Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@:13]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C@H:15]([CH3:16])[O:14]1.C(=O)([O-])[O-].[Li+].[Li+].CN(C)C=O>C(OCC)(=O)C>[N:18]1([CH2:17][C@@:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])([OH:14])[C@H:15]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH3:16])[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1cncn1)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 110 °C
Reaction time: 24 h
Yield: 50.9 %

Procedure:
A mixture of 1H-1,2,4-triazole (1.17 g), (2R,3S)-2-(2-fluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl] oxirane (2 g), lithium carbonate (6.32 g) and dimethylformamide (40 ml) was stirred for 24 hours at 110° C. After cooling, to the mixture was added ethyl acetate (50 ml). The mixture was filtered to remove insoluble substances. The filtrate was distilled under reduced pressure. The residue was dissolved in ethyl acetate (100 ml). The mixture was washed with saturated saline (30 ml ×2). The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel chromatography (silica gel 50 g, eluent: ethyl acetate/acetone=4.1) to give (2R,3R)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-(2-fluorophenyl)-2-butanol (1.32 g).
Reaction SMILES: [C:1]([C:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)([O:3][CH3:4])=[O:2].[Al]>O1CCCC1.C(OCC)(=O)C>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 66.8 %

Procedure:
A solution of 32.78 g of benzyl α-(3-carbomethoxy-7-oxo-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-α-isopropylideneacetate in 500 ml of tetrahydrofuran containing 5% water is mixed with aluminium amalgam which has been prepared from 22.95 g of aluminium and 0.5% aqueous solution of mercuric chloride, and the mixture stirred at room temperature for 50 minutes. The reaction mixture is diluted with ethyl acetate and filtrated through a layer of Hyflo Super Cel. The filtrate is dried on sodium sulfate and concentrated under reduced pressure to yield the residue, which is crystallized from ether to yield 22.02 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diaza-bicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 61% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=3)[NH2:17])[N:11]=2)[N:8]=1.N1C=CC=CC=1.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([NH:17][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26])[CH:18]=3)[N:11]=2)[N:8]=1
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)cn2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)cn2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
To a stirred solution of 5-(6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.050 g, 0.206 mmol) in acetonitrile (5 mL) containing pyridine (0.618 mmol) is added trimethylacetylchloride (0.206 mmol). The mixture is stirred at room temperature for 4 hours, concentrated to dryness, then purified via chromatography (hexanes to EtOAc) to afford the title compound (0.060 g, 86%) as a white solid: Rf 0.57 (EtOAc); LCMS (m/z)=339.4 [M+H]+, tR=6.37 min. (10 min run)
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH2:34])[O:30][C:29]2=[O:35])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.FC1C=C(N2C[C@H](CN)OC2=O)C=CC=1N1CC[O:46][CH2:45][CH2:44]1>>[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:45](=[O:46])[CH3:44])[O:30][C:29]2=[O:35])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Yield: 90 %

Procedure:
The procedure is the same as in Example 45 except that the dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl-5-aminomethyl-1,3-oxazolidin-2-one (5a) was replaced by dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl)-5(S)-aminomethyl-1,3-oxazolidin-2-one ((S)-5b) to obtain (S)—N-((3-(3-fluoro-4-(4-morpholinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)acetamide (Linezolid) having a melting point of 78-179° C. and at a yield of 90%; [∝]D20=−9.1° (c 1.0, CHCl3); 1H NMR(CDCl3, 400 MHz) δ 7.43 (dd, J1=2.8 Hz, J2=14.4 Hz, 1H, Ar—H), 7.06 (dd, J1=1.6 Hz, J2=8.8 Hz, 1H, Ar—H), 6.94 (t, J=9.2 Hz, 1H, Ar—H), 6.17 (t, J1=6.0 Hz, 1H, NH), 4.80-4.74 (m, IH, CHO), 4.02 (t, J=8.8 Hz, 1H, CH2CHO), 3.86 (t, J=4.8 Hz, 4H, 2×OCH2), 3.75 (dd, J1=6.8 Hz, J2=8.8 Hz, 1H, CH2CHO), 3.71-3.58 (m, 2H, CH2NH), 3.06 (t, J=4.8 Hz, 4H, 2×NCH2), 2.02 (s, 3H, CH3CO); 13C NMR (CDCl3, 100 MHz) 171.4, 155.7 (d, J=245 Hz), 154.5, 136.4 (d, J=8.8 Hz), 132.8 (d, J=10.4 Hz), 118.6 (d, J=3.9 Hz), 113.8 (d, J=3.0 Hz), 107.4 (d, J=26.1 Hz), 72.0, 66.8, 50.8, 47.5, 41.7, 22.8; HR-TOF-MS (+Q) m/z: 338.1518 (Calculated [C16H20FN3O4+H]+: 338.1516).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>CS(C)=O>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1

Procedure:
A mixture of 10-[[6-chloro-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3.2 g), K2CO3 (5 g) and the 2-dimethylamino-ethylamine (5 ml) is heated in dimethylsulfoxide (80 ml) for 6 hours at 100° C. (with stirring). The reaction mixture is quenched with water and the solid which separates, is filtered off and washed well with water. Examination of the TLC (CHCl3 :MeOH; 3:1) showed the products to be sufficiently pure to be used for further reactions without purification. Yield 3.2 g, 85%, mass spectrum (CI) 376 (M+1).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([S:14](=[O:21])(=[O:20])[NH:15][CH2:16][C:17]([OH:19])=[O:18])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:11][CH:10]=[C:9]([S:14](=[O:20])(=[O:21])[NH:15][CH2:16][C:17]([OH:19])=[O:18])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc2c(S(=O)(=O)NCC(=O)O)ccc(O)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(S(=O)(=O)NCC(=O)O)ccc(OCc3ccccc3)c2o1
Yield: 56.1 %

Procedure:
A mixture of the 7-hydroxy compound (1.8 g) obtained in Example 28 (Compound No. 28), K2CO3 (1.6 g) and benzylbromide (2.9 g) in DMF was stirred at 80° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, which was purified by a silica-gel column chromatography to give 1.3 g of 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-benzyloxybenzofuran as yellow crystals. After the obtained product was added to 20 ml of 2N-NaOH aqueous solution and the mixture was stirred for 30 minutes, the resultant was acidified to form precipitate, which was recrystallized with ethanol to give 0.4 g of 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-benzyloxybenzofuran. The physical constants are shown in Table 4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[CH3:18][S:19]C.[Cl-].[NH4+]>O1CCCC1.O>[F:12][C:4]1[CH:3]=[C:2]([S:19][CH3:18])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1ccc(Br)cc1F
Reactant: CSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(SC)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 g of 4-bromo-2-fluoro-1-methoxymethoxybenzene was dissolved in 50 mL anhydrous tetrahydrofuran, and 13.4 mL n-butyl lithium (1.59 M hexane solution) was added dropwise thereto at −70° C. After the mixture was stirred for 1 hour, 2.1 ml dimethyl sulfide was added dropwise thereto and stirred at −70° C. for 1 hour, and after the temperature of the reaction solution was raised to 0° C., the solution was stirred for 1 hour. An aqueous saturated ammonium chloride solution was added thereto, the mixture was stirred for 30 minutes, and water added to the mixture which was then extracted with ethyl acetate. The extract was dried over sodium sulfate and purified by silica gel chromatography (hexane/ethyl acetate) to give 3.67 g of 2-fluoro-1-methoxymethoxy-4-methylsulfanyl benzene. 4 mL solution of 4 N hydrogen chloride in ethyl acetate was added to this reaction product and left for 1 hour. Water was added to the product which was then extracted with ethyl acetate and purified by silica gel chromatography (hexane/ethyl acetate) to give 1.01 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1(C)C=CC=CC=1>[OH:20][CH:18]([CH3:19])[CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:12][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: CC1CO1
Solvent: Cc1ccccc1
Product: CC(O)CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 50 °C
Yield: 54.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (500 mg, 2.3 mmol) and propylene oxide (1g, 17 mmol) in 25 ml toluene was heated to 50° C. in an autoclave for 7 days. The cooled reaction was concentrated in vacuo and purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (4:1, v/v). Concentration of the appropriate fractions afforded 350 mg (54.9%) of 3-[1-(2-hydroxyprop-1-yl)-4-piperidinyl]-6-fluoro-1 H-indazole as a foam.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:27]2[N:35]3[C@@H:30]([CH2:31][CH2:32][CH:33](P(=O)(OCC)OCC)[C:34]3=[O:36])[CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1.C(O)C>O1CCCC1>[F:26][C:24]1[CH:23]=[C:22]([C@H:27]2[N:35]3[C@@H:30]([CH2:31][CH2:32]/[C:33](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:34]3=[O:36])[CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[CH:25]=1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cc(F)cc(F)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cc(F)cc(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
