Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)[N:5]=[CH:4][N:3]=1.Cl.[N:34]1([CH2:38][CH2:39][N:40]2[CH:44]=[C:43]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[C:47]([Cl:52])[CH:46]=3)[N:42]=[C:41]2[CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:56]2[CH2:57][CH2:58][CH:53]([C:41]3[N:40]([CH2:39][CH2:38][N:34]4[CH2:37][CH2:36][CH2:35]4)[CH:44]=[C:43]([C:45]4[CH:50]=[CH:49][C:48]([F:51])=[C:47]([Cl:52])[CH:46]=4)[N:42]=3)[CH2:54][CH2:55]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1Cl
Agent: Cl
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 4-[1-(2-Azetidin-1-yl-ethyl)-4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=481, obsd.=481).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:18]CC3C=CC(OC)=CC=3)[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH2:18])[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CNc2cc(N[C@H]3CC[C@H](N)CC3)nn3ccnc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N[C@H]2CC[C@H](N)CC2)nn2ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To N6-(trans-4-aminocyclohexyl)-N8-(4-methoxybenzyl)imidazo[1,2-b]pyridazine-6,8-diamine from 1b in dichloromethane (5 mL) was added TFA (2 mL). After stirring at RT for 2 hours, the reaction solution was concentrated in vacuo To provide crude N6-(trans-4-aminocyclohexyl)imidazo[1,2-b]pyridazine-6,8-diamine that was used without further purification. LC/MS, m/e 247.16 (M+1). HPLC Rt, 0.73 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1([F:12])[F:11].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][C:7]2([F:11])[F:12])[C:3]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COC(=O)C(CC1CCCC1(F)F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1(F)F)c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Yield: 11.4 %

Procedure:
A mixture of 2-(3,4-dichloro-phenyl)-3-(2,2-difluoro-cyclopentyl)-propionic acid methyl ester (265 mg, 0.73 mmol) and 2-aminothiazole (18 mg, 0.18 mmol) in a solution of magnesium methoxide in methanol (7.4 wt. % , 0.28 iL, 0.19 mmol) was heated to 110° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(2,2-difluoro-cyclopentyl)-N-thiazol-2-yl-propionamide (8.3 mg, 23%) as a yellow oil: EI-HRMS m/e calcd for C17H16F2Cl2N2OS (M+H)+ 405.0402. found 405.0407.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([CH2:28][CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cccc(CCN2CCOCC2)c1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
2-[(2,5-dichloro-4-pyrimidinyl)amino]-N,N-dimethylbenzamide (300 mg, 0.96 mmol), 3-[2-(4-morpholinyl)ethyl]aniline (198 mg, 0.96 mmol) were combined in a vessel with 10 mL of isopropanol and TFA (74 μL, 0.96 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction mixture was concentrated to dryness. The crude product was purified via semi-preparative HPLC to afford the title compound as a white solid (83 mg, 18%): Mass (M+H)+=481, 483.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]=[N+:26]=[N-:27])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([Sn:32]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:35][CH2:36][CH2:37][CH3:38])[C:33]#[CH:34])[CH2:29][CH2:30][CH3:31]>O1CCOCC1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[C:22]([N:25]5[CH:34]=[C:33]([Sn:32]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[N:27]=[N:26]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(N=[N+]=[N-])cc32)n1)c1ccccc1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccc3ncn(-c4ccnc(N[C@@H](C)c5ccccc5)n4)c3c2)nn1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution containing 95 mg of 2-[(S)-1-phenylethylamino]-4-[6-azidobenzimidazol-1-yl]pyrimidine and 386 μL tributyl-ethynylstannane in 2 mL 1,4-dioxane was stirred at 100° C. for 48 hours under 1 atm of nitrogen. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 139 mg of the title compound. RF: 0.4 (5% MeOH in CH2Cl2). 1H NMR (500 MHz, CD3OD): δ0.91 (t, J=7.4 Hz, 3H), 1.25 (t, J=8.1 Hz, 2H), 1.39 (m, 2H), 1.57 (d, J=6.9 Hz, 3H), 1.65 (m, 2H), 5.22 (q, J=7.1 Hz, 1H), 7.03 (d, J=5.5 Hz, 1H), 7.0-7.4 (m, 5H), 7.76 (m, 1H), 7.85 (d, J=8.7 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.50 (s, 1H), 8.91 (m, 2H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 673.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([CH2:15][C:16]([NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7]([O:32]CC3C=CC=CC=3)[CH:6]=[CH:5][C:4]=2[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([CH2:15][C:16]([NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])([CH3:17])[CH3:18])[C:10]=2[C:9]2[CH:8]=[C:7]([OH:32])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccc(O)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Yield: 54 %

