Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[N:10]([CH2:20][CH3:21])[CH2:11][CH2:12][NH:13]C(=O)C(F)(F)F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH2:1]([O:8][C:9](=[O:22])[N:10]([CH2:11][CH2:12][NH2:13])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.7 %

Procedure:
To a solution of compound N (24.9 g, 78.2 mmol) in MeOH (300 ml) was added a solution of LiOH (3.8 g, 156 mmol) in water (30 ml). The reaction mixture was stirred at room temperature for 5 h. Next the solvents were evaporated to ¾ of initial volume followed by the dilution with water (200 ml). The solution was extracted with EtOAc (200 ml×2) and the organic layer was washed with brine (100 ml), dried over MgSO4 and evaporated in vacuo. Residue was dissolved in ether (200 ml) and treated with 2 N HCl/ether (200 ml). The formed precipitate was filtered, washed with ether and dried in vacuum to provide hydrochloride salt of compound O (12.1 g, 46.7 mmol) as white solid. LC-MS [M+H] 222.9 (C12H18N2O2+H, calc: 223.2).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([C@@H:10]([C@@H:26]([CH2:32][CH3:33])[CH2:27][C:28]([F:31])([F:30])[F:29])[C:11](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:12])=[N+]=[N-]>C1COCC1>[NH2:7][C@@H:10]([C@@H:26]([CH2:32][CH3:33])[CH2:27][C:28]([F:29])([F:30])[F:31])[CH2:11][OH:12]
Reactant: CC[C@@H](CC(F)(F)F)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](CC(F)(F)F)[C@H](N)CO
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a gray slurry of LAH (100 mg, 2.65 mmol) in THF (3 mL) at −10° C. was added (4R)-3-[(2S, 3S)-2-azido-3-ethyl-5,5,5-trifluoropentanoyl]-4-benzyl-1,3-oxazolidin-2-one (300 mg, 0.78 mmol) as a solution in THF (2 mL) dropwise over 5 min. The resulting slurry was allowed to warm to 25° C. for 19 h. The reaction was quenched by sequential addition of H2O (0.3 mL), 1N NaOH (0.9 mL) and H2O (0.3 mL) at 0° C. The precipitate that formed after 5 h was filtered off The mother liquor was dried over MgSO4, filtered and concentrated to obtain (2S, 3S)-2-amino-3-ethyl-5,5,5-trifluoropentan-1-ol as a light yellow oil (145 mg, 98%). Mass Spectrum (−ESI): 184 (M−H)−.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(C1SC=C(C2C=CC=C(N)C=2)N=1)=O)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)c1nc(-c2cccc(N)c2)cs1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and 4-(3-amino-phenyl)-thiazole-2-carboxylic acid ethyl ester were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.51 (1H, s), 8.05 (1H, s), 7.88 (1H, s), 7.63 (1H, d), 7.49 (3H, m), 7.40-7.27 (2H, m), 7.07 (1H, d), 4.70 (1H, d), 4.45 (1H, d), 4.27 (2H, m), 2.95 (1H, m), 2.81 (1H, m), 2.06-1.56 (14H, m), 1.28 (4H, m). The compound was further characterised the N-methyl-D-glucamine salt. Found: C, 57.65; H, 6.41; N, 9.83%; C33H35N5O5S.C7H17NO5.1.5H2O requires: C, 57.51; H, 6.63; N, 10.06%.
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH:19]=[O:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(OCC)C>[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH:19]([OH:20])[CH3:5])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccnc(C=O)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc(C(C)(C)C)ccn1
Temperature: 25 °C
Yield: 93 %

