[O-])CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)CC(CC(=O)OC(C)(C)C)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c(Cl)c1
Yield: 52.3 %

Procedure:
Mono-tert-butyl 3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]glutarate (245 mg) and DMF (2 mL) were mixed. After an addition of 2-chloro-4-methylphenylamine (67 mg), HOBt.H2O (87 mg) and WSC.HCl (108 mg) to the mixture, the reaction mixture was stirred at RT. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: ethyl acetate/hexane=1/4) to give the title compound (131 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:19][CH2:20][C@@H:21]([N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[CH3:15][C:10]1[N:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8](=[O:16])[N:7]([CH3:17])[C:6]1[CH:18]=[C:2]([O:19][CH2:20][C@@H:21]([N:26]3[C:27](=[O:36])[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]3=[O:35])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:3]=[CH:4][C:5]2=1
Reactant: CC(C)C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)ccc21
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc21
Yield: 48.4 %

Procedure:
8-Chloro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (1.4 g, 5.41 mmol) and (S)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (4.01 g, 16.23 mmol) were subjected to Buchwald coupling as described in Example 16, Part H) to give (S)-2-(1-((4,6-dimethyl-5-oxo 5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione as yellow solid (1.4 g, 2.62 mmol, 49% yield). LC/MS (ESI) m/e 470.2 [(M+H)+, calcd for C28H28N3O4 470.2]; LC/MS retention time (method C): tR=2.05 min.