Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:24])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH2:4]1>C(O)C.O.[Fe]>[NH2:21][C:17]1[CH:16]=[C:15]([CH:5]2[CH2:4][C:3]([CH3:2])([CH3:24])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=3)[NH:6]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C#N)cc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Yield: 92.9 %

Procedure:
To a round bottom flask, iron powder (9.13 g, 162.7 mmol) and concentrated hydrochloric acid (0.16 mL) were added to a mixture of 4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (5 g, 16.3 mmol) in ethanol (50 mL) and water (12 mL). The resultant mixture was allowed to stir at reflux for 1.5 h. The mixture was filtrated and the filtered cake was washed by ethanol several times. The ethanol was removed under vacuum. The residue was dissolved in ethyl acetate (100 mL) and water (50 mL), separated the organic layer. The organic layer was washed by brine twice and dried over anhydrous sodium sulfate. Filtered and concentrated to provide 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile as yellow solid (4.2 g, yield: 85%). MS (ESI+APCI) 278.2.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]4[C:26]([CH3:27])=[CH:25][C:24](Br)=[CH:23][C:22]=4[O:29][CH3:30])[CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[ClH:1].[C:31]([N:34]1[CH2:39][CH2:38][N:37]([C:24]2[CH:25]=[C:26]([CH3:27])[C:21]([O:20][CH2:19][CH2:18][CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:7]4[C:4]5[CH:5]=[CH:6][S:2][C:3]=5[CH:10]=[CH:9][CH:8]=4)[CH2:12][CH2:13]3)=[C:22]([O:29][CH3:30])[CH:23]=2)[CH2:36][CH2:35]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc(Br)cc(C)c1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(C(C)=O)CC2)cc(C)c1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 90 °C
Reaction time: 22 h
Yield: 13.7 %

Procedure:
1-benzo[b]thiophen-4-yl-4-[3-(4-bromo-2-methoxy-6-methylphenoxy)propyl]piperazine hydrochloride (0.5 g, 0.98 mmol), 1-acetyl piperazine (0.15 g, 1.2 mmol), palladium acetate (11 mg, 0.048 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP)(63 mg, 0.098 mmol) and sodium t-butoxide (0.23 g, 2.3 mmol) were added to toluene (10 ml) and the mixture was stirred under an argon atmosphere at 90° C. for 22 hours. The reaction mixture was cooled to room temperature and filtrated by cerite. The filter cake was washed with ethyl acetate. The filtrate and wash liquid were combined and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=11:1→1:1). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. A 1N hydrochloric acid/ethanol solution was added to this and the crystal produced was filtrated and dried to obtain 1-acetyl-4-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}-piperazin hydrochloride (75 mg, 14% yield) as white powder.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[F:15])=O.C(N(CC)CC)C.C([O:43][C:44](=[O:48])[C@H:45]([CH3:47])[NH2:46])C>CCOCC>[F:15][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:6]=1[NH:5][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:46][C@H:45]([C:44]([OH:48])=[O:43])[CH3:47])=[O:11]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1F
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1F

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-3-fluoro-4-(hexadecylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the N-[3-fluoro-4-(hexadecylamino)benzoyl]alanine as a white, crystalline solid.
Reaction SMILES: C1(CO[C:9](=O)[N:10]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH:24][C:25]2[C:30](=[O:31])[N:29]([C:32]3[CH:37]=[C:36]([C:38]([NH:40][CH2:41][CH3:42])=[O:39])[CH:35]=[CH:34][C:33]=3[CH3:43])[CH:28]=[CH:27][N:26]=2)([CH3:23])[CH3:22])C)C=CC=CC=1>[Pd].C(O)C>[CH2:41]([NH:40][C:38](=[O:39])[C:36]1[CH:35]=[CH:34][C:33]([CH3:43])=[C:32]([N:29]2[CH:28]=[CH:27][N:26]=[C:25]([NH:24][C:21]([CH3:22])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12][NH:10][CH3:9])[CH3:23])[C:30]2=[O:31])[CH:37]=1)[CH3:42]
Reactant: CCNC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCN(C)C(=O)OCc3ccccc3)c2=O)c1
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCNC)c2=O)c1
Yield: 0.2 %

