Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[Si:7]([CH2:14][CH2:15][SH:16])([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].[OH-].[K+]>O>[Si:7]([CH2:14][CH2:15][S:16][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9]
Reactant: C=CC(=O)OC
Reactant: CO[Si](CCS)(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)CCSCC[Si](OC)(OC)OC
Temperature: 60 °C
Yield: 87 %

Procedure:
A mixture of 26 gms of methyl acrylate (0.3 mols) and 36.4 gms of (CH3O)3SiCH2CH2SH was catalyzed by adding 1 ml. of N/2 alcoholic KOH into a 250 ml., round bottomed glass flask, with stirring. An exothermic reaction raised the temperature to 60° C. The mixture was refluxed for 30 minutes and then distilled under vacuum to recover 46 gms of water-white product with a boiling point at 0.7 mm Hg pressure of 115°-125° C. for an 87 percent yield of (CH3O)3Si(CH2)2S(CH2)2COOCH3.d420 =1.115, ND25 =1.4546. One tenth gram mol (26.8 gms) of this product was saponified by refluxing for one hour with 4 grams of NaOH (0.1 mol) in 80 gms of H2O. Methanol and other volatiles were taken off until the temperature, with auxiliary heating, reached 100° C. The residue was diluted to 100 gms with water to give a 1 molal solution of (Na)O1.5 Si(CH2)2S(CH2)2COONa.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27](=NO)(N)[CH2:28][CH2:29][CH2:30]C>CN(C)C=O>[CH2:27]([C:19]1[N:18]=[C:16]([C:15]2[N:14]=[CH:13][N:12]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=4[C:8](=[O:26])[N:9]4[CH2:25][CH2:24][CH2:23][C@H:10]4[C:11]=23)[O:17][N:20]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCC(N)=NO
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: CCCCc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 2 h

Procedure:
11.0 g (30 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole are dissolved in 50 ml of N,N-dimethylformamide, whereupon the solution is treated with 3.96 g (34 mmol) of valeramidoxime and the mixture is heated to 85° for 3 hours. The reaction mixture is evaporated to dryness. The residue is dissolved in 50 ml of glacial acetic acid and the mixture is stirred at 110° for 2 hours. The reaction mixture is subsequently evaporated and the residue is chromatographed on silica gel while eluting with ethyl acetate. After evaporation of the eluate there is obtained (S)-1-(3-butyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 181°-182°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH2:14][CH3:15]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1cc(C(=O)O)ccc1Br
Solvent: C1CCOC1
Product: CCCCOc1cc(CO)ccc1Br
Temperature: 65 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
A solution of 20.1 (0.68 g, 2490 μmol) in THF (5 mL) was treated with borane THF complex (4979 μL, 4979 μmol) and stirred overnight at 65° C. The reaction mixture was quenched with MeOH, diluted with EtOAc, and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by combiflash (10 to 50% EtOAc/hexanes) yielding 20.2 (659.3 mg, 102% yield).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34](O)=[O:35].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:34]([C:26]2[NH:25][C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:35])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1cc2ccccc2[nH]1

