Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)=[O:13].IC.[C:28]([O-])([O-])=O.[Na+].[Na+].COC1C=C(C(C2C=CC(OC)=C(OC)C=2OC)=O)C=C(OC)C=1>>[CH3:28][O:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:13]
Reactant: COc1cc(C(=O)c2ccc(OC)c(OC)c2O)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2OC)c1
Agent: [Na+]
Solvent: CI
Product: COc1cc(C(=O)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Yield: 84 %

Procedure:
(2-hydroxy-3,4-dimethoxyphenyl)-(3,4,5-trimethoxyphenyl)methanone (4.44 g, 12.75 mmol), iodomethane (1.59 ml, 25.51 mmol), and Na2CO3 (2.7 g, 25.51 mmol) were treated in the same manner as described above for the synthesis of (3,5-Dimethoxy-phenyl)-(2,3,4-trimethoxy-phenyl)-methanone. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give (2,3,4-trimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone as an off-white solid (3.88 g, 84%); mp, 122-124° C.: 1HNMR (CDCl3) δ 7.11 (d, J=8 Hz, 1H, Ar), 7.08 (s, 2H, Ar), 6.73 (d, J=8 Hz, 1H, Ar), 3.94 (s, 6H, 2OCH3), 3.91 (s, 3H, OCH3), 3.86 (s, 6H, 2OCH3), 3.81 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 194.4, 156.1, 152.9, 152.7, 142.6, 142.3, 133.5, 126.5, 124.9, 107.6, 106.8, 62.1, 61.1, 56.4, 56.3; Anal. Calcd. For C19H22O7: C, 62.98; H, 6.12. Found: C, 63.14; H, 6.13. The product was carried over to the next step.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].C[O:22][C:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:23](=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)CCCCCCc1ccc2c(n1)NCCC2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)CCCCCCc1ccc2c(n1)NCCC2
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of diisopropylamine (5.17 mL, 36.9 mmol) in anhydrous tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium in hexanes (16.2 mL of a 2.5 M solution). After 5 minutes, t-butyl acetate (4.97 mL, 36.9 mmol) was added. After an additional 5 minutes, 7-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-heptanoic acid methyl ester 29-4 (3.4 g, 12.3 mmol) in tetrahydrofuran (30 mL) was added and the solution was warmed to −40° C. for one hour. The reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with ethyl acetate to give 29-5 as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([NH:7][NH:8][C:9](=[NH:11])[NH2:10])=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:10]=[C:9]([NH2:11])[NH:8][N:7]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: N=C(N)NNC(=O)c1ccc(Cl)c(Cl)c1
Solvent: O
Product: Nc1nc(-c2ccc(Cl)c(Cl)c2)n[nH]1
Yield: 89.3 %

Procedure:
A solution of 2-(3,4-dichlorobenzoyl)hydrazinecarboximidamide (9.5 g, 38.62 mmol) in water (150 ml) was stirred for 7 h at reflux. The solids were collected by filtration to afford 3-(3,4-dichlorophenyl)-1H-1,2,4-triazol-5-amine as an off-white solid (7.9 g, 89%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18](O)=[O:19])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:18]([NH:21][CH2:22][C:23]3[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[O:19])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nn(C(C)(C)C)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (210 mg, 0.768 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (158 mg, 1.037 mmol), 1-hydroxy-7-azabenzotriazole (209 mg, 1.537 mmol), EDC (295 mg, 1.537 mmol), N-methylmorpholine (0.338 mL, 3.07 mmol), and DMSO(10 mL). The final product was collected as 0.280 g (89%). LCMS E-S (M+H)=408.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (dddd, 4 H), 1.69 (m, 9 H), 2.12 (s, 3 H), 2.22 (m, 4 H), 2.33 (s, 3 H), 4.34 (d, J=4.80 Hz, 2 H), 5.87 (s, 1 H), 7.04 (s, 1 H), 8.55 (m, 1 H), 11.51 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH:3]1[CH2:33][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[H-].[Na+].[CH3:44]I>CN(C=O)C>[CH:19]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[C:3]([CH3:44])([CH2:33][CH:34]=[CH:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:4](=[O:32])[N:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:6]2[CH:25]=[CH:24][CH:23]=[CH:22][C:7]1=2)([CH3:21])[CH3:20]
Reactant: CI
Reactant: CC(C)N(C(=O)CN1C(=O)C(CC=Cc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(CC=Cc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.08 h
Yield: 51.9 %

