Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([CH3:18])[CH:7]=[CH:8][CH2:9]P(OCC)(OCC)=O)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:30][C:31]1([CH3:49])[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[C:36]2[CH2:35][C:34]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])([CH:42]=O)[CH2:33][C:32]1=2.Cl>C1COCC1.CCCCCC>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([CH3:18])[CH:7]=[CH:8][CH:9]=[CH:42][C:34]1([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:33][C:32]2[C:31]([CH3:30])([CH3:49])[CH2:39][CH2:38][C:37]([CH3:41])([CH3:40])[C:36]=2[CH2:35]1)[CH3:2]
Reactant: CCOC(=O)C=C(C)C=CCP(=O)(OCC)OCC
Reactant: CCCCCC1(C=O)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC1(C=CC=CC(C)=CC(=O)OCC)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
680 mg of 6-(diethoxyphosphoryl)-3-methyl-hexa-2,4-dienoic acid ethyl ester were dissolved in 10 ml of THF and treated dropwise with 2.25 ml of a 1 molar solution of lithium bis(trimethylsilyl)amide in hexane at −78° C. After 10 minutes of stirring, a solution of 500 mg of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbaldehyde in 5 ml of THF was added dropwise at −78° C. The reaction mixture was slowly warmed to −40° C. and kept at this temperature for 3 hours. The cold reaction mixture was poured in ice/water, acidified with 1 N HCl and extracted with ether. The organic phase was washed with water, dried (Na2SO4) and the solvent was evaporated. The crude oil was purified with medium pressure chromatography (silica gel, hexane/tert.-butyl methyl ether 1%) to give 250 mg of pure (2Z, 4E, 6E)-3-methyl-7-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-hepta-2,4,6-trienoic acid ethyl ester and 400 mg of (2E, 4E, 6E)-3-methyl-7-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-hepta-2,4,6-trienoic acid ethyl ester as colorless oils.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([O:29][CH3:30])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)(=O)C>C(O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([O:29][CH3:30])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A mixture of 1′-(3-Methoxy-4-nitro-phenyl)-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester (2.0 g, 4.77 mmol), iron powder (1.33 g, 23.85 mmol), 1N hydrogen chloride (9.54 mL, 9.54 mmol) in ethanol (50 mL) is stirred at 80° C. for 3 h. After cooling to room temperature, 2N hydrogen chloride (5 mL) and ethyl acetate are added and then the mixture is filtrated. After concentration in vacuo, the mixture is extracted with AcOEt, washed with brine, dried over sodium sulfate and evaporated to give 1′-(4-Amino-3-methoxy-phenyl)-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester (1.77 g, 95% yield) as pale purple solids.
Reaction SMILES: C[Al](C)C.Cl.[C:6]([O:10][C:11](=[O:15])[CH2:12][NH:13][CH3:14])([CH3:9])([CH3:8])[CH3:7].[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27](OCC)=[O:28])[O:26][C:22]=2[C:21]([F:32])=[C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[CH3:39])#[N:17].Cl>ClCCl>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]([CH2:14][NH:13][CH2:12][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:15])=[O:28])[O:26][C:22]=2[C:21]([F:32])=[C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[CH3:39])#[N:17]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)CNCC(=O)OC(C)(C)C)nc2c1C#N
Reaction time: 25 h
Yield: 87.3 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 4.50 ml, 4.63 mmol) was dropwise added at room temperature to a dichloromethane (6 ml) solution of N-methylglycine tert-butyl ester hydrochloride (840 mg, 4.63 mmol), followed by stirring for 25 hours. Subsequently, a dichloromethane (4 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (500 mg, 1.54 mmol) was dropwise added, followed by stirring for 23 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended and washed in diethyl ether to obtain the entitled compound (569 mg, 87%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[BrH:23].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:23][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:10][N:11]([CH:13]([CH2:15][CH3:16])[CH3:14])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Br
Reactant: CCC(C)n1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(C)n1cc(-c2ccnc(Br)c2)c(-c2ccc(Cl)s2)n1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To 2-Chloro-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.57 mmol) was added slowly 0.5 mL of a 33% solution hydrobromic acid in acetic acid. The resulting mixture was stirred in the microwave at 140° C. for 20 min. After cooling to room temperature, potassium carbonate (2 molar solution) was added and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel (hepthane:ethyl acetate 5:1 to 2:1) to afford 178 mg of 2-bromo-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (79% yield).
Reaction SMILES: [C:1]([CH:4]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:5][CH:6]=[CH2:7])(=O)[CH3:2].FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:5]([C:4]1[N:8]=[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[O:18][C:1]=1[CH3:2])[CH:6]=[CH2:7]
Reactant: C=CCC(NC(=O)c1ccc(OC)cc1)C(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCc1nc(-c2ccc(OC)cc2)oc1C
Yield: 75.4 %

