Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1nccn1Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: ClCc1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A mixture of 10 gm (45 mmole) of N-benzyl-2-hydroxymethylimidazole and 11 gm (92 mmole) of thionyl chloride was stirred at room temperature for 30 minutes before it was heated to reflux for 30 minutes. The excess thionyl chloride was removed under reduced pressure. The resultant residue (10 gm crude) was crystallized from ethanol/ether to obtain 8.7 gm of N-benzyl-2-chloromethylimidazole, m.p. 180°-182° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.C(=O)=O.CC(C)=O.[Na].[Cl:31][C:32]1[N:33]=[CH:34][CH:35]=[C:36]2[C:40]([C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])=[CH:39][NH:38][C:37]=12.[H-].[Na+]>C1COCC1>[Cl:31][C:32]1[N:33]=[CH:34][CH:35]=[C:36]2[C:40]([C:41]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:6]=[CH:5]4)([OH:46])[C:42]([F:43])([F:44])[F:45])=[CH:39][NH:38][C:37]=12
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: O=C(c1c[nH]c2c(Cl)nccc12)C(F)(F)F
Agent: O=C=O
Agent: [H-]
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2c(Cl)nccc12)C(F)(F)F
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a chilled (−78° C.) solution of 490 mg (1.68 mmol) of 5-bromo-1-(4-fluorophenyl)-1H-indazole in 5 mL of anhydrous THF was added 0.69 mL (1.73 mmol) of a 2.5 M solution of n-BuLi in hexanes. The mixture stirred for 5 minutes, and was then added to a chilled (dry ice-acetone) solution of the sodium salt of 1-(7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2,2,2-trifluoroethanone prepared by adding at room temperature 83 mg (2.08 mmol) of 60% sodium hydride in mineral oil to 374 mg (1.50 mmol) of 1-(7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2,2,2-trifluoroethanone (prepared as described in J. Org. Chem. 2002, 76, 6226) in 5 mL of THF. The mixture stirred for 30 minutes with the cold bath removed and was then diluted with 30 mL of saturated aqueous ammonium chloride and extracted with three 25 mL portions of ethyl acetate. The combined organic layers were washed with three 25 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was chromatographed on silica gel using dichloromethane to load the sample and then eluting with dichloromethane-hexanes (50-100% gradient) and then ethyl acetate-dichloromethane (0-25%) to afford partially purified product. A second column eluting with ether-hexanes (5-50% gradient) followed by solidifying the material from the column from ether-hexanes gave 344 mg (49%) of the title compound. MS m/z 461.25 (MH+).
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]2[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:29])=[N:12][C:11]=1[C:36](OC)=[O:37])(=O)C1C=CC=CC=1.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>CN(C=O)C>[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][C:36]([C:11]2[N:12]=[C:13]([CH:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]3[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[O:29])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[OH:9])=[O:37])=[CH:43][CH:42]=1
Reactant: COC(=O)c1nc(C2CCc3ccccc3N2C(=O)c2ccccn2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cn1c(C2CCc3ccccc3N2C(=O)c2ccccn2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
The residue of Step 2 was dissolved in DMF and 4-fluorobenzylamine (3 eq.) was added. The reaction mixture was stirred at 90° C. for 1 h. The title compound was purified by preparative HPLC and isolated as its trifluoroacetic salt (C18, gradient of CH3CN/H2O+0.01% TFA).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:1][C:2]1[C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)CCc1ncc(O)c(C(=O)OC)c1C(=O)OC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCc1ncc(OCC(=O)OC)c(C(=O)OC)c1C(=O)OC
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a mixture of dimethyl 5-hydroxy-2-(3-methoxy-3-oxopropyl)pyridine-3,4-dicarboxylate (5.10 g, 17.2 mmol) and potassium carbonate (12.3 g, 69.0 mmol) in acetone (100 mL) was added methyl bromoacetate (3.26 mL, 34.4 mmol) at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (5.14 g, yield 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(OC(=O)C)C>C1(C)C=CC=CC=1.O.CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1NCCc2sc(Br)cc21
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1NCCc2sc(-c3ccc(F)cc3)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
(4-Fluoro-phenyl)-dihydroxy-borane (232 mg, 1.66 mmol) was added to a stirred suspension of 2-bromo-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-14d: 300 mg, 1.38 mmol) and Na2CO3 (211.8 mg, 2.0175 mmol) in toluene (20 mL) and water (3 mL) with continuous argon purging. This was followed by the addition of Pd(PPh3)4 (159 mg, 0.138 mmol) and the resulting mixture was stirred at 100° C. overnight. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was filtered; the filtrate was washed with water, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 300 mg of the product (88% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:45])[C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH3:28][N:29]([CH3:45])[C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN(C)c1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-dimethylamino-pyrimidine-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 244. NMR (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29 (6H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 7.31 (1H, br. s), 9.30 (2H, s). MS (ESI+): 519.3 (100%)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][OH:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[NH:13]1[C:14]2[C:10](=[C:9]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[O:23][CH2:24][CH2:25][OH:26])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: OCCOc1cccc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCOc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a mixture of 4-(4,4,5 ,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (5.49 g, 22.5 mmol) and 2-(3-bromo-phenoxy)-ethanol (4.9 g, 22.5 mmol) in THF (68 mL) was added Palladium catalyst Pd(PPh3)4 (473 mg, 0.03 eq.) and the freshly prepared sodium hydroxide solution (2.7 g in 31.5 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine (4×), and dried over Na2SO4 and concentrated. The residue was purified on a silica gel column to give 5.4 g (95%) of 2-[3-(1H-indol-4-yl)-phenoxy]-ethanol.