Procedure:
Methylmagnesium bromide (9.7 ml, 29 mmole) is added to 20 ml dry tetrahydrofuran in an oven dried 100 ml two neck round bottom flask under nitrogen at 0° C. The solution is treated with 4-t-Butyl-2-pyridine-carboxaldehyde (3.8 g, 23.3 mmole) in 2×5 ml diethyl ether followed by 10 ml diethyl ether. The reaction is warmed to room temperature and then to reflux for 1 h. The mixture is cooled to 0° C., is quenched with 1×20 ml 10% hydrochloric acid, and the pH is adjusted to 9 with 2 N sodium hydroxide. The layers are separated, the aqueous layer is extracted with 4×25 ml dichloromethane, and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to give 3.9 g (93%) of 4-t-Butyl-2-(1-hydroxyethyl)-pyridine as a tan solid. Analytical material is obtained via recrystallization from hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:17]([C:14]1[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=1)[OH:18]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1ccncc1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a stirred solution of 5-fluoroindole (3.10 g, 23.0 mmol) in methanol (10.0 mL) was added 4-pyridinecarboxaldehyde (2.20 mL, 23.0 mmol), followed by addition of NaOH (2.5 mL, 50%) at 0° C. After stirring for 1 h at 0° C., the reaction Mixture was warmed to room temperature and stirred for 3 h, followed by the addition of water (10.0 mL). The precipitate was collected by filtration and dried under vacuum to afford 5.2 g (93%) of a light yellow solid: mp 171-173° C.; 1H NMR (DMSO, 400 MHz), 5.85 (d, 1H), 5.93 (d, 1H), 6.86-7.34 (m, 4H), 7.43 (dd, 2H), 8.48 (dd, 2H), 11.09 (br s, 1H); MS (EI) m/z 242 (M+); HRMS calcd for C14H12FN2O [M+H] 243.09337, found 243.09576.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[O:23]COC)=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:27])=[CH:4][N:3]=1.Cl>C1COCC1.C(=O)(O)[O-].[Na+].C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[OH:23])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:27])=[CH:4][N:3]=1
Reactant: COCOc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Oc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.4 %

Procedure:
Treat a solution of 2-chloro-5-fluoro-4-[7-(3-methoxymethoxy-pyridin-4-yl)-benzo[b]thiophen-2-yl]-pyrimidine (4 g, 10 mmol) in THF (10 mL) with 5 N HCl (3 mL). Stir the mixture at RT for 6 h. Concentrate the reaction in vacuo and dilute with saturated aqueous sodium bicarbonate and DCM. Separate the phases and filter each phase. Wash the solid from the organic phase with DCM to give the title compound (300 mg) as a tan solid. Wash the solid from the aqueous layer with water and dry to give the title compound (300 mg) as a tan solid. Combine the solids to give the title compound (600 mg; 17%) as a tan solid. MS (ES) m/z 358 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:28][CH2:29][CH:30]1[CH:34]([CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH2:33][C:32]([CH2:44]Br)=[CH:31]1)(C(C)(C)C)(C)C>>[OH:28][CH2:29][CH:30]1[CH:34]([CH2:35][OH:36])[CH2:33][C:32]([CH2:44][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:31]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CC(CO)C(CO)C2)c1
Yield: 17.9 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (51 mg).
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]=1[C:13]([O:15]CC)=[O:14].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C1=C(C)c2ccccc2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(C(=O)O)CCCc2ccccc21
Temperature: 70 °C
Reaction time: 5 h
Yield: 53.7 %

Procedure:
Ethyl 9-methyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (0.70 g, 3.04 mmol) was added to a mixture of a 2N aqueous sodium hydroxide solution and ethanol, and the resulting mixture was stirred at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with 35% hydrochloric acid and extracted twice with diethyl ether, and the extract solution was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.33 g of 9-methyl-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[CH2:11]([O-:13])[CH3:12].[Na+].CC(=O)OCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:13][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
To a mixture of 2-chloro-4-nitropyridine (170 g, 1070 mmol) in THF (2 L) was added sodium ethanolate (109.45 g, 1610 mmol) slowly at 0° C. The mixture was stirred at 25° C. for 12 h. LCMS and TLC (PE/EA=5:1, Rf=0.6) showed the reaction was finished. The mixture was filtered, and most solvent of the filtrate was removed in vacuo. The residue was extracted with EA (800 mL×3), and the organic layer was washed with saturated NaCl solution (1 L), dried over Na2SO4, filtered, and concentrated to give crude 2-chloro-4-ethoxypyridine (157 g, 1.0 mol, 92% yield) as a solid: 1H NMR (400 MHz, CD3OD) δ 8.15 (d, J=6.0 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.91-6.89 (m, 1H), 4.16-4.14 (m, 2H), 1.41-1.38 (m, 3H); ES-LCMS m/z 158 (M+H).
Reaction SMILES: [CH3:1][N:2](C)[C:3]1[CH:4]=[CH:5][C:6]([N+:36]([O-:38])=[O:37])=[C:7]([N:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=1>CCCCCC.C(OCC)(=O)C>[CH2:1]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([N+:36]([O-:38])=[O:37])=[C:7]([N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1cc(N(C)C)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1cc(NCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
tert.butyl 4'-[N-(5-dimethylamino-2-nitrophenyl)-pentanoylaminomethyl]biphenyl-2-carboxylate oil, Rf value: 0.35 (Silica gel: hexane/ethyl acetate=4:1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH:28]2[CH2:32][CH2:31][C:30]([OH:34])([CH3:33])[CH2:29]2)(=O)=O)=CC=1>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:28]2[CH2:32][CH2:31][C:30]([CH3:33])([OH:34])[CH2:29]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(C)(O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OC2CCC(C)(O)C2)cc(C)c1Br
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-bromo-3,5-dimethylphenol (300 mg) and Cs2CO3 (600 mg) in N,N-dimethylformamide (3 mL) is added 3-hydroxy-3-methylcyclopentyl 4-methylbenzenesulfonate (275 mg). The mixture is stirred for 12 hours at 50° C. and then partitioned between water and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (petrole ether/ethyl acetate 90:10→30:70). The enantiomers are separated by SFC on chiral phase (column: Daicel IA, 5 μm, 250 mm×10 mm; eluent: scCO2/(methanol+0.2% diethylamine) 85:15, 10 mL/min):
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cnccn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A mixture of 162b (110 mg, 0.20 mmol) and lithium hydroxide (84 mg, 2.0 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water and ethyl acetate. The water phase was separated and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 162 (85 mg, 85%) as pale yellow solid. MS-ESI: [M+H]+ 498.3. 1H NMR (500 MHz, CHCl3) δ 8.73 (d, J=2.5 Hz, 1H), 8.54 (d, J=5 Hz, 1H), 8.29 (s, 1H), 8.15-8.14 (m, 2H), 8.01 (d, J=2.5 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.37 (d, J=5 Hz, 1H), 6.91 (s, 1H), 4.66-4.65 (m, 1H), 4.52-4.51 (m, 1H), 4.32-4.31 (m, 1H), 4.18-4.17 (m, 1H), 4.14-4.12 (m, 1H), 3.90-3.88 (m, 1H), 3.75 (s, 3H), 2.62-2.57 (m, 4H), 1.92-1.88 (m, 3H), 1.80-1.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reaction time: 3 h
Yield: 94.4 %