Procedure:
The above prepared N-(1-acetyl-but-3-enyl)-4-methoxy-benzamide (6.45 g, 26.1 mmol) was stirred in a mixture of 43.9 ml of trifluoro-acetic acid (22 eq.) and 21.75 ml of trifluoro-acetic anhydride (6 eq.) for 7 h at 40° and for 16 h at ambient temperature. Pouring onto crashed ice, twofold extraction with EtOEt, three times washing with Na2CO3-solution, drying over natrium sulfate and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1) produced finally 4.51 g of the title compound as colorless oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][NH2+:21]3)[S:18][CH:19]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[O:42]([CH2:49][C:50](Cl)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]3[C:50](=[O:51])[CH2:49][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Clc1ccc(-c2csc([C@H]3CCCC[NH2+]3)n2)cc1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COc1ccccc1)N1CCCC[C@@H]1c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-[4-(4-chloro-phenyl)-thiazol-2-yl]-piperidinium trifluoroacetate (0.077 g, 0.20 mmol) in dry dichloromethane (2 mL) under argon was treated with triethylamine (0.079 g, 0.11 mL), dimethylaminopyridine (0.002 g, 0.020 mmol) and phenoxyacetyl chloride (0.033 g, 0.20 mmol). The mixture was stirred at room temperature for 16 h. The mixture was washed with water and saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residual oil was purified by preparative HPLC: Column: YMC-Pack Pro C18 RS, 20×50 mm, S-5 um, 8 nm, No 200504707(W); Gradient: 0-0.4 min: 30% acetonitrile in (water+0.1% HCO2H), 0.4-2 min: increse of acetonitrile fraction from 30% to 95%, 2.4-3.7 min: 95% acetonitrile, 3.7-3.8 min: decrease of acetonitrile fraction from 95% to 30%; Program end at 4 min; Flow: 30 ml/min. 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone was obtained after lyophilization as a light yellow oil (0.037 g, 46%), MS (ISP): 413.1, 415.4 (M+H)+.. 1H-NMR (CDCl3, 300 MHz): 7.81 (2H, d), 7.38 (3H, m), 7.27 (2H, m), 6.98 (3H, m), 6.11+5.58 (1H, bs), 4.82 (2H, m), 4.56+3.91 (1H, bd), 3.36+2.86 (1H, bt), 2.59 (1H, m), 1.75 (5H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:3][C:4]=3[CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: O=C1CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methylphenyl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (402 mg) described in Preparation Example 253 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (356 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:5]=[C:6]([O:19][CH:20]([CH3:22])[CH3:21])[C:7]=1[O:8]CC1C=CC([N+]([O-])=O)=CC=1.C(O)(=O)C>C1COCC1.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:5]=[C:6]([O:19][CH:20]([CH3:22])[CH3:21])[C:7]=1[OH:8]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2ccc([N+](=O)[O-])cc2)c(OC(C)C)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c(OC(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of the product isolated in step c (750 mg) and acetic acid (1.5 ml) in THF (50 ml) was added zinc dust (1.5 g) under vigorous stirring. The mixture was stirred for 2 h and then filtered. The mixture was diluted with EtOAc and washed with sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C@:11]12[N:27]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]4[C:35]5[CH2:40][NH:39][C:37](=[O:38])[C:36]=5[C:24]5=[C:25]([C:26]=43)[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=35)[C@H:15]([O:16]1)[CH2:14][C@@H:13]([NH:41][CH3:42])[C@H:12]2[O:43][CH3:44].C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[CH3:10][C:11]12[N:27]3[C:26]4=[C:25]5[N:17]([C:18]6[C:23]([C:24]5=[C:36]5[C:37](=[O:38])[NH:39][CH2:40][C:35]5=[C:34]4[C:33]4[C:28]3=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=[CH:20][CH:19]=6)[CH:15]([O:16]1)[CH2:14][CH:13]([N:41]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:42])[CH:12]2[O:43][CH3:44]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN[C@@H]1C[C@H]2O[C@@](C)([C@@H]1OC)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC1C(N(C)C(=O)c2ccccc2)CC2OC1(C)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4
Reaction time: 0.17 h

Procedure:
0.035 ml (0.3 mmol) of benzoyl chloride is added at room temperature to a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N,N-diisopropylethylamine in 2 ml of chloroform and the whole is stirred for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel (eluant:methylene chloride/ethanol 30:1); m.p. 235°-247° with colour turning brown.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[N:15]=[C:16]=[O:17].[NH:18]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH:12]([CH3:13])[CH3:14])=[O:10])=[CH:4][C:3]=1[NH:15][C:16]([N:18]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)C1CCCCN1
Solvent: c1ccccc1
Product: CCOC(=O)C1CCCCN1C(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Yield: 83.2 %

Procedure:
5.15 g (0.02 mol) of 2-fluoro-4-chloro-5-isopropoxycarbonylphenyl isocyanate were added to a solution of 3.2 g (0.02 mol) of ethyl pipecolate dissolved in 30 ml of benzene. The mixture was stirred at a temperature of 40° to 50° C. for an hour, washed with water, dried over anhydrous sodium sulfate, and then concentrated. The resulting crystals were recrystallized from a mixed solvent of n-hexane and ethyl acetate to give 6.9 g (yield 83.2%) of 1-(2-fluoro-4-chloro-5-isopropoxycarbonylphenyl)aminocarbonyl-2-ethoxycarbonylpiperidine. This compound was dissolved in 70 ml of toluene and hydrogen chloride was blown thereinto. The mixture was stirred at room temperature for three hours, washed with a saturated solution of sodium hydrogen carbonate, washed with water, dried over anhydrous sodium sulfate and then concentrated. The resulting crystals were recrystallized from a mixed solvent of toluene and ethyl acetate to give 2.6 g (yield 71.9%) of the desired product as white crystals with a melting point of 128°-129° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.S(=O)(=O)(O)[OH:16]>[OH-].[Na+]>[OH:13][C:9]1[CH:10]=[CH:11][C:12]2[C:3]([CH2:4][C:5]([OH:14])=[O:16])=[CH:2][O:6][C:7]=2[CH:8]=1
Reactant: O=c1cc(CCl)c2ccc(O)cc2o1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1coc2cc(O)ccc12
Yield: 83 %

Procedure:
4-(Chloromethyl)-7-hydroxy-2H-chromen-2-one (10.9 g, 51.8 mmol) was dissolved in 1 M aqueous sodium hydroxide solution (500 mL), and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool, acidified with concentrated sulfuric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.27 g, yield 83%) as brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[N:12]=[C:11]([NH:22]C(=O)C(C)(C)C)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[N:12]=[C:11]([NH2:22])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Yield: 76 %

Procedure:
Using the general procedure described above, the reaction of 7 (209 mg, 0.47 mmol) and 1 N NaOH provided 128 mg of AAG103 as a white solid in 76% yield. TLC Rf 0.36 (chloroform-methanol 15:1); mp 233.6° C.; 1H NMR (DMSO-d6) δ 6.26 (s, 2H, NH2, exch), 7.09-8.09 (m, 8H, Ar—H), 8.44 (s, 1H, 4-NH, exch), 11.32 (s, 1H, 9-NH, exch). Anal. Calculated (C16H12BrN5): C, 54.25; H, 3.41; N, 19.77; Br, 22.55. Found: C, 54.38; H, 3.48; N, 19.56; Br, 22.29.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:9][C:10]([O:12][C@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[CH2:31][C:30]1[C:29]([Cl:49])=[CH:28][N+:27]([O-:50])=[CH:26][C:25]=1[Cl:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(CN(CC(=O)O)C(=O)OC(C)(C)C)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(CN(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino)acetic acid (0.209 g, 0.642 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.150 g, 0.357 mmol), EDC (0.205 g, 1.071 mmol), and DMAP (0.087 g, 0.714 mmol) in DCM (5 ml) was stirred at RT overnight. The reaction mixture was diluted with DCM (20 ml) and washed with HCl 1M and with NaHCO3 5%. The organic layer was dried over Na2SO4, and the solvent was removed under vacuum. The crude was purified by chromatography on silica gel column (DCM:EtOAc=70:30) affording (S)-4-(2-(2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino) acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.258 g, 0.355 mmol, 99% yield, MS/ESI+ 727.3 [MH]+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Se](=O)=[O:22].O>O1CCOCC1>[CH:1]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1)=[O:22]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1SC
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C=O)nc(-c2ccccc2)nc1SC
Yield: 58.9 %

