Azzindani/Open_Reaction_Data huggingface dataset:
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[C:68]([O:73][CH3:74])=[N:69][CH:70]=[CH:71][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[C:68]([O:73][CH3:74])=[N:69][CH:70]=[CH:71][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: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: COc1ncccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
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: COc1ncccc1-c1nc2cc(F)cc(F)c2c(Nc2cc(N3CCOCC3)cnc2N2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 2 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-(2-methoxypyridin-3-yl)-3-methylquinoline (0.10 g, 0.312 mmol) and Pd2dba3 (0.011 g, 0.012 mmol) in toluene (3.12 mL) was added sodium t-butoxide (0.075 g, 0.78 mmol). The reaction mixture was heated to 120C. and stirring continued for 2 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-(2-methoxy-3-pyridinyl)-3-methyl-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.33 (1H, dd, J=4.9, 1.8 Hz), 7.76 (1H, m), 7.64 (2H, br. s.), 7.11 (1H, dd, J=7.2, 5.1 Hz), 7.00 (1H, m), 6.39 (1H, br. s.), 3.96 (3H, s), 3.92 (4H, br s), 3.78-3.86 (4H, m), 3.39 (2H, br. s.), 3.06 (6H, br. s.), 2.00 (3H, s). Mass Spectrum (ESI) m/e=549.3 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH:12]=O)[CH2:3][CH2:2]1.Cl.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:30]2[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:16]3[O:15][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH:17]=3)=[O:25])[CH2:32][CH2:31]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2o1
Reactant: O=CCC1CCOc2ccccc21
Agent: Cl
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)c1cc2ccccc2o1
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethanal (875 mg, 5 mmol) and 4-(2-benzofurancarboxamido)piperidine hydrochloride (1.4 g, 5 mmol)under a nitrogen atmosphere, borane/pyridine complex (0.5 ml, excess) was added. The reaction was stirred overnight (ca 15 h) and evaporated to an oily gum which was neutralized by careful addition of 10% hydrochloric acid. The acidic solution was extracted with diethyl ether. The diethyl ether extracts were discarded. The acidic aqueous layer was basified by dropwise addition of 50% sodium hydroxide. The ethyl acetate layer was washed with distilled water, dried (Na2SO4), filtered and evaporated to afford an oily gum (520 mg). The resulting gum was purified by chromatography on silica (eluant: chloroform/ethanol/ammonium hydroxide; 85/14/1) to afford an oil (260 mg) which was crystallized from diethyl ether to afford the title compound (150 mg, 7%), mp=146°-8°. Anal: C25H28N2O3 0.5 H2O, Calc. C, 72.62; H, 7.07; N, 6.77; Found C,72.40; H, 6.94; N, 6.83.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:21][C@H:22]([CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C@H:23]([CH3:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.Br[C:44]1[C:45]([O:52][CH3:53])=[N:46][C:47]([O:50][CH3:51])=[N:48][CH:49]=1>C(O)C.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>[CH3:51][O:50][C:47]1[N:46]=[C:45]([O:52][CH3:53])[C:44]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C@H:23]([C@H:22]([OH:21])[CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH3:34])=[CH:30][CH:29]=2)=[CH:49][N:48]=1
Reactant: COc1ncc(Br)c(OC)n1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
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: CCO
Solvent: Cc1ccccc1
Product: COc1ncc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c(OC)n1
Temperature: 120 °C

Procedure:
Toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.200 g, example 15f)), and tetrakis(triphenylphosphine)palladium(0) (0.020 g) were added to a solution of 5-bromo-2,4-dimethoxypyrimidine (0.209 g) in ethanol (1 ml). The mixture was heated at 120° C. for 4 hours.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[SH:17]>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17][Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Sc1cc(Cl)ccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClSc1cc(Cl)ccc1Cl
Yield: 85.6 %

