Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][N:7]=[C:6]([N:10]2[C:14]([NH:15][C:16]3[CH:17]=[C:18]([NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH:19]=[CH:20][C:21]=3[CH3:22])=[CH:13][C:12]([CH3:36])=[N:11]2)[CH:5]=1)=O.[N:37]1([CH2:43][CH2:44][NH2:45])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.CS(C)=O>CC(O)C>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:17][C:16]=1[NH:15][C:14]1[N:10]([C:6]2[CH:5]=[C:4]([NH:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:9]=[CH:8][N:7]=2)[N:11]=[C:12]([CH3:36])[CH:13]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)n(-c2cc(S(C)=O)ncn2)n1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)n(-c2cc(NCCN3CCOCC3)ncn2)n1
Temperature: 80 °C

Procedure:
The mixture of N-{3-[2-(6-Methanesulfinyl-pyrimidin-4-yl)-5-methyl-2H-pyrazol-3-ylamino]-4-methyl-phenyl}-3-trifluoromethyl-benzamide (20 mg, 0.04 mmol) and 2-Morpholin-4-yl-ethylamine (100 uL) in 2-propanol is heated to 80° C. for 3 hours. The reaction mixture is cooled to room temperature and condensed. The crude product is then treated with 1 mL DMSO and purified by LC/MS to afford N-(4-Methyl-3-{5-methyl-2-[6-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yl]-2H-pyrazol-3-ylamino}-phenyl)-3-trifluoromethyl-benzamide.
Reaction SMILES: [Si](C)(C)(C)C.[CH3:6][C:7]1[CH:12]([OH:13])[CH2:11][CH2:10][C:9]([CH3:15])([CH3:14])[C:8]=1/[CH:16]=[CH:17]/[C:18](/[CH3:28])=[CH:19]/[CH:20]=[CH:21]/[C:22](/[CH3:27])=[CH:23]/[C:24]([OH:26])=[O:25].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1>>[CH3:6][C:7]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]([CH3:14])([CH3:15])[C:8]=1/[CH:16]=[CH:17]/[C:18](/[CH3:28])=[CH:19]/[CH:20]=[CH:21]/[C:22](/[CH3:27])=[CH:23]/[C:24]([OH:26])=[O:25]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1O
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Solvent: C[Si](C)(C)C
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1=O

Procedure:
Melting points (mp) are determined with a Fischer-Johns melting point apparatus and are uncorrected. Proton magnetic resonance spectra (1H NMR) are recorded in CDCl3 on a Mac NMR 5.3 300 MHz spectrometer (internal standard Me4Si, (δ=0), and high resolution mass spectra (HRMS) are determined on a Kratos Aspect Systems instrument, EI mode. Elemental analyses are performed by Chemisar Laboratories Inc., Guelph, Ontario, Canada. TLC is done on silica gel GHLF precoated plates (250 microns) purchased from Analtech, while flash column chromatography (FCC) is performed on silica gel (Merck grade 9385, 230-400 mesh, 60 Å) according to Still's method. (Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for Preparative Separation with Moderate Resolution. J. Org. Chem., 43, 2923-2925, 1978). “Pet. ether” refers to light petroleum, bp 40-60° C. [11,12-3H] All-trans-retinoic acid (ATRA, 51.8 (Ci/mmol) is purchased from New England Nuclear Life Science Products, Inc., while unlabeled ATRA is purchased from Sigma-Aldrich Chemical Co., St. Louis, Mo. Liarozole fumarate is obtained from Janssen Pharmaceutica, Beerse, Belgium. (±)-4-Hydroxy-ATRA and 4-oxo-ATRA are prepared using a well-known technique (Samokyszyn, V. M.; Gall, W. E.; Zawada, G.; Freyaldenhoven, M. A.; Chen, G.; Mackenzie, P. I.; Tephly, T. R.; Radominska-Pandya, A. 4-Hydroxyretinoic Acid, a Novel Substrate for Human Liver Mcrosomal UDP-glucuronosyltransferase(s) and Recombinant UGT2B7. J. Biol. Chem. 2000, 275, 6908-6914.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH2:35][CH:36]=[CH2:37])([CH3:6])[CH3:5]>C(O)C>[CH3:1][O:2][C:3](=[O:38])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:27][CH:28]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH2:35][CH2:36][CH3:37])([CH3:5])[CH3:6]
Reactant: C=CCc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OC
Solvent: CCO
Product: CCCc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
2-(2-Allyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester (0.060 g, 0.115 mmole) was dissolved in absolute ethanol (10 mL). After purged the solution with N2 for 15 min, 10% Pd/C (0.030 g). The reaction was stirred under a hydrogen balloon at room temperature for 2 hours. The catalyst was removed through filtration, and solvent was removed on rota-vapor to provide a colorless oil (0.053 g, 88%). Mass [EI+] 523 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][OH:25])=[CH:18][CH:17]=1>[C].[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C/CO)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCO)cc1
Yield: 89.8 %

