Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.[CH2:13]([C@H:15]1[CH2:20][C@H:19]2[C@H:21]3[C@H:30]([CH2:31][CH2:32][C@:17]2([CH3:18])[C@H:16]1[O:34][C:35](=[O:38])[CH2:36]Br)[C@@H:29]1[C:24](=[CH:25][C:26](=[O:33])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3)[CH3:14]>CC(C)=O>[CH2:13]([C@H:15]1[CH2:20][C@H:19]2[C@H:21]3[C@H:30]([CH2:31][CH2:32][C@:17]2([CH3:18])[C@H:16]1[O:34][C:35](=[O:38])[CH2:36][O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:29]1[C:24](=[CH:25][C:26](=[O:33])[CH2:27][CH2:28]1)[CH2:23][CH2:22]3)[CH3:14]
Reactant: O=C(O)c1ccccc1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)c1ccccc1
Yield: 89.1 %

Procedure:
In 30 ml of acetone is dissolved 0.49 g of benzoic acid, and 2 ml of 2 N-NaOH and 5 ml of water are added, followed by addition of 0.88 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 3 hours. After cooling, the solvent is distilled off under reduced pressure and the residue is extracted with 100 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a silica gel column. After passage of 350 ml of diisopropyl ether, the solvent is distilled off under reduced pressure. To the residue is added a small amount of diisopropyl ether, followed by filtration to give 0.86 g of the above-identified compound as a white powder.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17]Br)[CH:16]=1.[NH4+].[Cl-]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][O:9][CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[CH:16]=1
Reactant: OC1CCOCC1
Reactant: BrCc1cncc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1cncc(COC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a suspension of 60% NaH (640 mg, 16 mmol) in DMF (80 mL) is added tetrahydro-pyran-4-ol (1.6 g, 16 mmol) at 0° C. After the mixture is stirred at room temperature for 0.5 h, 3-bromo-5-bromomethyl-pyridine (1.6 g, 6.4 mmol) is added at 0° C. under N2 atmosphere. The mixture is stirred at room temperature for 16 hrs. Then saturated NH4Cl aqueous solution is used to quench the reaction and the mixture is extracted with DCM. The organic layers are combined, dried over Na2SO4, filtered and concentrated. The crude product is purified by flash column chromatography to give 700 mg of 3-bromo-5-(tetrahydro-pyran-4-yloxymethyl)-pyridine.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[CH2:5][C@H:4]1[NH2:11].[CH:12]1[C:24]2[CH:23]([CH2:25][O:26][C:27](ON3C(=O)CCC3=O)=[O:28])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl.CO.C(O)(=O)C>O.O1CCOCC1>[CH:12]1[C:24]2[CH:23]([CH2:25][O:26][C:27](=[O:28])[NH:11][C@@H:4]3[CH2:5][C@H:6]([CH2:9][OH:10])[C@@H:7]([OH:8])[C@H:3]3[OH:2])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
(1R,2S,3R,4R)-2,3-Dihydroxy-4-(hydroxylmethyl)-1-aminocyclopentan hydro-chloride (70.0 g, 380 mmol) was dissolved in water (660 ml) and FmocOSU (N-(9-Fluorenylmethoxycarbonyloxy)-succinimid) (148.5 g, 440 mmol) solved in dioxan (2.00 l) was added. Then saturated sodium hydrogencarbonate solution (800 ml, 880 mmol) was added slowly. The mixture was stirred 3 h at room temperature until TLC (Silicagel Merck 60, chloroform/methanol/acetic acid 8:2+0.1% v/v/v) showed complete consumption of the educts. The obtained precipitate was filtered off and the filtrate was added to water (6.00 l). The resulting suspension was stirred for 5 min and then stored 12 h at 4° C. The resulting suspension was filtered. The obtained solid was washed with cold water (3.00 l) and dried 12 h under reduced pressure at 45° C. over calcium chloride. For a further purification the crude product was suspended in ethylacetate, stirred 1 h, filtered and dried under reduced pressure yielding 134 g (95%) of the title compound as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:9]2[CH2:14][CH2:13][NH:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:33][C:32](=[O:35])[NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)[C:11]([CH3:16])([CH3:15])[CH2:10]2)=[CH:22][CH:21]=1
Reactant: O=C(CCl)Nc1cccc(F)c1
