Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10](C#N)[C:11]([C:24]#[N:25])=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=1.[OH-].[Na+].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>CN1CCN(C)C1=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:11]([C:24]#[N:25])=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:22])[CH3:23])[N:15]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2Br)ccc1=O
Reactant: COc1ccc(CN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(CNc2nc(-c3ccccc3Br)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Temperature: 27.5 °C
Reaction time: 100 h

Procedure:
To a solution of 5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2,3-pyrazinedicarbonitrile (3.00 g) in 1,3-dimethyl-2-imidazolidinone (6 ml), (4-methoxybenzyl)amine (0.96 ml) was added and the mixture was stirred at 25-30° C. for 100 hours. After addition of 0.5N aq. NaOH (15 ml), the mixture was stirred for one hour and a precipitate was collected by filtration to give a solid. The solid was dissolved in EtOAc, washed with water, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give 5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-2-pyrazinecarbonitrile as an amorphous solid (2.58 g) containing 6-(2-bromophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-2-pyrazinecarbonitrile.
Reaction SMILES: [Cl-].[NH4+].Cl.[CH3:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:18]([O-])=O)[C:16]=1[Cl:17])[C:11]([OH:13])=[O:12])(=[O:7])=[O:6]>[Fe].O>[ClH:17].[CH3:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([NH2:18])[C:16]=1[Cl:17])[C:11]([OH:13])=[O:12])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(N)c1Cl
Temperature: 50 °C
Yield: 123.5 %

Procedure:
A vigorously stirred mixture of iron powder (9.2 g.), ammonium chloride (880 mg.) water (27 ml.) and concentrated hydrochloric acid (0.1 ml.) is heated on a steam bath while 3-methylsulfonyl-4-chloro-5-nitrobenzoic acid (7.8 g.) is added in small portions during a one hour period. The reaction mixture is heated on a steam bath for 18 hours, cooled and filtered. The filter cake is suspended in water (75 ml.), basified with 10N sodium hydroxide, warmed to 50° C. and filtered. Acidification of the filtrate with hydrochloric acid gives pure 3-methylsulfonyl-4-chloro-5-aminobenzoic acid (4.3 g.; 62%) which melts at 277.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([O:7]C)=O.[NH2:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([NH:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:7]
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Reactant: Cc1ncccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncccc1NC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.14 g, 0.34 mmol) and 3-amino-2-methylpyridine (0.04 g, 0.37 mmol) in anhydrous THF (10 mL), was added lithium bis(trimethylsilyl)amide solution (1.3 mL, 1 M in THF, 1.3 mmol), at about −40° C. The resulting mixture was stirred for about 30 min, at about −40° C., and then quenched by the addition of water (10 mL) and ethyl acetate (130 mL). The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol 100:0 to 0:100) and prep-HPLC (Table 2, Method a) to afford 3-chloro-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.0162 g, 0.03 mmol, 9%). LC-MS (Table 1, Method b) Rt=3.70 min, m/z 491 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.56 (3H, s), 2.70-2.90 (2H, m), 3.26-3.35 (1H, m), 3.63-3.71 (1H, m) 3.60-4.00 (1H, br s) 3.84 (3H, s) 6.91 (1H, s) 7.09 (1H, ddd, J=1.2, 4.8, 7.9 Hz) 7.21 (1H, dd, J=4.8, 8.2 Hz) 7.44 (1H, d, J=8.0 Hz) 7.58-7.64 (3H, m) 7.80 (1H, d, J=8.0 Hz) 7.92 (1H, d, J=2.0 Hz) 8.28-8.34 (2H, m) 8.48-8.51 (1H, m).
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([CH3:11])[NH:8][C:7]1=[O:12].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[N:10]=[C:9]([CH3:11])[NH:8][C:7]1=[O:12]
Reactant: COc1ccccc1C=C1N=C(C)NC1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=NC(=Cc2ccccc2O)C(=O)N1
Temperature: -40 °C
Yield: 83.5 %

