Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].N1C=CN=C1.[CH:26]([Si:29](Cl)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])([CH3:28])[CH3:27].O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(C)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10 g) and 1H-imidazole (3.79 g) in DMF (100 mL) was added triisopropylsilyl chloride (9.54 mL) at 0° C. The mixture was stirred at room temperature for 3 days, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/Hexane=1/10) to give the title compound (11.5 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].C(O[C:12]([C:14]1[CH:19]=[C:18]([NH2:20])[CH:17]=[C:16]([C:21]([O:23]CCCC)=O)[CH:15]=1)=[O:13])CCC>C(O)CCC>[NH2:20][C:18]1[CH:19]=[C:14]([C:12]([NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])=[O:13])[CH:15]=[C:16]([C:21]([NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])=[O:23])[CH:17]=1
Reactant: NC(CO)CO
Reactant: CCCCOC(=O)c1cc(N)cc(C(=O)OCCCC)c1
Solvent: CCCCO
Product: Nc1cc(C(=O)NC(CO)CO)cc(C(=O)NC(CO)CO)c1
Temperature: 70 °C
Yield: 96 %

Procedure:
A mixture of 2-amino-1,3-dihydroxypropane (31 g, 340 mmol) and 5-amino-1,3-benzenedicarboxylic acid di-n-butyl ester (20.0 g, 68.2 mmol) is heated to 125° C. for 3 hours while the n-butyl alcohol which forms is distilled off. After cooling the reaction mixture to about 70° C. the solution is diluted with methanol (0.35 L) and a solid product crystallizes out. After 4 hours at room temperature the mixture is filtered and the solid on filter is washed with methanol (30 mL) and dried yielding the compound of the title (21.4 g, 65.5 mmol, yield: 96%).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][S:12][C:13]1[CH2:14][C@@H:15]2[CH:32]([CH:33]([O:35][C:36](=[O:38])[CH3:37])[CH3:34])[C:31](=[O:39])[N:16]2[C:17]=1[C:18]([O:20]CC1C=CC([N+]([O-])=O)=CC=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:44]>O1CCOCC1.C(O)C.O.[Pd]>[CH2:1]([O:8][C:9]([CH2:11][S:12][C:13]1[CH2:14][C@@H:15]2[CH:32]([CH:33]([O:35][C:36](=[O:38])[CH3:37])[CH3:34])[C:31](=[O:39])[N:16]2[C:17]=1[C:18]([O-:20])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:44]
Reactant: CC(=O)OC(C)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC(=O)OCc3ccccc3)C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC(=O)OC(C)C1C(=O)N2C(C(=O)[O-])=C(SCC(=O)OCc3ccccc3)C[C@H]12

Procedure:
A solution of p-nitrobenzyl 2-benzyloxycarbonylmethylthio-6-(1-acetoxy)ethyl-carbapen-2-em-3-carboxylate (5.6 mg, 0.01 mmol) in dioxane (0.60 ml) is diluted with ethanol (0.05 ml) and water (0.35 ml) containing sodium bicarbonate (1.0 mg, 0.012 mmol). The solution is treated with 10% palladium on charcoal (5.5 mg) and hydrogenated at 40 psi for 30 minutes. The mixture is diluted with water (3 ml) and centrifuged to remove the catalyst which is washed with more water (2×1 ml). The combined aqueous supernatant is washed with ethyl acetate (4×2 ml), filtered through a cotton plug, concentrated in vacuo to ca. 1 ml, and lyophilized to yield the title compound as an amorphous solid: UV (0.1 M pH 7 phosphate buffer) 299 nm; NMR (D2O) δ1.30 (d, 3, J=6.7, CH3), 2.13 (s, 3, COCH3), 2.81 (dd, 1, J=9 and 18, H1a), 3.05 (dd, 1, J=10 and 18, H1b), 3.31 (dd, 1, J=3 and 5, H6), ~3.7(m, SCH2, obscured by impurities), 4.07 (m, 1, H5), 5.21 (m, 1, CHCH3), 5.27(s, 2, CH2 φ) and 7.48 (s, 5, C6H5); electrophoresis in 0.05 M pH 6.9 buffer at 2 KV for 20 minutes gives a single bioactive zone moving 3-5 cm toward the anode; HPLC on a C18Bondapak Reverse phase column using 10% THF/H2O at 1.0 ml/min gives a UV visible peak at retention time 17.4 mins (4.8 mins for thienamycin).
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:28].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[CH:13][C:14]([CH:21]=[O:28])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:25]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)=O
Reactant: C=Cc1cc(Cl)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-vinylbenzoate (0.12 g) in a mixed solvent of acetone (2.00 mL)-acetonitrile (2.00 mL)-water (2.00 mL) were added osmium oxide (fixed catalyst I) (0.04 g) and sodium periodate (0.36 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[NH2:11][C:12]1[C:13]([OH:29])=[C:14]([C:26](=[O:28])[CH3:27])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[C:26]([C:14]1[C:13]2[O:29][C:2](=[O:3])[NH:11][C:12]=2[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:28])[CH3:27]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)oc12
Temperature: 92.5 °C
Reaction time: 4 h