Reactant: CC1(C)CN(C(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CN(C(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1cccc(F)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 283 mg of 1-[bis(4-fluorophenyl)methyl]-3,3-dimethylpiperazine and 204 mg of N-(3-fluorophenyl)chloroacetamide was dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide, and 1 g of anhydrous potassium carbonate was added to the resulting solution. The reaction mixture was then stirred at 80° C. for 16 hours, after which ethyl acetate was added, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to give a purified 1-[bis(4-fluorophenyl)methyl]-4-[(3-fluorophenyl)carbamoylmethyl]-3,3-dimethylpiperazine.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:4]1)[CH3:2].C(O)(=O)C.Cl>O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([F:14])[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Temperature: 100 °C
Yield: 93.3 %

Procedure:
To 20.0 g (63 mmol) of the 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, ethyl ester, was added 200 ml of acetic acid and 150 ml of 6N hydrochloric acid in 70 ml of water. The mixture was maintained at 100° C. for two hours. It was cooled, filtered, and washed with diethyl ester, to give 17 g of the title compound, mp 229°-230° C.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[NH2:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:15]([F:25])[CH:14]=2)[CH2:8]1.C(OC(=O)C)(=O)C>O>[CH3:2][C:1]([NH:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[C:15]([F:25])[CH:14]=2)[CH2:8]1)=[O:3]
Reactant: CC(=O)O
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
(S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one acetate (3.5 g, 10 mmol) was dissolved in 20 mL of water. The solution was heated to 50° C. and then acetic anhydride (0.72 g, 12 mmol) was added dropwise and stirred at 50° C. for 2 hours. The mixture was cooled down to 0° C. to crystallize, filtered, washed with water, dried and recrystallized with ethyl acetate to provide 3.0 g of Linezolid in 88% yield.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH3:19])(=O)=O)=CC=1.C(O)C#CCC.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(O)CC#C.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(Cl)(Cl)Cl.CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cu]I.CCOCC.O>[CH2:11]([OH:10])[CH2:12][C:13]#[C:14][CH2:15][C:16]#[C:17][CH2:18][CH3:19]
Reactant: CC/C=C\C/C=C\CCOS(=O)(=O)c1ccc(C)cc1
Agent: [Cu]I
Agent: C#CCCO
Agent: CCC#CCO
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCC#CCC#CCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3Z,6Z)-nona-3,6-dienyl p-toluenesulfonate can be prepared from 2-Pentyn-1-ol by dissolving 2-Pentyn-1-ol (1.03 g, 12 mmol) in chloroform (10 ml) and adding pyridine (1.90 g, 24 mmol) followed by p-toluenesulfonyl chloride (3.43 g, 18 mmol) in small portions with constant stirring. After about 4 hrs, ether (30 ml) and water (7 ml) can be added and the organic layer can be washed successively with HCl (7 ml), 5% NaHCO3, water (7 ml) to produce pent-2-ynyl p-toluenesolfonate. Pent-2-ynyl p-toluenesolfonate (1.37 g, 5.78 mmol, 1.1 eq) can be added at low temperature under nitrogen to a well-stirred suspension in DMF (15 ml) of but-3-yn-1-ol (368 mg, 5.25 mmol), sodium carbonate (834 mg, 7.87 mmol), tetrabutylammonium chloride (1.46 g, 5.25 mmol) and copper(I) iodide (1.00 g, 5.25 mmol). The mixture can then be stirred at room temperature for about 48 hrs, and ether (30 ml) and 1M HCl (30 ml) can be added, the organic phase can be collected and washed with brine, and dried over sodium sulfate to produce nona-3,6-diyn-1-ol. Nona-3,6-diyn-1-ol (198 mg, 1.45 mmol) can be hydrogenated at atmospheric pressure, in the presence of a mixture of quinoline (44 mg) and palladium (5%) on calcium carbonate (100 mg), poisoned with lead in methanol (25 ml). After several hours, the methanol can be evaporated in vacuo, quinoline can be removed by silica gel column chromatography using ether-hexane (35:65) as the eluent to produce (3Z,6Z)-nona-3,6-dien-1-ol. (3Z,6Z)-Nona-3,6-dien-1-ol (167 mg, 1.19 mmol) can be dissolved in chloroform (5 ml) and the solution can be cooled in an ice bath. Pyridine (376 mg, 4.76 mmol) can be added, followed by p-toluenesulfonyl chloride (340 mg, 1.78 mmol) in small portions with constant stirring. The mixture can be stirred for about 24 hrs at low temperature, and ether (15 ml) and water (5 ml) can be added, the organic layer can be collected and washed successively with 1 N HCl (10 ml), 5% NaHCO3, water (10 ml), and brine (10 ml), and then dried over Na2SO4 to produce (3Z,6Z)-nona-3,6-dienyl p-toluenesulfonate.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[N:4]([CH3:20])[N:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:12][C@@H:11]2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:7]=1.[CH3:22][C:23]1[S:27][C:26]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:25][N:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:22][C:23]1[S:27][C:26]([CH2:28][N:29]([C:2]2[C:3](=[O:21])[N:4]([CH3:20])[N:5]=[C:6]([O:8][CH2:9][C@H:10]3[CH2:12][C@@H:11]3[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=3)[CH:7]=2)[C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:25][N:24]=1
Reactant: Cc1nnc(CNC(=O)OC(C)(C)C)s1
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(Br)c(=O)n(C)n2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(N(Cc3nnc(C)s3)C(=O)OC(C)(C)C)c(=O)n(C)n2)nc1
Temperature: 85 °C

Procedure:
A mixture of 4-bromo-2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-one (5) (90 mg, 0.26 mmol), tert-butyl (5-methyl-1,3,4-thiadiazol-2-yl)methylcarbamate (6) (119 mg, 0.52 mmol), Pd(OAc)2 (9 mg, 0.052 mmol), BINAP (36 mg, 0.057 mmol) and Cs2CO3 (127 mg, 0.39 mmol) in toluene (4 mL) under N2 was heated at 85° C. for 20 h. After cooled to rt, The mixture was diluted with EtOAc (20 mL), washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with PE/EA (1/2) to give the title compound as a oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[F:10].[C:11]([S:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([S:15][C:16](=[O:21])[CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[F:10])[C:18](=[O:20])[CH3:19])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(Cl)cc1F)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-chloro-2-fluorobenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH3:3].C[Al](C)C.CCCCCC.C([O:25][C:26]([C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]2[CH:38]=1)=O)C.Cl>ClCCl>[CH2:10]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:26]([C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][N:31]2[CH:38]=1)=[O:25])[CH2:11][CH3:12]
Reactant: CCCN(CCC)CCCCN
Reactant: CCOC(=O)c1cn2cc(C#N)ccc2n1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCN(CCC)CCCCNC(=O)c1cn2cc(C#N)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
The compound (263 mg) obtained in Example 1-2 was dissolved in dichloromethane (4.0 ml) and a 15% trimethyl aluminum/hexane solution (1.08 ml) was dropped thereto. The whole was stirred at room temperature for 15 minutes. The solution was added with the compound (300 mg) obtained in Example 19-1 and stirred for additional 20 hours. The resultant was heated to 40° C. and stirred for additional 7 hours, and then 1 mol/l hydrochloric acid was added to stop the reaction, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated saline solution and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (237 mg) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([CH3:30])[N:29]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C:28]1[N:29]=[C:24]([C:17]2[CH:18]=[CH:19][C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:15][CH:16]=2)[C:25]([NH2:31])=[N:26][CH:27]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1cnc(N)c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cnc(N)c(-c2ccc(Oc3ccccc3)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 3-bromo-5-methylpyrazin-2-amine (108 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (148 mg) as a pale yellow solid.