Procedure:
To a solution of ethyl 4-methyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (5 g 17.4 mmol) in 1.4-dioxane (50 mL) was added selenium dioxide (9.6 g, 86.5 mmol) and water (1.5 mL) and the reaction mixture was refluxed for 12 hours. Dioxane was removed in a vacuum and the crude solid suspended in ethyl acetate and filtered. The filtrate was concentrated and purified by column chromatography over silica gel using 10% ethyl acetate in petroleum ether as eluent to give the desired product (3.1 g). 1H-NMR (400 Hz, CDCl3): δ 10.10 (s, 1H), 8.54 (d, J=7.2 Hz, 2H), 7.56-7.43 (m, 3H), 4.47 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.64 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); MS m/z 303.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]([C:23]1[N:28]=[C:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH:26]=[C:25]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:24]=1)[C:11](=[O:22])[NH:12][C:13]1[S:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:43][O:44][CH2:45]Br>CN(C=O)C>[CH2:1]([O:8][CH2:9][N:10]([C:23]1[N:28]=[C:27]([O:29][CH2:30][C:31]([F:32])([F:33])[F:34])[CH:26]=[C:25]([O:35][CH2:36][C:37]([F:39])([F:40])[F:38])[N:24]=1)[C:11](=[O:22])[N:12]([CH2:43][O:44][CH3:45])[C:13]1[S:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCBr
Reactant: O=C(Nc1ccc(C(F)(F)F)s1)N(COCc1ccccc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN(C(=O)N(COCc1ccccc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)s1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To a solution of 3-(benzyloxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (250 mg, 0.41 mmol) in anhydrous DMF (2.5 mL), with an internal temperature of ≦−10° C., was slowly added NaH (20 mg, 0.5 mmol, 60% dispersion in mineral oil). The mixture was stirred 30 minutes resulting in a clear yellow solution. To this solution was slowly added a solution of bromomethyl methyl ether (51.6 mg, 0.41 mmol) in anhydrous DMF (0.5 mL). After 2.5 h the reaction was quenched with ice and diluted with EtOAc (25 mL). The mixture was extracted with H2O (3×15 mL) and brine (15 mL). The EtOAc solution was dried (Na2SO4), filtered and evaporated to give crude product. The crude product was purified by silica gel chromatography (2 to 6% EtOAc in pet ether) to afford the product as a pale yellow gum (185 mg, 69%). 1H NMR (400 MHz, Acetone-d6) δ 7.29-7.08 (m, 6H), 6.82 (d, J=3.9 Hz, 1H), 5.90 (s, 1H), 5.40 (s, 2H), 5.10 (s, 2H), 4.79 (q, J=8.7 Hz, 4H), 4.69 (s, 2H), 3.27 (s, 3H); ESIMS m/z 649 ([M+H]+).
Reaction SMILES: Cl.Cl[CH:3]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.Br.BrC1C2NC(=[O:26])C=CC=2CCC1>O>[OH:26][CH:3]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: O=c1ccc2c([nH]1)C(Cl)CCC2
Reactant: O=c1ccc2c([nH]1)C(Br)CCC2
Agent: Br
Agent: Cl
Solvent: O
Product: O=c1ccc2c([nH]1)C(O)CCC2

Procedure:
Starting materials for the preparation of the ketone of the invention are 8-chloro-5,6,7,8-tetrahydro-2-quinolone hydrochloride or 8-bromo-5,6,7,8-tetrahydro-2-quinolone hydrobromide, which are hydrolyzed with the 4- to 8-fold amount of water, at a temperature of from 50° to 100° C., preferably 80° to 100° C., to form 8-hydroxy-5,6,7,8-tetrahydro-2-quinolone which, after cooling of the neutralized solution (neutralization for example by means of ammonia) precipitates in crystallized form as trihydrate. In order to prepare the ketone of the invention, it is however required to oxidize the anhydrous 8-hydroxy-5,6,7,8-tetrahydro-2-quinolone with manganese dioxide. The necessary dehydration of the trihydrate formed first is generally carried out by distillation removal of the hydration water as azeotropic mixture with, for example, butyl acetate, chloroform, butanol, toluene or cyclohexanone. Butyl acetate and cyclohexanone have proved to be especially suitable as agents for forming an azeotropic mixture (=water entrainers), because they allow particularly economic operations due to their good dissolving power, relatively high boiling point and minimal miscibility with water.
Reaction SMILES: [Br:1][CH2:2][C:3](OCC)([O:38]CC)[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].Cl>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:38])[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Agent: Cl
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (6.5 g) in methylene chloride (60 ml) was added conc. hydrochloric acid (6 ml) at 3° to 5° C., and the mixture was stirred from under ice-cooling to at ambient temperature for 8 hours. After methylene chloride (100 ml) was added to the reaction mixture, it was washed with water and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain benzhydryl 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.5 g).