Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4].[CH3:23][S:24]C1C=C(NC2C(C(OC)=O)=CC=CN=2)C=CC=1.C1(NC2C(C(OC)=O)=CC=CN=2)C=CC=CC=1>>[CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([S:24][CH3:23])[CH:21]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1cccnc1Nc1cccc(SC)c1
Reactant: CCCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Agent: COC(=O)c1cccnc1Nc1ccccc1
Product: CCCCc1c(O)c2cccnc2n(-c2cccc(SC)c2)c1=O

Procedure:
Prepare the 3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)one by the process of Example 1 by replacing the methyl 2-(3-methylthiophenylamino)-3-pyridine carboxylate with an equivalent amount of methyl 2-phenylamino-3-pyridine carboxylate.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:22][C:23]([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])=[O:25]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOC(=O)Cl
Yield: 264.6 %

Procedure:
Phytanol (48.8 g, 163.5 mmol), and triphosgene (16.17 g, 54.66 mmol) were dissolve in 300 ml of dichloromethane, stirred and cooled on an ice bath. Anhydrous pyridine (12.93 g, 163.5 mmol) was added dropwise over a period of 1 hour. The reaction mixture was stirred for an additional 1 h at room temperature, and then quickly extracted with extra methylene chloride and ice water. The organic layer was pooled, dried over Na2SO4 and evaporated to dryness to yield 52.22 g (88.7%) of phytanyl chloroformate as yellow liquid. 1H NMR in CDCl3: δ0.83, 0.85, 0.86, 0.88, (4s, each 3H, CH3), 0.91 (d, 3H, J=6.0 Hz, CH3), 0.95-1.40 (m, 20H, CH2), 1.39-1.68 (m, 4H, CH), 1.68-1.88 (m, 1H, OH), 4.27-4.47 (m, 2H, CH2OH).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)=[C:15](Cl)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.C1COCC1.[CH3:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CO>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)=[C:15]([C:39]4[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc3c2Cl)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc3c2-c2ccc(C)cc2)cc1
Temperature: 70 °C
Yield: 61.2 %

Procedure:
To a stirring solution of 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (41.7 mg, 0.10 mmol) in a 1:1 mixture of THF and methanol (4 mL) at room temperature under argon was added 4-methylphenylboronic acid (40.8 g, 0.30 mmol), PXPd (16.2 g, 0.03 mmol), and K2CO3 (41 mg, 0.3 mmol). The resulting suspension was heated at 70° C. under argon for 10 min. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, water (25 mL) and EtOAc (25 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to obtain 29 mg of the title compound as a white lyophilate. HPLC/MS: retention time=4.36 min, [M+H]+=474. 1H NMR (CDCl3): δ 7.78 (d, J=7.5 Hz, 1H), 7.59 (d, J=7.1 Hz, 2H), 7.50 (d, J=7.1 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 7.09-7.00 (m, 6H), 6.65 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccc(-c2ccccc2O)n[nH]1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1ccc(=O)[nH]n1
Reaction time: 4 h

Procedure:
A mixture of 6-(2-hydroxyphenyl)-3(2H)-pyridazinone (20 g), acetic anhydride (60 ml) and pyridine (10 drops) was heated and stirred on a steam-bath for 13/4 hours. The mixture was evaporated under reduced pressure, and the residual oil was treated with water (100 ml) and methanol (10 ml) and was allowed to crystallise to give 6-(2-acetoxyphenyl)-3(2H)-pyridazinone (22.7 g) m.p. 181°-183.5°. A sample recrystallised from 50% aqueous ethanol had m.p. 182.5°-184.5°.
Reaction SMILES: N1C=CN=C1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1COCC1.O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.9 %

