Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10][N:11]([CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])[CH:12]=1)=[O:5])[CH3:2].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C)C=O>[C:23]1([C:9]2[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][N:11]([CH2:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([NH:36][CH2:35][C:34]4[CH:37]=[CH:38][C:31]([C:30]([F:39])([F:40])[F:29])=[CH:32][CH:33]=4)=[O:18])[CH:15]=3)[N:10]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)O)c2)nc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
A mixture of 3-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazol-1-ylmethyl]benzoic acid (700 mg), 4-trifluoromethylbenzylamine (390 mg), 1-hydroxybenzotriazole monohydrate (340 mg), WSC (430 mg), and N,N-dimethylformamide (30 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-phenyl-1-[3-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (900 mg, yield: 91%) was obtained as an oily substance from the fraction eluted with acetone-hexane (1:2, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[ClH:14]>[Pd].C(O)C>[Cl-:14].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH3+:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: Cl
Reactant: CS(=O)(=O)c1cc(F)ccc1C#N
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)ccc1C[NH3+]
Product: [Cl-]
Reaction time: 8 h

Procedure:
4-fluoro-2-(methylsulfonyl)benzonitrile (5.6 g, 28.11 mmol) was added to a dry Parr bottle. Ethanol (50 mL) and conc HCl (10 mL) were added and the reaction solution put under an Argon atmosphere. 10% Pd/C (1 gram) was added and the reaction vessel placed on a Parr hydrogenation apparatus. The reaction was placed under an atmosphere of H2 (50 psi) and shaken overnight. After overnight the ratio of starting material to product was 50:50. The reaction was filtered through celite and concentrated slightly. Conc. HCl (10 mL) and 10% Pd/C (1 gram) were added and the reaction was again put under H2 (50 psi). The reaction was again shaken overnight. The crude reaction was filtered through celite and concentrated to afford the desired material as a white solid.
Reaction SMILES: CS(O[CH2:6][C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)(=O)=O.FC(F)(F)C1C=CC(C2(C[C:33]#[N:34])CCCC2)=CC=1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:7]2([CH2:6][C:33]#[N:34])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OCC1(c2cccc(Cl)c2)CCCC1
Reactant: N#CCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CCC1(c2cccc(Cl)c2)CCCC1

Procedure:
2-(1-(3-Chlorophenyl)cyclopentyl)acetonitrile (498) was synthesized from (1-(3-chlorophenyl)cyclopentyl)methyl methanesulfonate (497) following the procedure described for [1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetonitrile (241).
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[C:8]([Cl:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18].C(O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[OH:1][C:2]1[C:9]([Br:10])=[C:8]([Cl:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:3]=1[CH:4]=[N:17][OH:18]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(Br)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=NO)c(O)c(Br)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 2.25 g (7.72 mmol) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzaldehyde and 0.59 g (8.49 mmol) of hydroxylamine hydrochloride in 15 ml of 1:1:1 tetrahydrofuran:ethanol:water was cooled in an ice-water bath. Sodium bicarbonate (0.78 g, 9.26 mmol) was added in small portions over 15 minutes. After stirring overnight at ambient temperature, water (25 ml) was added and the solid was filtered and dried. There was obtained 2.00 g (6.52 mmol, 85%) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzaldehyde oxime as a white solid after crystallization from cyclohexane mp 175°-177° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:29])[C:6]=2[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)N=C(c2ccccn2)c2cc(Br)c(Cl)cc2O1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)N=C(c2cccc[n+]2[O-])c2cc(Br)c(Cl)cc2O1
Reaction time: 5 h
Yield: 25.8 %

Procedure:
To a solution of Compound 88(10.0 g) in dichloromethane (130 ml) was added 70% m-chloroperbenzoic acid (20.0 g) at 0° C. and the mixture was stirred at 2° to 4° C. for 5 hours. A solution of sodium sulfite (32 g) in water (130 ml) was added slowly and stirred for 1 hour with ice-cooling. The organic layer was separated, washed successively with 5% aqueous sodium carbonate solution and saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by chromatography on silica gel and crystallized from diethyl ether to obtain 2-(6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazin-4-yl)pyridine 1-oxide (2.7 g) (Compound 89).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>CC(N(C)C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][C:10]([F:16])([F:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: FC1(F)CCNCC1
Reactant: Brc1ccc(Br)nc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: FC1(F)CCN(c2ccc(Br)cn2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
2,5-Dibromopyridine (1.30 g) was heated with 4,4-difluoropiperidine (2 g) in dimethylacetamide (4 ml) at 120° C. for 24 h, then at 150° C. for 8 h. The solution was allowed to cool, then poured into water (30 ml). The aqueous phase was extracted with ether (×3) and the combined extracts washed with water, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography gave the product as a colourless oil (0.70 g).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)[CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC/C=C/CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC/C=C/CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-3-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([CH3:19])([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[C:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:33][CH:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH2:24]2)[C:10]1=[O:18])([CH3:8])[CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CC(C)(C)OC(=O)C(C)(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2c1C(Cn1c(=O)n(C(C)(C)C(=O)OC(C)(C)C)c3ccccc31)CN2C
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
To a mixture of 2-methyl-2-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid tert-butyl ester (130 mg, 0.47 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (250 mg, 0.73 mmol) in DMF (2.5 mL) was added K2CO3 (200 mg, 1.45 mmol). The mixture was stirred at 100° C. for 4 hours. The mixture was diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 30% EtOAc in Hexane as the eluent to afford the desired 2-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-2methyl-propionic acid tert-butyl ester (138 mg, 68%).
Reaction SMILES: Cl.[NH:2]([C:4]1(O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[NH2:3].C(O[CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[C:23]([O-:26])(=[O:25])[CH3:24].[Na+]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[N:3][N:2]([C@H:4]2[CH2:9][CH2:8][C@@H:7]([OH:25])[CH2:6][CH2:5]2)[C:21]=1[NH2:22])=[O:17])[CH3:20].[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[N:3][N:2]([C@H:4]2[CH2:9][CH2:24][C@H:23]([OH:26])[CH2:6][CH2:5]2)[C:21]=1[NH2:22])=[O:17])[CH3:20]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CC(=O)[O-]
Reactant: NNC1(O)CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn([C@H]2CC[C@@H](O)CC2)c1N
Product: CCOC(=O)c1cnn([C@H]2CC[C@H](O)CC2)c1N
Temperature: 70 °C