Procedure:
The procedure of Preparation 7 was repeated, reacting a slurry of N-chlorosuccinimide (3.72 g., 27.9 mmoles) in 50 ml. of carbon tetrachloride with 2,5-dichlorothiophenol (5.0 g., 27.9 mmoles) in 25 ml. of carbon tetrachloride. 2,5-Dichlorobenzenesulfenyl chloride (5.1 g.) was isolated as an oil.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C@H]1N(C)CCN(C2CCCC[C@@]2(C(C2C=CC=C(OC(F)(F)F)C=2)C)O)C1)C.Cl.Cl.[CH2:34]([CH:36]1[NH:41][CH2:40][CH2:39][N:38]([CH2:42][C@@H:43]([C:55]2([OH:61])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]([F:54])([F:53])[F:52])[CH:45]=2)[CH2:37]1)[CH3:35]>>[ClH:1].[ClH:1].[CH2:34]([C@H:36]1[N:41]([CH3:3])[CH2:40][CH2:39][N:38]([CH2:42][C@@H:43]([C:55]2([OH:61])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]2)[C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]([F:53])([F:54])[F:52])[CH:45]=2)[CH2:37]1)[CH3:35]
Reactant: CC[C@@H]1CN(C2CCCC[C@]2(O)C(C)c2cccc(OC(F)(F)F)c2)CCN1C
Reactant: CCC1CN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CCN1
Agent: Cl
Product: CC[C@@H]1CN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CCN1C

Procedure:
In an analogous manner to Example 24, 1-{(1S)-2-[(3R)-3-ethyl-4-methylpiperazin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethylcyclohexanol dihydrochloride was prepared from 1-{(1S)-2-(3-ethylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (See Example 350). HRMS: calcd for C22H33F3N2O2+H+, 415.25669; found (ESI, [M+H]+), 415.2563.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:8]2[CH2:9][C@@H:5]([CH2:6][CH2:7]2)[C@@H:4]1[C:10]([O:12][CH3:13])=[O:11].C([O-])(=O)C.[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C@@H:3]2[C@@H:8]3[CH2:9][C@@H:5]([CH2:6][CH2:7]3)[C@@H:4]2[C:10]([O:12][CH3:13])=[O:11])=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Methyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (0.5 g, 2.43 mmol) was dissolved in methanol (12 mL). Sodium acetate (0.4 g, 4.86 mmol) was added followed by 4 Å powdered molecular sieves (0.5 g) and 4-fluoro-benzaldehyde (0.302 g, 2.43 mmol). Sodium cyanoborohydride (0.305 g, 4.86 mmol) was added and the mixture was stirred at 25° C. for 3 h. The mixture was poured into ethyl acetate (300 mL) and shaken with saturated aqueous sodium bicarbonate solution (200 mL). Both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, methyl (1R,2S,3R,4S)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (0.675 g, 2.43 mmol, 99%), as a clear oil. LC-MS (ESI) calcd for C16H20FNO2 277.15, found 278.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@@H:11]([CH3:15])[C:12]([OH:14])=O)[CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][NH:33][C:32]=3[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][N:33]([C:12](=[O:14])[C@@H:11]([N:3]4[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]4[CH3:1])[CH3:15])[C:32]=3[CH:31]=[N:30]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)cn1[C@@H](C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
To a solution of (2S)-2-[2-methyl-4-(trifluoromethyl)imidazole-1-yl]propanoic acid (0.020 g, 0.09 mmol) in CH2Cl2 (3 mL) was added oxalyl chloride (0.040 mL, 0.46 mmol) and DMF (1 drop). After 20 min at room temperature, the mixture was concentrated in vacuo and the residue was added to another flask containing 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (0.028 g, 0.13 mmol) and NEt3 (0.060 mL, 0.43 mmol) in CH2Cl2 (3 mL). The resulting mixture was stirred at room temperature for 20 min, quenched with saturated aqueous NaHCO3 solution (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-8% MeOH/EtOAc) to afford the titled compound (0.030 g, 44%, TFA salt) as a white solid. 1H NMR (TFA salt) (400 MHz, CDCl3) δ 9.70 (s, 1H), 8.43 (s, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.42 (dd, J=9.2, 8.8 Hz, 2H), 7.20 (dd, J=8.8, 8.4 Hz, 2H), 5.61 (q, J=7.2 Hz, 1H), 3.89 (m, 2H), 2.84 (dd, J=6.2, 6.2 Hz, 2H), 2.65 (s, 3H), 2.15 (m, 2H), 1.84 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H19F4N5O [M+H]+ (free form) 422.1, found 422.1; The titled compounds were analyzed by chiral normal phase chromatography (RegisPack, 25 cm×4.6 mm, 5 micron, cat#793104, 0.1% DEA/IPA, 0.7 mL/min). The (S)-enantiomer (major) had a retention time of 7.2 min and the (R)-enantiomer (minor) had a retention time of 6.2 min (isolated in 19:1 er).
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[CH3:25])=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[CH3:24][O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:15]2[CH:14]=[CH:13][C:12]([CH3:25])=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=2)[CH:22]=1
Reactant: COc1ccnc(-c2ccc(C)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccnc(-c2ccc(C)c(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give (5-(4-methoxypyridin-2-yl)-2-methylphenyl)-guanidine dihydrochloride (127 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([C:17]([CH3:29])([CH2:27][CH3:28])[CH2:18][NH:19]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=2)[NH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([C:17]([CH3:29])([CH2:27][CH3:28])[CH2:18][NH2:19])[CH:14]=[CH:15][CH:16]=2)[NH:4][N:3]=1
Reactant: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(-c2ccnc3[nH]nc(Cl)c23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)(CN)c1cccc(-c2ccnc3[nH]nc(Cl)c23)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
tert-butyl 2-(3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-methylbutylcarbamate (60 mg, 0.1446 mmol) was dissolved in dry DCM (2 mL) and cooled in an ice-bath. TFA (2 mL,) was added slowly dropwise and the resultant was stirred at 0° C. for ˜25 minutes and at RT for ˜45 minutes. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc and saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a slightly yellow gum. The resulting mixture was purified by column chromatography (9% MeOH/1% NH4OH in DCM, ˜50 mL silica) to give a white solid (25.2 mg, 55% Yield).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Br)=[C:11]([Br:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)CN1[C:25](=[O:26])C(Br)=C(Br)C=N1>CO>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:26][CH3:25])=[C:11]([Br:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Br)c(Br)cnn1CC(F)(F)F
Reactant: O=c1c(Br)c(Br)cnn1Cc1ccccc1
Solvent: CO
Product: COc1c(Br)cnn(Cc2ccccc2)c1=O