Procedure:
41 mL phenyl chloroformate are added dropwise to a solution of 47 g (183 mmol) 1-(3-amino-4-benzyloxy-2-hydroxy-phenyl)-ethanone (known from U.S. Pat. No. 4,460,581) in 135 mL pyridine, whereupon the temperature rises to 75° C. The mixture is stirred for 4 hours at 90-95° C., poured onto ice and acidified with hydrochloric acid. The precipitated solid is suction filtered, washed with diethyl ether and heated in 500 mL 95% acetonitrile for 30 minutes at reflux temperature. After cooling the solid is filtered off and washed with acetonitrile and diethyl ether.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[C:21]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[CH:20]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]>>[CH3:8][S:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[CH:20]=2)=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: Cc1ccccc1Nc1cc(-c2ccc(NS(C)(=O)=O)cc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1Nc1cc(-c2ccc(NS(C)(=O)=O)cc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 4-(4-(methanesulfonamido)phenyl)-2-(2-methylanilino)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, solid matter was filtrated to give 4-(4-(methanesulfonamido)phenyl)-2-(2-methylanilino)benzoic acid 52 mg of a yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[CH3:10]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])CCCCCBr
Reactant: CO
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a 2 liter round bottom flask, charge with 99.7 g (0.511 mol) of 6-bromohexanoate (Aldrich Chemical Co., Milwaukee, Wis.) and 1 liter of methanol, was bubbled hydrogen chloride gas for 1-2 minutes. The mixture was stirred at 20-30° C. for 18 h and then concentrated via rotary evaporation. The residue was diluted with 500 mL of diethyl ether and washed with 150 mL of de-ionized water, 200 mL of saturated sodium bicarbonate, and then once again with 200 mL of de-ionized water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated via rotary evaporation. The residue was distilled under vacuum to afford 99.6 g of the product (1) as a colorless oil (93%): b.p.=93-96° C. at 3 mm Hg: 1H NMR (d6-DMSO) d 3.57 (3H, 5), 3.51 (2H, t), 2.30 (2H, t), 1.78 (2H, pentet) and 1.62-1.28 (4H, m) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[C:2]([Cl:1])[C:11]1=2)[CH:30]=[CH2:29]
Reactant: CC1(C)OB(c2ccc3c(c2Cl)NCCO3)OC1(C)C
Reactant: C=CCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)c(Cl)c21
Temperature: 70 °C
Yield: 84.2 %

Procedure:
A solution of 5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.504 g, 1.426 mmol, Ref. WO20100130034) and K2CO3 (0.504 g, 3.65 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, then treated with allyl bromide (0.8 mL, 9.17 mmol). The reaction tube was sealed and then heated (70° C.) for 22 h, then cooled and diluted with water (50 mL) and extracted into EtOAc (50 mL). The organic layer was washed with water, brine, then dried (Na2SO4), filtered, concentrated, and purified by biotage chromatography (4 g SiO2, 0% (3 CV), 0-40% (15 CV), 40% (2 CV); EtOAc in hexanes) to afford the desired product (0.403 g, 1.201 mmol, 84% yield) as a clear viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 6.15-6.02 (m, 1H), 5.31 (dd, J=17.2, 1.4 Hz, 1H), 5.28-5.21 (m, 1H), 4.18-4.13 (m, 2H), 3.59 (d, J=6.0 Hz, 2H), 3.14-3.07 (m, 2H), 1.36 (s, 12H). LCMS (M+H)=336.9.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH3:8])[N:4]([CH3:9])[N:3]=1.[CH:10]([O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])=[O:15])([CH3:12])[CH3:11].ClCCCC>C(Cl)Cl>[CH3:9][N:4]1[C:5]([S:7][CH3:8])=[N:6][C:2]([NH:1][C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:14]([O:13][CH:10]([CH3:12])[CH3:11])=[O:15])(=[O:24])=[O:23])=[O:27])=[N:3]1
Reactant: CSc1nc(N)nn1C
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Solvent: CCCCCl
Product: CSc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)nn1C

