Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[O:7][C@@H:6]([O:11][C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]3[C:15]([CH:16]=[C:17]([NH:29][C:30](=[O:39])OCC4C=CC=CC=4)[C:18](=[O:28])[O:19]3)=[CH:14][CH:13]=2)[C@@H:5]2[O:40]C(=O)[O:42][C@H:4]12.CCN=C=NCCCN(C)C.[NH:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:57]=[C:56]1C(O)=O.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[OH:40][C@@H:5]1[C@H:4]([OH:42])[C@@H:3]([O:2][CH3:1])[C:8]([CH3:10])([CH3:9])[O:7][C@H:6]1[O:11][C:12]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:20]2[C:15]([CH:16]=[C:17]([NH:29][C:30]([C:56]3[NH:55][C:63]4[C:58]([CH:57]=3)=[CH:59][CH:60]=[CH:61][CH:62]=4)=[O:39])[C:18](=[O:28])[O:19]2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2ccc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2-c2ccccc2)OC1(C)C
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](Oc2ccc3cc(NC(=O)c4cc5ccccc5[nH]4)c(=O)oc3c2-c2ccccc2)OC1(C)C
Reaction time: 12 h
Yield: 9.1 %

Procedure:
Palladium on carbon (10%, 14 mg) was added to 25f (68.0 mg, 0.12 mmol) in anhydrous THF (800 μL) and the solution was placed under an atmosphere of H2. After 12 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (52.0 mg, 99%). EDCI (18.5 mg, 0.096 mmol) and 1H-indole-2-carboxylic acid (12.4 mg, 0.077 mmol) were added to the amine (17.5 mg, 0.039 mmol) in 30% pyridine/CH2Cl2 (1.10 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (8.20 mg, 36%). Triethylamine (150 mL) was added to the carbonate (8.2 mg, 0.014 mmol) in MeOH (1.00 mL) and CH2Cl2 (1.00 mL). After 48 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford 26n as a colorless amorphous solid (4.00 mg, 51%, 18% over 3 steps): 1H NMR (CD2Cl2, 500 MHz) 9.23 (s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 7.71 (dd, J=8.0, 0.7 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.51-7.48 (m, 3H), 7.46-7.44 (m, 1H), 7.37-7.32 (m, 4H), 7.19-7.17 (m, 2H), 5.53 (d, J=2.4 Hz, 1H), 3.86 (s, 1H), 3.76-3.73 (m, 2H), 3.51 (s, 3H), 3.23 (d, J=9.1 Hz, 1H), 2.41 (s, 1H), 1.34 (s, 3H), 1.05 (s, 3H); 13C NMR (CD2Cl2, 125 MHz) δ 159.1, 157.9, 154.5, 147.3, 136.0 (2C), 130.7 (2C), 129.8, 129.2, 127.3, 127.1, 127.0, 126.9, 124.5, 122.8, 121.6, 121.2, 120.3, 113.7, 111.4, 111.1, 103.1 (2C), 97.5, 83.2, 77.7, 70.1, 67.5, 60.8, 21.9, 21.7; IR (film) νmax 3427, 2961, 2924, 2853, 2062, 1643, 1614, 1537, 1362, 1236, 1094, 1041, 962, 791, 739, 698 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C32H30N2O8, 593.1900. found, 593.1890.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].CS(O[CH2:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15]1)(=O)=O>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2([CH2:13][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:17][CH2:16][CH2:15]2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCC1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(C2(Cn3cncn3)CCC2)cc1
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
4.1 g of 1,2,4-triazole in 15 ml of N,N-dimethylformamide were added to 0.66 g of sodium hydride (80% strength dispersion in mineral oil) in 15 ml of N,N-dimethylformamide at room temperature, under nitrogen. The mixture was stirred for 30 minutes, after which 5.1 g of [1-(4-chlorophenyl)-cyclobut-1-yl]-methyl methanesulfonate in 15 ml of N,N-dimethylformamide were added dropwise, and the mixture was stirred for 24 hours at room temperature and for 12 hours at 100° C., then hydrolyzed with water and extracted with ethyl acetate. 2.6 g of 1-(4-chlorophenyl)-1-(1,2,4-triazol-1-ylmethyl)-cyclobutane of melting point 124°-125° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].O/[N:23]=[C:24](\[NH2:32])/[CH2:25][CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29]>>[NH2:32]/[C:24](=[N:23]\[O:10][C:9](=[O:11])[C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])/[CH2:25][CH2:26][NH:27][S:28](=[O:30])(=[O:29])[CH3:31]
Reactant: CS(=O)(=O)NCC/C(N)=N/O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)CCNS(C)(=O)=O

Procedure:
Method as for preparation 2 using (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (preparation 168) (670 mg, 2.25 mmol) and (1Z)-N′-hydroxy-3-[(methylsulfonyl)amino]propanimidamide (preparation 30) (700 mg, 2.50 mmol) as starting materials to afford the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14](C(C)(C)C)[C:13]([OH:20])=[C:12](C(C)(C)C)[CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a solution of 5.0 g (15 mmol) of 4-(4'nitrophenyl)-2,6-di-tert-butylphenol in 50 mL of toluene was added a solution of 9.2 g (69 mmol) of aluminum chloride in 10 mL of nitromethane. This mixture was stirred at ambient temperature for 4 hours and poured into 100 mL of 1N HC1 mixed with ice. The resulting aqueous mixture was extracted with two 100-mL portions of ethyl acetate. Combination, drying (MgSO4), and concentration of the organic layers resulted in crystallization of 2.3 g (69% yield) of yellow 4-(4'-nitrophenyl)phenol, which may also be named as 4'-nitro-(1,1'-biphenyl)-4-ol: 1H NMR (DMSO-d6) 6.93 (d, 2H, J=9Hz), 7.64 (d, 2H, J=9Hz), 7.82 (d, 2H, J=9Hz), 8.25 (d, 2H, J=9Hz), 9.98 (broad s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=1>>[CH3:30][N:29]1[C:25]([CH2:24][N:15]2[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:22])[CH:12]=3)[C:14]2=[O:21])=[CH:26][C:27]([CH3:31])=[N:28]1
Reactant: Cc1cc(CCl)n(C)n1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)n(C)n1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole. MS 412 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.23 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>C(O)(C)C>[CH2:10]([O:12][C:13]([C:14]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cccc(Cl)c1
Yield: 76 %

Procedure:
Upon boiling a solution of 7.1 g of 3-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 40 ml of isopropanol for 8 hours, 2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 121° C is obtained.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH:15]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:16]3[CH:15]=[C:14]([C:5]4[CH:4]=[C:3]([OH:2])[N:7]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=5)[N:6]=4)[CH:19]=[CH:18][CH:17]=3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccc4c(c3)OCO4)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2cccc(-c3ccc4c(c3)OCO4)c2)nn1-c1ccccn1
Yield: 98 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 39 of Example C-13 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.F[C:16]1[C:17]([CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)=[N:18][CH:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[C:17]([CH:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: CC(=O)N1CCC(c2nccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of 4-(pyridin-2-ylamino)phenol (47 mg, 0.25 mmol), 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (56 mg, 0.25 mmol), and cesium carbonate (123 mg, 0.376 mmol) in DMSO (0.85 mL) was heated at 80° C. for 20 h. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, then 3% MeOH in EtOAc, to provide 1-(4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as off-white solid. MS (ESI, pos. ion) m/z: 389.9 (M+1). IC50 (uM) 0.003589.
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].[Cl-].[NH4+].CN(C)[CH2:21][CH2:22]N(C)C>N1C=CC=CC=1>[CH3:13][CH:12]([CH2:11][CH2:10][CH2:9][CH:21]([CH3:22])[CH2:7][CH2:6][CH2:5][C:2]([CH3:1])([OH:16])[C:3]#[C:4][C:4]#[C:3][C:2]([CH3:1])([OH:16])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH3:14]
Reactant: CN(C)CCN(C)C
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)(O)C#CC#CC(C)(O)CCCC(C)CCCC(C)C
Yield: 81.8 %

Procedure:
In a 1-l. three-necked and round-bottomed flask were placed 10.5 g of 3,7,11-trimethyldodeca-l-yne-3ol, 5.0 g of ammonium chloride, 12.0 g of tetramethylethylenediamine and 675 ml of pyridine. The mixture was reacted at temperatures of 50° - 55°C for 6 hours under an oxygen atmosphere. After completion of the reaction, the alcohol as a starting material was not detected. After distillation of pyridine from the reaction mixture, 300 ml of benzene and 200 ml of water were added to the residue and after decantation, the organic layer was washed with 3N--H2SO4 and then water and dried. The benzene solution was distilled off to give 8.55 g of 2,6,10,15,19,23-hexamethyltetracosa-11,13-diyne-10,15-diol as viscous liquid. This compound was treated with active carbon and purified in the same manner as in reference 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[CH:13][C:12]=2[C:16](OCC)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[CH:13][C:12]=2[CH2:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1cnoc1-c1ccc(OC)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(-c2oncc2CO)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of ethyl 5-(3,4-dimethoxyphenyl)isoxazole-4-carboxylate (8.40 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 65 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(3,4-dimethoxyphenyl)-4-isoxazolylmethanol (6.85 g, yield 96%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 83–84° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1.[CH3:22]/[C:23](=[CH:26]\[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[CH:24]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CCCCCC.C(OCC)(=O)C.ClCCCl>[CH3:22]/[C:23](=[CH:26]\[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[CH2:24][NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1
Reactant: C/C(C=O)=C\c1ccccc1
Reactant: NCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C/C(=C\c1ccccc1)CNCC1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Yield: 86 %

Procedure:
A mixture of 4-aminomethyl-1-(1-naphthylsulfonyl)piperidine (intermediate in the preparation of the compound of Example 34, 450 mg, 1.5 mmol), (E)-2-methyl-3-phenylpropenal (438 mg, 3.0 mmol), acetic acid (240 mg, 4.0 mmol), and 1,2-dichloroethane (50 mL) was stirred under argon at room temperature for 3 h before sodium triacetoxyborohydride (1.27 g, 6.0 mmol) and more acetic acid (360 mg, 6.0 mmol) were added. After 16 h saturated aqueous sodium bicarbonate (50 mL) was added, and the aqueous and organic phases were separated. The aqueous phase was extracted with dichloromethane (50 mL twice), and the combined organic phases were dried (anhydrous sodium sulfate) and evaporated under vacuum. Column chromatography (silica gel, gradient of ethyl acetate in hexane rising to 100% ethyl acetate) provided 4-(N-(2-methyl-3-phenyl-2-(E)-propenyl)aminomethyl)-1-(1-naphthylsulfonyl)piperidine (561 mg, 86% yield) as an oil. TLC Rf=0.18, 100% ethyl acetate.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([P:35](Cl)(Cl)=[O:36])=[CH:31][CH:30]=1>CCCCCC.C(OCC)C.C1CCCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([P:35]2(=[O:36])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:31][CH:30]=1
Reactant: O=P(Cl)(Cl)c1ccc(Cl)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=P1(c2ccc(Cl)cc2)c2ccccc2CN1c1ccccc1
Temperature: 26 °C
Reaction time: 2 h
Yield: 9.8 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (4.03 g, 0.063 mol) in hexane was added to a solution of tetramethylethylenediamine (1.86 g, 0.016 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. The suspension was stirred for 2 hours at 26° C. and then cooled to 0° C. A solution of 4-chlorophenylphosphonic dichloride (7.35 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was rapidly added to the suspension. After stirring for 15 minutes at 0° C., the resulting mixture was stirred for 2 hours at 26° C. The reaction mixture was cooled to 0° C., then quenched with the rapid addition of 6 ml. of acetic acid. After stirring for 15 minutes, the cyclohexane was removed on a rotary evaporator and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then water, dried with sodium sulfate and concentrated in vacuo to yield a blue oil. The blue oil was separated on a silica gel column using first methylene chloride then a 3:1 mixture of methylene chloride:ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to yield a crude product. The crude product was slurried in anhydrous diethyl ether to yield 1-(4-chlorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.0 g, 5% yield) as a white crystalline solid having a melting point of 180°-182° C. and the following analysis:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.C(N(CC)CC)C.[NH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1>CC(C)=O.CN(C)C1C=CN=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.3 %