Procedure:
2-Benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone is prepared according to the method of Example 83B starting with 2-benzyl-4,5-dibromo-3(2H)-pyridazinone, in place of 2-(2,2,2-trifluoroethyl)-4,5-dibromo-3(2H)-pyridazinone and substituting methanol in place of isopropanol.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[C:7]2[OH:12])[CH:20]=[CH2:19]
Reactant: Oc1cccc2c(O)cccc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2c(O)cccc12
Temperature: 25 °C

Procedure:
Into a 1,000 ml two-necked flask equipped with a refluxing condenser, 20.0 g of 1,5-dihydroxynaphthalene (Sigma-Aldrich), 51.81 g of K2CO3, and 500 ml of acetone were charged and mixed at room temperature. Then, the reaction temperature was set to 80° C., and homogeneous mixture was refluxed (hereinafter, the temperature written during the synthesis represents the set temperature of the refluxing apparatus and was higher than about 10° C. to 15° C. than true reaction temperature of reaction medium). During the refluxing, 13.5 ml of allyl bromide (Sigma-Aldrich) was added in a dropwise manner and allowed to react overnight. After finishing the reaction, the reaction mixture was cooled to room temperature and was filtered using Celite. The solvent was evaporated to obtain a coarse product. A reaction product was extracted from the coarse product using ethyl acetate, washed three times using water, and dried using MgSO4. MgSO4 was filtered off, and solvents were removed by using an evaporator to obtain an intermediate product (11), 5-(allyloxy)naphthalene-1-ol. The reaction scheme in the 1st step and the NMR data of the intermediate product (11) thus obtained are as follows.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:28][CH2:27][C:15]2([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][NH:17][C:16]2=[O:26])[CH2:14][CH2:13]1)=O.[BH4-].[Na+].C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>N1C=CC=CC=1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[CH2:10][N:12]1[CH2:28][CH2:27][C:15]2([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][NH:17][C:16]2=[O:26])[CH2:14][CH2:13]1
Reactant: O=C(C1=Cc2ccccc2C1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1=Cc3ccccc3C1)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
Crude 8-(1H-inden-2-ylcarbonyl)-1-phenyl-1,3,8-triazaspiro-[4.5]decan-4-one (11.4g) is dissolved in dry pyridine (250 ml), treated with sodium borohydride (6.0g), and the resulting mixture is refluxed for 16 hours under a nitrogen atmosphere. The pyridine solution is cooled, poured into 2 liters of ice water, stirred for 1 hour and the precipitates filtered off. The crude product is dissolved in chloroform and washed with water and saturated sodium bicarbonate solution. Concentration of the dried chloroform solution gives a crude solid which is a mixture of compounds. Column chromatography through silica gel using ethyl acetate followed by high pressure liquid chromatography with 4:1 ethyl acetate/hexane gives 1.3g of the title compound, melting point 184°14 186° C.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][NH2:25].O>C(OCC)(=O)C>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:25][CH3:24])=[C:3]([N+:21]([O-:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1[N+](=O)[O-]
Reactant: CN
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1c([N+](=O)[O-])c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 55 °C
Yield: 92.1 %

