Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[N:9][N:10](C(OCC)=O)[C:4]=2[CH:3]=1.[C:21]1([C@H:27]([NH:29][C:30]([NH2:32])=[O:31])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(P(C(C)(C)C)C1N(C2C(C3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2C2C=CC=CC=2)N=CC=1)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O-])([O-])=O.[K+].[K+]>COCCOC.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]>[CH3:20][O:19][CH2:18][CH2:17][O:16][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:32][C:30]([NH:29][C@@H:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:28])=[O:31])=[CH:3][C:4]=2[NH:10][N:9]=1
Reactant: CCOC(=O)n1nc(OCCOC)c2cnc(Cl)cc21
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccnn1-c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COCCOc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 85 °C
Reaction time: 16 h

Procedure:
Ethyl 6-chloro-3-(2-methoxyethoxy)-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (100 mg, 0.334 mmol), (R)-1-(1-phenylethyl)urea (68.5 mg, 0.417 mmol), bippyphos (15.21 mg, 0.030 mmol), Pd2(dba)3 (7.4 mg, 8.08 μmol), and tripotassium phosphate (106 mg, 0.500 mmol) were taken up in DME (1.6 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 85° C. for 16 h. Room temperature was attained, the reaction mixture filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. The residue was taken up in MeOH (3 mL) and K2CO3 (118 mg, 0.854 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. The mixture was filtered through Celite and the filtrate concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (0-10% MeOH-DCM) followed by purification by mass triggered, reverse phase prep-HPLC. The fractions containing pure product were concentrated in vacuo, lyophilized, and dissolved in MeOH. The solution was filtered through a PS—HCO3 cartridge, eluting with MeOH. The filtrate was concentrated in vacuo to give (R)-1-(3-(2-methoxyethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C18H21N5O3 [M+1]+ 356. found 356. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 7.75 (br s, 1H), 7.48 (s, 1H), 7.34-7.31 (m, 4H), 7.25-7.20 (m, 1H), 4.88-4.82 (m, 1H), 4.81-4.39 (m, 2H), 3.71-3.69 (m, 2H), 3.30 (s, 3H), 1.39 (d, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>O1CCCC1>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)([O-:21])=[O:20]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1Oc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a stirred solution of 2-hydroxynaphthalene (5 g, 34.7 mmol) in anhydrous tetrahydrofuran was added 2-fluoronitrobenzene (4.90 g, 34.7 mmol) at room temperature. The resultant mixture was heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water, the resulting mixture was extracted twice with methylene chloride and the combined extracts were dried (MgSO4). The resultant organic layer was concentrated under reduced pressure to yield 9.2 g of the title compound of Step A as an oil. Rf 0.45 (silica gel, 4:1 hexane-ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1.[CH2:17](O)[CH2:18][OH:19].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]2[O:19][CH2:18][CH2:17][O:14]2)=[C:8]([CH3:15])[CH:7]=1
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cc(C)c(C2OCCO2)c(C)c1

