Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH:50]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)([CH3:52])[CH3:51]>>[CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:56]6[CH2:57][CH2:58][N:53]([CH:50]([CH3:52])[CH3:51])[CH2:54][CH2:55]6)=[O:36])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C(C)C)CC4)cc3)cn2)cc1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid obtained in Step A in Example 1-D-19 and 1-isopropylpiperazine (30.4 μl, 0.212 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone as a yellow solid (64.4 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-113) as a colorless powder (38.7 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:4]4[C:5]([F:9])=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=4)[CH2:18]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)CNCC2
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)CN(c1nc(Cl)ncc1F)CC2

Procedure:
In a like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-1,2,3,4-tetrahydroisoquinoline were reacted to provide 2-chloro-N4-[2-(2-chloro-5-fluoropyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.08 (d, 1H, J=3.0 Hz), 7.95 (d, 1H, J=6.0 Hz), 7.50-7.42 (m, 2H), 7.21 (d, 1H, J=8.4 Hz), 6.96-6.90 (m, 1H), 4.95 (s, 2H), 4.04 (t, 2H, J=5.7 Hz), 2.99 (t, 2H, J=5.7 Hz); 19F NMR (282 MHz, CDCl3): −42555, −44573; LCMS: purity: 98%; MS (m/e): 410 (MH|).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][C:7]([S:10]([N:12]=[C:13]1[CH2:16][O:15][CH2:14]1)=[O:11])([CH3:9])[CH3:8]>O1CCCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:13]1([NH:12][S:10]([C:7]([CH3:9])([CH3:8])[CH3:6])=[O:11])[CH2:16][O:15][CH2:14]1
Reactant: c1cscn1
Reactant: CC(C)(C)S(=O)N=C1COC1
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2nccs2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of n-butylithium in hexanes (1.6 M, 2.5 mL, 3.99 mmol) was added dropwise to a solution of thiazole (364 mg, 4.23 mmol) in tetrahydrofuran (30 mL) at −78° C. The resulting mixture was stirred for 30 min at −78° C. before a solution of 2-methyl-n-(oxetan-3-ylidene)propane-2-sulfinamide (CAN 1158098-73-7, 500 mg, 2.85 mmol) in tetrahydrofuran (3.5 mL) was added dropwise at −78° C. The reaction solution was stirred for an additional 30 min at −78° C. before being warmed to 22° C., and then was quenched with saturated aqueous ammonium chloride solution. The crude reaction mixture was then partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined. The combined layers were washed with saturated aqueous sodium chloride solution, and the washed solution was dried with sodium sulfate and evaporated down to dryness. The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to give the title compound (495 mg, 67%). MS (ESI, m/z): 261.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[C:6](F)[C:7]=1[F:8].Cl.C(Cl)Cl.[C:15]([O-])([O-])=[O:16].[Na+].[Na+]>C[O-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[C:6]([O:16][CH3:15])[C:7]=1[F:8]
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: O=C([O-])[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(N)cc(F)c1F

Procedure:
A mixture of 3,4,5-trifluorobenzenamine (40 g; 272 mmol) in NaOMe (30% in MeOH) (250 ml) was heated at reflux for 16 h. The reaction mixture was then poured onto ice with 37% aqueous HCl (150 ml)( ). CH2Cl2 was added and the pH of the reaction mixture was adjusted to pH=7-8 using an aqueous solution of Na2CO3. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography over silica gel (eluent: 50:50 heptane/CH2Cl2 to pure CH2Cl2). The pure fractions were collected and the solvent evaporated in vacuo.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]1[CH2:26][C:24](=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21]C=2)[CH2:17]1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:8]2([C:23]3[C:18](=[CH:17][CH:16]=[CH:26][CH:24]=3)[CH2:19][CH2:20][CH2:21]2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: O=C1CCCc2ccccc21
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC2(CCCc3ccccc32)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane, 25 mmol of α-tetralone and 70 mL of tetrahydrofuran. The product was recrystallized from ethyl acetate/diethyl ether (m.p. 117°-119° C.). 1H NMR (CDCl3) δ 1.7-1.9 (m, 1 H), 1.9-2.1 (m, 2 H), 2.1-2.3 (m, 1 H), 2.7-3.0 (m, 2 H), 2.95 (d, 1 H), 3.1 (d, 1 H), 3.5 (s, 2 H), 7.1-7.2 (m, 1 H), 7.2-7.3 (m, 2 H), 7.4-7.5 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
Trans-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (502 mg, 1.36 mmol) (from example 23, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (0.358 mL, 1.36 mmol) dissolved in water (0.500 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (0.083 mL, 1.36 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of hydrogen chloride (7.02 mL, 42.13 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (50 mL). The combined organic phase were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (242 mg, 52.6%) was isolated as a white solid. 1H NMR (600 MHz, CDCl3) δ 1.60-1.72 (m, 1H), 1.94 (d, 1H), 1.98-2.07 (m, 1H), 2.60 (d, 1H), 2.78-2.94 (m, 2H), 3.77 (s, 3H), 4.25 (s, 1H), 5.51-5.71 (m, 2H), 6.94-6.99 (m, 1H), 7.02-7.09 (m, 1H), 7.17 (dd, 1H). MS m/z 337 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)([CH3:17])[CH3:16])=[CH:6][CH:5]=1
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(N)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: CC(C)(Oc1ccc(N)c2ccccc12)c1ccnc(N)c1
Yield: 99.1 %