Procedure:
Imidazole (1.80 g, 26.1 mmol) and p-methoxyphenol (1.62 g, 13.05 mmol) were suspended in THF (30 mL) and placed under nitrogen. Tert-butyldimethylsilyl chloride (2.23 g, 14.36 mmol) was added and the mixture was stirred for 15 hours at room temperature. The thick white mixture was diluted with water (50 mL) and extracted with ether (3×15 mL). The organic solvent was removed under reduced pressure to give the product as a clear liquid (2.33 g, 75%). Characterization matched literature.
Reaction SMILES: [CH2:1]([CH:5]1[CH:17]2[C:9]([C:10]3[C:15]([CH2:16]2)=[C:14]([CH3:18])[C:13]([O:19]C)=[CH:12][CH:11]=3)=[C:8]([CH3:21])[C:7](=[O:22])[CH2:6]1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([CH:5]1[CH:17]2[C:9]([C:10]3[C:15]([CH2:16]2)=[C:14]([CH3:18])[C:13]([OH:19])=[CH:12][CH:11]=3)=[C:8]([CH3:21])[C:7](=[O:22])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CC(=O)C(C)=C2c3ccc(OC)c(C)c3CC21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC1CC(=O)C(C)=C2c3ccc(O)c(C)c3CC21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 9a butyl-4,8-dimethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (84 mg, 0.28 mmol) in anhydrous CH2Cl2 (3 mL) was placed under a nitrogen atmosphere, cooled in an acetone-dry ice bath, and treated with 1M BBr3 in CH2Cl2 (1.11 mL, 1.11 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water (20 ml) containing 2N HCl (2 mL) followed by brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 10% EtOAc in CH2Cl2. The UV visible product band was eluted with EtOAc and the solvent evaporated under vacuum. The residue was lyophilized from benzene-methanol to afford 9a butyl-4,8-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8](Br)[SiH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH2:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]([SiH:9]([CH3:11])[CH3:10])[O:15][C:16]2[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: OCc1ccc(O)cc1
Reactant: C=CCc1ccc(C(Br)[SiH](C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: C=CCc1ccc(C(Oc2ccc(CO)cc2)[SiH](C)C)cc1
Yield: 92.8 %

Procedure:
A solution of 4-allyldimethylsilylbenzyl bromide (4 Scheme 13, 2.7 g, 10 mmol), 4-hydroxybenzyl alcohol (12.5 g, 10 mmol), tetrabutylammonium iodide (100 mg) and powdered K2CO3 (2.1 g, 15 mmol) in acetone (60 mL) was stirred at 60° C. for 22 h. The precipitated sol was filtered and the filtrate was concentrated. The crude oil was purified by column chromatography (1:3 ethyl acetate/hexanes) to afford a colorless oil (2.9 g, 94%); 1H NMR (300 MHz, CDCl3) δ 0.37 (s, 6 H), 1.84 (d, J=6.30 Hz, 2 H), 2.72 (s, OH, 1 H), 4.58 (s, 2 H), 4.93 (s, 1 H), 4.97 (m, 2 H), 5.09 (s, 1 H), 5.86 (ddt, J=16.80 Hz, 10.50, 8.10 Hz, 1 H), 7.01 (d, J=8.40 Hz, 2 H), 7.30 (d, J=8.40 Hz, 2 H), 7.48 (d, J=7.90 Hz, 2 H), 7.61 (d, J=7.90 Hz, 2 H); 13C NMR (75 MHz, CDCl3) −3.1 (2 C), 24.0, 65.0, 70.2, 113.9, 115.2 (2 C), 127.1 (2 C), 128.9 (2 C), 133.8, 134.2 (2 C), 134.8, 138.1, 138.7, 158.6. HRMS (EI) calcd for C19H24O2Si 312.1545, found 312.1547.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].CN1CCOCC1.ClC(OCC)=O.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:32][CH:29]1[CH2:30][CH2:31][O:26][CH2:27][CH2:28]1)=[O:9])([O-:3])=[O:2]
Reactant: NC1CCOCC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NC1CCOCC1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Under nitrogen atmosphere, 3-nitrobenzoic acid (1.00 g, 5.98 mmol) was taken in THF (20 ml) and the mixture was cooled to 0° C. followed by addition of N-methylmorpholine (0.85 ml, 7.78 mmol) and ethyl chloroformate (6.58 mmol). The reaction mixture was stirred for 30 min at 0° C. and tetrahydro-2H-pyran-4-amine (0.6 ml, 5.98 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under vacuum and the residue was taken in ethyl acetate (20 ml), washed with water and brine, dried over sodium sulfate and concentrated under vacuum to afford the solid product (1.2 gm).
