Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][C:4]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:2].[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[C:19]([O:18][C:17]([N:16]([C:4]1[N:5]=[C:6]2[C:11]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:9]=[CH:8][N:7]2[C:3]=1[CH2:1][CH3:2])[S:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:34])=[O:33])=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1c(NC(=O)OC(C)(C)C)nc2c(C(F)(F)F)cccn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(N(C(=O)OC(C)(C)C)S(=O)(=O)c2ccccc2)nc2c(C(F)(F)F)cccn12
Reaction time: 0.17 h

Procedure:
To a solution of compound 13-C (0.450 g, 1.37 mmol) in DMF (7.5 mL) at room temperature was added 95% NaH (0.086 g, 3.42 mmol) and the reaction mixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.362 g, 2.05 mmol) dissolved in DMF (2.5 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of H2O and the solution was extracted with ethyl acetate. After separation of the organic and aqueous layers a sufficient amount of water was added to remove any dissolved DMF from the organic layer. The organic layer was dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give compound 13-D (0.552 g, 86%); MS m/z (M+H+) 470.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>CN(C=O)C.CCOCC>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=2)=[CH:27][CH:28]=1
Reactant: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of (4-bromobenzyl)triphenylphosphonium bromide (396 g; 0.77 mol) in 2.5 L of DMF at 0° C., was added 37 g (0.92 mol) of NaH (60% in oil) in four portions. The solution was stirred 1 hr at 0° C. followed by the addition of 109 g (0.77 mol) of 4-chlorobenzaldehyde in two portions. This mixture was warmed up to room temperature, stirred 1 hr and quench by pouring the reaction into a 5° C. mixture of 10 L of water and 2.5 L of Et2O. Aqueous layer was extracted with Et2O, combined organic layers were washed with brine and dried over Na2SO4. Volatiles were removed under reduced pressure and the residue was dissolved in 1.5 L of cyclohexane and filtered through a pad of silica gel (wash with cyclohexane). 16 g of one isomer cristallized out of the solution as a white solid and after evaporation of the volatiles, 166 g of the other isomer 1-bromo-4-[2-(4-chlorophenyl)vinyl]benzene was isolated.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8](=[CH2:12])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[CH2:12])[CH2:9][CH2:10][OH:11])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: C=C(CCO)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: C=C(CCO)c1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 100 °C

Procedure:
A toluene solution (5 mL) containing the intermediate from Step A (441 mg, 2.4 mmol), 4-(trifluoromethoxy)phenyl boronic acid (746 mg, 3.62 mmol), K3PO4 (865 mg, 4.08 mmol), 2-(dicyclohexylphosphino)biphenyl (68 mg, 0.19 mmol) and Pd(OAc)2 (22 mg, 0.098 mmol) was heated at 100° C. under an argon atmosphere. After 1 hour the solution was partitioned between water and ethyl acetate. The organic phase washed with 1N NaOH, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. LCMS1 3.71 min. (M+H)=309.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([O:19][CH:20]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:18])[C:12]([NH2:15])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:15][C:12]2[C:11]([NH:16][C:17]([O:19][CH:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[O:18])=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:14][CH:13]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Yield: 72.2 %