Procedure:
N-{2-[4-Amino-8-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide (1.25 g, 2.36 mmol) was dissolved in 40 mL of ethanol and 10% palladium on carbon (0.58 g) was added. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. An additional 0.21 g of 10% palladium on carbon was added and the reaction was shaken under 50 psi (3.4×105 Pa) of hydrogen for three more hours. The reaction was filtered through CELITE filter agent, and the filter cake was washed with 100 mL of ethanol. The filtrate was concentrated under reduced pressure. The resulting off white solid was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 10-30% CMA in chloroform to provide 0.56 g of N-{2-[4-amino-8-hydroxy-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide as a white powder, m.p. 231-232° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1Cl
Yield: 25.6 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.5 g, 14.6 mmol) and SOCl2 (2.7 mL, 36.4 mmol) in benzene (75 mL), followed by 2-chloroaniline (3.1 mL, 29.1 mmol) and CHCl2 (75 mL). The product chromatographed in CH2Cl2 is to provide 1.05 g of a yellow orange solid (26%). 1H NMR (CDCl3) δ: 8.54 (d, J=8.1 Hz, 1H); 8.30 (br s, 1H); 7.41 (dd, J=1.5, 8.0 Hz, 1H); 7.33 (t, J=7.8 Hz, 1H); 7.10 (t, J=8.1 Hz, 1H); 7.09 (dt, J=1.6, 7.8 Hz, 1H); 6.78 (dd, J=0.4, 7.9 Hz, 1H); 6.63 (dd, J=0.9, 8.2 Hz, 1H); 4.69 (br s, 2H). MS (ES): m/z 303.0 (M+22), 281.0 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15].[NH4+].[OH-]>O=P(Cl)(Cl)Cl>[N+:1]([C:4]1[C:5]2[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCC=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
3-Nitro-benzene-1,2-diamine (1.0 g, 6.54 mmol) and butyraldehyde (630 μL, 7.19 mmol) were stirred in POCl3 (10 mL) at 85° C. for 3 hours. The reaction was cooled to ambient temperature and poured over ice. The resulting mixture was basified with NH4OH. The precipitate was filtered and washed with ice water to give 1.17 g of the sub-title compound that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[C:18]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]4)[C:19]([Cl:21])=[CH:20][C:13]=3[N:12]=2)=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:32])[CH:3]=1.[F:33][C:34]([F:42])([F:41])[C:35]1([C:38](O)=[O:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:9]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[C:18]([N:22]4[CH2:27][CH2:26][CH:25]([C:28]([F:30])([F:29])[F:31])[CH2:24][CH2:23]4)[C:19]([Cl:21])=[CH:20][C:13]=3[N:12]=2)=[CH:8][C:5]([CH2:6][NH:7][C:38]([C:35]2([C:34]([F:42])([F:41])[F:33])[CH2:37][CH2:36]2)=[O:39])=[C:4]([F:32])[CH:3]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Cn1c(Nc2cc(CN)c(F)cc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)c(F)cc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to the procedure in Example 94, step (c) using 4-chloro-2-fluoro-5-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine (270 mg; 0.55 mmol), 1-trifluoromethyl-cyclopropanecarboxylic acid (85 mg; 0.55 mmol), HBTU (209 mg; 0.55 mmol), TEA (111 mg; 1.10 mmol) and DMF (5 mL)
Reaction SMILES: C(O[CH:5]([C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]3[S:36][CH2:37][CH2:38][CH2:39][N:33]3[C:32]=2[CH:40]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[S:36]1[C:34]2=[N:35][C:31]3[CH:30]=[CH:29][C:28](/[CH:5]=[C:6]4\[C@@H:7]5[N:11]([C:12]\4=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]5)=[CH:40][C:32]=3[N:33]2[CH2:39][CH2:38][CH2:37]1
Reactant: CC(=O)OC(c1ccc2nc3n(c2c1)CCCS3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5n(c4c3)CCCS5)C(=O)N12
Yield: 18.4 %