Procedure:
3,5-Dihydro-5-(2′-methoxybenzylidene)-2-methylimidazol-4-one (1.28 g) was dissolved in dichloromethane (20 ml) and boron tribromide (4.5 g) was added dropwise while stirring at −40° C. Thereafter, the mixture was stirred for 2 hr under ice-cooling and the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3,5-dihydro-5-(2′-hydroxybenzylidene)-2-methylimidazol-4-one (1 g) as red crystals. The crystals and (S)-glycidyl nosylate (1.3 g) were dissolved in dimethylformamide (20 ml) and potassium carbonate (1.38 g) was added. The mixture was heated at 50° C. for 2 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product (1.12 g). This oily product and 4-(naphthalen-2-yl)piperidine were dissolved in methanol (15 ml) and the mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.23 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[C:29]([Cl:45])=[CH:28][N:27]=1>>[Cl:45][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)c2OC
Yield: 34.2 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (163 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (156 mgs) were combined to give the title compound as off-white solid (101 mgs) 1H-NMR (CDCl3, 400 MHz): 9.67 (s, 1H), 8.57 (d, J=8.6 Hz, 1H), 8.31 (d, J=8.8 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.69 (t, J=8.1 Hz, 1H), 7.60-7.58 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 4.49-4.43 (m, 1H), 4.40-4.31 (m, 1H), 3.87 (s, 3H), 3.59-3.52 (m, 1H), 3.31-3.28 (m, 1H), 3.18-3.13 (m, 1H), 2.80-2.70 (m, 1H), 2.61-2.53 (m, 1H), 2.06-1.99 (m, 1H), 1.37-1.33 (m, 6H), 1.22 (t, J=6.1 Hz, 3H), LC/MS: found (M+H)+=655.57; MP:245-247° C.
Reaction SMILES: [Bi](Cl)(Cl)Cl.CC1C=CC(S(O[CH2:16][C:17]2([C:20]([F:23])([F:22])[F:21])[CH2:19][O:18]2)(=O)=O)=CC=1.[C:24]1([N:30]2[C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([NH2:39])[C:33]=3[CH:32]=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])[O-].C(N(CC)C(C)C)(C)C>ClCCl.C(Cl)(Cl)Cl.O1CCCC1>[C:24]1([N:30]2[C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([NH:39][CH2:16][C:17]4([C:20]([F:21])([F:22])[F:23])[CH2:19][O:18]4)[C:33]=3[CH:32]=[N:31]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CO2)cc1
Reactant: Nc1cccc2c1cnn2-c1ccccc1
Agent: Cl[Bi](Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)C1(CNc2cccc3c2cnn3-c2ccccc2)CO1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
Bismuth chloride (623 mg, 1.98 mmol) was added to a suspension of [2-(trifluoromethyl)-2-oxiranyl]methyl 4-methylbenzenesulfonate (5.85 g, 19.76 mmol) and 1-phenyl-1H-indazol-4-amine (4.13 g, 19.76 mmol) in dry dichloromethane (8 ml) and the mixture stirred at room temperature over the weekend. The resulting thick suspension was diluted with dichloromethane and stirred overnight. The mixture was then diluted with chloroform (200 ml) and sodium sulphate (30 g) and polymer supported carbonate resin (Fluka, ca. 3.5 mmoles carbonate/g resin, 11 g) were added and the mixture stirred overnight. LCMS showed no evidence for cyclisation to the target epoxide. Dry tetrahydrofuran (50 ml) and N,N-diisopropylethylamine (0.85 ml, 4.88 mmol) were then added and the mixture stirred overnight when LCMS indicated complete reaction. The mixture was filtered and the filtrate was washed with water. The aqueous phase was back-extracted with dichloromethane and the combined organic phases were dried and evaporated to give crude product which was purified by silica gel chromatography using the Flashmaster II (2×100 g cartridges) eluting with a 0 to 50% dichloromethane:ethyl acetate gradient over 40 minutes to give the title compound (3.74 g).
Reaction SMILES: CN(C=O)C.[ClH:6].Cl.[NH2:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28](=[NH:30])[NH2:29])[CH:24]=3)[CH:19]=2)=[O:16])=[CH:12][CH:11]=1.[C:31](O)(=[O:36])[CH2:32][C:33]([OH:35])=[O:34].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:6].[C:33]([CH2:32][C:31]([NH:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28](=[NH:29])[NH2:30])[CH:24]=3)[CH:19]=2)=[O:16])=[CH:12][CH:11]=1)=[O:36])([OH:35])=[O:34]
Reactant: O=C(O)CC(=O)O
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CC(=O)O)o3)ccc2c1
Yield: 57.5 %

