Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:16][C:17]#[N:18])=[CH:8][N:9]2[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:5][C:4]=1[F:19].[CH2:20](N)[CH2:21][NH2:22]>C(O)C>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:16][C:17]3[NH:22][CH2:21][CH2:20][N:18]=3)=[CH:8][N:9]2[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:5][C:4]=1[F:19]
Reactant: CS(=O)(=O)n1cc(CC#N)c2cc(F)c(Br)cc21
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)n1cc(CC2=NCCN2)c2cc(F)c(Br)cc21
Reaction time: 72 h

Procedure:
Hydrogen chloride gas was bubbled through a cold (0° C.) suspension of (6-Bromo-5-fluoro-1-methanesulfonyl-1H-indol-3-yl)-acetonitrile (0.215 g, 0.65 mmol) in anhydrous ethanol (20 ml) for 15 minutes. The reaction mixture was refrigerated for 72 hours and the solvent was removed under reduced pressure. The solid residue was re-dissolved in anhydrous methanol (10 ml), and ethylene diamine (0.05 ml, 0.77 mmol) was added. The reaction mixture was heated to reflux for 24 hours and the solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography over silica gel eluting with 7% methanol in dichloromethane with 0.1% concentrated ammonium hydroxide to give 6-Bromo-3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-5-fluoro-1-methanesulfonyl-1H-indole, which was recrystallized from methanol and ether (0.133 g, 55%). 1H NMR (DMSO) d: 3.56 (s, 3H), 3.82(s, 4H), 4.07 (s, 2H), 7.84 (s, 1H), 7.90 (d, 1H, J=9.1 Hz), 8.10 (d, 1H, J=5.8 Hz), 10.23 (bs, 1H). M+H: 374.
Reaction SMILES: [C:1]([NH:8][C:9]([N:18]1C=CC=N1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:24][O:25]N.CO.C(N(CC)CC)C>C1COCC1>[CH3:24][O:25][NH:18][C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[N:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CONC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of N,N′-di-Boc-1H-pyrazole-1-carboxamidine (450 mg, 1.45 mmol) and methoxyamine hydrochloride (151 mg, 1.81 mmol) in THF (3 mL) aid methanol (3 mL) was slowly added triethylamine (183 mg, 1.81 mmol). After stirring at room temperature for 64 hours, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The salts were removed by filtration. The filtrate was concentrated under reduced pressure and triturated with ether to provide the crude product that was used without further purification.
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].N1C=CC=CC=1.[CH:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([C:35]([N:37]2[CH2:42][CH2:41][C:40]4([CH2:51][C:50](=[O:52])[C:49]5[C:44](=[CH:45][CH:46]=[C:47]([C:53]6[CH:54]=[N:55][N:56]([CH3:58])[CH:57]=6)[CH:48]=5)[O:43]4)[CH2:39][CH2:38]2)=[O:36])[CH:31]=[C:30]3O)[CH2:24][CH2:23]1>C(Cl)(Cl)Cl.O>[F:6][C:5]([F:8])([F:7])[S:2]([O:1][C:30]1[C:29]2[C:34](=[C:25]([CH:22]3[CH2:24][CH2:23]3)[CH:26]=[CH:27][CH:28]=2)[N:33]=[C:32]([C:35]([N:37]2[CH2:38][CH2:39][C:40]3([CH2:51][C:50](=[O:52])[C:49]4[C:44](=[CH:45][CH:46]=[C:47]([C:53]5[CH:54]=[N:55][N:56]([CH3:58])[CH:57]=5)[CH:48]=4)[O:43]3)[CH2:41][CH2:42]2)=[O:36])[CH:31]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(O)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OS(=O)(=O)C(F)(F)F)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tf2O (0.224 ml, 1.327 mmol) was added to a stirred solution of pyridine (0.358 ml, 4.42 mmol) and 1′-[(8-cyclopropyl-4-hydroxyquinolin-2-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one (450 mg, 0.885 mmol) in CHCl3 (4.5 ml) at −50° C. and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with CHCl3 and H2O, the organic layer was washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by silicagel column chromatography (hexane/EtOAc) to give intended compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)(Cl)Cl>[C:33]([NH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3])(=[O:35])[CH3:34]
Reactant: CC(C)(N)c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(F)cc3)ncc2C#N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of the compound of Example 20 (100 mg 0.29 mmol) in CHCl3 (8 mL) was added pyridine (0.1 mL) and acetic anhydride (0.1 mL). The reaction was stirred at ambient temperature for 6 h. The reaction was then washed with 2M HCl and saturated NaHCO3, dried (MgSO4), and concentrated under reduced pressure to give the title compound (103 mg) as a yellow solid, m.p. 212-216°. δH 8.69 (1H, s), 8.06 (2H, d, J 8.4 Hz), 7.63-7.60 (2H, m), 7.56 (2H, d, J 8.4 Hz), 7.12-7.08 (2H, m), 5.82 (1H, s), 2.03 (3H, s) and 1.74 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:24]1[N:25]=[CH:26][N:27](S(C2C=CC(C)=CC=2)(=O)=O)[CH:28]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1c[nH]cn1