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 106 mg (0.661 mmol) of indole-2-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR87## is obtained (89 mg, 32%) as white crystals with melting point 254° C. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.56, FD-MS: M+ =505, 507; IR: 3430, 3290, 1625 cm-1.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.[S-:10][C:11]#[N:12].[K+]>O>[NH:12]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]=2[N:2]=[C:11]1[SH:10]
Reactant: NC1CCCCC1=O
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: Sc1nc2c([nH]1)CCCC2
Temperature: 100 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
Dissolve 2-amino-cyclohexanone hydrochloride (2.2 g, 14.7 mmol) and potassium thiocyanate (1.4 g, 14.7 mmol) in water (10 mL). Stir the solution at 100° C. in a sealed flask for 16 h. Cool the mixture and store the mixture at 4° C. for 16 h. Filter off the resulting solid and wash with water (20 mL). Collect the solid, slurry in diethyl ether (20 mL) and filter. Dry the solid in a vacuum oven at 50° C. for 2 h to obtain the title compound as a tan solid (1.4 g, 62%). MS (ES+) m/z: 155.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][CH2:10][OH:11])=[N:6][C:5]([S:12][CH3:13])=[CH:4][N:3]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:13][S:12][C:5]1[N:6]=[C:7]2[CH:8]=[C:9]([CH:10]=[O:11])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CSc1cnc(N)c(C#CCO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CSc1cnc2[nH]c(C=O)cc2n1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of the compound obtained in Example 34 (4) (123 mg) in acetone (40 ml), manganese dioxide (1.86 g) was added and the mixture was stirred at −15 to 30° C. for-1 hour. The reaction solution was filtered through Celite and concentrated under reduced pressure to obtain 60 mg (49.3%) of the desired product as a yellow powder.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]C(=O)C(C)(C)C>Cl>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH:3]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[NH:2][CH3:1]
Reactant: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1cccnc1
Agent: Cl
Product: CNC(Cc1ccccc1N)c1cccnc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A stirred solution of 7.13 g of N-[2-[2-(methylamino)-2-(3-pyridinyl)ethyl]phenyl]-2,2-dimethylpropanamide in 90 ml of 6N hydrochloric acid was refluxed for 5.5 hours and then allowed to stand overnight at room temperature. The solution was decanted over crushed ice, diluted with water (200 ml) and basified with 50% sodium hydroxide solution. The mixture was extracted with dichloromethane (3×150 ml) and the combined, organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500 A, silica gel, sample applied in dichloromethane, eluted with 2% triethylamine in methanol). Concentration of the appropriate fractions yielded 4.69 g of 2-amino-N-methyl-α-(3-pyridinyl)benzeneethanamine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:14][CH:13]=1)[C:7]([CH3:23])=[CH:6]2.[CH2:24]([N:26](CC)[CH2:27][CH3:28])[CH3:25].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][CH2:20][CH2:21][N:26]3[CH2:27][CH2:28][CH2:25][CH2:24]3)=[CH:16][CH:17]=1)[C:7]([CH3:23])=[CH:6]2
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)cc(C)n2-c1ccc(C#CCCO)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: COc1ccc2c(c1)cc(C)n2-c1ccc(C#CCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 4.1 %

Procedure:
To a solution of 4-[4-(5-Methoxy-2-methylindol-1-yl)phenyl]but-3-yn-1-ol (60 mg, 0.19 mmol) in methylene chloride (1 mL) at 0° C. was added triethylamine (54 μL, 0.39 mmol) and methanesulfonylchloride (18 μL, 0.39 mmol). After the solution was stirred at 0° C. for 2 hours, pyrrolidine (163 μL, 1.95 mmol) was added and the reaction was allowed to warm to room temperature overnight. After the reaction was quenched with water, the organic layer was dried over MgSO4, and concentrated. The residue was purified by HPLC to give the desired indole (2.8 mg). LC-MS (C24H26N2O calc'd 358) m/z 359 (M+H); 1H NMR (300 MHz, CDCl3) d 7.53 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.03 (d, J=2.4 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.73 (dd, J=2.7, 9.0 Hz, 1H), 6.32 (s, 1H), 3.85 (s, 3H), 2.92-2.83 (m, 4H), 2.76 (m, 4H), 2.28 (s, 3H), 1.88 (m, 4H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:5]=2[O:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.ClCCCl>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[C:10]=3[OH:11])[C:31]2=[O:40])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Oc1cccc2c1OCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1O)OCCO2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.3 %