Procedure:
To a mixture of 210 ml of DMF and 90 ml of pyridine were added 10 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrochloride, 13.6 g of malonic acid and 320 mg of DMAP, then 10.8 g of DCC was added to the mixture with stirring and ice-cooling, and the mixture was stirred for 24 hours. The precipitate was removed by filtration and the filtrate was added dropwise to 3 l of acetone. The precipitate was collected by filtration to obtain 6.5 g of the intended product as a white solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][C:22]=1[CH3:23])[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12][C:11]2=[O:24].[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26].N#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[C:20]2[C:10]([C:11](=[O:24])[CH2:12][C:13]3([O:19]2)[CH2:18][CH2:17][CH2:16][O:15][CH2:14]3)=[CH:9][C:8]=1[C:31]1[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=1)[C:25]#[N:26]
Reactant: Cc1cc2c(cc1Br)C(=O)CC1(CCCOC1)O2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1cccc(C#N)c1)C(=O)CC1(CCCOC1)O2
Temperature: 100 °C
Yield: 96 %

Procedure:
To a 10 mL CEM microwave test tube was charged with Cs2CO3 (147 mg, 0.45 mmol), PdCl2(PPh3)2 (8 mg, 0.011 mmol), 6-bromo-7-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (70 mg, 0.225 mmol), 3-cyanophenylboronic acid (43 M2, 0.293 mmol), dioxane (4 mL) and H2O (0.2 mL), the system was swept with N2 and sealed, and heated in a CEM microwave reactor at 100° C. for 10 min. The reaction mixture was filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0-20%) to give 3-(7-methyl-4-oxo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-6-yl)benzonitrile (72 mg). MS ESI +ve m/z 334 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[C@H:8]3[C@H:13]([CH2:14][CH2:15][C:6]=2[CH:5]=1)[NH:12][CH2:11][CH2:10][CH2:9]3)([O-:3])=[O:2].[CH2:18](Br)[CH:19]=[CH2:20]>C1COCC1>[CH2:20]([N:12]1[C@@H:13]2[C@H:8]([C:7]3[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[CH2:15][CH2:14]2)[CH2:9][CH2:10][CH2:11]1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc2c(c1)CC[C@@H]1NCCC[C@@H]21
Solvent: C1CCOC1
Product: C=CCN1CCC[C@H]2c3ccc([N+](=O)[O-])cc3CC[C@@H]21
Temperature: 50 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
(4aS,10bS)-8-Nitro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (0.50 g, 1.51 mmol) was dissolved in THF (30 mL) and allyl bromide (0.40 g, 3.30 mmol) added. The solution was stirred at 50° C. for 8 h, room temperature for 18 h and then evaporated. The residue was partitioned between ethyl acetate and NaOH (2M), and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and separated by column chromatography (dichloromethane: 0-3% MeOH) to give the product as a yellow oil (0.40 g, 97%).
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[C:5]([Br:13])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1>O>[Br:13][C:5]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:2][S:3][CH:4]=1
Reactant: CCCCCCc1c(Br)sc(Br)c1Br
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCc1cscc1Br
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
Compound 51 (70 g, 0.173 mol) was mixed with dry THF (400 mL). To this mixture, 7-butyllithium (138 mL, 2.5M in hexane, 0.345 mol) was added dropwise at −78° C. under argon. The resulting mixture was stirred for 10 minutes, then water (30 mL) was added to quench the reaction. The THF was evaporated and the organic was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), water (70 mL) and dried over MgSO4. After evaporation of the solvent, the resulting crude product was purified by vacuum distillation (72-74° C. at 0.17 mbar) to yield 52 (35.3 g, 82.6% yield). GC/MS: 246 g/mol (M-1). 1H NMR (CD2Cl2): δ 7.22 (s, 1H), 6.96 (s, 1H), 2.57 (t, 2H), 1.61 (m, 2H), 1.32 (m, 6H), 0.88 (t, 3H). 13C NMR: 141.92, 122.87, 120.95, 112.89, 31.88, 30.07, 29.53, 29.20, 22.88, 14.14.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:9]([CH2:10][O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7][N:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5]1.[CH3:29]I.O>C1COCC1>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([O:11][CH2:10][C@@H:9]2[CH2:8][CH2:7][N:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C@H:4]2[O:3][CH3:29])(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1COS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
Reaction under nitrogen atmosphere. Sodiumhydride (0.3 mol) was added to a solution of 1,1-dimethylethyl trans-3-hydroxy-4-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-1-piperidinecarboxylate [described in WO-00/37461 as intermediate (1-c)] (0.27 mol) in THF (1300 ml). The mixture was stirred for 30 minutes. Methyliodide (0.54 mol) was added and the resulting reaction mixture was stirred for 90 minutes. A small amount of water was added. The solvent was evaporated and the residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 1,1-dimethylethyl trans-4-[[[(4-methylphenyl)sulfonyl]oxy]-methyl]-3-methoxy-1-piperidinecarboxylate (intermediate 62).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[N:12]=2)=[N:8][CH:9]=1)([O-])=O.C(=O)=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[N:12]=2)=[N:8][CH:9]=1
Reactant: Nc1cccc(Nc2ccc([N+](=O)[O-])cn2)n1
Agent: [Pd]
Agent: O=C=O
Solvent: CO
Product: Nc1ccc(Nc2cccc(N)n2)nc1
Reaction time: 2 h

Procedure:
2,6-Diaminopyridine (9.2 mmol, 1.0 g) and 2-fluoro-5-nitropyridine (4.6 mmol, 0.65 g) were dissolved in 6 mL of DMSO. The solution was heated to 80° C. for 18 h. The solution eventually turned dark red. The reaction mixture was cooled to room temperature and purified directly by flash column chromatography (silica, EtOAc:Hexanes=1:3) to give N2-(5-nitropyridin-2-yl)pyridine-2,6-diamine as a reddish crystalline solid (0.21 g, 20% yield): 1H NMR (500 MHz, CDCl3) δ 9.13 (d, 1H, J=3.0 Hz), 8.36 (dd, 1H, J=3.0 Hz, J2=9.5 Hz), 7.94 (d, 1H, J=9.5 Hz), 7.66 (s, 1H), 7.46 (t, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0 Hz), 6.23 (d, 1H, J=8.0 Hz), 4.46 (s, 2H); Ms m/z (relative intensity) 232 (M+1, 100), 186 (57). The nitro compound (0.78 mmol, 0.18 g) and 10% Pd/C (20 mg) were added to a 20 mL test tube equipped with a stir bar, dry ice (0.5 g) was added to the mixture just before MeOH (7 mL) was added. The suspension was then put into a pressure vessel under 80 psi of H2. The reaction mixture was stirred for 2 hours. The solution turned from yellow to colorless. The reaction mixture was transferred into a 10 mL syringe and was then filtered through an Acrodisc syringe Filter into a 100 mL round bottom flask containing 37% aqueous HCl (4 mL). The solvent was then evaporated and azeotroped to dryness with toluene and absolute ethanol (3×30 mL of 1:1 mixture). The product was obtained as a grayish yellow powder in quantitative yield.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)=[N:4][CH:3]=1.O.NN>C1COCC1.[Ni]>[S:6]1[CH:2]=[CH:3][N:4]=[C:5]1[C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccc(-c2ncc(Cl)s2)c1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(-c2nccs2)c1
Yield: 86.4 %