Procedure:
To [2-[2-[1-[[4-[5-[(ethylamino)carbonyl]-2-methyl phenyl]-3,4-dihydro-3-oxopyrazinyl]amino]-1-methylethyl]phenoxy]ethyl]methyl-carbamic acid phenylmethyl ester (Example 220d, 1.10 g) was added ethanol (10 mL) and this was pumped through a Pd/C cartridge at 1 mL/min under max H2 at 50° C. on an H-Cube hydrogenator. The solvents were removed in vacuo and the residue then taken up in acetonitrile. Purification by preparative HPLC (ACE column, 0.2% TFA: acetonitrile eluent) followed by treatment with SCX resin (eluting with methanol (discarded) followed by 7N NH3 in methanol and collected the basic fractions) and trituration with diethyl ether afforded the title product (2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[C:10]([Cl:14])[C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:19]=1
Reactant: O=C(O)COc1cc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)c1cccc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)COc2cc(Cl)c(Cl)cc2Cl)c1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
The mixture of (2,4,5-trichloro-phenoxyacetic acid (127.8 mg, 0.5 mmol), 3-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol), 4-dimethylaminopyridine (122.2 mg, 1.0 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (520.3 g, 1.0 mmol) in DMF (5.0 mL) was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 3-[2-(2,4,5-trichloro-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (166.4 mg, 85.6% yield).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([CH3:21])[CH2:6][C:7]1[N:8]([CH:18]2[CH2:20][CH2:19]2)[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)C.[OH-].[Na+]>CO>[CH:18]1([N:8]2[C:7]([CH2:6][CH:5]([CH3:21])[C:4]([OH:22])=[O:3])=[CH:11][N:10]=[C:9]2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)C(C)Cc1cnc(-c2ccncc2)n1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1cnc(-c2ccncc2)n1C1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
3-(3-cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionic acid ethyl ester (1.02 g, 3.40 mmol) was mixed with MeOH (8 ml) and sodium hydroxide (1N in water, 5.1 ml, 5.10 mmol). This mixture was left stirring at r.t. for 5 h, followed by concentration in-vacuo. The isolated residue was treated with aq. HCl (2N, 6 ml) to isolate the title compound (702 mg, 76%). 1H-NMR (DMSO-d6): 8.63 (dd, 2H), 7.74 (dd, 2H), 6.82 (s, 1H), 3.55 (m, 1H), 3.09 (m, 1H), 2.82 (m, 2H), 1.19 (d, 3H), 1.08 (m, 2H), 0.56 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:25]=1)[N:7]=[C:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11]2.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].[F-].[Cs+].O>C1COCC1.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>[C:21]([O:20][C:18]([NH:17][C:8]1[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=3)=[CH:25][C:6]=2[N:7]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccc(-c3cccc(C#N)c3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture of (1E,4E)-ethyl 8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate (2.05 g, 5 mmol), 3-cyanophenylboronic acid (1.47 g, 10 mmol), CsF (2.28 g, 15 mmol), and Pd(PPh3)4 (0.345 g, 0.3 mmol) in anhydrous THF (100 mL) was refluxed for 12 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography to afford 1.12 g (52%) of (1E,4E)-ethyl 2-(tert-butoxycarbonylamino)-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][N:11]([C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCCc2[nH]cnc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of crude 1,4,5,6,7,8-hexahydrocycloheptaimidazole-4-carboxylic acid methyl ester (8.75 g, approx. 45.0 mmol, J. Am. Chem. Soc. 1976, 98, 984) in dichloromethane (100 ml) were added triethylamine (15.4 ml, 111 mmol) and a solution of triphenylmethyl chloride (18.5 g, 66.4 mmol) in dichloromethane (100 ml). The resulting mixture was stirred at 20° C. overnight. The mixture was washed with water and dried with magnesium sulfate. Filtration, concentration, and column chromatography (silica gel, gradient elution with heptane/ethyl acetate 9:1 to 1:1) yielded 5.5 g (28%) of the title compound as a solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11][C:10]=1[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH3:24][N:22]([CH3:23])[C:20]([C:10]1[CH:11]=[CH:12][C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7])=[O:21]
Reactant: COC(=O)Nc1ccc(C(=O)N(C)C)c(S(=O)(=O)NC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccc(C(=O)N(C)C)c(S(N)(=O)=O)c1
Yield: 112.2 %