Procedure:
To a solution of 2,3-dihydro-1,4-benzodioxin-5-ol (3.60 g, 23.7 mmol) in anhydrous tetrahydrofuran (80 mL) at 0° C. was added isopropylmagnesium chloride (11.8 mL, 2 M solution in tetrahydrofuran, 23.7 mmol). The mixture was stirred at 0° C. for 45 min, concentrated in vacuo, and 1,2-dichloroethane (60 mL) was added. The mixture was cooled to 0° C. and a solution of 1-benzhydrylindoline-2,3-dione (4.94 g, 15.8 mmol) in 1,2-dichloroethane (70 mL) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 60 h, and heated to 83° C. and stirred for 3.5 h. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo and saturated aqueous ammonium chloride (250 mL) was added. The mixture was extracted with ethyl acetate (250 mL followed by 2×100 mL). The organic phase was washed with water (150 mL) and brine (150 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and a solid was precipitated by the addition of hexanes to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (5.10 g, 69%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.14 (s, 1H), 7.43-7.30 (m, 9H), 7.22 (d, J=8.7 Hz, 1H), 6.97-6.79 (m, 3H), 6.52 (s, 1H), 6.44 (d, J=8.7 Hz, 1H) 6.26 (d, J=7.8 Hz, 1H), 4.22 (s, 4H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>CCO>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][CH2:28][O:29][CH2:30][C:31]([OH:33])=[O:32])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCOCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1nc(C(=O)NCCOCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 150 °C
Yield: 12.6 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.075 mmol), (2-amino-ethoxy)-acetic acid (60 mg, 0.50 mmol), and NaOMe (20 mg, 0.37 mmol) in EtOH (5 mL) was refluxed for 16 h, then heated at 150° C. in a microwave reactor for 2 h. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH about 2, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (5-80% EtOAc/hexanes+2% AcOH) to give 4 mg of the title compound as a pale yellow solid. MS: (+) m/z 423.19 (M+1).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)=[O:18])=[C:10]3[CH:9]=2)[C@@H:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[CH2:4]1)#[N:2].[OH-:45].[Na+].OO>CO>[C:1]([C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([N:19]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[O:18])=[C:10]3[CH:9]=2)[C@@H:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[CH2:4]1)(=[O:45])[NH2:2]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C#N)C[C@@H]4c4cccc(F)c4)cc23)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C(N)=O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-35) (25 mg, 0.042 mmol) in MeOH (1 mL) was cooled to 0° C. A 1M NaOH solution (0.17 mL, 0.17 mmol) and 30% H2O2 (0.01 mL) were added to the reaction and stirred at 0° C. for 1 hour followed by room temperature for 1 hour. The reaction was concentrated to dryness and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted twice with EtOAc and the combined organics were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica chromatography with EtOAc/hexane gradient as eluent to yield 5-((2R,4S)-4-carbamoyl-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-54). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=7.7 Hz, 1 H), 7.78 (s, 1 H), 7.32-7.27 (m, 1H), 7.18 (d, J=8.5 Hz, 4 H), 7.14-7.09 (m, 1 H), 7.00-6.92 (m, 2 H), 6.89 (d, J=8.6 Hz, 4 H), 6.85 (s, 1 H), 6.15 (dd, J=2.7, 7.6 Hz, 1 H), 5.75 (bs, 1 H), 5.54 (bs, 1 H), 5.05 (d, J=7.7 Hz, 1 H), 4.72 (d, J=15.7 Hz, 2 H), 4.51 (d, J=15.8 Hz, 2 H), 4.04-3.97 (m, 1H), 3.88-3.82 (m, 1 H), 3.81 (s, 6 H), 3.23-3.11 (m, 1 H), 2.87-2.73 (m, 1 H), 2.19 (ddd, J=1.4, 6.5, 12.3 Hz, 1 H). MS m/z 608.3 (M+1)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[C:14]2[CH3:21].O.[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:12]1[C:11]([O:10][CH3:9])=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([CH3:21])=[CH:15][CH:16]=[N:17]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nccc(C)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2nccc(C)c2c1Br
Reaction time: 1 h

Procedure:
N-bromosuccinimide (0.57 g, 3.2 mmol) is added at RT to a mixture of 6-methoxy-4-methylquinoline (0.5 g, 2.9 mmol) in conc. sulfuric acid (5 ml). The mixture is stirred for 1 h and poured onto ice-water. The water phase is made basic with an aqueous solution of sodium hydroxide (1 mol/l) and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 256 mg (35%). HPLC-MS: M+H=252/254; tR=1.09 min (METHOD—1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][OH:18])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[C:24]([F:27])[C:25]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]2[CH2:17][O:18][C:25]2[C:24]([F:27])=[CH:23][C:22]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:21][C:20]=2[F:19])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: OCc1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of the product prepared in Step D (1.33 g, 4.84 mmol, 1 eq), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (1.78 g, 7.74 mmol, 1.6 eq), 1,1′-(azodicarbonyl)dipiperidine (2.52 g, 9.68 mmol, 2 eq) and tri-n-butylphosphine (3.08 mL, 12.1 mmol, 2.5 eq) in toluene (85 mL) was heated to 60° C. under N2. After 3 hr, heptane (170 mL) was added and the resulting suspension allowed to cool to room temperature over 30 min. The resulting white solid byproduct was filtered, washed with heptane, and the filtrate concentrated. The resulting residue was purified by flash chromatography (120 g column) eluting with 2 to 12% EtOAc/heptane to yield ethyl 3-(4-((1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl)methoxy)-3,5-difluorophenyl)propanoate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:32][CH:33](Br)[CH3:34])(=[O:31])[CH:28]([CH3:30])[CH3:29].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:33]([O:32][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH3:34])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Reactant: CC(Br)OC(=O)C(C)C
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(=O)C(C)C)=CCS[C@H]12)c1csc(N)n1

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer) was reacted with 1-bromoethyl isobutyrate in the presence of sodium iodide to give 1-isobutyryloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 120°-125° C. (decompn.).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[CH:10]2)(=O)C.[OH-].[Na+]>Cl>[NH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[CH:10]2
Reactant: CC(=O)Nc1cccc2ccc(=O)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc2ccc(=O)[nH]c12
Temperature: 0 °C
Yield: 91.1 %

