Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=[O:12].S(Cl)(O)(=O)=O.S([O-])([O-])=O.[Na+].[Na+].O[NH:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:39].S(Cl)(Cl)=O.N>O1CCOCC1.O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:39])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[O:12]
Reactant: O=C(NCCc1ccc(S(=O)O)cc1)N1Cc2ccccc2C1=O
Reactant: CCCCNC(=O)NO
Agent: N
Agent: O=S(=O)(O)Cl
Agent: O=S([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1

Procedure:
3.4 g of 4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfinic acid (crude product, prepared by reduction of the sulfochloride with sodium sulfite) and 1.4 g of N-hydroxy-N'-butyl-urea are suspended in 40 ml of dioxane and a solution of 1 ml of thionyl chloride in 10 ml of dioxane is added dropwise while stirring. The mixture is then heated for 2 hours to 60° C., whereby a limpid solution is formed. The solution is poured into water, the precipitated substance is treated with dilute ammonia, filtered, acidified and the reaction product is recrystallized from dilute acetone. The N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-butyl-urea obtained melts at 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21].Cl>O.C(O)C>[ClH:1].[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-dimethylaniline (36 μl, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature. The resulting precipitate was filtered, washed with water and aqueous ethanol to give a white solid (28 mg, 42%). 1H NMR (CDCl3): 8.77 (dd, J=1.5, 4.5 Hz, 2H), 8.27 (dd, J=1.5, 4.5 Hz, 2H), 7.24 (d, J=7.8 Hz, 1H), 7.18 (s, 1H), 7.11 (dd, J=1.8, 7.8 Hz, 1H), 6.99 (s, 1H), 6.62 (s, 1H), 2.38 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)=[O:26])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25](=[O:26])[C:27]3[CH:34]=[CH:33][C:30]([C:31]4[NH:1][C:4]5[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][C:9]=5[N:10]=4)=[CH:29][CH:28]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3[nH]ccc3c2)cc1
Reactant: COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COc1ccc2nc(-c3ccc(C(=O)Nc4ccc5[nH]ccc5c4)cc3)[nH]c2c1

Procedure:
Compound 654 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitroanisole and 4-(5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C23H18N4O2: 383.14; found: 383.01.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C:9](=[O:19])[NH:8][C:7]1=[O:20])=[O:5])[CH3:2].CI.[C:23](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:10][C:9](=[O:19])[N:8]([CH3:23])[C:7]1=[O:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C(=O)NC(=O)C[C@H]1c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)[C@@H]1C(=O)N(C)C(=O)C[C@H]1c1ccc(F)cc1
Reaction time: 7.5 h

Procedure:
A solution of compound E1 (±)-trans-3-ethoxycarbonyl-4(4'-fluorophenyl)piperidin-2,6-dione (1.0 g) in anhydrous dimethylformamide was stirred and cooled to about 0° and methyl iodide (0.67 g) and anhydrous potassium carbonate (0.51 g) added. The mixture was stirred at 0°-2° for 7.5 hours, after which it was diluted with water and extracted with ethyl acetate (100 ml). The extract was washed with water, brine and dried over anhydrous sodium sulphate. Evaporation gave the title compound as a pale yellow oil, ca. 90% pure by n.m.r. spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:13]([OH:15])=O)[CH:6]=[N:5]2.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:13]([NH:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1)=[O:15])[CH:6]=[N:5]2
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc2ncc(C(=O)O)nc2cc1C
Solvent: CN(C)C=O
Product: Cc1cc2ncc(C(=O)Nc3nnn[nH]3)nc2cc1C

Procedure:
6,7-Dimethyl-2-quinoxalinecarboxylic acid (0.7 g) and N,N'-carbonyldiimidazole (0.84 g) in dimethylformamide (10 ml) were stirred and heated at 60° for 6 hours. 5Amino-1H-tetrazole (0.66 g) was added and the mixture was stirred and heated at 60° for a further 30 minutes. The solid was collected and dissolved in aqueous dimethylaminoethanol. Aqueous acetic acid was added and the solid was collected and dried. It had m.p. 304° (d) (46%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][C:21]([CH3:25])=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:32]([O:35][CH2:36][CH2:37]Br)(=[O:34])[CH3:33]>CN(C)C=O>[C:32]([O:35][CH2:36][CH2:37][N:18]1[C:19]2=[N:20][C:21]([CH3:25])=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OCCBr
Reactant: Cc1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2ccc(C)nc21
Temperature: 60 °C
Reaction time: 16.5 h
Yield: 69.1 %