Procedure:
A mixture of 5-bromo-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-nitro-1H-pyrazole-3-carbonitrile (EP 295118 A1, 50 mg, 0.12 mmol) and methylamine (2M in tetrahydrofuran, 1.0 mmol, 2.0 mmol) was heated at 55° C. for 2.5 h. To the reaction mixture was added water (5 ml), followed by ethyl acetate (5 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the titled compound (42 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:36][C:37]1[CH:38]=[C:39]([NH:44][CH2:45][C:46](O)=[O:47])[CH:40]=[C:41]([Cl:43])[CH:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:36][C:37]1[CH:38]=[C:39]([NH:44][CH2:45][C:46]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[O:47])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl(S)-piperidin-3-ylcarbamate (500 mg, 2.5 mmol), in DMF (5 mL) was added EDCI (573 mg, 3.0 mmol), HOBt (405 mg, 3.0 mmol), 2-(3,5-dichlorophenylamino)acetic acid (550 mg, 2.5 mmol) and DIEA (0.5 mL, 3.0 mmol) at 0° C. The reaction mixture was stirred at rt overnight, the reaction mixture was diluted with EtOAc and washed with water. The water layer was extracted with the EtOAc and the combined organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (900 mg, 98%) of the titled intermediate. LCMS: m/z: [M+1]=402.
Reaction SMILES: ClC1SC2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=CC=CC=4)[N:14](CC4NN=NN=4)[C:13]3=O)=[O:10])=[CH:8]C=2C=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:6][CH:7]1[CH2:8][C:21]2[C:12](=[CH:13][N:14]=[CH:15][CH:20]=2)[NH:11][C:9]1=[O:10]
Reactant: O=C(NC1Cc2ccccc2N(Cc2nnn[nH]2)C1=O)c1cc2cc(Cl)sc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1Cc2ccncc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 319.5 %

Procedure:
tert-Butyl (2-oxo-1,2,3,4-tetrahydro-1,7-naphthyridine-3-yl)carbamate (Method 29, 284 mg) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). After stirring at ambient temperature for 1 hour the reaction mixture was evaporated under reduced pressure and the residue triturated with ether (20 mL), to give a light brown solid which was collected by filtration, washed with ether and dried to give the title compound (346 mg, 82%) as a bis trifluoracetate salt.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.C(=O)(O)[O-].[K+]>CC(CC)=O>[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][O:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1Br
Reactant: CCOC(=O)c1cnc2c(O)cccn2c1=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cnc2c(OCc3ccccc3Br)cccn2c1=O
Yield: 85.3 %

Procedure:
To a solution of 4.7 g of 9-hydroxy-4-oxo-4H-pyrido-[1,2-α] pyrimidine-3-carboxylic acid, ethyl ester, 7.2 g of o-bromobenzyl bromide, and 200 ml of ethyl methyl ketone is added 4.0 g of anhydrous potassium bicarbonate, and the mixture is stirred and heated under reflux for 18 hours. The cooled mixture is filtered and the filtrate is concentrated in vacuo to give a solid residue. This is recrystallized successively from 1:1 toluene-skellysolve and from 2-propanol to give about 6.9 g of the named product, m.p. about 164°-166°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([OH:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:20]([OH:22])=[O:21])=[CH:26][CH:27]=2)=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(CCC(=O)O)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 21.6 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made ni example 2), 4-(2-carboxyethyl)benzeneboronic acid (0.039 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.0084 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[C:12]=1[NH2:18].[CH:19](O)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][O:10][C:11]1[C:12]2[N:18]=[CH:19][NH:17][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=CO
Reactant: Nc1cccc(OCCNCc2cccs2)c1N
Product: c1csc(CNCCOc2cccc3[nH]cnc23)c1

Procedure:
The general procedures used in example 2 utilizing 3-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-benzene-1,2-diamine (4c) and formic acid afforded: