Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][S:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:15]=1
Reactant: Sc1ncnc2ccccc12
Reactant: ClCc1cccnc1
Product: c1cncc(CSc2ncnc3ccccc23)c1
Yield: 35.6 %

Procedure:
The title compound(3.34 g) was prepared from 4-mercaptoquinazoline(6.0 g) and 3-chloromethylpyridine(5.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([CH:14]=[C:15]2[O:19][CH2:18][O:17][C:16]=12)C=O.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([OH:28])[CH:14]=[C:15]2[O:19][CH2:18][O:17][C:16]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccccc1-c1cc(C=O)cc2c1OCO2
Solvent: ClCCl
Product: COc1ccccc1-c1cc(O)cc2c1OCO2
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
A solution of 3-(2-methoxyphenyl)-4,5-methylenedioxybenzaldehyde (0.850 g, 3.32 mmol), m-chloroperbenzoic acid (1.431 g, 8.29 mmol) in CH2Cl2 (25 mL) was heated to reflux overnight. The resulting orange mixture was evaporated, dissolved into MeOH (15 mL) and 2.5 M NaOH (6 mL) and stirred for 45 minutes. The dark mixture was diluted with ethyl acetate and acidified with 1.0 N HCl. The layers were separated and the organics washed successively with water, 0.5 M NaHCO3, water, brine and dried (MgSO4). The mixture was filtered, evaporated and the residue was purified on silica gel (hexane:ethyl acetate 4:1) to give 0.55 g of 3-(2-methoxyphenyl)-4,5-methylenedioxyphenol (68%) as a tan solid, 1H NMR (500 MHz; CDCl3): δ 3.82 (s, 3H); 5.91 (s, 2H); 6.40–6.45 (m, 2H); 6.99 (d, J=9.0 Hz, 1H); 7.02 (d, J=7.0 Hz, 1H); 7.40–7.30 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.CS(O[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)(=O)=O.[OH-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:9][C:5]1[C:6]([O:8][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: CS(=O)(=O)OC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Yield: 95.3 %

Procedure:
A three-necked flask (500 cc) equipped with a mechanical stirrer was charged with 5-amino-2-chloro-4-fluorophenol (10.0 g, 61.9 mmol), cyclopentyl methanesulfonate (10.3 g, 62.9 mmol) and tetrabutylammonium bromide (0.51 g, 1.58 mmol) to prepare a solution in toluene (50 mL). Subsequently, 48% sodium hydroxide in aqueous solution (30 mL) was added slowly and the mixture was stirred under heating at 80° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (150 mL) was added, followed by extraction with toluene (50 mL×2). The organic layers were combined, washed with water (100 mL×2) and placed under vacuum to distil off the solvent, thereby giving 4-chloro-5-cyclopentyloxy-2-fluoroaniline (13.5 g, 59.0 mmol; yield=95.2%; purity on HPLC=98.6%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=3[CH:13]=2)[CH:9]=O)=[C:4]([N+:23]([O-])=O)[CH:3]=1>CCO.CC(O)=O.[Fe]>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:23][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(CN(C=O)c3ccc(I)cc3[N+](=O)[O-])cc2s1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Temperature: 25 °C
Yield: 68 %

Procedure:
A stirred mixture of N-(4-iodo-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide and iron powder (16.7 g, 20 mmol) in EtOH (140 mL) and HOAc (60 mL) was heated at reflux for 1 h. The mixture was cooled to rt and filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and 0.5 M aq Na2CO3 (100 mL). The organic layer was separated and further washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (5.9 g, 68%) as a yellow solid that did not require further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.03 (d, J=1.0 Hz, 1H), 7.97 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.49 (dd, J=1.4, 8.5 Hz, 1H), 7.37-7.43 (m, 2H), 5.60 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 438 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([CH2:13][CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([CH2:13][CH:14]([C:15]([O:17][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:16])[CH2:18][CH3:19])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(Cc1ccc(C(=O)OC(C)(C)C)s1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2-(5-tert-Butoxycarbonylthiophen-2-yl)methyl-butanoic acid (20.6 g, 72.2 mmol) was dissolved in N,N-dimethylformamide (100 mL), potassium carbonate (10.4 g, 75.3 mmol) and benzyl bromide (13.0 g, 76.0 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. 0.5 N-Hydrochloric acid solution and ethyl acetate were added to the obtained residue, the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent of the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (27.0 g, 72.1 mmol, 96%).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][CH:3]=[C:2]1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[S:1]1[C:5](/[CH:6]=[CH:21]/[CH:22]=[O:23])=[CH:4][CH:3]=[C:2]1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2cccs2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting [2,2′-bithiophene]-5-carboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 221 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:10][CH2:11][N:12]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:13][CH2:14]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: CCc1cnc(Cl)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(c3nc4cc(Br)ccc4[nH]3)CC2)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.6 %