Lithium hydroxide (56.8 mg) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.12 g) and diethyl [(3S,8aR)-3-(3,5-difluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (0.25 g) in tetrahydrofuran (1.0 mL)-ethanol (4.0 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.22 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH:17]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH2:8]([NH:9][S:23]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:25])=[O:24])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCc1ccccc1)C1CCCCC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-phenylethylamine (0.60 g, 4.97 mmol) in 45 ml CH2Cl2 at room temperature was added Et3N (0.83 ml, 5.97 mmol). The mixture was stirred for 5 min, and then cyclohexanesulfonyl chloride (1.0 g, 5.47 mmol) was added at this temperature.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:31]3[CH:30]=[N:29][C:28]([N:25]4[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]4)=[CH:33][CH:32]=3)=[CH:14][C:6]1=2
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(Cc3cc(F)ccc3F)CCN4)cn2)CC1
Yield: 53 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (50 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a beige solid (53% yield). M.p. 192-193° C., LCMS: m/z=437.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.34 (s, 3H), 2.52-2.58 (m, 4H, 3.43-3.50 (m, 2H), 3.52-3.59 (m, 4H), 3.60-3.65 (m, 2H), 4.47 (s, 2H), 4.90 (s, 1H), 6.62 (m, 2H), 6.91-7.09 (m, 3H), 7.52 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 8.2 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4](C1C=CC=CC=1O[Si](C(C)(C)C)(C)C)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].I[CH3:38]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:38]
Reactant: CI
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccccc2O[Si](C)(C)C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.06 g (0.014 mmol) of [(tert-butyl-dimethylsilanyloxy)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamino)-acetic acid methyl ester dissolved in 50 mL of DMF was added 0.618 g (0.015 mmol) of a 60% oil dispersion of sodium hydride. The reaction was stirred for 30 min at room temperature and then 2.62 mL of iodomethane was added. After 5 h the reaction was diluted with water and extracted with ether. The combined organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide [4-tert-butyl-dimethyl-silanyloxy)-phenyl]-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic acid methyl ester as a white waxy solid. Electrospray Mass Spec 518.4 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[CH:10](O)=[O:11].[OH-].[NH4+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH:10]=[O:11])=[N:6][CH:7]=1
Reactant: NCc1ccc(F)cn1
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=CNCc1ccc(F)cn1
Yield: 90.1 %

Procedure:
In a round-bottomed flask, (5-fluoro-pyridin-2-yl)methylamine (557 mg, 4.42 mmol) was dissolved in 88% formic acid (3.6 ml, 82.6 mmol). The brown solution was stirred at reflux in an oil bath overnight. The reaction mixture was cooled to 0° C. and adjusted carefully to pH=9 by addition of 25% aqueous ammonium hydroxide. The mixture was diluted with water and the aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 614 mg (90%) of N-(5-fluoro-pyridin-2-ylmethyl)-formamide as a brown oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:9]#[N:10])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:13][CH:14]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: N#CCc1ccc(F)cc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(c1ccc(F)cc1)c1ccc(Cl)cn1
Yield: 96.8 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (9.13 g), 2-chloro-5-chloropyridine (10.0 g.) and sodium 4-methylphenylsulfinate (24.1 g) in THF (280 ml) was added sodium hydride (5.41 g, 60%) at 0° C., and the mixture was heated to reflux for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 5-chloro-2-(α-cyano-4-fluorobenzyl)pyridine (16.14 g) as yellow oil.
Reaction SMILES: C(O[C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)C1C=CC=CC=1.[Na].[CH:24](=O)[CH:25]=[CH:26][CH2:27]C.C(O)(=O)C>C(O)C.[Pd]>[CH2:25]([CH:26]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:11][CH:9]=[CH:27]1)[CH3:24]
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CCC=CC=O
Agent: [Pd]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)NC=CC1CC
Reaction time: 1 h
Yield: 63 %