Procedure:
Using a similar procedure to that described in Example 48, Part C, N4-(tert-butoxycarbonyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl]-1,2,4-benzenetriamine (380 mg, 0.86 mmol) and 4-chlorobenzoyl chloride (0.12 mL, 0.95 mmol) yielded 360 mg (72%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>CCOCC>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:21](=[O:22])[C:20]1[CH:19]=[C:18]([O:17][CH3:16])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=1)#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1cc(C(=O)Nc2ccccc2C#N)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 2-aminobenzonitrile (20 g, 169.30 mmol, 1.00 equiv), ether (500 mL) and potassium carbonate (75 g, 542.65 mmol, 3.21 equiv). This was followed by the addition of 3,4,5-trimethoxybenzoyl chloride (40 g, 173.43 mmol, 1.02 equiv) in several batches at reflux. The mixture was stirred overnight at reflux. The resulting solution was cooled to room temperature. The reaction was then quenched by the addition of 500 mL of water. The solids were collected by filtration. This resulted in 22 g (42%) of N-(2-cyanophenyl)-3,4,5-trimethoxybenzamide as a yellow solid. MS (ESI) m/z 313 ([M+H]+).
Reaction SMILES: OP(OP(O)(O)=O)(=O)O.C([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:33][CH2:32][C@@H:31]([NH:34][C:35]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:36]=3[CH:37]=[CH:38][N:39]=[CH:40]4)[CH2:30]2)[CH:23]=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>O1CCCC1>[CH:40]1[C:41]2[C:36](=[C:35]([NH:34][C@@H:31]3[CH2:32][CH2:33][N:29]([CH2:28][C:24]4[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=4)[O:21][CH2:20][CH2:19][OH:18])[CH2:30]3)[CH:44]=[CH:43][CH:42]=2)[CH:37]=[CH:38][N:39]=1
Reactant: O=C(OCCOc1cccc(CN2CC[C@@H](Nc3cccc4cnccc34)C2)c1)c1ccccc1
Agent: O=P(O)(O)OP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCOc1cccc(CN2CC[C@@H](Nc3cccc4cnccc34)C2)c1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a 500 mL flask equipped with an internal temperature probe and a mechanical stirrer were added 50 g of (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethyl benzoate diphosphate (from Example 8), 72 mL of tetrahydrofuran and 90 mL of 2 N sodium hydroxide. The resulting mixture was warmed to 38-42° C. and held for 24 hours. Upon disappearance of starting material the tetrahydrofuran was removed by rotary evaporation. The resulting mixture was extracted with 200 ml of isopropyl acetate and washed with water (2×135 mL). The organic layer was concentrated and the residue was azeotropically dried by repeated rotary evaporation with isopropyl acetate. Crude product of (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol was isolated as a foamy solid (6.5 g, 99% yield). Crude (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol (2.0 g, 5.5 mmol) was combined with 55 mL of a 0.1 M solution of 2,5-dihydroxybenzoic acid in ethanol. The mixture was gently heated to ˜50° C. with stirring to give a solution. The solution was cooled to ˜22° C. and the slurry was stirred for 2 hours and the solid was isolated by filtration. Approximately 2.15 g of the (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethanol 2,5-dihydroxybenzoic acid salt was obtained as a solid (80% yield).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[F:15][C:16]([F:23])([F:22])[CH2:17][CH2:18][C:19](O)=[O:20]>CN(C)C1C=CN=CC=1.CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:19](=[O:20])[CH2:18][CH2:17][C:16]([F:23])([F:22])[F:15]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: O=C(O)CCC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CCC(F)(F)F)NC1C(=O)Nc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (5.60 g, 29.3 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimde hydrochloride (6.75 g, 35.2 mmol) and 4(dimethylamino)pyridine (0.183 g, 1.5 mmol) in 100 mL DMF, add 4,4,4-trifluoro butyric acid dropwise at 0-5° C. After addition, stir the reaction mixture at ice-water. After half an hour, warm to RT. After stirring overnight, remove solvent DMF under reduce pressure and suspend the residue in 200 mL of mixed solvent (CHCl3: i-PrOH=3:1). Collect the solid via vacuum filtration to give the title compound (6.87 g, yield 74%): mass spectrum (APCI) (m/e): 316.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 2H), 8.60 (d, 1H, J=7.2 Hz), 7.24-7.15 (m, 4H), 4.74 (d, 1H, J=7.2 Hz), 2.58 (t, 2H, J=7.2 Hz), 2.39-2.35 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.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]>[Cl:19][C:5]1[C:6]2[C:7](=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=2)[C:2]([NH:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Nc1cc(CO)ncn1
Reactant: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Cl)c2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: OCc1cc(Nc2ncc(Cl)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 25.5 %

Procedure:
A suspension of 4-bromo-7-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine (200 mg, 0.53 mmol), (6-amino-pyrimidin-4-yl)-methanol (73 mg, 0.58 mmol), Pd2(dba)3 (24 mg, 0.025 mmol), Xantphos (31 mg, 0.05 mmol) and cesium carbonate (347 mg, 1.1 mmol) in dioxane (3 mL) was sealed in a microwave vial, purged with nitrogen, and irradiated in a microwave reactor at 150° C. for 30 min. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH2 silica gel flash chromatography (0-2% methanol in ethyl acetate), to afford the title compound as a pale yellow solid (57 mg, 34% yield). 1H (400 MHz, DMSO-d6+d-TFA): δ 9.36 (s, 1H), 9.04 (s, 1H), 8.27 (bs, 1H), 8.16 (s, 1H), 7.80 (d, J=1.2 Hz, 1H), 7.78 (s, 1H), 7.70 (dd, J=9.0, 7.3 Hz, 1H), 4.67 (s, 2H). LCMS (Method B): RT=3.19 min, m/z: 421 [M+H+].
Reaction SMILES: C([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:11]([F:25])[CH2:10]1)C1C=CC=CC=1.CCCCCC>[Pd].C(OCC)(=O)C>[F:25][CH:11]1[CH:12]([O:15][CH2:16][CH2:17][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10]1
Reactant: O=C(COC1CCC(OCc2ccccc2)CC1F)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OC1CCC(OCCc2ccccc2)C(F)C1
Yield: 92.2 %