Procedure:
To a stirring solution of 200 mg (0.37 mmol) of 2-[2,4-Dioxo-5-phenyl-3-(3-phenyl-allyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 41, in 3 mL of DMF at 0° C. is added 16 mg (0.41 mmol, 1.1 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 5 min, then 25 mL (0.41 mmol, 1.1 equiv) of methyl iodide is added. The reaction mixture is stirred 30 min at 0° C. then 19 h at RT and quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. Purification of the resulting oil via reverse phase MPLC using a C-18 column and 70% acetonitrile/30% H2O with 0.1% TFA as eluent followed by lyophilization afforded 107 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.53-7.05 (m, 18H), 6.79 (m, 1H), 6.15 (m, 1H), 5.97 (d, 1H, J=15.7), 5.09 (m, 1H), 4.44 (d, 1H, J=16.4), 3.95 (d, 1H, J=16.4), 3.07 (m, 2H), 2.28 (d, 1H, J=7.1), 1.61 (s, 3H), 1.14 (m, 6H); low resolution MS (FAB)m/e 558 (MH+), 423, 223.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[N:9]([CH3:24])[C:10]([CH3:23])=[CH:11][C:12](=[O:22])[C:13]=2[O:14]CC2C=CC=CC=2)=[O:7])[CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([NH:5][C:6]([C:8]2[N:9]([CH3:24])[C:10]([CH3:23])=[CH:11][C:12](=[O:22])[C:13]=2[OH:14])=[O:7])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)n1C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(=O)c(O)c(C(=O)NC2CCC2)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51.5 %

Procedure:
A mixture of N-cyclobutyl-3-benzyloxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide (1.528 g, 4.68 mmol, 1.0 equiv), 10% Pd on activated carbon (200 mg, wet), and ethanol (200 ml) was stirred under 50 psi of H2 at room temperature for 2.5 h. The catalyst was filtered through Celite® and the filtrate was evaporated to give a solid, which was recrystallized from MeOH gave the titled compound (0.57 g, 51.5%) as a white solid. M.p. 277.3° C. (dec); 1H-NMR (DMSO-d6, 400 MHz) δ 1.68-1.70 (m, 2H, cyclobutyl H), 1.95-2.01 (m, 2H, cyclobutyl H), 2.20-2.26 (m, 2H, cyclobutyl H), 2.29 (s, 3H, CH3), 3.41 (s, 3H, NCH3), 4.31-4.35 (m, 1H, CH), 6.13 (s, 1H, CH), 8.98 (br, 1H, NH); MS (m/z) 237 (M++1), 185, 166, 123.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9](I)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cu][C:19]#[N:20]>CS(C)=O.CO>[CH:1]1([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[C:9]([C:19]#[N:20])=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1cnc2c(c1)c(I)nn2CC1CCCC1
Reactant: N#C[Cu]
Solvent: CO
Solvent: CS(C)=O
Product: N#Cc1nn(CC2CCCC2)c2ncc(F)cc12
Temperature: 150 °C

Procedure:
Under an atmosphere of argon, 6.370 g (purity 83%, 15.447 mmol) of 1-(cyclopentylmethyl)-5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine and 1.522 g (16.992 mmol) of copper(I) cyanide were initially charged in 45 ml of absolute DMSO, and the mixture was heated at 150° C. for 1.5 h. After cooling, the reaction was diluted with methanol and filtered through Celite. The organic phase was washed twice with a mixture of 25% strength aqueous ammonia solution and saturated aqueous ammonium chloride solution (v/v=1:3), then washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. This gave 3.670 g (purity 86%, 97% of theory) of the target compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1>C(O)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]([OH:15])=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reaction time: 3 h