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:30])[CH:13]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[CH:7][CH2:6]1)[CH3:3].N1CC[CH2:33][CH2:32]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:30])[CH:13]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[NH:14][C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[O:16])=[CH:9][CH2:10]2)[CH2:1][CH2:33][CH2:32][CH2:3]1
Reactant: C1CCNC1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2cccs2)=CC1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=CCC(=NN2CCCC2)C=C1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.24 mmol) from Example 19, a pre-mixed pyrrolidine (0.11 mL, 1.32 mmol) and HOAc (0.11 mL, 1.92 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (24 mg). MS 482.1 and 484.1 (M+H, Cl pattern).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1>C1COCC1>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C@:13]12[CH2:2][C@H:20]1[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([I:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1
Reactant: O=C1Nc2ccc(F)cc2/C1=C/c1ccc2c(I)n[nH]c2c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 53.9 %

Procedure:
Trimethylsulfoxonium iodide (173.8 mg, 0.789 mmol) was added to a suspension of sodium hydride (94.76 mg, 4.12 mmol) (60% dispersion in oil) in THF (4.0 mL) at room temperature. The mixture was stirred for 15 min after which time a solution of (Z)-5-fluoro-3-((3-iodo-1H-indazol-6-yl)methylene)indolin-2-one (160 mg, 0.394 mmol) in THF (2.4 mL) was added. The solution was stirred at 50° C. for 7 h prior to quenching the reaction mass over 10% NH4Cl solution (15 mL) at room temperature. The product was extracted using ethyl acetate (15 mL×2) and the organic layer was dried over Na2SO4 and evaporated in vacuo. Trituration with hexane (5 mL) gave the title compound as a cream solid (89 mg, 53.7%). 1H NMR (400 MHz, d6-DMSO) δ 13.50 (s, 1H), 10.65 (s, 1H), 7.50 (s, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.85-6.81 (m, 2H), 5.81 (d, J=8.4 Hz, 1H), 3.22 (m, 1H), 2.43 (m, 1H), 2.01 (m, 1H); MS ESI 420.0 [M+H]+, calcd for [C17H11FIN3O+H]+ 420.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20](=[O:29])COC3C=CC=CC=3)[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10].[S:30](=[O:34])(=[O:33])([OH:32])[OH:31].[CH3:35][OH:36]>>[S:30]([OH:34])([OH:33])(=[O:32])=[O:31].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][N:15]([C:20]([O:36][CH2:35][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:29])[CH2:16][CH2:17][C:18]=2[N:19]=1)=[O:10]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)COc1ccccc1)CC2
Reactant: CO
Agent: O=S(=O)(O)O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-(2-aminophenyl)-5-(phenoxyacetyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]-pyridine-2-carboxamide obtained in example 172 in methanol cooled to 0° C. A solution of sulphuric acid in methanol (1:1) was added slowly and stirred at room temperature for 3 hrs. White precipitated solid was filtered out and dried to afford title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:6]2[CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[C:30]1(=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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].O>[C:15]1([O:14][CH2:13][CH2:12][CH2:11][N:6]2[C:7]3[C:3](=[C:2]([CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:30]4=[O:36])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[C:5]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)c1cc2c(Br)cccc2n1CCCOc1cccc2ccccc12
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
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(C3CCCCC3=O)cccc2n1CCCOc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 106B (438 mg) and cyclohexanone (196 mg) in dioxane (3 ml) was added tris(dibenzylideneacetone)dipalladium(0) (5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 7 mg) and Cs2CO3 (652 mg). The mixture was stirred at 80° C. under nitrogen overnight. After cooling, the reaction mixture was diluted with ethyl acetate and shaken with water. The product was extracted with ether (200 ml×3). The combined organic extracts were washed with water, brine, and dried over Na2SO4. After filtration, concentration of the mixture and flash column purification (3% ethyl acetate in hexane) provided EXAMPLE 