Procedure:
To an ethyl acetate (100 mL) solution of (−) 2-{[4-(Benzyloxy)-2-fluorocyclohexyl]oxy}-1-phenylethanone (1.44 g, 4.18 mmol) was added 10% palladium on carbon (0.200 g). The resulting mixture was hydrogenated using a balloon. After 20 h the contents of the reaction flask were filtered through celite® and the filtrate evaporated under reduced pressure. Flash column chromatography (hexane:ethyl acetate, 60:40) gave 3-Fluoro-4-(2-phenylethoxy)cyclohexanol as a colorless oil (0.918 g, 92% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH:21]([O:20][C:11]1[CH:12]=[CH:13][C:14]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:15][C:10]=1[C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:7][CH2:6]1)=[O:9])([CH3:23])[CH3:22]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of 0.29 mmol (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone in 6 ml dichloromethane at 0° C. were added successively 0.73 mmol triethylamine and 0.35 mmol methanesulfonyl chloride. The reaction mixture was stirred at 0° C. for 20 min and then at RT for 2 h. The reaction mixture was then diluted with dichloromethane, washed with water, and the organic phase dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light brown solid (yield 93%). MS (m/e): 420.1 (M+H+, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[C:19](=[S:22])([O-:21])[CH3:20].[K+]>CC(C)=O.[I-].[K+]>[C:19]([S:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8])(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(-c2nc(CSC(C)=O)c(C)o2)cc1
Yield: 91.4 %

Procedure:
A solution of methyl 4-[4-(chloromethyl)-5-methyl-1,3-oxazol-2-yl]benzoate (10 g, 37.64 mmol, 1.00 equiv), potassium ethanethioate (5 g, 43.78 mmol, 1.16 equiv) and potassium iodide (300 mg, 1.81 mmol, 0.05 equiv) in acetone (160 mL) was stirred at 35° C. under nitrogen for 30 min. The product was precipitated by the addition of 250 mL water. The precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 10.5 g (91%) of methyl 4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30]C)=[O:29])[CH2:23]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]3)[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: COC(=O)C1CCCNC1
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Product: COc1ccc(Nc2cc(N3CCCC(C(=O)O)C3)nn3ccnc23)nc1OC
Temperature: 160 °C
Yield: 15.4 %

Procedure:
A suspension of 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (200 mg, 0.65 mmol) and methyl piperidine-3-carboxylate (400 mg, 2.8 mmol) was heated at 160° C. for 2 h under N2. After cooling to room temperature, the residue was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylic acid (40 mg, 15%) as a red solid. LC-MS: 399 [M+1]+, tR=1.261 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c2c1C
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:4]1[CH:3]=[C:2]([C:24]2[CH:23]=[N:22][C:31]3[C:26]([CH:25]=2)=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1ccc2ccccc2n1
Product: O=C(c1ccc(-c2cnc3ccccc3c2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-Quinoline boronic acid. MS (M+H) 404.2
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH:20]=[C:13]3[C:14](Cl)=[N:15][CH:16]=[C:17]([F:18])[C:12]3=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:21][Si](C)(C)C>C(#N)CC>[Br:21][C:14]1[C:13]2=[CH:20][N:10]([C:3]3[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:4]=3[C:5]#[N:6])[N:11]=[C:12]2[C:17]([F:18])=[CH:16][N:15]=1
Reactant: C[Si](C)(C)Br
Reactant: N#Cc1cccc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Solvent: CCC#N
Product: N#Cc1cccc(Cl)c1-n1cc2c(Br)ncc(F)c2n1
Temperature: 110 °C
Yield: 96.1 %