Procedure:
To a solution of 5-chloro-2-(3-nitro-phenyl)-thiazole (20.0 g, 69.6 mmol) in THF (260 ml) was added hydrazine monohydrate (13.5 ml, 278 mmol) and Raney nickel (2 g). The resultant mixture was stirred at ambient conditions for 1 hour and then filtered through celite. The filtrate was evaporated to dryness and the filtrate was partitioned between ethyl acetate and saturated, aqueous sodium carbonate. The organic layer was dried over sodium sulphate and concentrated in vacuo. The concentrate was eluted through silica gel with a mixture of ethyl acetate and ligroin (1:3 v/v) to afford the desired product (10.6 g, 72%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH3:21])[C:18](=[O:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH3:22][Li]>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH3:21])[C:18]([OH:20])([CH3:22])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: [Li]C
Reactant: CC(=O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)(C)O

Procedure:
The ketone of Example 8 is reacted with methyl lithium by the method of Example 17 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH3:42])/[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH3:42])/[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Yield: 52.2 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylate (1.65 g, 2.65 mmoles) and anisole (0.5 ml) was treated with TFA (5 ml) at room temperature for 1 hour. The mixture was diluted with IPE. The resulting precipitate*1 was collected by filtration and chromatographed on a column of the packing (50 ml) of a PrepPAK cartridge (Waters) with 20-30% methanol to yield 605 mg (52%) of the title compound. Estimated purity 90% (by HPLC). Mp.>160° C. (grad. dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[NH4+].[Cl-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:14])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: CCCCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCC(O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a 3-neck flask equipped with an overhead stirrer, dropping funnel and thermometer was added 6-methoxy-2-naphthaldehyde (70.760 g, 380 mmol) and Et2O (1400 mL). The stirred suspension under N2 was cooled in an ice bath followed by the slow addition of hexylmagnesium bromide (228 mL of a 2 M solution in Et2O) over 1 h. Temperature was kept below 12° C. After the addition, the reaction was stirred for 3 h at room temperature then cooled in an ice bath and slowly quenched w/saturated aq. NH4Cl (250 mL). After quenching, the ice bath was removed and the mixture was stirred for a half-hour then diluted with H2O (750 mL) to dissolve all solids. The layers were separated and the aqueous layer extracted with Et2O (3×200 mL). The combined organics were washed with water (3×200 mL), and brine (2×200 mL), dried over Na2SO4, filtered, rotovap'd and dried in vacuo to give the desired product as an off-white solid (101.1 g, 371.2 mmol, 98%) with mp 71-74° C. 15 g of crude alcohol was recrystallized from hexane to give the desired product as a white solid (11.7 g) with mp 71-73° C; 1H NMR (DMSO-d6) δ 0.82 (t, J=6.7 Hz, 3H), 1.15-1.38 (m, 8H), 1.58-1.71 (m, 2H) 3.85 (s, 3H), 4.58-4.64 (m, 1H), 5.14 (d, J=4.3 Hz, 1H), 7.12 (dd, J=2.6, 9.0 Hz, 1H), 7.26 (d, 2.4 Hz, 1H), 7.42 (dd, J=1.5, 8.4 Hz, 1H), 7.70 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), IR (solid) 3280, 2920, 2860, 1610, 1270, 1170, 1040, and 860 cm−1; mass spectrum [ESI], m/z 255 (MH—H2O)+;
Reaction SMILES: [C:1]([CH:6]([CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:20]([CH:22](C(OCC)=O)[C:23](OCC)=O)[CH3:21]>>[C:1]([CH:6]([C:18]1[CH:23]=[CH:22][CH:20]=[CH:21][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: CCOC(=O)C(CC)CCCCCC1=CCCC1=O
Product: CCOC(=O)C(CCCCCC1=CCCC1=O)c1ccccc1

Procedure:
This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carbethoxyoctyl)cyclopent-2-en-1-one by substituting diethyl phenylmalonate for diethyl ethylmalonate.