Procedure:
Conc. HNO3 (22.49 g, 357 mmol) was added to a solution 1-(5-fluoro-2-hydroxyphenyl)ethanone (50 g, 325 mmol) in acetic acid (300 mL) at 0° C. and stirring was continued at 20° C. for 3 h. The reaction mixture was quenched with ice cold water. The separated solid was filtered and washed with cold water and dried to afford 1-(5-fluoro-2-hydroxy-3-nitrophenyl)ethanone (Int-49) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.6 (1H, s), 8.3-8.2 (1H, dd), 8.2-8.1 (1H, dd), 2.7 (3H, s).
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Br)cc4)cc3)c2cc1OC
Yield: 64 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (3 ml) with heat, 4-bromophenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 50 minutes. The separated crystals were filtered and washed with toluene to obtain 56 mg of the title compound (yield: 64%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:29][O:30][CH2:31][C:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:12]([C@@H:10]1[CH2:11][C@:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14](=[O:16])[NH:38][S:35]([C:32]1([CH2:31][O:30][CH3:29])[CH2:34][CH2:33]1)(=[O:37])=[O:36])=[CH2:13]
Reactant: COCC1(S(N)(=O)=O)CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(COC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A solution of (1R,2S)-1-[(tert-butoxycarbonyl)amino]-2-ethenylcyclopropanecarboxylic acid (132 mg) in THF (3 mL) was added 1,1′-carbonyldiimidazole (283 mg). The mixture was stirred 4 hours at reflux. The mixture was cooled to room temperature and a solution of 1-(methoxymethyl)cyclopropanesulfonamide (125 mg; Li et al., 2006, Synlett 5:725) and DBU (0.438 mL) in THF (3 mL) was added via cannula. The mixture was stirred for 40 hours at room temperature. The reaction was quenched with 1N HCl and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (ISCO) to give the desired product (120 mg). 1H NMR (400 MHz, CDCl3): 5.71-5.62 (m, 1H), 5.29 (d, 1H), 5.16 (d, 1H), 3.36 (s, 2H), 2.15 (dt, 1H), 1.89 (dd, 1H), 1.75-1.68 (m, 2H), 1.49 (s, 9H), 1.34-1.30 (m, 1H), 1.08-1.03 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([O:17][CH3:18])=[CH:10][C:9]=1[O:19][CH3:20])=[O:7]>[Pd].C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([O:17][CH3:18])=[CH:10][C:9]=1[O:19][CH3:20])=[O:7]
Reactant: COc1cc(OC)c([N+](=O)[O-])cc1C(=O)CCCCCl
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(=O)CCCCCl)cc1N
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A mixture of 5-chloro-1-(2,4-dimethoxy-5-nitrophenyl)-1-pentanone (2.9 g, 9.6 mmol), prepared as in Example 12, 10% palladium on carbon (650 mg) and THF (approximately 170 mL) was stirred 3 hours under a hydrogen atmosphere (15 psi). The mixture was filtered and concentrated and the residue was purified by column chromatography eluting with hexane/ethyl acetate (60:40) to give 5-chloro-1-(5-amino-2,4-dimethoxyphenyl)-1-pentanone (1.9 g, 7 mmol), m.p. 87°-88° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=[C:28]1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9]([C:28]2[O:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH:29]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1-c1cc2ccccc2o1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 2-benzofuranboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=O)[CH3:20])[C:3]=1[S:22]([CH3:24])=[O:23].Cl.[NH2:26][CH2:27][CH2:28][SH:29].C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2([CH3:20])[NH:26][CH2:27][CH2:28][S:29]2)[C:3]=1[S:22]([CH3:24])=[O:23]
Reactant: NCCS
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CS(=O)c1c(C2(C)NCCS2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Yield: 1.7 %