Procedure:
4.2 g (7.61 mmol) of diethyl 2-(4-tert-butoxycarbonylaminobutyl)-2-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]malonate were dissolved in 190 ml of methanol and stirred with 4.66 g (30.45 mmol) of 1-hydroxybenzotriazole hydrate at RT for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel (CH2Cl2:MeOH 9:1). The product-containing fractions were concentrated and the oil obtained was dissolved in ethyl acetate and washed with saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated. This gave 2.14 g (71%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10](I)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[F:16][C:17](I)([F:19])[F:18]>[Cu].N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([C:17]([F:19])([F:18])[F:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c(I)cccc12
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c(C(F)(F)F)cccc12
Temperature: 130 °C
Yield: 60.4 %

Procedure:
A mixture of 5-iodo-1-naphthalenecarboxylic acid methyl ester [8.8 g, 28 mmoles, described by C. Seer and R. School, Justus Leibigs Ann. Chem., 398, 82 (1913)], trifluoromethyl iodide (12 g, 61.2 mmoles), freshly prepared copper powder (5.7 g, prepared according to the procedure of R. Q. Brewster and T. Groening, "Organic Syntheses", Coll. Vol. II, John Wiley and Sons, New York, N.Y., U.S.A., 1948, p. 445) and pyridine (45 ml) was charged into a stainless steel autoclave. The vessel was shaken and heated at 130° C. for 24 hr and cooled to room temperature. The mixture was filtered to remove insoluble material. The filtrate was washed with 1N aqueous HCl, water and brine, dried (MgSO4) and concentrated to dryness. The residue was crystallized from methanol to give 4.3 g of 5-(trifluoromethyl)-1-naphthalenecarboxylic acid methyl ester, NMR (CDCl3) δ 4.0 (s, 3H), 8.0 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([OH:43])[CH:40]=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:42]=[N:41][CH:40]=[C:39]([OH:43])[CH:38]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cncc(O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)c1-c1cncc(O)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (183 mg, 0.31 mmol) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-ol (102 mg, 0.46 mmol), (1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex 25 mg, 0.03 mmol) and a 2M aqueous solution of cesium carbonate in dioxane (462 μl). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 100% hexane/AcOEt, 0-8% AcOEt/MeOH) to give 56 mg (40% yield) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1nc(Cl)ccc1Cc1c[nH]c2ncccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(Cl)ccc1Cc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a clear solution of 3-(6-chloro-2-methoxypyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (28, 0.516 g, 1.88 mmol) in dimethylformamide (10 mL) was added sodium hydride (60% dispersion, 0.113 g, 2.82 mmol). After stirring at room temperature for 30 minutes, triisopropylsilyl chloride (600 μL, 2.83 mmol) was added. The reaction was stirred at room temperature for 2 hours, then poured into aqueous (1 M) sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried (magnesium sulfate), filtered and volatiles were removed by rotary evaporation to give a crude solid. The compound was purified by silica gel column chromatography eluting with 2% ethyl acetate in hexanes. This provided 732 mg of the desired compound as a white, crystalline solid (29, 1.70 mmol, 90%). MS (ESI) [M+H+]+=430.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCN4CCCC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (97 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]=2[CH:8]=[N:7]1)[CH3:2].[Cl-].[OH:18][NH3+:19].N.[Cl-].[NH4+]>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[N:19][OH:18])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2=O
Reactant: [NH3+]O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cn1ncc2c1CCCC2=NO
Temperature: 25 °C