Procedure:
To a stirred solution of 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester, (2.2 g, 10 mmol) and ethane-1,2-diol (1.86 g, 30 mmol) in toluene (50 mL) was added p-TsOH.H2O (38 mg, 0.2 mmol) and the solution was refluxed using a Dean-Stark apparatus overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (5:1) as eluent to give 3-(4-[1,3]dioxolan-2-yl-3,5-dimethylphenyl)-propionic acid methyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17]1([NH2:21])[CH2:20][CH2:19][CH2:18]1.ClC1C2N(C(C)=NN=2)C2C(N=1)=CC=CC=2.C1(N)CCCC1>>[CH:17]1([NH:21][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][CH2:18]1
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: NC1CCC1
Agent: Cc1nnc2c(Cl)nc3ccccc3n12
Agent: NC1CCCC1
Product: CCc1nnc2c(NC3CCC3)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 2 substituting 4-chloro-1-ethyl [1,2,4]triazolo[4,3-a]quinoxaline and cyclobutyl amine for 4-chloro-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline and cyclopentanamine respectively; mp 215°-217° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[O:25])[CH:23]=2)=[O:16])=[CH:10][CH:9]=1.[CH3:35][S:36][CH2:37]Cl.O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:26]3[C:34]4[CH:33]=[N:32][CH:31]=[N:30][C:29]=4[N:28]([CH2:35][S:36][CH3:37])[CH:27]=3)=[O:25])[CH:23]=2)=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Reactant: CSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Potassium carbonate (38 mg, 0.275 mmol) was added to a stirring solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 60.0 mg, 0.153 mmol) in DMF (1.0 mL) at room temperature. After 10 min, chloromethyl methyl sulfide (19 μL, 0.23 mmol) was added to the mixture and the reaction was stirred for 24 hours at room temperature. Water (3 mL) was added to the mixture and it was extracted with EtOAc (3×5 mL). The combined organic fractions were washed with water (5 mL), brine (5 mL), dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow oil. The crude material was purified by column chromatography on silica gel (gradient of 100% DCM to 90:10:1 DCM/MeOH/NH3) to give the title compound as a pale yellow solid in 36% yield, 25 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[Cl:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Nc1ccccc1Cl
Product: Clc1ccccc1NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
6-Bromo-N-(2-chlorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (200 mg, 0.76 mmol) and 2-chloroaniline (193 mg, 1.51 mmol) in a similar manner as described above to give 43 mg (15%) of a white solid; 1H-NMR (DMSO-d6): δ 11.08 (s, 1H), 7.57 (d, 1H), 7.27-7.23 (m, 2H), 7.16-7.12 (m, 2H), 6.92 (d, 1H), 6.64-6.60 (m, 1H), 5.12 (d, 1H), 4.95-4.90 (m, 1H), 2.71-2.56 (m, 2H), 2.04-1.76 (m, 4H); MS m/z (M−1) 373, 375.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.C([O:12][C:13](=[O:43])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=3Br)[CH:24]=2)=[CH:18][C:17]=1[CH3:42])C>>[Cl:29][C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([O:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][C:36]=2[C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[CH:26]=1)[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:43])=[O:12])=[C:17]([CH3:42])[CH:18]=1
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cc(Cl)cc(Oc3ccc(C(F)(F)F)cc3-c3cncnc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using pyrimidine-5-boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-chloro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester to afford about 31 mg (22%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C27H20O4F3N2Cl 528, found 529 (M+1, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Si]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([F:25])[CH:19]=1)(C(C)(C)C)(C)C>C(O)(CC)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:17]([N:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:7][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:33]=3)=[CH:28][C:27]2=[O:42])[CH2:16][OH:15])=[CH:19][C:20]=1[F:25]
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Solvent: CCC(C)O
Product: Cn1cc(Nc2nccc(-c3ccn([C@H](CO)c4ccc(Cl)c(F)c4)c(=O)c3)n2)cn1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
A solution of 1-methyl-1H-pyrazol-4-amine (0.054 g, 0.56 mmol) and (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (0.060 g, 0.11 mmol) in sec-BuOH (1 mL) was heated to 120° C. in a microwave reactor for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate and washed with H2O (2×). The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with DCM/MeOH (25:1) to give (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.013 g, 26%). 1H NMR (400 MHz, CD3OD) δ 8.50 (d, J=5.0 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J=7.0 Hz, 1H), 7.58 (s, 1H), 7.48 (m, 1H), 7.34-7.28 (m, 2H), 7.20-7.17 (m, 2H), 7.06 (m, 1H), 6.12 (m, 1H), 4.28 (m, 1H), 4.19 (m, 1H), 3.88 (s, 3H); m/z (APCI-pos) M+1=441.1, 443.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12].[H][H].C(OCC)(=O)C>CO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:11]([OH:13])[CH3:12]
Reactant: [H][H]
Reactant: CC(O)c1cc([N+](=O)[O-])ccc1N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1cc(N)ccc1N
Yield: 100 %

Procedure:
Catalytic hydrogenation of 6 (27.0 g, 150 mmole) under 60 psi hydrogen pressure with 10% Pd/C (2.7 g) in anhydrous MeOH (150 mL)/ethyl acetate (150 mL) was completed in 2.5 h. The catalyst was removed by filtration over Celite. The filtrate was evaporated under vacuum to afford 1-(2,5-diamino-phenyl)-ethanol 1 (22.83 g, 100 % yield). Mp 124° C.; 1HNMR (400 MHz, DMSO-d6) δ1.26 (d, 3H, J=6.4 Hz), 4.15 (d, 4H, J=10.7 Hz), 4.61-4.65 (m, 1H), 4.94 (d, 1H, J=3.6 Hz), 6.24 (dd, 1H, J=2.5, 8.2 Hz), 6.36 (d, 1H, J=8.2 Hz), 6.45 (d, 1H, J=2.5 Hz); MS m/z 152 (M+); Anal. Calcd. for C8H12N2O: C, 63.13. H, 7.95. N, 18.41.O, 10.51. Found: C, 62.83. H, 7.90. N, 18.46. O, 10.17.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[CH2:8][CH2:9][N:10]([CH3:37])[C:11]1[C:12]([NH2:36])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:38][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:37])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:36][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Reaction time: 1.5 h
Yield: 39.5 %

Procedure:
A solution of acryloyl chloride (34.5 mg, 0.38 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 170 mg, 0.38 mmol) and DIPEA (0.073 mL, 0.42 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH2Cl2 (25 mL) and washed with sat.NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (75 mg, 39%) as a cream solid after trituration with diethyl ether; 1H NMR: 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.20-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s); m/z: ES+ MH+ 500.42.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:24].[CH3:25][NH:26][OH:27].Cl.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:26]([CH3:25])[O:27][C:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)([C:11]([F:14])([F:13])[F:12])[CH:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: CNO
Reactant: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1Br

Procedure:
300 mg 1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (IVa), 80 mg MeNHOH.HCl and 100 mg triethylamine were refluxed in 2 ml of ethanol for 18 hours. After evaporation of the solvent the residue was purified on silica gel giving 210 mg (65%) of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole (IIIa) as a colorless resin.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[N:8][CH:7]=1)=[O:5].[CH3:13][Mg]Br.[Cl-].[Na+]>O1CCCC1>[N:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH3:13])=[CH:7][N:8]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccnnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccnnc1
Reaction time: 1 h
Yield: 42 %

Procedure:
To N-methoxy-N-methylpyridazine-4-carboxamide (1.13 g, 6.76 mmol) in tetrahydrofuran (22 mL), methylmagnesium bromide (10.1 mL, 10.1 mmol, 1M in diethyl ether) was added dropwise at 0° C. in a nitrogen stream, and the resulting solution was stirred for 1 hour. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with chloroform, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2→0/1) to give the desired product (42% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl-].[CH3:23][O:24][C:25](=[O:31])[CH2:26][CH2:27][C:28](O)=[O:29]>N1C=CC=CC=1>[C:28]([O:21][C:18]1[CH:17]=[CH:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:20][CH:19]=1)(=[O:29])[CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:31]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(O)cc2)cc1OC
Reactant: COC(=O)CCC(=O)O
Agent: [Cl-]
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Oc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 90 %

Procedure:
Compound 1 (50 mg) and succinic acid monomethyl ester chloride (44 μL) were dissolved in pyridine (1 mL), followed by stirring for a whole day and night. After completion of reaction, the resultant reaction mixture was concentrated to dryness under reduced pressure, followed by purification by means of silica gel chromatography employing a chloroform/methanol system, to thereby produce the target product (63 mg, yield: 90%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:12][NH2:13])=[S:11])[CH3:2].C(O)(=O)C.[N:18]([O-])=O.[Na+]>O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[S:11][N:18]=[N:13][N:12]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCc1ccccc1NC(=S)NN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccccc1Nc1nnns1

Procedure:
To a stirred and cooled mixture of N-(2-ethylphenyl)hydrazinecarbothioamide (0.500 g, 2.56 mmol) and acetic acid (2.00 mL, 17.5 mmol) was added sodium nitrite (0.177 g, 2.56 mmol) in water (1 mL). The mixture turned yellow upon addition and the reaction was stirred for 1 hour. The solid was filtered and the title compound was obtained as an orange solid (0.389 g, 73%): 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.42-7.28 (m, 4H), 2.76 (q, J=7.5 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 138.69, 137.90, 130.38, 128.28, 128.14, 121.60, 24.73, 14.79; ESIMS m/z 179 ([M+H]-N2+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([C:25]([F:28])([F:27])[F:26])([O:20][Si](C)(C)C)[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[C:11]=1[O:18][CH3:19])([CH3:9])[CH3:8])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:29])[C:5]([C:25]([F:27])([F:26])[F:28])([OH:20])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[C:11]=1[O:18][CH3:19])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)(C)c1ccc(Cl)c(F)c1OC)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Temperature: 25 °C
Yield: 77.4 %

Procedure:
4.71 g (10.26 mmol) of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in 57 ml of tetrahydrofuran and mixed with 3.24 g (10.26 mmol) of tetrabutylammonium fluoride: after stirring over the weekend at room temperature, the reaction mixture is mixed with water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with brine. After the drying, the solvent is spun off, and the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 3.07 g (77.4%) of the desired compound is isolated.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)C1C=CC=CC=1.[ClH:23].CO>[Pd]>[ClH:23].[F:22][C:19]1[CH:18]=[CH:17][C:16]([N:11]2[CH2:10][CH:9]3[CH2:15][CH2:14][CH:12]2[CH2:13][NH:8]3)=[CH:21][CH:20]=1
Reactant: Fc1ccc(N2CC3CCC2CN3Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1ccc(N2CC3CCC2CN3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
2-Benzyl-5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.2]octane (1.1 g, 3.71 mmol) was dissolved in 1N hydrochloric acid/methanol (60 mL); 10% palladium on carbon (0.50 g) was then added under nitrogen. A hydrogenation was then carried out at 1 atmosphere for 2 hours. The reaction mixture was then filtered through Celite and concentrated to yield 2-(4-fluorophenyl)-2,5-diazabicyclo[2.2.2]octane, hydrochoride salt (0.90 g, 100%) as an off-white solid which had the following properties: Mp. 154-156° C.; 1H NMR CDCl3 δ: 9.74 (brd s, 1H), 9.67 (brd s, 1H), 7.00 (t, J=9.1 Hz, 2H), 6.68-6.61 (m, 2H), 4.07 (s, 1H), 3.70 (brd s, 1H), 3.63 (d, J=11.2 Hz, 1H), 3.29 (d, J=10.8 Hz, 1H), 3.23 (brd s, 2H), 2.19-2.04 (m, 1H), 1.95-1.83 (m, 1H), 1.81-1.64 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:7][NH2:8])[CH3:3].[CH:20]([O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](O)=[O:33])[CH:28]=[CH:29][CH:30]=1)([CH2:22][CH3:23])[CH3:21].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH2:2]([O:4][C:5](=[O:19])[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:7][NH:8][C:32](=[O:33])[CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH:20]([CH2:22][CH3:23])[CH3:21])[CH:26]=1)[CH3:3]
Reactant: CCC(C)Oc1cccc(CC(=O)O)c1
Reactant: CCOC(=O)C(CN)c1ccc(OC)c(OC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CNC(=O)Cc1cccc(OC(C)CC)c1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
To a stirred solution 3-amino-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester hydrochloride (6.5 g, 25.8 mmol) and (3-sec-butoxy-phenyl)-acetic acid (5.9 g, 28.4 mmol) in N,N-dimethylformamide (130 mL) was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium hexaflurophosphate (HBTU) (11.8 g, 31.1 mmol) and diisopropylethylamine (14.8 mL, 85.0 mmol). The reaction mixture was stirred at room temperature for 15 hrs. The solvent was evaporated and the residue was diluted with ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with 1N hydrogen chloride solution (50 mL), water (50 mL), saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane, 100% ethyl acetate) afforded 3-[2-(3-sec-butoxy-phenyl)-acetylamino]-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester (11.2 g, 98% yield) as a red oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Yield: 91.2 %

Procedure:
An amount of 15.14 g (58.9 mmol) of 9-bromoanthracene, 7.2 g (59 mmol) of phenylboronic acid, and 1 g of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 100 ml of toluene and 25 ml of ethanol. Then, 50 ml of 2M sodium carbonate solution was added to the mixed solvent and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 13.65 g (53.7 mmol) of 9-phenylanthracene. The yield was 91.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Fc1ccc(-c2cc(CCl)ccn2)cc1F
Product: COc1ccc(N(Cc2ccnc(-c3ccc(F)c(F)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3,4-difluorophenyl)pyridine (240 mg) were condensed in the same manner as described in Example 9 to give the title compound.