Procedure:
A solution of 4-(2-(4-nitronaphthalen-1-yloxy)propan-2-yl)pyridin-2-amine (41) (282 mg, 0.87 mmol) in MeOH (45 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo to afford the title compound (42) (253 mg, 89%) as a brown foam: m/z 294 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18](OC)=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:30][CH:31]([F:33])[F:32])[C:26]([F:29])([F:28])[F:27])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:36])=O>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:24])=[N:17][C:18]([Cl:36])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([O:30][CH:31]([F:32])[F:33])[C:26]([F:28])([F:29])[F:27])=[CH:4][CH:3]=1
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 100 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
A mixture of 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (Example 185, 2.10 g, 4.27 mmol) and phosphoryl chloride (11 mL) was stirred at 100° C. for 5 hr. The mixture was concentrated in vacuo, diluted with water, neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether/n-hexane to give the title compound as a colorless powder (889 mg, 1.79 mmol, 42%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example E.47) (0.197 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.097 g, 48%). MS (ISP) 407.3 [(M+H)+]; mp 224° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C[Al](C)C.C(O[C:17]([C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[C:26]([N:28]2[C:32]([CH3:33])=[N:31][C:30]([CH3:34])=[N:29]2)[N:25]=[C:24]([S:35][CH3:36])[N:23]=1)=O)C>C1(C)C=CC=CC=1>[CH3:34][C:30]1[N:31]=[C:32]([CH3:33])[N:28]([C:26]2[N:25]=[C:24]([S:35][CH3:36])[N:23]=[C:22]([C@@H:20]3[CH2:21][C@H:19]3[C:17]3[N:2]([CH3:1])[C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:9]=3)[CH:27]=2)[N:29]=1
Reactant: CNc1ccccc1N
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(SC)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CSc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2C)n1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To N1-methylbenzene-1,2-diamine (2.01 g, 16.5 mmol, 1.1 eq.) dissolved in toluene (20 mL) was added trimethylaluminium solution (2.0 M in toluene, 22.5 mL, 44.98 mmol, 3.0 eq.) under nitrogen at 0° C. dropwise. The reaction was stirred at a temperature between 10° C. to 20° C. for 30 minutes followed by the addition of ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropanecarboxylate (1-4) (5.00 g, 14.99 mmol, 1.0 eq.) in toluene (80 mL) and the reaction was heated to 130° C. for 12 hours. The reaction was cooled to room temperature and quenched with saturated sodium bicarbonate (100 mL) then extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrate to dryness. The crude product was purified by silica gel column chromatography (0-30% acetone in dichloromethane) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-5) as a pale pink solid. 1H NMR (400 MHz, CDCl3) δ 7.72-7.67 (m, 1H), 7.56 (s, 1H), 7.31-7.22 (m, 3H), 3.81 (s, 3H), 2.90 (s, 3H), 2.86-2.76 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.06-1.97 (m, 2H). LRMS m/z (M+H) 392 found, 392 required. m.p. 157-159° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[O:12]=[CH:13][C:14]([Cl:17])([Cl:16])[Cl:15]>Cl(O)(=O)(=O)=O>[CH3:1][N:2]([CH:13]([OH:12])[C:14]([Cl:17])([Cl:16])[Cl:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CNC(=O)Nc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CN(C(=O)Nc1ccccc1)C(O)C(Cl)(Cl)Cl

Procedure:
1-methyl-3-phenyl urea (7.5 g, 0.05 mol) was reacted with 7.5 g (0.05 mol) of chloral without solvent. The mixture was shaken for a short period of time. After, 3 drops of perchloric acid were added and the mixture heated gently for a few minutes to give a homogenous viscous oil. Upon cooling, the product formed as a glass. The chemical analysis showed: %Cl, calculated 35.8, found 35.8; %N, calculated 9.4, found 8.0. The product is the fifth compound tabulated in Table I.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[CH2:6][C:7]([CH:9]1[C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1)=[O:8])C.Cl>CO>[CH3:1][O:3][C:4]([C:5]1[O:20][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[C:7](=[O:8])[CH:6]=1)=[O:21]
Reactant: CCOC(=O)C(=O)CC(=O)C1COc2ccccc2C1=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(=O)c2c(o1)-c1ccccc1OC2