Procedure:
A mixture of 0.7 grams (0.00486 mole) of 3-amino-1-methyl-5-methylthio-1H-1,2,4-triazole and 4.0 grams of 2-(isopropoxycarbonyl)benzenesulfonylisocyanate was stirred in 12 ml of dry methylene chloride at ambient temperature overnight. After addition of 4 ml of 1-chlorobutane, a white solid precipitated which was filtered, washed with 1-chlorobutane and dried, yield 1.3 grams, m.p. 192°-194°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13])[CH:2]=[CH2:3].[CH3:14][C:15]([CH3:17])=O.C(=O)([O-])[O-].[K+].[K+].ICC=C>C(OCC)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[O:13][CH2:17][CH:15]=[CH2:14])[CH:2]=[CH2:3]
Reactant: CC(C)=O
Reactant: C=CCc1cccc([N+](=O)[O-])c1O
Agent: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C=CCOc1c(CC=C)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred solution of 2-allyl-6-nitrophenol (100 mg, 0.0006 mol) in acetone (4 mL, 0.06 mol) at 0° C. in an ice bath was added potassium carbonate (0.092 g, 0.00067 mol) followed by 3-iodo-1-propene (0.11 g, 0.00067 mol) under an atmosphere of nitrogen. The reaction mixture was stirred for 1 h at 0° C. then warmed to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 10% HCl, water, dried over magnesium sulfate and concentrated in vacuo. The reaction mixture was purified by ISCO chromatography on silica gel (12 g) using ethyl acetate-hexane (10%-50%) to give 1-allyl-2-allyloxy-3-nitrobenzene as a yellow oil (93 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, 1H, J=8.0 Hz), 7.44 (d, 1H, J=7.8 Hz), 7.16 (t, 1H, J=8.08, 7.8 Hz), 5.90-6.13 (m, 2H), 5.40 (d, 1H, J=17 Hz), 5.29 (d, 1H, J=10 Hz), 5.15 (d, 1H, J=10 Hz), 5.09 (d, 1H, J=17 Hz), 4.50 (d, 2H, J=5.8 Hz), 3.49 (d, 2H, J=6.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]2.[CH2:16]([NH:23][C:24]1[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH2:16]([NH:23][C:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:29]=1[CH2:30][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCCCN1Cc2cc(N)ccc2C1=O
Reactant: O=Cc1cnccc1NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCN1Cc2cc(NCc3cnccc3NCc3ccccc3)ccc2C1=O
Reaction time: 48 h
Yield: 16.9 %

Procedure:
5-Amino-2-butylisoindolin-1-one (48.1 mg, 0.236 mmol) was added to a solution of 4-(benzylamino)nicotinaldehyde (50 mg, 0.236 mmol) in acetic acid (0.5 mL). Sodium triacetoxyborohydride (100 mg, 0.471 mmol) was added and the reaction mixture was stirred for 2 days. After the addition of more triacetoxyborohydride (50 mg, 0.235 mmol) and stirring for 6 h, water and sat aqueous NaHCO3 solution were added. The mixture was extracted with EtOAc, the combined org. layers washed with water and dried (MgSO4). Purification by HPLC provided 5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one (16 mg, 13%). ESI-MS [M+H+]=401.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([Cl:15])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2cccc(Cl)c2)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1 g, 3.9 mmol), 3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL) was stirred at room temperature. The reaction was quenched with NaHCO3 (sat aq solution, 30 mL×3). The organic phase was separated, dried (MgSO4), and filtered. The volatiles were evaporated and the residue was purified by column chromatography (SiO2, pentane:EtOAc, 4:1) to give 4-chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide; MS (posESI) m/z=349.2 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li:31])(C)(C)C>O1CCCC1.CCCCC>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[CH:12]=[C:11]2[Li:31])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Reactant: [Li]C(C)(C)C
Agent: CN(C)CCN(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1

Procedure:
A solution of 0.645 g (2.5 mmols) of 1-benzenesulphonyl-1H-pyrrolo[3,2-c]pyridine and 0.755 ml (5 mmols) of tetramethylethylenediamine in 5 ml of tetrahydrofuran was cooled to -70° C. and 5 mmols of tert-butyl lithium in pentane were added, care being taken that the temperature did not exceed -60° C. The reaction medium was then stirred to obtain a solution of 1-benzenesulphonyl-2-lithio-1H-pyrrolo[3,2-c]pyridine which was used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:34]=[CH:33][C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH:28]2[CH2:32][CH2:31][N:30]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:15])[CH2:29]2)=[CH:33][CH:34]=1
Reactant: Clc1ccc(CC2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(Cc2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.3 mg). Calcd for C21H18C12 N2O2: 400.0745, found 400.0750.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].ClC(Cl)C.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[N:4]1[CH:16]=[CH:20][CH:19]=[CH:18]1
Reactant: Nc1c(Br)cccc1Br
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Brc1cccc(Br)c1-n1cccc1