Reaction SMILES: C(O)C.[NH2:4][CH:5]1[C:26](=[O:27])[N:7]2[C:8]([C:13]([O:15]CC3C=CC([N+]([O-])=O)=CC=3)=[O:14])=[C:9]([CH3:12])[CH2:10][S:11][C@H:6]12.Cl>[Fe].O.CO>[NH2:4][CH:5]1[C:26](=[O:27])[N:7]2[C:8]([C:13]([OH:15])=[O:14])=[C:9]([CH3:12])[CH2:10][S:11][C@H:6]12
Reactant: CC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a mixture of ethanol (120 ml) and water (25 ml), p-nitrobenzyl 7-amino-3-methyl-3-cephem-4-carboxylate (10 gm) was added. Iron powder (10 gm) was charged at 30° C., followed by the addition of concentrated HCl (12.5 ml) in a methanol (10 ml) and water (2.5 ml) mixture over a period of 15 minutes. The reaction mixture was stirred for 1 hour. After completion of the reaction, aq. KHCO3 was added to bring the pH to 8.0, followed by the addition of activated carbon. After stirring 10 minutes, the mixture was filtered. To the filtrate was added aq. HCl to bring the pH to 4.0. The product thus separated was filtered and dried to yield 4.3 gm (70.3%) of 7-amino-3-methyl-3-cephem-4-carboxylic acid as a white solid product. M.p. 217°-219° C.(d). IR(KBr) cm-1 3150, 1800, 1650, 1625, 1525, 1420, 1350, 790. NMR (D2O-DCl) δ :2.1 (s, 3 H,--CH3), 5.41(d, 1 H, S--CH), 5.86(m, 1 H, N--CH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.IC.[C:15](=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:15])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(-c2c[nH]cn2)cc1
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1cnc(-c2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of Step 1 product (3.1 g, 13.90 mmol) in 50 mL of THF was added iodomethane (1.74 mL, 27.8 mmol) and cesium carbonate (5.43 g, 16.68 mmol). The reaction was stirred at rt overnight. EtOAc (150 mL) was added to the reaction, and the mixture was washed with water (2 times) and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by silica column (10-80% EtOAc in hexanes) to give 2.8 g (yield 85%) 4-(4-bromophenyl)-1-methyl-1H-imidazole. LCMS: [M+1]+=237.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[C:10]#N)[CH:5]=[CH:6][C:7]=1[F:8].CC(C[AlH]CC(C)C)C.C1C[O:26]CC1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:26])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C#N)c1ccc(F)c(Br)c1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C=O)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a stirred solution of 2-(3-bromo-4-fluorophenyl)-2-methylpropanenitrile (29 g, 120 mmol) in THF (500 mL) at −78° C. was dropwise added DIBALH (1M in toluene, 360 mL, 3 eq) over 2 h. After the reaction mixture was stirred at same temperature for 30 minutes, it was allowed to warm to room temperature. After the reaction was complete, the mixture was quenched by 1N HCl and extracted with EA. The separated organic layer was dried over MgSO4 and evaporated in vacuo to give 2-(3-bromo-4-fluorophenyl)-2-methylpropanal (27 g, 92%). 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 7.47-7.44 (m, 1H), 7.19-7.15 (m, 1H), 7.12 (t, J=8.4 Hz, 1H), 1.45 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH:10]([OH:14])[C:11]#[C:12][CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.CC(C(C)CC=C(C)C)=CC=O.CC1C(C(=O)C#CC)C(C)(C)CCC=1>CO>[CH3:1][C:2]1[CH:3]([C:10](=[O:14])/[CH:11]=[CH:12]\[CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: CC#CC(O)C1C(C)=CCCC1(C)C
Agent: CC#CC(=O)C1C(C)=CCCC1(C)C
Agent: CC(C)=CCC(C)C(C)=CC=O
Solvent: CO
Product: C/C=C\C(=O)C1C(C)=CCCC1(C)C