Procedure:
3-Chloro-2-(4-chloro-7-fluoropyrazolo[4,3-c]pyridin-2-yl)-benzonitrile (890 mg, 2.9 mmol) was suspended in propionitrile (30 mL), under an atmosphere of nitrogen and bromotrimethylsilane (2.0 mL, 15 mmol) was added. The reaction mixture was heated at 110° C. for 3.5 hours. The resultant mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether to afford the title compound as a yellow solid (980 mg, 96% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (d, J=2.5 Hz, 1H), 8.25-8.21 (m, 3H), 7.94 (t, J=8.1 Hz, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:11])=[C:5]([NH2:10])[C:6]([NH2:9])=[N:7][CH:8]=1.[CH:12](O)=O.[OH-].[Na+]>P(=O)(O)(O)O>[Cl:2][C:3]1[C:4]([CH3:11])=[C:5]2[N:10]=[CH:12][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: Cc1c(Cl)cnc(N)c1N
Reactant: O=CO
Agent: Cl
Agent: O=P(O)(O)O
Agent: [Na+]
Product: Cc1c(Cl)cnc2[nH]cnc12
Temperature: 130 °C

Procedure:
The material from Step 2 (1 g) was dissolved in phosphoric acid (20 ml), then added to formic acid (10 ml) and heated (130° C.) for 1 h, and then cooled to RT for 3 d. The reaction mixture was then poured into ice (200 g) and the pH adjusted with 30% (w/v) aq. NaOH until solids formed. The solids were removed via filtration and rinsed with water. The filtrate (aqueous) was concentrated to dryness and extracted with hot EtOH repeatedly. The EtOH extracts were combined and concentrated to solids (3 g). The solids were extracted with hot MeCN (4×80 ml); the combined MeCN extracts were cooled to RT and solids precipitated. The precipitates were filtered (Celite) and the filtrate was concentrated to yield 6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine (0.278 g). MS (ESI+) for m/z 168 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[N:12]=[C:13]([C:16]([N:22]2[CH2:23][CH2:24][NH:19][C:20](=[O:25])[CH2:21]2)=[O:17])[S:14][CH:15]=1
Reactant: O=C1CNCCN1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCNC(=O)C3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (160 mg; 0.53 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). Piperazin-2-one (Aldrich) (63.7 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (41) as a yellow powder (47.7 mg; 25%). 1H NMR (DMSO-d6, 300 MHz) δ 2.14 (s, 3H), 2.48 (s, 3H), 3.25-3.40 (m, 2H), 3.82 (m, 1H), 4.15 (m, 1H), 4.45 (m, 1H), 4.86 (m, 1H), 8.03 (s, 1H), 8.19 (br s, 1H), 12.17 (s, 1H). M− (ESI): 364.05; M+ (ESI): 365.97. HPLC (method A), Rt: 2.14 min (purity: 99.5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:15][CH2:14]1.[CH3:27][O-:28].[Na+]>CO>[CH3:27][O:28][C:2]1[CH:7]=[N:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[NH:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:15][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCNc2c(Cl)cnn(C)c2=O)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1N1CCN(CCNc2c(OC)cnn(C)c2=O)CC1

Procedure:
4.2 g (0.011 mol) of 5-chloro-2-methyl-4-((2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)amino)-3(2H)-pyridazinone are heated in methanol, in which 0.010 mol of sodium methylate is dissolved, under reflux for 50 hours and then concentrated in vacuo. The residue is taken up in water, when 1.6 g of 5-methoxy-2-methyl-4-((2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)amino)-3(2H)-pyridazinone (38.9% of theory) precipitate out. The solid is filtered off with suction, dried, dissolved in acetone and converted by addition of fumaric acid at the reflux temperature into 1.50 g (24.5% of theory) of fumarate, m.p. 144°-148° C.; C 54.0%, H 6.1%, N 12.5%, O 27.4%, UV in 0.1N H
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([O:21][NH2:22])[CH3:20]>>[CH2:19]([O:21][NH:22][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:2]=[CH:7][C:6]([I:8])=[CH:5][CH:4]=1)[CH3:20]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Reactant: CCON
Product: CCONC(=O)c1ccncc1Nc1ccc(I)cc1

Procedure:
N-ethoxy-3-(4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.40 mmol of O-ethyl-hydroxylamine LC/MS [9.14 min; 418 (M+1)]