Procedure:
A mixture of 1 g (2.5 mmol) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-acetyl4-methylsulfinyl-1H-pyrazole, 0.284 g (2.5 mmol) of 2-aminoethanethiol hydrochloride, 348 microliters (2.50 mmol) of triethylamine, 50 mg of p-toluenesulfonic acid and 30 ml of benzene was heated to reflux with removal of water overnight. The mixture was successively cooled, filtered, evaporated, chromatographed so as to give 20 mg of the title compound as white solid; melting point 85° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:34])[N:20]2[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]2[C:17]=1[C:18]([C:12]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13])=[C:19]([CH3:34])[N:20]2[CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Cc1cc2c(Cl)cc(Cl)cc2n1CCN1CCOCC1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3cc(Cl)cc(Cl)c23)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (29 mg, 0.14 mmol) and 4-(2-(4,6-dichloro-2-methyl-1H-indol-1-yl)ethyl)morpholine (44 mg, 0.14 mmol) in 1 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.17 mL, 0.31 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 3% MeOH in CH2Cl2 to give CBX007 (50 mg, 0.10 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46 (s, 3H), 2.55 (t, J=4.4 Hz, 4H), 2.74 (t, J=6.9 Hz, 2H), 2.77 (s, 3H), 3.74 (t, J=4.5 Hz, 4H), 4.25 (t, J=6.9 Hz, 2H), 7.10 (d, J=1.7 Hz, 1H), 7.21 (d, J=7.4 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.42 (d, J=7.3 Hz, 1H), 7.60-7.74 (m, 2H), 8.10 (d, J=7.7 Hz, 1H), 8.94 (d, J=8.2 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.09, 20.60, 42.21, 54.54, 57.91, 67.28, 108.62, 116.44, 122.84, 123.78, 124.66, 125.62, 126.70, 126.93, 127.12, 128.03, 128.18, 131.09, 131.49, 133.51, 137.34, 137.57, 140.30, 142.76, 194.75. MS m/z 481.6 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([OH:14])(=[O:13])[CH3:12].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:14][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COC(C)=O

Procedure:
71 ml of ethyl 4-chloro-3-oxobutyrate are reacted with 57 ml of acetic acid and 132 ml of triethylamine in 1 l of dimethylformamide by the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[N:11][C:12]([NH:15][NH2:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:17](OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[N:11]([C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][N:15]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(Nc2cccc(Cl)c2)nn1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)Cc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reaction time: 0.5 h

Procedure:
(Step 5-i) N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine (1 g, 4.25 mmol)) was taken up in ethanol (10 mL) and diethyl malonate (2 g, 12.76 mmol) was added. After microirradiation at 150° C. for 30 min, the reaction mixture was concentrated to dryness, taken up in ethyl acetate, and filtered to give the product, ethyl 2-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)acetate, as a solid (1.1 g, 3.3 mmol, 78% yield).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=4)[N:19]([CH3:28])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=4)[N:19]([CH3:28])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(C#N)ccc21
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
In a round-bottomed flask, 2-(5-cyano-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (80 mg, 0.16 mmol) was dissolved in dichloromethane (0.8 ml) and trifluoroacetic acid (0.5 ml, 6.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was suspended in dichloromethane (0.8 ml) and ethylenediamine (0.65 ml, 9.63 mmol) was added. The light yellow suspension was stirred at room temperature for 1 h then water and ethyl acetate were added. The suspension was filtered and washed with hot water and ethyl acetate. The product collected was dried under high vacuum to provide 43 mg (73%) of 2-(5-cyano-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow powder. MS: (M+Na)+=396; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.48 (br. s., 1H), 9.10 (s, 1H), 8.87 (s, 1H), 8.41 (s, 1H), 7.93-8.05 (m, 1H), 7.78-7.90 (m, 2H), 4.23 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCN(c3ccc([N+](=O)[O-])c(Nc4ccccc4)c3)CC2)cc1
Yield: 39 %

Procedure:
A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.5 g, 1.7 mmol), 4-methylbenzene-1-sulfonyl chloride (0.32 g, 1.7 mmol) and triethylamine (0.60 ml, 4.2 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. N-(2-nitro-5-(4-tosylpiperazin-1-yl)phenyl)benzenamine (0.30 g, 40%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.46 (s, 3H), 3.24 (t, J=4.5 Hz, 4H), 3.42 (t, J=4.5 Hz, 4H), 6.42 (d, J=9.6 Hz, 1H), 6.64 (s, 1H), 7.28-7.65 (m, 9H), 8.14 (d, J=9.5 Hz, 1H), 9.90 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 22.0, 45.5, 48.4, 48.5, 99.5, 99.6, 125.0, 106.8, 126.4, 128.2, 129.6, 130.3, 130.4, 132.7, 138.9, 144.8, 145.6.