Procedure:
3-Chloro-2,4-difluoro-benzoic acid 1a (3.00 g, 15.6 mmol) is added to a stirred solution of concentrated H2SO4 (16 mL) and fuming nitric acid (0.85 mL, 20.3 mmol). After 3 hours a precipitate forms. The yellow slurry is poured onto ice water (100 mL). The aqueous mixture is extracted with diethyl ether (3×). The organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 3.50 g (95%) of clean desired product as a pale yellow solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN.C[CH2:18][N:19]=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:18][NH:19][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.7 %

Procedure:
BOC-β-alanine (0.50 g, 2.64 mmol) was dissolved in 4 mL DMF. Methylamine hydrochloride (198 mg, 2.93 mmol) and DMAP (427.2 mg, 3.50 mmol) were added, followed by EDCI (1.06 g, 5.53 mmol). After stirring at room temperature for 2 days the solvent was removed in a stream of nitrogen and the residue dried in vacuo. It was dissolved in 5 mL 1 M HCl, and the solution was extracted five times with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to yield 0.43 g (2.13 mmol, 81%) of BOC-β-alanine methylamide (14) as a white solid. mp. 117-118° C., 1H-NMR (300 MHz, CDCl3) δ 5.78 (b, NH), 5.15 (b, NH), 3.38 (q, J=6.1 Hz, 2 H), 2.78 (d, J=4.8 Hz, 3 H), 2.36 (t, J=6.1 Hz, 2 H), 1.40 (s, 9 H) 13C-NMR (75.5 MHz, CDCl3) δ 171.74 (C), 79.15 (C), 36.41 (CH2), 36.03 (CH2), 28.17 (3 CH3), 26.04 (CH3). ##STR27##
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:16]([CH3:19])([O-:18])=[O:17].Cl.CN.C([O-])(=O)C.[Na+]>>[CH3:1][N:2]([CH3:15])[C:3]1[C:4](/[CH:5]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1
Reactant: C[N+](=O)[O-]
Reactant: CN(C)c1nc(C(F)(F)F)ccc1C=O
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Product: CN(C)c1nc(C(F)(F)F)ccc1/C=C/[N+](=O)[O-]
Reaction time: 5 h
Yield: 66.8 %

Procedure:
2-(dimethylamino)-6-(trifluoromethyl)nicotinaldehyde (50 mg, 0.229 mmol) was diluted with nitromethane (86.9 μl, 1.60 mmol) followed by the addition of methylamine hydrochloride (9.28 mg, 0.138 mmol) and sodium acetate (11.3 mg, 0.138 mmol). After stirring for 5 hours, the reaction was loaded directly onto silica gel and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate hexanes to yield the desired compound (40 mg, 0.153 mmol, 66.8% yield).
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[Br:14][C:15]1[CH:20]=[C:19]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:18]=[CH:17][C:16]=1[NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]>C(#N)C>[Br:14][C:15]1[CH:20]=[C:19]([S:21](=[O:24])(=[O:23])[N:22]=[C:3]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:5][CH3:6])[CH:18]=[CH:17][C:16]=1[NH:25][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28]
Reactant: NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1
Reactant: CCN=C(SC)N1CC(C)(C)C=N1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1)N1CC(C)(C)C=N1
Yield: 1.4 %