Procedure:
Intermediate 1 (500 mg, 1.69 mmol) and 2-chloro-5-ethylpyrimidine (264 mg, 1.86 mmol) were dissolved in propan-2-ol (25 ml). To this mixture N,N-Diisopropylethyl amine (1.8 ml, 10.1 mmol) added and stirred at 90° C. for 12 h. After completion of the reaction, propan-2-ol was removed to obtain the crude. Crude was purified by combiflash using a mixture of AcOET and Petether (40:60) as eluent to afford the titled compound (0.2 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][OH:4].[H-].[Na+].[F:8][C:9]([F:20])([F:19])[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1>CN(C=O)C>[CH3:5][C:2](=[CH2:1])[CH2:3][O:4][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][C:9]([F:8])([F:19])[F:20])=[CH:12][CH:13]=1
Reactant: C=C(C)CO
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COCc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of 2-methyl-2-propen-1-ol (120) (2.34 mL, 27.8 mmol) in anhydrous DMF (10 mL, then 2×2 mL to rinse) was added to a suspension of 60% NaH (1.32 g, 33.1 mmol) in anhydrous DMF (10 mL) under N2 at 0° C. and the mixture was stirred at 0° C. for 30 min. 4-(Trifluoromethoxy)benzyl bromide (5.1 mL, 31.9 mmol) was added and the mixture was stirred at room temperature for 21 h. The resulting mixture was added to ice/aqueous NaHCO3 (200 mL) and extracted with 25% EtOAc/petroleum ether (2×200 mL) and 50% EtOAc/petroleum ether (3×200 mL). The extracts were washed with water (200 mL), the volatile solvents were removed, and the residual oil was chromatographed on silica gel. Elution with petroleum ether firstly gave foreruns, then further elution with 0-15% CH2Cl2/petroleum ether gave 1-{[(2-methyl-2-propenyl)oxy]methyl}-4-(trifluoromethoxy)benzene (121) (6.57 g, 96%) as an oil that was used directly in the next step; 1H NMR (CDCl3) δ 7.37 (dt, J=8.7, 2.3 Hz, 2H), 7.19 (br d, J=8.0 Hz, 2H), 5.00 (m, 1H), 4.94 (m, 1H), 4.48 (s, 2H), 3.94 (s, 2H), 1.77 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18](/[CH:19]=[CH:20]\[CH3:21])[C:4]=2[O:3]1>C1COCC1.CO.[Pd]>[CH3:1][C@H:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH2:19][CH2:20][CH3:21])[C:4]=2[O:3]1
Reactant: C/C=C\c1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl (2S)-2-methyl-8-[(1Z)-prop-1-en-1-yl]-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (390 mg) in THF-MeOH (2:1, 15 ml) was added 10% palladium on carbon (50 mg), and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction solution was filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→15% ethyl acetate/hexane) to give the title compound (366 mg, 93%) as a colorless oil.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19]>CC(O)CCC>[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH:19][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: COc1ccc2c(Cl)cnnc2c1
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: COc1ccc2c(Nc3ccc(C)c(O)c3)cnnc2c1

Procedure:
A suspension of 4-chloro-7-methoxycinnoline hydrochloride (196 mg, 0.85 mmol) and 3-hydroxy-4-methylaniline (123 mg, 1 mmol) in 2-pentanol (5 ml) was heated at reflux for 2 hours. After cooling, the solid was filtered off, washed with isopropanol, ether and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-7-methoxycinnoline as the hydrochloride salt (yellow solid, 215 mg, 80%).
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C:15]([NH:23]C(=O)OCC1C=CC=CC=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])([O:13][CH2:14][C:15]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:7]
Reactant: CC(C)(C)OP(=O)(OCC(C)(NC(=O)OCc1ccccc1)c1ccccc1)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OP(=O)(OCC(C)(N)c1ccccc1)OC(C)(C)C