Procedure:
A mixture of (E)-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propen-1-ol (3.1 g), palladium-carbon (5%, 0.5 g) and ethyl acetate (50 ml) was subjected to catalytic hydrogenation under 1 atmospheric pressure at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to yield 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propan-1-ol (2.8 g, 90%), which was recrystallized from ethyl acetate--hexane to give colorless needles, m.p.99°-100° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][CH:70]=[C:71]([O:73][CH3:74])[CH:72]=2)[C:56]=1[CH3:75].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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]>[N:38]1([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][CH:70]=[C:71]([O:73][CH3:74])[CH:72]=4)[C:56]=3[CH3:75])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: COc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cncc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.050 mmol), 2,5-dimorpholinopyridin-3-amine (0.099 g, 0.37 mmol), 4-chloro-5,7-difluoro-2-(5-methoxypyridin-3-yl)-3-methylquinoline (0.10 g, 0.312 mmol) and Pd2dba3 (0.011 g, 0.012 mmol) in toluene (3.1 mL) was added sodium t-butoxide (0.075 g, 0.78 mmol). The reaction mixture was heated to 120° C. and stirring continued for 5 h. The reaction was cooled to rt and diluted with water (15 mL). The mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-2-(5-methoxy-3-pyridinyl)-3-methyl-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (2H, t, J=2.1 Hz), 7.80 (1H, br. s.), 7.67 (1H, d, J=2.7 Hz), 7.49-7.54 (1H, m), 6.99-7.09 (1H, m), 6.38 (1H, br. s.), 3.97 (3H, s), 3.91 (4H, br. s.), 3.79-3.86 (4H, m), 3.21 (4H, br. s.), 3.00-3.09 (4H, m), 2.18 (3H, s). Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (118 mg, 89%), MS (ISP) m/z=443.5 [(M+H)+], mp 236.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17]CC2C=CC=CC=2)=O)[CH2:11][CH2:10]1.N1CCCCC1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][CH2:51][CH2:52]C(O)=O>CN(C=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15](=[O:17])[CH2:52][CH2:51][CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)[CH2:13][CH2:14]1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ncccn2)CC1
Reactant: O=C(O)CCCc1cccs1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(CCCc1cccs1)N1CCC(CNc2ncccn2)CC1
Reaction time: 2 h

Procedure:
Benzyl 4-[(2-pyrimidinylamino)methyl]-1-piperidinecarboxylate (EXAMPLE 16) was hydrogenated as described in EXAMPLE 30, Step 1. The resulting piperidine was combined with EDC (1.3 equiv.), HOBT (1.0 equiv.), and 4-thiophen-2-yl-butyric acid (1.0 equiv.) in DMF and stirred for 2 h. The resulting reaction solution was partitioned into ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated and washed with pH 4.5 citric acid buffer (10% citric acid and sodium hydroxide), dried (sodium sulfate), and concentrated to yield the desired 1-[4-(pyrimidin-2-ylaminomethyl)-piperidin-1-yl]4-thiophen-2-yl-butan-1-one. M.S. (M+1): 345.25
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:8])[CH2:2]1.C([O-])(=O)C.[Na+].BrBr.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)(=O)C>[NH2:20][C:18]1[S:19][C:2]2[C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH2:7][C:1]=2[N:17]=1
Reactant: NC(N)=S
Reactant: O=C1CCCCC(=O)C1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2c(s1)C(=O)CCCC2
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
Cycloheptane-1,3-dione (20.0 g, 159 mmol) [prepared according to Organic Process Research & Development 1998, 2, 379] is taken up in 200 mL acetic acid and sodium acetate (14.3 g, 174 mmol) is added. The reaction mixture is stirred for 10 min, cooled to 10° C. and than bromine (8.99 mL, 174 mmol) is added dropwise over a period of 20 min. The reaction mixture is allowed to come to RT and stirred for 2 h. Thiourea (13.2 g, 174 mmol) is added and the reaction mixture is heated to 85° C. and stirred for 1 h. The reaction mixture is stirred overnight at RT, filtered and the solids are washed with 200 mL petroleum ether. The solids are taken up in water, filtered and the filtrate is basified to pH 8 with aqueous ammonia. The precipitated solids are filtered off and dried in vacuo. Yield: 10.0 g. HPLC-MS: tR=0.14 min, (M+H)+=183. 1H NMR (DMSO-d6): δ 7.81 (s, 2H), 2.84 (t, 2H), 2.58 (t, 2H), 1.81 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([OH:9])[CH3:8].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:10][S:11]([O:9][C@@H:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8])(=[O:13])=[O:12]
Reactant: C[C@@H](O)c1ccccn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H](OS(C)(=O)=O)c1ccccn1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirred solution of 0.27 g (2.2 mmol) of commercially available (1R)-1-pyridin-2-ylethanol in 5 mL of anhydrous dichloromethane was added 0.53 g (4.3 mmol) of 4-(dimethylamino)pyridine followed by 0.20 mL (2.6 mmol) of methanesulfonyl chloride. The resulting mixture was stirred with gradual warming to ambient temperature over 1 h. The resulting mixture was quenched with water and extracted with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford the title compound as a yellow oil (0.35 g, 81% yield).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][C:1]=2[OH:11])[CH:6]=1.[CH3:12][N:13]([C:19]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)N(C)C
Agent: Oc1cccc2ccccc12
Product: CCOC(=O)N(C)c1cccc2ccccc12