106C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:32][CH2:33][CH3:34])[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[C:1]([N:27]1[CH2:26][CH2:25][CH:24]([O:23][C:19]2[CH:20]=[CH:21][C:22]3[C:13]4[N:12]([CH2:32][CH2:33][CH3:34])[C:11]([CH2:10][CH2:9][O:8][CH3:7])=[N:31][C:14]=4[C:15]([NH2:30])=[N:16][C:17]=3[CH:18]=2)[CH2:29][CH2:28]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)C(C)C)CC4)ccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutyryl chloride (0.273 mL, 2.61 mmol) was added dropwise to a stirred solution of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (prepared as described in Part A of Example 388, 1.00 g, 2.61 mmol) in chloroform at 0° C. After 2 hours, the solution was allowed to warm to ambient temperature for 1 hour. Saturated aqueous sodium carbonate (15 mL) and water (10 mL) were added and the mixture was allowed to stir for 16 hours. The mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile afforded 1.00 g of 7-[(1-isobutyrylpiperidin-4-yl)oxy]-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a flocculent white solid, mp 165-166° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([NH2:15])[CH2:11][CH2:10]1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.C([BH3-])#N.[Na+]>CO.O1CCOCC1>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([NH:15][CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: CN1CCN(N)CC1
Reactant: O=Cc1nccs1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(NCc2nccs2)CC1
Temperature: 0 °C
Yield: 236.2 %

Procedure:
Commercially available 1,3-thiazole-2-carbaldehyde (0.388 mL, 4.42 mmol) and commercially available 4-methyl-1-piperazinamine (0.532 mL, 4.42 mmol) were dissolved in MeOH (20 mL) and cooled to 0° C. Then methyl orange indicator and enough 4M HCl in dioxane was added to keep the reaction mixture acidic and a light pinkish color. Then sodium cyanoborohydride (0.555 g, 8.84 mmol) was added and the reaction was left to stir. The reaction mixture was evaporated to provide crude 4-methyl-N-(1,3-thiazol-2-ylmethyl)-1-piperazinamine as a beige-yellow solid (2.2168 g). LCMS: (M+H)+=213.0.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29].O>C(OCC)(=O)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH:29]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: CN(C)CCN
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 42 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and a solution of 2 parts by volume of N,N-dimethyl-ethylenediamine in 3 parts by volume of water with a yield of 42% of theory. Orange yellow crystals; m.p. 123°-125° C. (ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[N:17][C:16]([N:19]([CH3:30])[CH:20]4[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)=[CH:15][CH:14]=3)=[C:9]([O:31]C)[CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1.Cl>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[N:17][C:16]([N:19]([CH3:30])[CH:20]4[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]4)=[CH:15][CH:14]=3)=[C:9]([OH:31])[CH:8]=2)[N:3]=1
Reactant: COc1cc(-n2ccc(N)n2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Solvent: CN1CCCC1=O
Product: CN(c1ccc(-c2ccc(-n3ccc(N)n3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 190 °C
Yield: 72.7 %

Procedure:
A degassed mixture of 6-(4-(3-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (135 mg, 0.310 mmol), K2CO3 (42.8 mg, 0.310 mmol) and thiophenol (0.032 mL, 0.310 mmol) in NMP (2 mL) was heated at 190° C. under microwave radiation for 20 min. After addition of another 0.05 mmol of thiophenol and K2CO3, the mixture was heated at 190° C. under microwave radiation for another 10 min. The mixture was acidified to pH 2-3 with 1 M HCl aqueous solution, then loaded on a 5 g SCX column. The column was washed with MeOH and eluted with 2 N NH3 in MeOH. The collected fractions were concentrated and dissolved in a mixture of MeOH and DMSO, then purified by preparative HPLC to give 95 mg of 5-(3-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol as a dark yellow solid. LCMS Rt=0.47 min (LCMS method Q), MS (M+1)=422.3, HRMS: 422.2672 [M+H+].
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCOCC1.O.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]>[Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:34]5[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccncc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
A solution of the compound (232 mg, 0.5 mmol) obtained in Example 1-2), 4-pyridylboronic acid (61 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.05 mmol), tricyclohexylphosphine (17 mg, 0.12 mmol), and tripotassium phosphate (186 mg, 0.85 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 30:70, gradient) to obtain the title compound (174 mg, 69%) as a light yellow oily substance.