Procedure:
8-Acetylaminocarbostyril (21.5 g, 0.106 mol) was suspended in 190 ml of 20% hydrochloric acid and the suspension was stirred while heating under reflux for 1 hour. The reaction mixture was poured into ice water and neutralized with 5 N sodium hydroxide. Crystals which formed were collected by filtration to give 15.47 g of 8-aminocarbostyril.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:17]([C:16](=[O:21])[CH3:15])[C:18](=[O:20])[CH3:19])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: CC(=O)C(=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(C)=O

Procedure:
The procedure described in Example 1 was repeated by using 2.53 g 3,5-dinitrobenzaldehyde and 2.43 g of 2,4-pentanedione. Yield 0.8 g, mp 101°-105° C.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9](C(OC(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH2:21]([N:23]1[C:35]2[CH:34]=[CH:33][C:32]([NH2:36])=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][NH:9][C@H:8]([C:18]([NH:36][C:32]2[CH:33]=[CH:34][C:35]3[N:23]([CH2:21][CH3:22])[C:24]4[C:29]([C:30]=3[CH:31]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1CN[C@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 80% purity by LC/MS. MS(ESI+): m/z=377.2.
Reaction SMILES: [C:1]([C:3](=[C:19]([OH:21])[CH3:20])[C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:5])#[N:2].C(C1S[C:27]([C:30]2[CH:35]=CC(F)=C[CH:31]=2)=CC=1)(O)=O>>[C:1]([C:3](=[C:19]([OH:21])[CH3:20])[C:4]([NH:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:30]([CH3:35])([CH3:31])[CH3:27])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:5])#[N:2]
Reactant: CC(O)=C(C#N)C(=O)Nc1ccc(-c2ccc(F)cc2)s1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)s1
Product: CC(O)=C(C#N)C(=O)Nc1ccc(-c2ccc(C(C)(C)C)cc2)s1

Procedure:
2-Cyano-N-[5-(4-fluorophenyl)thien-2-yl]-3-hydroxybut-2-enamide, m.p. 232°-234° C. (from 2-carboxy-5-(4-fluorophenyl)thiophene).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]([OH:10])=[C:8]([CH:11]=O)[C:7]([CH2:13][OH:14])=[CH:6][N:5]=1.[ClH:15].Cl.Cl.[O:18]([CH2:20][CH:21]([F:25])[CH2:22][NH:23][CH3:24])[NH2:19]>C(O)C>[ClH:15].[OH:10][C:9]1[C:4]([CH3:3])=[N:5][CH:6]=[C:7]([CH2:13][OH:14])[C:8]=1[CH:11]=[N:19][O:18][CH2:20][CH:21]([F:25])[CH2:22][NH:23][CH3:24]
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CNCC(F)CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNCC(F)CON=Cc1c(CO)cnc(C)c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 ml of 1N sodium hydroxide solution and 408 mg (2 mmol) of pyridoxal hydrochloride are added to a solution of 390 mg (2.0 mmol) of N-(3-aminoxy-2-fluoropropyl)-methylamine dihydrochloride in 10 ml of ethanol and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then concentrated to dryness by evaporation and the title compound is crystallised from ethyl acetate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[CH2:4].[CH:12](OCC)=[O:13]>>[CH:12]([NH:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[CH2:4])=[O:13]
Reactant: CCOC=O
Reactant: C=C[C@@H](N)Cc1ccccc1
Product: C=C[C@H](Cc1ccccc1)NC=O

Procedure:
(S)-3-Amino-4-phenyl-1-butene (5.2 g, 35.4 mmol) was dissolved in ethyl formate (100 ml) and the solution was refluxed with heat for 6 hours. After completion of reaction, the solution was concentrated under reduced pressure to give the desired compound as an orange oil. Yield: 6.44 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](O)[CH3:13]>>[N+:8]([C:6]1[CH:7]=[C:12]([C:13]2[O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)[CH:3]=[CH:4][CH:5]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCO
Product: O=[N+]([O-])c1cccc(-c2nc3cc([N+](=O)[O-])ccc3o2)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To 11.5 grams (0.05 mole) of 3-nitrophenylchloroxime are added 150 milliliters of ethanol. To the mixture are added 23.1 grams (0.15 moles) of 2-amino-4-nitrophenol. The mixture is stirred under nitrogen at about 30° C. overnight and filtered to yield 2-(m-nitrophenyl)-5-nitrobenzoxazole.