Procedure:
Diethyl benzyloxycarbonylaminomalonate (11.5 g, 38 mM) was dissolved in dry ethanol (50 ml) and added to a solution of sodium (150 mg) in dry ethanol (10 ml). Pent-2-enal (3.2 g 38 mM) in ethanol (10 ml) was added dropwise to the stirred mixture and the solution stirred for 1 hr. A solution of acetic acid (0.29 ml) in ethanol (1 ml) was then added and the solution hydrogenated for 2 hrs at atmospheric pressure using palladium on carbon (5%) as catalyst. The catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in chloroform and the solution washed with brine containing a little sodium bicarbonate, dried (Na2SO4) and evaporated. Distillation of the residue at 15 mm Hg gave 4-ethyl-5,5-dicarboethoxy-2-pyrroline (5.65 g) as a colourless oil b.p. 115°-120° (15 mm Hg) I.R. 1715, 1610 cm-1.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]([OH:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:17][C:10]2[C:11]([C:13]([O:15][CH3:16])=[O:14])=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[N:21]=1
Reactant: COC(=O)c1nc(-c2ccccc2)ccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Reaction time: 72 h

Procedure:
1.0 g (4.4 mmol) of methyl 6-phenyl-3-hydroxypicolinate, 0.8 g (4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.6 g (4 mmol) of potassium carbonate were added to 20 ml of DMF, and were reacted at 80° C. for 0.5 hour. After the reaction, the reaction content was poured into water, and was extracted with ethyl acetate. The organic layer thus obtained was washed with water and a saturated salt water, dried and treated with an appropriate amount of Florisil. Ethyl acetate was then distilled off under reduced pressure, and the residue was crystallized by adding 20 ml of hexane thereto and allowing to stand for 3 days. The crystal thus obtained was washed with hexane/isopropyl ether to obtain an aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH:19]1([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CC2)cc1F
Temperature: 90 °C
Yield: 81.1 %

Procedure:
A stirred suspension of trifluoro-methanesulfonic acid 3-fluoro-4-nitro-phenyl ester (5.6 g, 19 mmol), cyclopropyl boronic acid (2.09 g, 23.3 mmol) Pd(dppf)Cl2 (1.24 g, 1.5 mmol) and 2M aqueous cesium carbonate (30 mL, 60 mmol) in toluene (20 mL) was degassed before being heated at 90° C. under an argon atmosphere for 2.5 hours. The reaction mixture was allowed to cool to room temperature before filtering through a pad of Celite®, washing with ethyl acetate. The filtrate was washed (water, brine), and then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-30% ethyl acetate in pentane) to give the title compound as a yellow solid (2.79 g, 81%). 1H NMR (DMSO-d6, 400 MHz) 8.03 (1 H, t, J=8.39 Hz), 7.28 (1 H, dd, J=13.19, 1.91 Hz), 7.16 (1 H, dd, J=8.61, 1.90 Hz), 2.14-2.05 (1 H, m), 1.21-1.05 (2 H, m), 0.92-0.82 (2 H, m).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][CH:4]([OH:6])[CH3:5].C(Cl)Cl.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)CCCC(C)CC(C)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)CC(C)CCCC(C)C
Reaction time: 3 h

Procedure:
A solution of 47 g. of 4,8-dimethylnonan-2-ol in 250 ml. of methylene chloride is cooled to about 10° as a solution of 46.4 g. of sodium dichromate in 125 ml. of water is added. The mixture is maintained at about 10° as a solution of 46.3 g. of sulfuric acid in 100 ml. of water is added over about 45 minutes. The mixture is allowed to attain room temperature and, after about 3 hours, the organic layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic materials are washed with saturated potassium bicarbonate, water and saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 4,8-dimethylnonan-2-one.