Reaction SMILES: [I-].[CH3:2][CH:3]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:4].C(O[K])(C)(C)C.[Br:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]=[C:3]([CH3:4])[CH3:2])=[CH:35][N:36]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)=Cc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of (1-methylethyl)(triphenyl)phosphonium iodide (72.2 g) in N,N-dimethylformamide (200 mL) was added a solution of tert-butoxy potassium (20.1 g) in N,N-dimethylformamide (100 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. To the reaction solution was added dropwise a solution of 6-bromopyridine-3-carbaldehyde (20.8 g) in N,N-dimethylformamide (200 mL) at 0° C. The reaction solution was allowed to warm to room temperature, and stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:99-40:60, volume ratio) to give the title compound (16.2, yield 68%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)[CH2:22]1>>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][N:28]=2)[CH2:22]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COC1CCCN(c2ccc(N)cn2)C1
Product: COC1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine. LCMS calcd for C22H21F3N4O3 (m/e) 446, obsd 447 (M+H).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([C:15]4[CH:20]=[CH:19][C:18]5[O:21][CH2:22][O:23][C:17]=5[CH:16]=4)=[N:7][C:8](=[O:14])[NH:9]3)=[CH:4][C:3]=2[O:2]1.[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>CN(C=O)C>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([C:15]4[CH:20]=[CH:19][C:18]5[O:21][CH2:22][O:23][C:17]=5[CH:16]=4)=[N:7][C:8]([O:14][CH2:27][CH:28]4[CH2:30][CH2:29]4)=[N:9]3)=[CH:4][C:3]=2[O:2]1
Reactant: BrCC1CC1
Reactant: O=c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2[nH]1)OCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc2c(cc1-c1nc(OCC3CC3)nc3cc4c(cc13)OCO4)OCO2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 16.5 %

Procedure:
To a suspension of 6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-quinazolin-2-one (310 mg, 1.00 mmol) in DMF (7 mL) was added NaH (97%, 32 mg, 1.33 mmol). The mixture was stirred at 25° C. for 45 min, then (bromomethyl)cyclopropane (0.2 mL, 2.0 mmol) was added. The resulting mixture was then heated at 100° C. for 6 h. cooled to rt, poured into ice-water (50 mL) and stirred for 30 min. The resulting precipitate was collected by filtration and the solid was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous MgSO4, and the solvent was removed in vacuo. This crude product was separated by chromatography in silica gel. Elution with hexane:acetone (65:35) gave 6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)-2-(cyclopropylmethoxy)-quinazoline as yellow solid (60 mg); mp 175-182° C.; 1H NMR (CDCl3) 7.31 (s, 1H), 7.21-7.25 (m, 3H), 7.14 (s, 1H), 6.93-6.96 (d, J=8.4, 1H), 6.09 (s, 2H), 6.06 (s, 2H), 4.29-4.31 (t, J=7.2, 2H), 3.2 (s, 1H); 0.63 (s, 2H), 0.41 (s, 2H); C20H16N2O5; C 65.93, H 4.43, N 7.69. Further elution with the same solvents gave 1-cyclopropylmethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazolin-2(1H)-one as pale yellow solid (75 mg); mp 255-260° C.; 1H NMR (CDCl3) 7.18-7.36 (m, 3H), 6.82-7.02 (m, 3H), 6.11 (s, 2H), 6.06 (s, 2H), 4.22 (d, J=6.8, 2H), 1.18-1.40 (m, 1H), 0.41-0.78 (m, 4H); C20H16N2O5; C 65.93, H 4.43, N 7.69.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14](=O)[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[N:25][OH:26])[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Yield: 76.5 %

Procedure:
A mixture of 2 g (6.1 mmol) 1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone, 0.869 g (12.5 mmol) hydroxylamine, hydrochloride and 1.03 g (12.5 mmol) sodium acetate in 25 mL ethanol was heated to reflux for 2 h. After cooling to room temperature water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a ethyl acetate. The product containing fractions were evaporated to yield 1.6 g (77%) of the title compound as colorless viscous oil. MS (m/e): 343.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[Cl:10][O-].[Na+].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:10][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: [O-]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1n[nH]cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 3-trifluoromethyl-1H-pyrazole (500 mg, 3.67 mmol) in glacial acetic acid (5 ml) was added a 10% solution of sodium hypochlorite in water (2188 μl, 3.67 mmol). The reaction mixture was stirred at RT overnight and then neutralized with sat. sodium carbonate, and extracted with DCM. The organic layers were combined washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the desired product (480 mg, 77%) as a white solid which did not require further purification. MS (ISP) 169.0 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([N+:11]([O-])=O)[C:3]=1[NH:14][C:15](=[O:17])[CH3:16]>[Pd].CO>[NH2:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1c(C)cc(N)cc1N
Reaction time: 2 h

Procedure:
A mixture of 45.0 g (0.188 mol) N-(2-methyl-4,6-dinitro-phenyl)-acetamide and 4.50 g palladium on charcoal (Pd/C 10%) in 1.400 L methanol was hydrogenated for 2 h at RT under a hydrogen atmosphere. The catalyst was removed by suction filtering and the filtrate was evaporated to dryness i.vac. The residue was triturated in diethyl ether, suction filtered and dried. The crude product obtained was used directly for the next step.