Procedure:
1.48 g of N-tert.-butyl-2-dimethylaminocarbonyl-5-methoxycarbonylamino-benzenesulfonamide (Example f) are stirred in 25 ml of trifluoroacetic acid for 18 hours. After the acid has been distilled off, the residue is suspended in toluene. Renewed concentration gives 1.40 g of the sulfonamide; m.p.: 75-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]1[N:40]=[CH:41][C:42]([NH:45]C(=O)OC(C)(C)C)=[N:43][CH:44]=1>CN(C=O)C>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([CH2:38][NH:1][C:2]2[CH:3]=[C:4]([NH:9][C:10](=[O:30])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[CH:5]=[CH:6][C:7]=2[CH3:8])=[N:40][CH:41]=1
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(N)c3)cc2C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(NCc4cnc(N)cn4)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution N-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (70 mg, 0.17 mmol) in DMF (0.5 mL) were added K2CO3 (69 mg,0.50 mmol) and tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (48 mg,0.17 mmol). The reaction mixture was stirred for 8 hours at room temperature after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography using (5% MeOH/CH2Cl2) as a solvent to afford title compound (50 mg, 47% yield). MS m/z: 628 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29](=[O:42])[N:30]([CH3:41])[C:31]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17](I)[C:10]=12.[N:43]1([C:49]([C:51]2[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=2)=[O:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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:3]=[C:4]([C:28]2[C:29](=[O:42])[N:30]([CH3:41])[C:31]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17]([C:54]3[CH:53]=[CH:52][C:51]([C:49]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[O:50])=[CH:56][CH:55]=3)[C:10]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
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: [Cl-]
Solvent: C1COCCO1
Product: COc1ccc(Cn2nc(-c3ccc(C(=O)N4CCOCC4)cc3)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A suspension of 5-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.013 g, 0.019 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.005 g, 0.02 mmol), Pd(PPh3)4 (0.001 g, 0.0009 mmol) and lithium chloride (0.003 g, 0.08 mmol) in dioxane (0.5 mL) and 2 M aqueous Na2CO3 (0.5 mL) was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to yield 0.014 g crude product as a yellow gum. The crude material was used without further purification in the following step. LRMS (APCI pos) m/e 738 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>C1COCC1>[CH3:35][N:34]1[C:27]2[N:28]([C:29](=[O:31])[N:30]=[C:25]([O:3][CH2:4][C:5]3[CH:6]=[N:7][C:8]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=4)=[C:9]([CH:12]=3)[C:10]#[N:11])[CH:26]=2)[CH2:32][CH2:33]1
Reactant: N#Cc1cc(CO)cnc1Oc1cccc(C(F)(F)F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1cnc(Oc3cccc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (6.46 mg, 0.162 mmol), 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)nicotinonitrile (31.7 mg, 0.108 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (20 mg, 0.11 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O>CO.[OH-].[Pd+2].[OH-]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To 2-nitro-4-(trifluoromethyl)benzamide (1000 mg, 4.27 mmol), in MeOH (15 mL) was added palladium hydroxide 20% by weight (230 mg) and the mixture was stirred at rt overnight. The reaction mixture was filtered through Celite washing with MeOH. The crude mixture was concentrated in vacuo to afford 2-amino-4-(trifluoromethyl)benzamide (840 mg, 96%). LC-MS (ESI) m/z 205 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:33])[NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH2:21][CH2:20]2)=[C:4]2[N:10]=[C:9]([CH:11]3[CH2:13][CH:12]3[C:14]([O:16]CC)=O)[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:35]>>[Br:1][C:2]1[C:3]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][C:26](=[O:33])[NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH2:23][CH2:24]2)=[C:4]2[N:10]=[C:9]([CH:11]3[CH2:13][CH:12]3[C:14]([NH2:35])=[O:16])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)C1CC1c1nc2c(N3CCN(CC(=O)Nc4nccs4)CC3)c(Br)cnc2[nH]1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)C1CC1c1nc2c(N3CCN(CC(=O)Nc4nccs4)CC3)c(Br)cnc2[nH]1