Procedure:
At 170° C. and 100 mm Hg, 14 g of alpha-naphthol and 18 g of dimethyl urethane were reacted in the presence of 1.5 g of titanium tetra-isopropylate. In 5 hours a 32% convertion of naphthol was obtained, with total selectivity to methyl naphthyl urethane.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:23])[NH:8][C:9](=[O:22])[N:10]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=2[Cl:21])[CH:11]=1)([O:3]CC)=[O:2]>Cl.C(O)(=O)C>[C:1]([C:6]1[C:7](=[O:23])[NH:8][C:9](=[O:22])[N:10]([NH:12][C:13]2[C:14]([Cl:21])=[CH:15][C:16]([Cl:20])=[CH:17][C:18]=2[Cl:19])[CH:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1cn(Nc2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn(Nc2c(Cl)cc(Cl)cc2Cl)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
5-Carbethoxy-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione is dissolved in a hot mixture of concentrated HCl and glacial acetic acid (1:1) and is refluxed for 10 hours. The reaction mixture is cooled to RT and filtered, giving 5-carboxy-1-(2,4,6-trichloroanilino)-2,4-pyrimidinedione.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]2[N:9]([CH:27]([CH3:29])[CH3:28])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+].CO>C1COCC1>[CH:27]([N:9]1[C:8]2[CH:30]=[CH:31][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:24])([F:26])[F:25])[CH:19]=[CH:18][C:16]=2[N:17]=1)([CH3:29])[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 89 %

Procedure:
1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimid azole-5-carboxylic acid (500.0 mg) was prepared by following General Procedure E starting from 1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (580.0 mg) and lithium hydroxide (2.0 N solution, 3.0 mL), MeOH (2.0 mL) and THF (2.0 mL). LCMS: m/z 438; and 1H NMR (DMSO-d6, 400 MHz): δ 8.17 (1H, m), 7.96 (1H, m), 7.84-7.82 (1H, m), 7.72-7.70 (1H, m), 7.64-7.61 (1H, m), 7.40-7.37 (1H, m), 5.16-5.13 (1H, m), 1.59-1.58 (6H, d), —NH proton and —COOH signals were not observed.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C[O-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:24][C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[C:27]([CH2:33][O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[N:26]=2)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.C(O)(=O)C.C([BH3-])#N.[Na+]>O.CO>[F:2][CH:3]1[CH2:6][N:5]([CH2:31][C:29]2[CH:28]=[C:27]([CH2:33][O:34][CH2:35][C:36]([F:38])([F:39])[F:37])[N:26]=[C:25]([NH:24][C:14]3[CH:15]=[CH:16][C:17]([N:18]4[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]4)=[C:12]([O:11][CH3:10])[CH:13]=3)[N:30]=2)[CH2:4]1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reactant: FC1CNC1
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(CN3CC(F)C3)n2)ccc1-n1cnc(C)c1
Reaction time: 0.03 h