Procedure:
A solution of 4,5-diisopropylfuran-2-carboxylic acid (50 mg, 0.255 mmol) and cyanuric chloride (71 mg, 0.385 mmol) in acetone (3 ml) was added with triethylamine (142 μl, 1.021 mmol), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was added with methyl 4-aminobenzoate (77 mg, 0.510 mmol), and the mixture was further stirred for 14 hours. The reaction solvent was evaporated, then the residue was dissolved in pyridine (1 ml), the solution was added with 4-dimethylaminopyridine (1 mg, 8.20 μmol), and the mixture was stirred at room temperature for 4 hours. Pyridine was evaporated, and then the reaction mixture was dissolved in 10% methanol-chloroform, the solution was added with silica gel (1.0 g), and the mixture was evaporated to dryness. The residue was purified by silica gel chromatography [hexane-ethyl acetate (6:1)] to obtain methyl 4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (75 mg, 89%) as colorless prisms.
Reaction SMILES: [CH3:1][Li].[C:3]([CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9])#[N:4]>C1COCC1>[CH3:1][C:8]1[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:3]([NH2:4])[N:9]=1
Reactant: [Li]C
Reactant: N#CCc1ccccc1C#N
Solvent: C1CCOC1
Product: Cc1nc(N)cc2ccccc12
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a dry flask under N2 containing methyllithium (13 mL, 21 mmol) in THF (40 mL) at 0° C. was added a solution of 2-(cyanomethyl)benzonitrile (1.00 g, 7.03 mmol) in THF (20 mL) dropwise. After 10 minutes the ice bath was removed and the mixture was allowed to warm to ambient temperature. The mixture was quenched with saturated aqueous NH4Cl and then concentrated. The mixture was extracted twice with CH2Cl2, and the combined organic extracts were washed with brine and dried (Na2SO4). Purification by chromatography (SiO2, 10% acetone/hexanes) afforded the title compound 0.71 g (79% yield). MS (ESI) m/z 159 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])(C)[O:7]2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23](=[O:26])[CH2:24][CH3:25]>CN(C)C=O>[CH3:13][C:11]1([CH3:12])[CH:8]([CH3:10])[O:7][B:6]([C:4]2[CH:5]=[N:1][N:2]([CH2:22][C:23](=[O:26])[CH2:24][CH3:25])[CH:3]=2)[O:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(=O)Cn1cc(B2OC(C)C(C)(C)O2)cn1
Temperature: 90 °C
Yield: 14.8 %

Procedure:
Pyrazole-4-boronic acid pinacol ester (1 g, 1 equiv, 5.15 mmol) was dissolved in dimethylformamide (15 mL) followed by the addition of Cs2CO3 (0.86 g, 1.5 equiv, 7.73 mmol) and 1-bromo-2-butanone (1.1 equiv, 5.67 mmol, 0.86 g). The mixture was heated at 90° C. overnight. The reaction was extracted into ethyl acetate and washed with water (3×) and brine (3×). The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20) to return the title compound (0.19 g, 14% yield). 1H NMR 500 MHz (DMSO) δ 0.97 (3H, t) 1.26 (12H, s), 2.50 (2H, q), 4.71 (2H, s), 7.65 (1H, s), 8.04 (1H, s). MS m/z 265 (M+H+)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)=[CH:11][N:10]([C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[N:28][N:29]=4)[N:26]=3)[N:9]=2)=[CH:4][CH:3]=1.NC1C=C(C2C(C3C=CC(F)=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1.[CH:58]1([C:61](Cl)=[O:62])[CH2:60][CH2:59]1>>[CH:58]1([C:61]([CH2:20][NH:19][C:15]2[CH:14]=[C:13]([C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][N:10]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([CH:27]=[N:28][N:29]=5)[N:26]=4)[CH:11]=3)[CH:18]=[CH:17][N:16]=2)=[O:62])[CH2:60][CH2:59]1
Reactant: O=C(Cl)C1CC1
Reactant: CNc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Agent: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Product: O=C(CNc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1)C1CC1
Yield: 79.4 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 100 mg (0.26 mmol) of 3-(4-fluorophenyl)-4-(2-methylaminopyridin-4-yl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 13-2) in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole, and using 81.2 mg (0.78 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 93.8 mg of the title compound as a pale yellow-powder. (Yield: 80%)
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH2:20])=[S:19])=[CH:16][C:3]1=2.Cl[CH2:22][CH:23]=O>C(O)C>[S:19]1[CH:23]=[CH:22][N:20]=[C:18]1[NH:17][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: O=CCCl
Reactant: NC(=S)Nc1ccc2c(c1)C(=O)Nc1ccccc1N2
Solvent: CCO
Product: O=C1Nc2ccccc2Nc2ccc(Nc3nccs3)cc21
Yield: 40 %

Procedure:
To a solution of (11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-2-yl)-thiourea (Example 9, 75 mg, 0.26 mmol) in ethanol (10 mL) was added chloroacetaldehyde (50% in water, 0.1 mL). The solution was refluxed for 5 hr and then concentrated under vacuum and poured into water (5 mL). The solution pH was adjusted to 9 with aqueous saturated sodium bicarbonate and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent evaporated. The residue was recrystallized from ethanol/hexanes to give yellow solid (30 mg, 40%).