Procedure:
A solution of ethyl 2-(6-bromo-7-(4-(2-oxo-2-(thiazol-2-ylamino)ethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopropanecarboxylate (15 mg, 0.028 mmol) in ammonium hydroxide (2.5 mL) was heated in a sealed tube at 100° C. for 16 h. After this time, LC-MS analysis showed that only the desired product was present. Evaporation of the solvents in vacuo provided the product (9 mg, 64%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 1.40 (app. quintet, J=4.4 Hz, 1H, cyclopropane CHAHB), 1.46-1.51 (m, 1H, cyclopropane CHAHB), 2.20-2.24 (m, 1H, cyclopropane CH), 2.40 (br s, 1H, cyclopropane CH), 2.74 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.38 (s, 2H, NCH2CO), 3.54 (br s, 4H, piperazine N(CH2)2), 6.53 (d, J=3.7 Hz, 1H, thiazole H-4 or H-5), 6.83 (br s, 2H, NH2), 6.92 (d, J=3.7 Hz, 1H, thiazole H-4 or H-5), 7.02 (br s, 1H, CONH), 7.74 (br s, 1H, imidazo[4,5-b]pyridine H-5);
Reaction SMILES: [O:1]([C@H:9]([CH3:13])[CH2:10][CH2:11][OH:12])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:24][C:25]1[CH:26]=[C:27]([N:32]2[C:37](=[O:38])[C:36](Br)=[C:35]([Br:40])[CH:34]=[N:33]2)[CH:28]=[CH:29][C:30]=1[F:31]>C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([N:32]2[C:37](=[O:38])[C:36]([O:12][CH2:11][CH2:10][C@H:9]([O:1][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3])[CH3:13])=[C:35]([Br:40])[CH:34]=[N:33]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(F)c(F)c1
Reactant: C[C@H](CCO)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a stirred, 0° C. solution of the product from Example 545B (3.4 g, 10 mmol) in THF (20 mL) was added 1M sodium bis(trimethylsilyl)amide in THF (12 mL, 12 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, then it was transferred to a stirred, −30° C. solution of 2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (3.66 g, 10 mmol) in THF (100 mL). The reaction mixture was stirred at −30° C. for 1 hour, then overnight while warming to room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with brine (2×20 mL), then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 90:10 hexane/ethyl acetate) to provide the title intermediate (2.5 g, 51%).
Reaction SMILES: C[C:2]1([C:12]([O-:14])=[O:13])[CH2:7][CH:6]=[CH:5][C:4](C)([C:8]([O-:10])=O)[NH:3]1.[CH3:15]O.[BH4-].[Na+]>ClCCl>[OH:10][CH2:8][C:4]1[N:3]=[C:2]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C(=O)[O-])C=CCC(C)(C(=O)[O-])N1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2,6-dimethylpyridine-2,6-dicarboxylate (950 mg, 4.87 mmol, 1.00 equiv) in a solvent mixture of methanol (33.2 mL) and dichloromethane (14.2 mL). NaBH4 (185 mg, 5.02 mmol, 1.00 equiv) was added to the reaction mixture in several batches at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 50 mL of NH4Cl (aq.). The resulting solution was extracted with 2×50 mL of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1-2:1) as eluent to yield 750 mg (92%) of methyl 6-(hydroxymethyl)pyridine-2-carboxylate as a white solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:28][OH:29])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[C:14]([OH:24])[C:15]([C:22]#[N:23])=[CH:16][CH:17]=4)[NH:12][C:11]=3[C:10]([CH3:26])([CH3:25])[C:9]=2[CH:27]=1.[CH3:30][Si](C=[N+]=[N-])(C)C.C(N(C(C)C)CC)(C)C>CO.C(Cl)(Cl)Cl>[OH:1][C@H:2]([CH2:28][OH:29])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[C:14]([O:24][CH3:30])[C:15]([C:22]#[N:23])=[CH:16][CH:17]=4)[NH:12][C:11]=3[C:10]([CH3:26])([CH3:25])[C:9]=2[CH:27]=1
Reactant: CC1(C)c2cc(OC[C@H](O)CO)ccc2C(=O)c2c1[nH]c1c(O)c(C#N)ccc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C#N)ccc2c3c([nH]c12)C(C)(C)c1cc(OC[C@H](O)CO)ccc1C3=O
Temperature: 25 °C
Reaction time: 31 h
Yield: 61.5 %

Procedure:
Under nitrogen atmosphere, 8-((R)-2,3-dihydroxy-propoxy)-4-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U8-4-2, 8.0 mg, 20.39 μmol) was dissolved in methanol (2.0 mL) and chloroform (2.00 mL), added with trimethylsilyldiazomethane (diethyl ether solution, 2 M, 15.3 μL, 30.58 μmol) and diisopropylethylamine (0.05 mL), and then stirred at room temperature for 31 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (methanol/dichloromethane) to obtain the title compound (5.1 mg, 62%).