Procedure:
3-Fluoroazetidine hydrochloride (25 mg, 0.23 mmol) was mixed with methanol (5 mL). Sodium methoxide (30 w % in methanol, 0.042 mL, 0.23 mmol) was added followed by 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carbaldehyde (80 mg, 0.19 mmol). The mixture was stirred for 2 min. Acetic acid (0.035 mL, 0.61 mmol) was added and the mixture was stirred for 5 min. Sodium cyanoborohydride (17 mg, 0.27 mmol) was added and the mixture was stirred at rt under nitrogen atmosphere for 1 h. Water was added and the mixture was stirred for 5 min. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a dry film 44 mg (48%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]([CH3:30])([CH3:29])[C:5]2=[N:6][CH:7]=1.[B:31]1(B2OC(C)(C)C(C)(C)O2)[O:35]C(C)(C)C(C)(C)[O:32]1.C([O-])(=O)C.[K+]>O1CCOCC1>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([B:31]([OH:35])[OH:32])[CH:3]=4)[C:8]([CH3:29])([CH3:30])[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B(O)O)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure O using 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (100 mg, 0.22 mmol), Pd(PCy3)2 (14.4 mg, 0.022 mmol), bis(pinacolato)diboron (60 mg, 0.24 mmol) and potassium acetate (35 mg, 0.32 mmol) in 1,4-dioxane (4.0 mL) and heating at 120° C. in the microwave for 1 h. After aqueous work up 1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid was obtained as a colorless film. Mass Spectrum (ESI) m/e=429 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([C:26](Cl)=[O:27])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:26]([C:24]4[CH:23]=[CH:22][C:21]5[O:16][CH2:17][CH2:18][O:19][C:20]=5[CH:25]=4)=[O:27])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1ccc2c(c1)OCCO2
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared following procedure and work up described for example 19, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 50 mg; 0.25 mmol; 1.0 eq.) and 2,3-dihydro-1,4-benzodioxine-6-carbonyl chloride (74 mg; 0.37 mmol; 1.5 eq.) as a white powder (34 mg, 37%). HPLC, Rt: 3.17 min. (purity 81.5%). LC/MS, M+(ESI): 363.0.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13].O=P(Cl)(Cl)[Cl:17]>CC#N.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:17][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cc(O)c([N+](=O)[O-])c(=O)[nH]1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: CC(C)c1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a suspension of 4-hydroxy-6-isopropyl-3-nitro-1H-pyridin-2-one (3.02 g, 15.2 mmol) in CH3CN (60 mL) at room temperature is added benzyltriethylammonium chloride (13.88 g, 61.0 mmol). The mixture is stirred at room temperature for 5-10 min, and then POCl3 (6.25 mL, 67.1 mmol) is added. The reaction mixture is stirred at room temperature for 15 min and then at reflux for 1 h. After cooling, the reaction mixture is concentrated in vacuo. The flask is then placed in an ice bath, and the residue treated with H2O (˜60 mL). The mixture is stirred for 4 h while slowly warming to rt. The solid that forms over this period of time is collected by filtration and then washed with H2O and a small amount of hexanes. 4-Chloro-6-isopropyl-3-nitro-1H-pyridin-2-one is obtained as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 13.13 (br s, 1H), 6.24 (s, 1H), 2.89 (sept, J=6.9 Hz, 1H), 1.31 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1ccc(C(=O)OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 93.4 %

Procedure:
20.6 g of the benzyl 4-nitrobenzoate are dissolved in 350 mL dioxane and this solution is combined with 6.9 g (49.9 mmol, 0.61 eq) Raney nickel. The mixture is hydrogenated at 5 bar H2 pressure for 16 h with stirring. The catalyst is filtered off and all the volatile constituents are eliminated in vacuo. 17 g benzyl 4-aminobenzoate are obtained.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:9]1([O:15][C:16]2[N:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.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>[CH:9]1([O:15][C:16]2[N:21]=[CH:20][C:19]([C:2]3[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OB(O)c1ccc(OC2CCCCC2)nc1
Reactant: Nc1nccnc1Cl
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Nc1nccnc1-c1ccc(OC2CCCCC2)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (53.5 mg) was added to a suspension of 3-chloropyrazin-2-amine (200 mg), 6-(cyclohexyloxy)pyridin-3-ylboronic acid (375 mg) and sodium carbonate (327 mg) in DME (5 mL) and water (1 mL) and the mixture was stirred at 90° C. under nitrogen for 3 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with IPE to give the title compound (332 mg) as brown gum.