Procedure:
The product of Example 442B (0.10 g, 0.21 mmol) and 20% palladium hydroxide on carbon (0.02 g) in ethyl acetate (1 mL) and methanol (1 mL) was stirred under an atmosphere of hydrogen or 18 hours. The reaction was filtered through a bed of celite and concentrated to give the title compound, which was used without further purification (0.073 g).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([O:7][CH3:8])=[O:6].Cl[C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[N:23]=[CH:24][C:17]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:22]1[C:18]2=[N:19][CH:20]=[N:21][C:16]([O:3][C@@H:4]([CH2:9][CH2:10][S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([O:7][CH3:8])=[O:6])=[C:17]2[CH:24]=[N:23]1
Reactant: COC(=O)[C@@H](O)CCS(C)(=O)=O
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCS(C)(=O)=O)Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
Sodium hydride (58.7 mg, 1.47 mmol) was added to (S)-methyl 2-hydroxy-4-(methylsulfonyl)butanoate (Intermediate AA2) (120 mg, 0.61 mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (357 mg, 0.67 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane to afford the product (160 mg, 61.6%). 1H NMR (400 MHz, CDCl3) δ 2.60-2.75 (2H, m), 3.01 (3H, s), 3.25-3.38 (2H, m), 3.82 (3H, s), 5.79-5.82 (1H, m), 7.44-7.54 (3H, m), 7.61-7.63 (1H, m), 8.34 (1H, s), 8.54 (1H, s); m/z (ES+) (M+H)+=425; HPLC tR=2.01 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:24]C)=[C:15]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:16]=1)=[O:10])=[O:5])C.Cl.N1C=CC=CC=1>O>[C:4]([C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([OH:24])=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1)=[O:10])([OH:5])=[O:3]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CCc1cc(C(=O)c2cccc(C(=O)O)c2)ccc1O
Temperature: 180 °C
Yield: 91.7 %

Procedure:
A mixture of 41.5 g of 5-[3-(ethoxycarbonyl)benzoyl]-2-methoxybenzenepropanoic acid, ethyl ester and 410 g of pyridine hydrochloride were heated at 180° C. for 4 hours. After cooling, water was added to the mixture while hot. As the mixture cooled, the title product precipitated from solution. Filtration of the solids and crystallization from ethanol/water provided 31.1 g of the title product, m.p. 197°-200° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[OH:24]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:24])[CH:5]=[N:4][C:3]=1[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20]
Reactant: C[C@H](Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To a solution of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine (Preparation 232, 130 mg, 0.37 mmol) in acetone (1 mL) was added an aqueous solution of Oxone® (1 mL, 287 mg, 0.44 mmol) dropwise with stirring at 0° C. for 15 minutes. The reaction mixture was diluted with water and extracted with DCM (3×5 mL). The mixture was filtered through a phase separation cartridge, the organic phase was washed with brine (3 mL) and filtered through another phase separation cartridge. The filtrate was dried by N2 blowing to give a crude product that was purified by silica gel column chromatography eluting with 0-30% EtOAc in heptane to give the title compound (62 mg, 69%) as colourless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)=[CH2:13])=[O:6])[CH3:3]>C(O)C.[Pd]>[CH3:23][C:2]([CH3:1])([O:4][C:5]([N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[CH3:13])=[O:6])[CH3:3]
Reactant: C=C(c1cccc([N+](=O)[O-])c1)c1nccn1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(c1cccc(N)c1)c1nccn1C(=O)OC(C)(C)C
Yield: 74.4 %