Procedure:
The acetylenic carbinol which was obtained as described above under paragraph (b) was oxidised as described for its isomer in Example 18, paragraph (c). Thus, 1.38 g. of carbinol gave 0.9 g. (66%) of 2,6,6-trimethyl-1-tetrolyl-2-cyclohexene, b.p. 100°-105°/0.7 Torr. NMR spectrum (CCl4): 0.96 (6 H, d badly resolved), 1.52 (3 H, m), 2.0 (3 H, s), 5.57 (1 H, m), 2.66 (1 H, m) ppm (δ).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[O:32][CH3:33]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([Br:24])=[C:26]([O:32][CH3:33])[CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(I)ccc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: COc1cc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)ccc1Br

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 2-bromo-5-iodoanisole in analogy to Example 1a): MS (ISN): 488.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)O)[CH:16]=3)[N:11]3[N:33]=[N:34][N:35]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=[N:39]C(N)=O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[NH2:39])[CH:16]=3)[N:11]3[N:33]=[N:34][N:35]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)N=S(=O)=O
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Product: Cn1cncc1C(N)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 160 °C
Reaction time: 5 h
Yield: 26106.5 %

Procedure:
A mixture of intermediate (3) (0.0061 mol) and sodium azide (0.0079 mol) in N,N-dimethylacetamide (DMA)(20 ml) was stirred at 50° C. for 18 hours. The mixture was cooled to room temperature and poured out into ice water. The precipitate was filtered off, washed with H2O thoroughly and taken up in CH2Cl2. The organic solution was dried, filtered and the solvent was evaporated. The residue was crystallized from CH3CN DIPE. The precipitate was filtered off and dried yielding 2.3 g (75%) of (±)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 4); mp. 232-233° C. d) A mixture of intermediate (4) (0.0573 mmol) and sulfonylurea (300 g) was stirred at 160° C. for 5 hours and then cooled. Ice water was added, then methylene chloride and the mixture was filtered over celite. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel. The pure fraction were collected and the solvent was evaporated yielding 7.5 g (26%) of (±)-5-(3-chlorophenyl)-α-(4-chloro-phenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine (intermediate 5). e) Intermediate (5) was separated into its enantiomers and purified by column chromatography over Chiralpak AD® (eluent: hexane/EtOH 50/50; 15-35 μm). The pure first (A) fractions were collected and the solvent was evaporated yielding 3.3 g of residue which was crystallized from CH3CN/DIPE. The precipitate was filtered off and dried, yielding 2.55 g of (−)-5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine (compound 1)[α]D20=−7.16°(c=5 mg/ml MeOH); mp.=178-180° C.; 1H-NMR (DMSO, 400 MHz) δ in ppm:
Reaction SMILES: [N:1]1([C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.N>[Ni].CO>[N:1]1([C:11]2[C:12]([CH2:17][NH2:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ncccc1N1CCCc2ccccc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ncccc1N1CCCc2ccccc21
Reaction time: 4 h

Procedure:
Raney-Ni slurry (6 g) was placed in a 1 L heavy-duty hydrogenation flask under a N2 blanket. The catalyst was allowed to settle and the supernatant was removed by suction. The catalyst was washed with anhydrous MeOH (100 mL×3) by settlement and suction. Then 3-(3,4-dihydro-2H-quinoline-1-yl)pyridine-2-carbonitrile (2.35 g, 10 mmol) was added as a MeOH solution (170 mL) and the mixture was saturated with NH3 by bubbling anhydrous NH3 through the mixture for 10 minutes at room temperature. The mixture was hydrogenated at 40 psi for 4 h at room temperature on a Parr hydrogenation apparatus. The mixture was filtered through a celite pad (60 mL sintered glass fumnel, 1 cm thickness) and the filter cake was washed with MeOH (total filtrate 200 mL). The filtrate was concentrated to dryness by rotary evaporation, and the residue was purified by silica gel column chromatography (200 mL silica, 10% MeOH/CH2Cl2 containing 1% NH4OH) to give C-[3-(3,4-dihydro-2H-quinoline-1-yl)pyridine-2-yl]methylamine as a yellow oil, 2.19 g (92%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17]CC)=O)=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH3:21][S:20][C:11]1[N:10]=[C:9]2[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:29][C:15](=[O:17])[C:14]2=[CH:13][N:12]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NNc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(=O)[nH]n(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
60 mL of triethylamine was added to tetrahydrofuran (200 mL) solution of 25 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 12.7 mL of phenylhydrazine, and stirred at room temperature for 18 hours. The solvent was concentrated under reduced pressure, water was added to the residue, then washed with ether, and made acidic with aqueous 5 N hydrochloric acid solution added thereto. The precipitated solid was taken out through filtration, and washed with water and 2-propanol to obtain 10.8 g of the entitled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1c(Cl)cc(Cl)cc1Cl
Yield: 51 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,4,6-trichlorobenzenesulfonyl chloride (15.4 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 51% yield (10.7 mg). MS (ESI+) calcd mass for C13H8Cl3N5O2S 402.946428, found 402.946218.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=2)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O.ClCCl>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=3)=[CH:11]4)=[N:14][N:15]=2)[N:18]=1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(Br)cc4c3)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(COCC[Si](C)(C)C)c5)cc4c3)n2n1
Temperature: 130 °C
Yield: 80.3 %

Procedure:
To a microwave vial was added 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (100 mg, 0.28 mmol, 1 equiv), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (113 mg, 0.35 mmol, 1.25 equiv), K2CO3 (78 mg, 0.566 mmol, 2.0 equiv) followed by 1,4-dioxane (3 mL) and water (1.5 mL). [0542] The solution was degassed with nitrogen for 10 min and then dichloro [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (10 mg, 0.014 mmol, 0.05 equiv) was added. The microwave vessel was capped and heated in a microwave reactor at 130° C. for 30 min. The mixture was cooled and portioned between dichloromethane and water. The organic phase was absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20) to give 6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-quinoline (106 mg, 80% yield). The solid was then added to a 20% solution of ethylene diamine in dimethylformamide and stirred for 3 hours. The solvent was removed and the residue triterated with ethanol to afford the title compound (65 mg, 85% yield). Analytical data presented in Table 2.