Procedure:
Hydrazino-cyclohexanol hydrochloride (1.920 g, 9.79 mmol) was dissolved in hot ethanol and then cooled slightly. Ethyl (ethoxymethylene)-cyanoacetate (1.520 g, 8.98 mmol) and anhydrous sodium acetate (2.013 g, 24.54 mmol) were added and the mixture was heated at 70° C. for 15 hours. After cooling to room temperature, the mixture was partitioned between methylene chloride and water. The aqueous phase was washed with a second portion of methylene chloride. The two organic phases were combined, washed with brine, dried over sodium sulfate and concentrated. Flash chromatography, eluting with a 0-20% methanol/ethyl acetate gradient, separated a large portion of the cis-trans mixture of isomers. After chromatography, pure fractions of each isomer were combined and crystallized from EtOAc-hexanes to give 5-amino-1-(cis-4-hydroxy-cyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.511 g, 23% (crop 1); 0.121 g, 5% (crop 2)) and 5-amino-1-(trans-4-hydroxy-cyclohexyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.625 g, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]1[C:21]([O:23]CC)=[O:22].[CH3:33][S:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]O)=[CH:37][CH:36]=1.[CH:43](O)(C)C>>[Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([S:34][CH3:33])=[CH:36][CH:37]=3)=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:43])=[CH:17][CH:16]=2)=[C:6]1[C:21]([OH:23])=[O:22]
Reactant: CC(C)O
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reactant: CSc1ccc(CO)cc1
Product: CSc1ccc(COc2ccc3c(c2)c(-c2ccc(C)cc2)c(C(=O)O)n3Cc2cc3c(cc2Cl)OCO3)cc1