Procedure:
To a solution of 6.8 g of the compound of Example 2 in 50 ml of dimethylformamide are added 4.1 g of potassium carbonate and 5 g of 2-bromoethyl acetate, and the mixture is stirred at 60° C. for 16.5 hours. The reaction mixture is poured into ice-cold water, and the precipitate is extracted with ethyl acetate. The extract is washed with water, dried and concentrated, and then the residue is recrystallized from hexane to give 5.9 g of 1-(2-acetoxyethyl)-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-6-methyl-1H-pyrazolo[-3,4-b]pyridine as pale yellowish green crystals, melting at 101.5°-103° C.
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:3]([CH2:4][CH3:5])([C:6]2[S:10][C:9]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[CH:7]=2)[CH2:1][CH3:2])=[CH:18][C:19]=1[CH3:24]
Reactant: COC(=O)CBr
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(OC)cc2s1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCC(CC)(c1ccc(OCC(=O)OC)c(C)c1)c1cc2ccc(OC)cc2s1
Yield: 48.9 %

Procedure:
To a mixture of 4-[1-ethyl-1-(6-methoxy-benzo[b]thiophen-2-yl)-propyl]-2-methyl-phenol (2.53 g, 7.43 mmol) and acetonitrile (25 mL) is added methyl bromoacetate (0.84 mL, 8.92 mmol), powdered potassium carbonate (4.10 g, 29.72 mmol), and potassium iodide (0.12 g, 0.74 mmol). The resulting slurry is stirred at reflux temperature for 2 h, filtered, and concentrated. The residue is dissolved in diethyl ether (100 mL), washed with water (75 ml), brine (75 mL), dried over MgSO4, filtered, and concentrated to give the title compound (1.5 g, 3.63 mmol, 49%). 1H NMR (CDCl3), δ 0.74 (t, J =7.2 Hz, 6H), 2.17 (q, J =14.7, 7.5 Hz, 4H), 2.25 (s, 3H), 2.30 (s, 2H), 3.80 (s, 3H), 3.86 (s, 3H), 3.60 (d, J=8.6 Hz, 1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 7.04 (s, 1H), 7.07 (s, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]([N:19]([CH:23]4[CH2:32][CH2:31][C:30]5[C:25](=[CH:26][C:27]([O:33]C)=[CH:28][CH:29]=5)[CH2:24]4)[CH2:20][CH2:21][CH3:22])=O)[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.B.C1COCC1.CO>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:19]([CH2:20][CH2:21][CH3:22])[CH:23]4[CH2:24][C:25]5[CH:26]=[C:27]([OH:33])[CH:28]=[CH:29][C:30]=5[CH2:31][CH2:32]4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCCN(C(=O)CN1CCN(c2ccc3[nH]ccc3c2)CC1)C1CCc2ccc(OC)cc2C1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCN1CCN(c2ccc3[nH]ccc3c2)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
To a stirring cold solution of compound 51 (220 mg, 0.492 mmol) in dry THF was added BH3.THF (211 mg, 2.46 mmol) and the reaction mixture was refluxed overnight. After cooling the reaction mixture to room temperature, 1 ml of methanol was added and the solvent was evaporated. The residue was dissolved in 15 ml of conc. HBr and refluxed for 1 h. The solvent was evaporated and the crude product was dissolved in dichloromethane (50 ml). The organic layer was washed with saturated NaHCO3 (30 ml) and dried over Na2SO4. The solvent was evaporated and the crude product was purified by flash column chromatography over silica gel using ethyl acetate/MeOH/Et3N (95:5:0.2) to afford 52 (20 mg). 1H NMR (400 MHz, CD3OD) δ 0.95 (t, 3H, J=7.6 Hz), 1.53-1.67 (m, 3H), 2.08 (d, 1H, J=9.6 Hz), 2.60-2.88 (m, 14H), 3.10-3.13 (m, 5H), 6.35 (d, 1H, J=2.8 Hz), 6.52-6.55 (m, 2H), 6.87 (d, 1H, J=8.8 Hz), 6.91-6.94 (dd, 1H, J=8.8 Hz and 2.4 Hz), 7.16-7.17 (m, 2H), 7.29 (d, 1H, J=8.8 Hz). Free base converted into oxalate salt, m.p. 179-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8](=O)[CH2:9][CH2:10][CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:8]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC=O
Reactant: Nc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCNc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 941 mg (10 mmol) of 3-aminopyridine and 0.9 mL of butyraldehyde in 30 mL of CH3OH was added 10 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 hour, then the reaction was cooled with an ice bath, and 650 mg (10.3 mmol) of sodium cyanoborohydride was added.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17](=[O:25])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]([O:25][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)=NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 8, Step A) (10.0 g, 37.1 mmol) and p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 mL) at 0° C. Further portions of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. The reaction mixture was then allowed to warm to room temperature and was stiffed overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with water (3×70 mL). The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield), which slowly formed crystals. Product recrystallized from ethyl acetate/hexanes melted at 99.5-100° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([CH3:33])=[CH:8][C:9]([CH3:32])=[C:10]([C:12]2[N:17]=[C:16]([CH:18]=[N:19][C:20]3[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH:29]([CH3:31])[CH3:30])[CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[CH2:2][CH:3]=[CH2:4].