Procedure:
To a stirred solution of (4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (222 mg, 10 mmol) in ethanol (10 mL) was added hydroxylammonium chloride (74 mg, 10.5 mmol). The reaction mixture was heated at reflux for 1 hour. After cooling to room temperature, a solution of concentrated ammonia and saturated ammonium chloride (10 mL, 1:5, v/v) was added to the reaction mixture. The resulting solution was extracted with ethyl acetate (25 mL×3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo to give 4-hydroxyimino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (203 mg, 85%) as a white solid, which was used for the next step without further purification. The above white solid contained a pair of isomers in 10 to 1 ratio as determined by 1HNMR. for the major isomer, 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (s, 1H), 4.89 (s, 2H), 4.26 (m, 2 H), 2.73 (t, J=6.4 Hz, 2 H), 2.58 (t, J=6.4 Hz, 2 H), 2.10 (t, J=6.4 Hz, 2 H), 1.31 (t, J=7.2 Hz, 3 H). MS calcd. for C11H15N3O3 237, obsd. (ESI+) [(M+H)+] 238.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([N:22]=[C:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1N=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A solution of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (7.69 g, 19.8 mmol) in 50 mL of methanol was cooled to 0° C. The solution was treated with sodium borohydride (1.12 g, 29.7 mmol) over 10 min. The reaction was allowed to slowly come to ambient temperature. After 2 h, the reaction was quenched with 15 mL of saturated NH4Cl solution and concentrated under reduced pressure to yield a tan solid residue. The solid was dissolved in 100 mL of CHCl3 and 25 mL of saturated K2CO3 solution then separated. The organic portion was washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated to yield a brown oil. The oil was purified by chromatography (SiO2, 98:2 CHCl3:MeOH) to yield 6.63 g of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine as a tan foam.
Reaction SMILES: C(OC([C:6]1[N:7]=[C:8]([C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=3)=[CH:22][CH:23]=2)[N:9]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[CH:10]=1)=O)C.[CH3:34][Mg]Br.CC[O:39][CH2:40][CH3:41]>C1COCC1>[Cl:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:18])[C:11]=1[N:9]1[CH:10]=[C:6]([C:40]([OH:39])([CH3:41])[CH3:34])[N:7]=[C:8]1[C:19]1[S:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=2)=[CH:22][CH:23]=1
Reactant: C[Mg]Br
Reactant: CCOCC
Reactant: CCOC(=O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Solvent: C1CCOC1
Product: CC(C)(O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(2,6-dichlorophenyl)-2-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1H-imidazole-4-carboxylic acid ethyl ester (300 mg, 0.58 mmol) in THF (3 mL) at 0° C. was added a 3.0M solution of methylmagnesium bromide in Et2O (0.80 mL, 2.4 mmol). After addition was completed the flask was removed from the ice-water bath and allowed to warm to ambient temperature.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].[C:10]([NH:12][C:13]([NH2:15])=[NH:14])#N.[OH-].[Na+]>>[NH:12]([C:10]1[NH:8][C:2]2[C:1]([CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N:7]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N#CNC(=N)N
Reactant: Cc1cccc(N)c1N
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc2nc(NC(=N)N)[nH]c12
Yield: 132.4 %

Procedure:
A mixture of 2,3-toluenediamine (12.45g, 0.102 mol)(5N HCl 40. 8ml, 0.204 mol) and cyanoguanidine (8.60g, 0.102 mol) was heated on a steam bath for 1 hour. The hot solution was then basified with 40% sodium hydroxide and allowed to cool. The resulting gummy material which separated was extracted into ether. The combined ether extracts were dried (Na2SO4) and treated with ethereal hydrogen chloride to give a pink precipitate (25.55g) m.p. 213°-222°C. This crude product was recrystallised from ethanol/ether. A first crop (14.90g), m.p. 236°-238°C. which contained some unreacted 2,2-toluenediamine was obtained but a second crop (5.00g) of colourless microcrystals m.p. 249°-250°C crystallised as pure 2-guanidino-4-methylbenzimidazole dihydrochloride monohydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COCCN1C(=O)CCCc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3)ncc1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
A microwave vessel was charged with 8-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (51.3 mg, 0.219 mmol), 2 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide, 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated at 120° C. for 60 minutes in a microwave reactor (sealed vessel). The reaction mixture was quenched with a slurry of saturated, aqueous, NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (56.8 mg, 61%) as a white powder that had the following properties: mp: 199-204° C.; LC/MS (ESI+): 513 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.37 (s, 1H), 9.34 (s, 1H), 8.52 (m, 1H), 8.19 (s, 1H), 7.48-7.38 (m, 2H), 7.35-7.30 (m, 2H), 7.22 (d, 1H, J=8.2), 6.97 (d, J=8.2, 1H), 4.05 (br s, 2H), 3.27 (br s, 2H), 3.09 (s, 3H), 2.74 (d, 3H, J=4.0), 2.54 (m, 2H), 2.10-1.90 (series of m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.[O:28]=[C:29]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C([O-])([O-])=O.[Na+].[Na+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:27][C:4]1[N:3]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:29](=[O:28])[C:30]([O:32][CH3:33])=[O:31])=[CH:40][CH:39]=2)[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=1
Reactant: COC(=O)C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C(=O)Nc1ccc(-c2cc(OC(c3ccc(-c4cccc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1
Yield: 57.4 %

Procedure:
4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (320 mg, 0.806 mmol), methyl 2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)acetate (320 mg, 0.95 mmol), dichlorobis(triphenylphosphine)palladium (79 mg, 0.11 mmol), and Na2CO3 (212 mg, 2.0 mmol) were added to a mixture of ethanol (10 mL) and water (10 mL) in a round-bottom flask. The flask was heated to reflux for 8 hours. The reaction mixture was cooled and solvent was removed. The residue was dissolved in 10 mL of 0.5 M NaOH solution, filtered, and the filtration was extracted with EtOAc. The organic portion was dried and the solvent was removed to get 250 mg of the above-named compound. 1H NMR (300 MHz, CD3OD): δ δ 7.90 (m, 2H), 7.77 (s, 3H), 7.60 (m, 2H), 7.44 (m, 2H), 7.22 (m, 1H), 7.10 (m, 1H), 7.05 (s, 1H), 6.83 (m, 1H), 5.09 (m, 1H), 3.67 (s, 3H); M+1=541.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(Cl)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-benzoyl chloride (46 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32ClN3O3+H: 518, observed: 518.