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (700 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 75 mg of product (Yield 18%) was collected. MP: >250° C.; H-NMR(D2O): δ 7.08(m, 6H), 3.70(m, 2H), 4.05(m, 2H), 3.13(m, 2H), 2.22(m, 2H); MS: 372.1(M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[NH3:26]>CO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:26])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: N
Reactant: COC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(-c4ccncc4)cc3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
Methyl 2-(4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxylate (160 mg, 0.5 mmol) was added to ammonia in methanol (30 mL) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, dried in vacuum. 140 mg of solid of 2-(4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 90%. 1H-NMR (400 MHz, DMSO-d6) δ 7.50-7.54 (t, J=8 Hz, 1H), 7.83-7.86 (m, 2H), 7.89-7.96 (brs, 2H), 7.99-8.01 (d, J=7.6 Hz, 2H), 8.08-8.10 (d, J=8.4 Hz, 2H); 8.44-8.46 (d, J=8.4 Hz, 2H); 8.71-8.72 (d, J=4.4 Hz, 2H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:13]([NH:15][C@@H:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Cl:21][C:22]1[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:21][C:22]1[C:27]([N:18]2[CH2:19][CH2:20][C@@H:16]([NH:15][C@@H:13]([C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[CH3:14])[CH2:17]2)=[N:26][CH:25]=[CH:24][N:23]=1
Reactant: C[C@@H](N[C@@H]1CCNC1)c1cccc2ccccc12
Reactant: Clc1nccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H](N[C@@H]1CCN(c2nccnc2Cl)C1)c1cccc2ccccc12
Yield: 35.1 %

Procedure:
To a solution of 162 mg of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidine dihydrochloride and 79.0 mg of 2,3-dichloro-pyrazine in 5 ml of ethanol was added 345 mg of potassium carbonate, and the mixture was stirred under reflux for 16 hours. The reaction mixture was filtered, and the solvent was evaporated, and to the residue was added a saturated aqueous sodium bicarbonate solution and chloroform, and the liquids were separated. The organic layer was dried, and the solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate-97:34→80:20) and by silica gel chromatography (hexane:ethyl acetate=90:10→0:100) to obtain 64.0 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine. (2) In 2 ml of chloroform was dissolved 64.0 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine, and 3 ml of a solution of 4M hydrochloric acid in dioxane was added to the mixture, and the resulting mixture was stirred. After the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitates were collected by filtration, washed with diethyl ether, and dried to obtain 63.9 mg of (R)-1-(3-chloropyrazin-2-yl)pyrrolidin-3-yl-[(R)-1-(naphthalen-1-yl)ethyl]amine dihydrochloride (the following Table A2, Example 2.001).
Reaction SMILES: [C:1]1([OH:7])C=CC=CC=1.[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.Cl.P(=O)(O)(O)O>CC(C)=O>[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:1]=[O:7]
Reactant: Oc1ccccc1
Reactant: Oc1cc2ccccc2cc1O
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CC(C)=O
Product: O=Cc1c(O)c(O)cc2ccccc12

Procedure:
The procedure of Production Example 3 was repeated except that phenol was replaced with 2,3-dihydroxynaphthalene, the 35% concentrated hydrochloric acid was replaced with 0.1 ml of phosphoric acid, and the reaction solution to be subjected to reflux was added with 100 g of acetone and then was heated under reflux, to give a 2,3-dihydroxynaphthalene-formaldehyde condensate.
Reaction SMILES: [CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[NH:5][S@](C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O)C.Cl.O1CCOCC1>>[CH:1]1([C@@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[NH2:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: N[C@H](c1ccc(C(F)(F)F)nc1)C1CC1
Reaction time: 0.5 h

Procedure:
(S)—N—((R)-cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.245 g, 0.000765 mol), ethanol (2.7 g, 0.059 mol), and 4.0 M of hydrogen chloride in dioxane (2.7 mL, 0.011 mol) are combined and stirred for 30 minutes. The mixture is allowed to stir overnight. The solvent is removed and the residue is dissolved in ethanol. After washing with ethanol for 3 times, the mixture is concentrated and the residue is dried under high vacuum overnight to obtain the title compound.
Reaction SMILES: [Na].[C:2]([NH:10]O)(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:13][C:14]([OH:16])=[O:15].Cl>C(O)C.O>[CH2:2]([NH:10][CH2:13][C:14]([OH:16])=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(NO)c1ccccc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)CNCc1ccccc1
Reaction time: 3 h