[C:34]1([Mg]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:7]([CH3:33])=[CH:8][C:9]([CH3:32])=[C:10]([C:12]2[N:17]=[C:16]([CH:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:19][C:20]3[C:25]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[CH:29]([CH3:31])[CH3:30])[CH:15]=[CH:14][CH:13]=2)[CH:11]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Br[Mg]c1ccccc1
Reactant: C=CCCOc1cc(-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)cc1C
Solvent: Cc1ccccc1
Product: C=CCCOc1cc(-c2cccc(C(Nc3c(C(C)C)cccc3C(C)C)c3ccccc3)n2)c(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In the glovebox, N-((6-(5-(but-3-enyloxy)-2,4-dimethylphenyl)pyridin-2-yl)methylene)-2,6-diisopropylaniline (1.527 g, 3.40 mmol) is dissolved in toluene (40 mL). Phenylmagnesiumbromide (3.0M in ether, 1.36 mL, 4.09 mmol) is added, and the reaction mixture stirred at room temperature for one hour, removed from the glovebox, and quenched by addition of water (60 mL), and ether (80 mL). The aqueous layer is washed with additional ether (40 mL), and the combined organic fractions are washed with brine, dried over magnesium sulfate and filtered. Solvents are removed in vacuo, and the crude product is purified by column chromatography using 10:1 hexanes:ethylacetate (Rf=0.39) to yield 1.27 g (72.0%) of a very pale yellow solid. The structure is assigned by 1H NMR as shown in FIG. 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:16]=[C:15]([C:17]([NH:19][C@@H:20]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[CH3:21])=[O:18])[S:14][C:11]=2[NH:12][N:13]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:35][CH2:36][OH:37]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:16]=[C:15]([C:17]([NH:19][C@@H:20]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[CH3:21])=[O:18])[S:14][C:11]=2[N:12]([CH2:35][CH2:36][OH:37])[N:13]=1
Reactant: OCCI
Reactant: Cc1noc([C@@H](C)NC(=O)c2cc3c(-c4ccc(F)cc4F)n[nH]c3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc3c(-c4ccc(F)cc4F)nn(CCO)c3s2)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
3-(2,4-Difluorophenyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide (203.5 mg, 0.523 mmol) and potassium carbonate (331.5 mg, 2.40 mmol) were dissolved in N,N-dimethylformamide (5.20 ml) at 25° C. 2-Iodoethanol (69 μL, 0.885 mmol) was added. The reaction was heated to 50° C. and stirred for 4 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (10 mL), and extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with saturated aqueous ammonium chloride (2×10 mL) and saturated aqueous sodium chloride (1×10 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 40 g column) on a CombiFlash purification system eluting with ethyl acetate-hexanes (0-100%). The title compound (129.6 mg, 0.299 mmol, 57.2% yield) was recovered as a light yellow/white solid. The undesired regioisomer, 3-(2,4-difluorophenyl)-2-(2-hydroxyethyl)-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-2H-indazole-6-carboxamide (33.1 mg, 0.076 mmol, 14.61% yield), was recovered as a light yellow/white solid. Title compound: HRMS [M+1] found=434.1091. 1H NMR (400 MHz, CDCl3): δ 7.99-7.89 (m, 1H); 7.61 (d, J=3.7 Hz, 1H); 7.01-6.91 (m, 2H); 6.80 (d, J=7.8 Hz, 1H); 5.60-5.51 (m, 1H); 4.39-4.34 (m, 2H); 4.15 (d, J=5.4 Hz, 2H); 2.90 (s, 1H); 2.40 (s, 3H); 1.70 (d, J=7.1 Hz, 3H). Regioisomer: HRMS [M+1] found 434.1095.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1>ClCCl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C@H:21]([O:30][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
tert-Butyldimethylsilylchloride (3.75 g) and imidazole (1.69 g) were added to a solution of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (4 g, Example 21a)) in dichloromethane. The mixture was stirred for 16 hours at room temperature. The white precipitate was collected by filtration and the filtrate concentrated under reduced pressure to give the sub-title compound as an oil (5.4 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.CCCCCC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:13][C:14]#[N:15]
Reactant: COc1ccc(O)cc1OC
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(OCC#N)cc1OC
Yield: 71.9 %