Procedure:
A solution of 1-(1,1-dimethylethyloxycarbonyl)-2-((3-nitrophenyl)ethen-2-yl)imidazole (500 mg, 1.59 mmol)in ethanol (50 ml) was hydrogenated at 30 psi in the presence of 10% palladium-on-carbon (50 mg) for 1 h. The catalyst was then removed by filtration and the solvent evaporated to afford the titled compound as a viscous oil (340 mg, 75% yield). 1H NMR (250 MHz, CDCl3) δ 1.60 (9H, s), 2.92-3.04 (2H, m), 3.22-3.36 (2H, m), 3.70 (2H, brs), 6.42-6.68 (3H, m), 6.87 (1H, d, J =2.5 Hz), 7.05 (1H, t, J=8 Hz), 7.32 (1H, d, J=2.5 Hz).
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:8]1[S:7][C:6]([CH2:5][O:4][CH3:3])=[N:10][CH:9]=1)(=[O:22])=[O:21]
Reactant: COCc1ncc(CO)s1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1ncc(COS(C)(=O)=O)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(methoxymethyl)thiazol-5-yl)methanol (319 mg, 2.00 mmol) in dry CH2Cl2 (15.0 mL) was treated at 0° C. with Et3N (0.36 mL, 2.59 mmol) followed by DMAP (25 mg, 0.20 mmol) and Ms-Cl (0.20 mL, 2.53 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (10 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 469 mg (quant.) of crude (2-(methoxymethyl)thiazol-5-yl)methyl methanesulfonate as an yellow oil: TLC: rf (1:4 hept-EA)=0.39. A solution of this crude material (469 mg) in DMF (4.5 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (2.35 g of a 9.6% solution in DMF, 1.98 mmol) in DMF (4.5 mL) pre-treated for 30 min with DIPEA (0.68 mL, 3.96 mmol) and the reaction mixture was stirred for 4 days at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.33. LC-MS-conditions 07: tR=0.72 min, [M+H]+=255.95.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1(C)[CH:8]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:7]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:6]2[S:5]1.[N-:31]=[N+:32]=[N-:33].[Na+].CC(C)=O>O>[N:31]([C:3]1([CH3:2])[CH:8]([C:9]([O:11][CH2:12][C:13]([Cl:15])([Cl:14])[Cl:16])=[O:10])[N:7]2[C:17](=[O:29])[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:6]2[S:5][CH2:4]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(N=[N+]=[N-])CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.4 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After acetone was distilled off under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with saturated sodium bicarbonate aqueous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small quantity of ether was added to the residue to give colorless crystals of 2,2,2,-trichloroethyl 3-azido-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (170 mg). This substance was recrystallized from carbon tetrachloride to give crystals melting at 136° to 140° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([CH3:16])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Br:17])=[CH:19][CH:20]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1nc(Cl)cc(-c2cc(Cl)ccc2C)n1
Product: Cc1nc(Nc2ccc(Br)cc2)cc(-c2cc(Cl)ccc2C)n1
Yield: 21 %

Procedure:
Following the method described in Example 38, 4-chloro-6-(5-chloro-2-methyl-phenyl)-2-methyl-pyrimidine and 4-bromoaniline provided the title compound (21% yield). 1H NMR (DMSO-d6) δ 2.48 (s, 3H, CH3), 2.54 (s, 3H, CH3), 6.71 (s, 1H, Ar), 7.36 (d, 1H, J=8.2 Hz, Ar), 7.42 (dd, 1H, J=8.2 Hz, J=2.2 Hz, Ar), 7.47 (d, 1H, J=2.1 Hz, Ar), 7.52 (d, 2H, J=8.8 Hz, Ar), 7.73 (d, 2H, J=8.8 Hz, Ar), 9.72 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[C:50]([CH3:51])=[CH:49][CH:48]=[CH:47][C:46]=1[O:52][CH3:53]>>[CH3:53][O:52][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([CH3:51])[C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C)c1OCCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4c(C)cccc4OC)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.081 g of 2-(4-bromobutoxy)-1-methoxy-3-methylbenzene are used to prepare the title compound. Rf=0.28 (2:1 EtOAc-heptane); Rt=6.15.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[C:25]([CH:34]=[CH:35][CH:36]=2)[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)OC1>>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:26][C:25]1[CH:34]=[C:35]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)[CH:36]=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)COB(c2cccc(OCc3ccccn3)c2)OC1
Product: FC(F)(F)c1ccc2c(-c3cccc(OCc4ccccn4)c3)ccnc2n1
Yield: 42.9 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-[3-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)phenoxymethyl]pyridine (83 mg, 0.28 mmol) as described in Example 7 part g), affording 5-[3-(pyridin-2-ylmethoxy)phenyl]-2-trifluoromethyl[1,8]naphthyridine (36 mg, 34%). δH (360 MHz, CDCl3) 5.28 (2H, s), 7.07-7.11 (2H, m), 7.20 (1H, dd, J 2.1 and 8.4), 7.23-7.30 (1H, m), 7.47-7.56 (3H, m), 7.73-7.78 (2H, m), 8.50 (1H, d, J 8.8), 8.61 (1H, d, J 4.6), 9.26 (1H, d, J 4.6). m/z (ES+) 382 [MH]+.