Procedure:
9.2 Grams (0.4 moles) of metallic sodium was dissolved in 300 ml of absolute ethanol. To the resulting solution, a solution of 27 g (0.2 moles) of benzhydroxamic acid in 600 ml of absolute ethanol was added dropwise 20°-25° C. with stirring for 3 hours. Subsequently, a solution of 9.5 g (0.1 mole) of chloroacetic acid in 100 ml of absolute ethanol was added dropwise and the resulting mixture wa stirred at 50° C. for 8 hours. After cooling the mixture, water was added and the mixture was neutralized with concentrated HCl. Ethanol was distilled off under vacuum and the pH of the residue was adjusted to 1 by addition of concentrated HCl. The precipitating crystal was recovered by filtration and dried to obtain benzamidooxyacetic acid in an amount of 8.2 g (yield, 42 mol %).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-c2ccccc2)c1
Product: ClCc1cccc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of 50 mg of 3-hydroxymethylbiphenyl in 1.5 mL thionyl chloride was heated at reflux temperature for 4 hr, cooled to room temperature and the solvent removed by evaporation under reduced pressure to yield 45 mg of 3-chloromethylbiphenyl which was used in the next step without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH2:32]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:44][CH2:45][N:40]([CH2:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:41][CH2:42]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1ccc(CCN2CCNCC2)cc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(CCc2ccccc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenethylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=618.98 (M+H+); retention time=0.64 minutes.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:48]=[CH:47][CH:46]=[CH:45][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[N:30][CH:31]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[Cl:24][C:23]1[C:18]([CH2:17][CH2:16][C:15]2[CH:45]=[CH:46][CH:47]=[CH:48][C:14]=2[C:11]2([C:8]([NH2:9])=[O:10])[CH2:13][CH2:12]2)=[N:19][C:20]([NH:25][C:26]2[CH:31]=[N:30][C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)nc3)ncc2Cl)CC1
Reaction time: 16 h
Yield: 77 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 4-(5-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A19 (79.0 mg, 0.137 mmol) in DCM (5 mL) and stirred for 16 hours. The volatiles were removed in vacuo and the resultant residue loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH (100 mL) and then with 5% NH4OH in MeOH (100 mL). The basic fractions were combined and the solvent was removed in vacuo to give the title compound 15 as a white solid (50 mg, 77%). 1H NMR (400 MHz, d4-MeOD) δ 8.74 (s, 1H), 8.36 (s, 1H), 8.21 (dd, J=8.6, 2.7 Hz, 1H), 7.45-7.22 (m, 5H), 3.30-3.17 (m, 6H), 2.95-2.80 (m, 3H), 1.99-1.96 (m, 2H), 1.86-1.76 (m, 2H), 1.64-1.63 (m, 2H), 1.19-1.07 (m, 2H). LCMS-C: rt 4.17 min; m/z 477.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[CH2:16][CH2:17][C:18]2[CH2:22][CH:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[O:20]N=2)=[CH:4][C:3]=1[CH3:28].B(O)(O)[OH:30]>[Pd].CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[CH2:16][CH2:17][C:18](=[O:30])[CH2:22][CH:21]([OH:20])[CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:4][C:3]=1[CH3:28]
Reactant: COC(=O)CC1CC(CCc2c(C)cc(C)cc2-c2ccc(F)c(C)c2)=NO1
Reactant: OB(O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)CC(O)CC(=O)CCc1c(C)cc(C)cc1-c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.1 g (0.26 mmol) of the isoxazoline from Step E, 50 mg of 10% palladium on carbon catalyst and 48 mg (0.78 mmol) of boric acid in 3 ml of methanol and 0.3 ml of water was stirred under hydrogen (1 atmosphere) at room temperature for 2.5 hours. The mixture was filtered and the filtrate was poured into brine and extracted with ether. The ethereal extract was washed with 5% (w/v) aqueous sodium bicarbonate solution, dried (MgS04), filtered and evaporated to dryness to give 92 mg (0.23 mmol, 89%) as a pale yellow oil. nmr (CDCl3) δ: 2.30 (6H, a methyl singlet and a methyl doublet), 2.33 (3H, s), 2.35-2.5 (6H, m), 2.75-2.85 (2H, m), 3.30 (H, d), 3.70 (3H, s), 4.37 (H, m), 6.83 (H, bs), 6.95-7.1 (4H, m). IR (neat) 3450, 1710 cm-1.