Procedure:
3.41 g (1 mol equiv.) N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 6.24 g (1.05 mol equiv.) N-(2-Bromo-4-sulfamoyl-phenyl)-2,2,2-trifluoro-acetamide were added to 100 mL acetonitrile. The reaction mixture was refluxed overnight, and subsequently volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH, and the organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O) afforded 7.1 g (83%) N-(2-bromo-4-{[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)-2,2,2-trifluoro-acetamide. 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J=7.3 Hz, 3H), 1.24 (s, 6H), 3.43-3.51 (m, 2H), 3.79 (br.s., 2H), 6.78 (s, 1H), 7.93 (dd, J=8.6, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.61 (br.s., 1H).
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>C(O)(=O)C>[C:12]([O:15][CH:7]1[CH2:6][C:5](=[O:11])[C:4]([CH2:1][CH:2]=[CH2:3])=[C:8]1[CH3:9])(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: C=CCC1C(=O)C=CC1(C)O
Agent: [Na+]
Solvent: CC(=O)O
Product: C=CCC1=C(C)C(OC(C)=O)CC1=O
Yield: 390.7 %

Procedure:
In the same apparatus as in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (15.2 g), acetic acid (45 ml) and sodium acetate (2 g) were charged and heated to reflux for 7 hours. After the completion of the reaction, acetic acid was evaporated off under reduced pressure. The residue was extracted with toluene (60 ml) and water (40 ml) and treated as in Example 1 to obtain 4-acetoxy-2-allyl-3-methyl-2-cyclopentenone (18.5 g). Yield, 95.3%. B.P., 100°-110° C./0.1-0.3 mmHg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[S:8].C(O[CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)(=O)C.N#N>[OH-].[K+].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([O:9][CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)=[S:8]
Reactant: COCCOCC(O)=S
Reactant: CC(=O)OC1CC(=O)N1
Agent: N#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COCCOCC(=S)OC1CC(=O)N1
Yield: 96 %

Procedure:
To a solution of 2-methoxyethoxythioacetic acid (990 mg.; 6.60 mmoles) in 1 N KOH (6.0 ml.) and water (30 ml.) was added in an ice-bath under nitrogen atmosphere 4-acetoxy-2-azetidinone (777 mg.; 6.00 mmoles). The reaction mixture was stirred at room temperature (N2) for 1 hr. and then extracted with methylene chloride (30 ml.×3). The extracts were washed with brine, dried (Na2SO4) and evaporated yielding 4-(2-methoxyethoxythioacetoxy)-2-azetidinone (1.26 g.; 5.76 mmoles; 96% yield) as a yellow oil. nmr (CDCl3): δppm 2.8-3.8 (2H, m, H-3), 3.40 (3H, s, --OCH3), 3.4-3.9 (4H, m, --CH2CH2 --O), 4.25 (2H, s, O=CCH2O--), 5.25 (1H, dd, J3-4 cis =5 Hz, J3-4 trans =3 Hz, H-4), 7.3 (1H, br.s, --NH), ir (neat): 3280 cm-1 (γN--H), 1770 (γc=o, β-lactam), 1690 (γc=o, thioester).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][CH2:25][C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][CH:27]=4)[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Reactant: BrCCc1c[nH]c2ccccc12
Product: Cc1nc(-c2ccn(CCc3c[nH]c4ccccc34)n2)sc1C(=O)NCc1ccc(F)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)thiazole-5-carboxylic acid 4-fluoro-benzylamide and 3-(2-bromo-ethyl)-1H-indole as describe in Example 83 and isolated as a yellow solid (0.056 g, 40% yield). 1H NMR (400 MHz, CDCl3) δ 8.01 (bs, 1H), 7.56 (d, J=8 Hz, 1H), 7.31-7.38 (m, 2H), 7.20-7.25 (m, 1H), 7.10-7.16 (m, 2H), 6.81 (d, J=2 Hz, 1H), 6.70 (d, J=2 Hz, 1H), 5.99-6.04 (m, 1H), 4.59 (d, J=4 Hz, 2H), 4.45 (t, J=7 Hz, 2H), 3.35 (t, J=7 Hz, 2H), 2.76 (s, 3H); MS (M+H)+=460.2; Rt=1.47 min; HRMS (M+H)+=460.16.