Procedure:
A solution of 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid ethyl ester [0.70 g, 2.4 mmoles, described above in (a)] in methanol is saturated with hydrogen chloride gas. The solution is heated at reflux temperature overnight and evaporated to dryness. The residue is chromatographed on silica gel using benzene-ethyl acetate (4:1). The eluate is evaporated and the residue is crystallized from chlorofrom-ether to give the title compound, m.p. 173°-174° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]=O)[CH:9]=O)=[CH:4][CH:3]=1.[CH3:13][NH:14][NH2:15]>C(O)C>[CH3:13][N:14]1[CH:11]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:9]=[N:15]1
Reactant: CNN
Reactant: Cc1ccc(C(C=O)C=O)cc1
Solvent: CCO
Product: Cc1ccc(-c2cnn(C)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixture of 2-(4-methylphenyl)-malondialdehyde (3.05 g), absolute ethanol (40 ml), and methylhydrazine (1.09 g) was stirred at room temperature for 18 hours and the volatiles removed at room temperature. Water was added and the mixture was extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solution was filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a steam bath with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (2.91 g), m.p. 107-108° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[NH:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.C(#N)C>O>[Br:22][C:16]1[C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:21])=[N:13][NH:14][C:15]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(OC[C@H](C)NC(=O)OC(C)(C)C)n[nH]1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1[nH]nc(OC[C@H](C)NC(=O)OC(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A mixture of methyl 3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-1H-pyrazole-5-carboxylate (2.00 g), N-bromosuccinimide (1.43 g) and acetonitrile (50 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white powder (2.20 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:21][O:22][CH2:23][C@H:24]1[C@H:33]2[CH2:34][CH2:35][N:36]([C:37]([C@H:39]3[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]3[NH2:45])=[O:38])[C@H:32]2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:25]1>>[CH3:21][O:22][CH2:23][C@H:24]1[C@H:33]2[CH2:34][CH2:35][N:36]([C:37]([C@H:39]3[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]3[NH:45][C:14]([C:13]3[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:18][CH:17]=3)=[O:16])=[O:38])[C@H:32]2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:25]1
Reactant: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: Cl
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
In the same manner as in Reference Example 19 and using 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid and (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine dihydrochloride, the title compound was synthesized.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:6]2[CH:10]=[N:9][N:8]=[C:7]2[C:11]2[CH:12]=[C:13]([NH:17][C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:27]=[N:28][C:29](F)=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH2:5][CH2:4]1.[CH:33]1([OH:37])[CH2:36][CH2:35][CH2:34]1>>[CH:33]1([O:37][C:29]2[N:28]=[CH:27][C:26]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([C:18]([NH:17][C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:7]5[N:6]([CH:3]6[CH2:5][CH2:4]6)[CH:10]=[N:9][N:8]=5)[CH:12]=4)=[O:19])[CH:25]=3)=[CH:31][CH:30]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2ccc(F)nc2)ccn1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2ccc(OC3CCC3)nc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
Sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol) was added to 0.5 mL of cyclobutanol and the reaction mixture was stirred for 10 minutes at room temperature. (N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-6-fluoro-3,4′-bipyridine-2′-carboxamide) (24 mg, 0.06 mmol) in cyclobutanol (0.2 mL) was added and the reaction mixture was heated to 90° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, neutralized with 1 M HCl and purified by reverse-phase HPLC to give the product as a white powder (15 mg, 55% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11]Cl)[CH:9]=[CH:10][C:4]=2[O:3]1.[OH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1Cc2cc(CCl)ccc2O1
Reactant: CON(C)C(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Nc1cccc(OCc2ccc3c(c2)CC(C)O3)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
2.8 g of 2,3-dihydro-2-methyl-5-benzofuranylmethyl chloride and 3.0 g of 1-(3-hydroxyphenyl)-3-methoxy-3-methylurea were dissolved into 20 ml of dried N,N-dimethylformamide, and 2.5 g of anhydrous potassium carbonate was added thereto. After the mixture was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was dried off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 3.7 g of Compound No. 46 shown in Table 2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH:33]=O)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH2:33][NH:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Product: Cc1ccc(N2CCN(CCNCc3cc(CC(C)C)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 69.2 %

Procedure:
Compound 29 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([Cl:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1Cl
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1Cl

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-chloro-4-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 533.