Procedure:
Following the procedure of Example 18(a)-18(b), except substituting ethyl 1-(2-chloro-4,5-methylenedioxybenzyl)-5-hydroxy-3-(4-methylphenyl)indole-2-carboxylate for ethyl 1-(2-chloro-4,5-methylenedioxybenzyl)-5-hydroxy-3-phenylindole-2-carboxylate and 4-methylthiobenzyl alcohol for isopropanol in step (a), the title compound was prepared as a white solid (38% overall). MS (MH-): 570.0
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[N:31]=[CH:30][C:14]2[NH:15][C@@H:16]([CH3:29])[CH2:17][N:18]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[Br:10][C:11]1[N:31]=[CH:30][C:14]2[N:15]([C:32](=[O:34])[CH3:33])[C@@H:16]([CH3:29])[CH2:17][N:18]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=3)(=[O:21])=[O:20])[C:13]=2[CH:12]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3cnc(Br)cc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2cnc(Br)cc2N(S(=O)(=O)c2ccc(C)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
N,N-Diisopropylethylamine (0.018 mL, 0.102 mmol) was added to a solution of (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydropyrido[3,4-b]pyrazine (0.013 g, 0.034 mmol) and acetyl chloride (3.6 μL, 0.051 mmol) in dichloromethane (2.0 mL), and the mixture stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(7-bromo-3-methyl-1-tosyl-2,3-dihydropyrido[3,4-b]pyrazin-4(1H)-yl)ethanone (0.010 g, 69%) as an off-white solid. MS (ESI, pos. ion) m/z 424, 426.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C@H:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)=[CH:5][CH:4]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C.Cl>[OH:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C@H:8]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[O:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: Oc1ccc(C[C@H]2CCc3ccccc3O2)cc1
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
(R)-(-)-3,4-Dihydro-2-(4-methoxybenzyl)-2H-benzopyran (812 mg, 3.2 mmol), and lithium iodide (750 mg, 5.6 mmol) were dissolved in 2,4,6-collidine (2 ml) and heated to reflux for 24 hours. The reaction mixture was cooled, diluted with ethyl acetate (20 ml) and 10% HCl (20 ml), and stirred for 10 minutes. The layers were separated and the aqueous portion was extracted with ethyl acetate (50 ml). The combined organics were washed with water (20 ml), brine (20 ml), and were dried MgSO4). The solvent was removed in vacuo and the residue purified on silica gel using hexanes/ethyl acetate (3:1) as eluent to afford 730 mg of a colorless oil which crystallized upon standing, mp 60°-62° C.; [α]D -110.2° (c 1.0, MeOH); 1H NMR (300 MHz, CDCl3) δ1.7 (m, 1H), 2.0 (m, 1H), 2.7-2.8 (m, 3H), 3.1 (dd, 1H), 4.2 (m, 1H), 6.8 (m, 3H), 7.0-7.2 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:16]([O:17][CH3:18])=[CH:15][C:8]([C:9]([O:11]CC#C)=[O:10])=[CH:7][C:6]=1[O:19][CH3:20])[C:2]#[CH:3].[OH-].[Na+].Cl>CO>[CH2:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:15][C:16]=1[O:17][CH3:18])[C:2]#[CH:3]
Reactant: C#CCOC(=O)c1cc(OC)c(OCC#C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1c(OC)cc(C(=O)O)cc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To 50 ml of methanol were added 15.5 g of 2-propynyl 4-(2-propynyloxy)-3,5-dimethoxybenzoate and 40 ml of a 15% aqueous sodium hydroxide solution, and the resulting mixture was stirred at 50° C. for 4 hours. Thereafter, the reaction mixture which had been allowed to cool to near room temperature was made acidic by addition of hydrochloric acid. The precipitated crystals were collected by filtration, and dried, and 13.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoic acid was obtained.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:19]([O-])([O-:21])=[O:20].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl>[N+:19]([C:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:6][CH:5]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
(+,−) Cis-propane-2-sulfonic acid (2-phenyl-cyclopentyl)-amide (560 mg, 2.1 mmol, prepared in example 16) was dissolved in 10 mL of trifluoroacetic acid and 534 mg (6.3 mmol) of sodium nitrate was added. The reaction was stirred 5 hours at room temperature. The reaction was diluted with methylene chloride and washed with water and dilute sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo to 620 mg of a crude yellow oil. This oil was purified by radial chromatography eluting with 98:2 methylene chloride:ethyl acetate to give 120 mg (18%) of the title compound as a white solid and also 400 mg (62%) which contained a small amount of ortho nitrated product. The NMR was consistent with the assigned structure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])O.[Na+].[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C(O)C>[CH:25]1([NH:31][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.19 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (295 mg, 2.32 mmol) and cyclohexylamine (288 mg, 2.32 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with ethyl acetate. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crystals that were purified by silica gel column chromatography to yield the title compound (191 mg, 48% yield) as orange crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin (II) chloride dihydrate (174 g, 772 mmol). The reaction mixture was heated at reflux for 4 h. LC/MS indicated some starting material remained, so added 20 mol % tin (II) chloride dihydrate and continued to heat at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with 2 N sodium hydroxide and the mixture stirred for 1 h. The mixture was then with methylene chloride (1 L), filtered through Celite, and washed with methylene chloride (500 mL). The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7% yield). The product was used crude in subsequent reactions. MS(ES)+ m/e 201.9, 203.9 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][CH2:14][CH2:13][O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClCCBr
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCCCl)C(C)=O
Yield: 100 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 60 g.), 1-bromo-2-chloroethane (54.1 g.), potassium carbonate (78 g.) and N,N-dimethylformamide (200 ml.) were treated in a similar manner to that of Example F-(1) to give ethyl 2-(2-chloroethoxyimino)-3-oxobutyrate (syn isomer, 83.6 g.), oil.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][NH:25][CH3:24])[S:7]1(=[O:23])=[O:22]
Reactant: CN
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccccc1F
Agent: Cl
Product: CNC/C=C/CN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.13 g, 0.33 mmol) was treated with methyl amine to give (2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbut-2-en-1-amine (105 mg) after treatment with HCl.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[CH:17]=[C:16]([C:28]([O:30]CC)=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[N:38]=2)[CH:7]=1)[CH3:2].[OH-].[Li+].Cl>O1CCCC1.CO.O>[CH2:1]([NH:3][C:4](=[O:43])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24])[CH:17]=[C:16]([C:28]([OH:30])=[O:29])[C:15]3=[O:33])=[C:8]([C:34]2[S:35][CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[N:38]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)C(C)C)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3[C@H](CO)C(C)C)cn1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 110, 213 mg, 0.35 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2 M lithium hydroxide (0.259 mL, 0.52 mmol). The reaction mixture was heated at 100° C. for 15 min in a microwave reactor. The reaction mixture was cooled to room temperature, diluted with water, and treated with 1 N HCl until pH 3-4. The precipitate that formed was collected by filtration, washed with water and hexanes. Purification via reverse phase HPLC (C18, acetonitrile/water 0-95% gradient) provided (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3-methylbutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (146.4 mg, 72%).