Procedure:
To a 200 mL round bottom flask was added 2,6-dibromoaniline (8.63 g, 34.7 mmol, 1.0 equiv.), dichloroethane (35.0 mL, 1.0 M), acetic acid (35.0 mL, 1.0 M), and 2,5-dimethoxytetrahydrofuran (10.5 mL, 3.3 M). A reflux condenser was fitted to the flask and the mixture was heated to reflux for 2 hours. During this time the solution slowly changes colors from clear to yellow. An aliquot was removed and the reaction was judged complete by NMR. The mixture was diluted with CH2Cl2, rinsed with H2O, and then rinsed with saturated aqueous K2CO3. The organic layer was dried over MgSO4 and filtered through a pad of SiO2 with CH2Cl2 as eluent. The oil was place under high vacuum overnight to remove the excess 2,5-dimethoxytetrahydrofuran. During this time 1-(2,6-dibromophenyl)-1H-pyrrole, 2, changes to a white solid (8.72 g, 29.1 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ7.68 (d, J=8.0 Hz, 2H), 7.18 (t, J=8.4 Hz, 2H), 6.72 (t, J=2.0 Hz, 2H), 6.42 (t, J=2.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5](OCC)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[CH2:5][OH:6]
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C)c1CO
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of ethyl 2-methoxy-6-methylbenzoate (1.23 g, 6.33 mmol) in dry diethyl ether (58 mL) was added LiAlH4 (0.467 g, 12.31 mmol) and the resultant mixture was heated to reflux for 2 hours then cooled to room temperature. The mixture was treated sequentially with water (0.45 mL), 15% aqueous NaOH (0.45 mL) and water (1.35 mL). The mixture was filtered through Celite© and the cake was washed with ether (200 mL). The filtrate was concentrated under reduced pressure and provided 0.96 g (99%) of 2-methoxy-6-methylbenzyl alcohol as a yellow solid. 1H NMR (CDCl3) δ 2.27 (t, 1H, J=6.3 Hz), 2.39 (s, 3H), 3.86 (s, 3H), 4.75 (d, 2H, J=6.3 Hz), 6.76 (d, 1H, J=8.4 Hz), 6.81 (d, 1H, J=7.8 Hz), 7.17 (dd, 1H, J=7.8, 8.4 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1>>[CH3:26][N:23]1[C:24]2[CH:25]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][C:11]3=[O:15])[CH:18]=[CH:19][C:20]=2[C:21]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]1=2
Reactant: O=c1cc(OCc2ccccn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 43 %

Procedure:
4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (110 mg, 0.54 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (113 mg, 43%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.63 (ddd, J=4.9, 1.6, 0.9 Hz, 1H), 7.75 (overlapping ddd, J=7.6, 1.8 Hz, 1H), 7.49 (t, J=7.3 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.29 (d, J=1.4 Hz, 1H), 7.26 (m overlapping with solvent, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.64 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 3.62 (s, 3H), 2.82 (t, J=5.4 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)CC2C=CC(OC)=CC=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1.CN1C(=O)CCC1.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[CH:31]1([NH:21][C:4]2[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:41][CH:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[CH:3]=2)[CH2:32][CH2:33]1
Reactant: CN1CCC(N)CC1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CN1CCC(Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
A microwave tube was charged with 6-chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (35 mg, 0.075 mmol), 1-methylpiperidin-4-amine (86 mg, 0.750 mmol) and NMP (1 mL). The reaction mixture was irradiated in a microwave (300 W) for 20 minutes at 100° C. The crude reaction mixture was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=30.463 minutes) was isolated and lyophilized to dryness. The crude material was dissolved in CH2Cl2 (2 mL) and treated with TFA (0.5 mL) and stirred at room temperature for 2 hours, then concentrated to dryness. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=24.643 minutes) was isolated and lyophilized to dryness to afford 8-(cyclopropylamino)-N-(3-fluoropyridin-4-yl)-6-(1-methylpiperidin-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (8.5 mg, 14.42%). HPLC Rt=2.681 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=425.0.