Procedure:
To a solution of 3,4-dimethoxyphenol (5.0 g, 32.4 mmol) in dry acetone (160 ml), were added chloroacetonitrile (2.05 ml, 32.4 mmol) and anhydrous K2CO3 (6.72 g, 48.6 mmol). The reaction mixture was stirred at reflux for 20 h under nitrogen. After cooling, the mixture was filtered and concentrated in vacuo. The residue was combined with H2O, extracted with CH2Cl2, and the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt/hexane: 3/7) gave the title product (4.5 g, 68%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19](=O)[CH2:20][CH3:21]>C(#N)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([CH2:20][CH3:21])[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Reactant: CCC(=O)CBr
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(CC)cs2)c(Br)cn1
Temperature: 0 °C

Procedure:
5-Bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 3, 6.06 g, 20 mmol) was suspended in acetonitrile (150 ml). 1-Bromobutan-2-one (30 mmol) was added and the reaction mixture was heated at reflux for 16 h. The reaction was cooled to 0° C. and the suspension was filtered. The solid was washed with acetonitrile (50 ml), collected, and dried in a vacuum oven at 50° C. for 4 hours to give an off white solid.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:19][CH:18]=1.O.Cl>O1CCCC1.C(O)C>[CH3:4][C:5]1[O:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:6]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:40][CH:41]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CO/N=C(\CCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
Lithium hydroxide monohydrate (177 mg) was added to a solution of ethyl E-6-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate (747 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (4.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoic acid (653 mg, yield 92%) as colorless crystals. m.p. 101-102° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:11]([C:12](=O)[C:13]3[C:18]2=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC>FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:20][C@H:19]2[C@H:11]([CH2:12][C:13]3[C:18]2=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[CH3:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cc2c1C(=O)[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)cc2c1C[C@@H]1CCN(Cc3ccccc3)C[C@H]21
Temperature: 20 °C
Reaction time: 72 h
Yield: 30.8 %

Procedure:
To a solution of cis-3-Benzyl-6-bromo-8-methyl-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (1.5 g, 4.0 mmol) in trifluoroacetic acid (15 mL) was added Et3SiH (10 mL). The reaction mixture was stirred at 20° C. for 3 days then concentrated in vacuo. The residue was basified with NH4OH then extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 9/1) to give the title compound (440 mg, 1.23 mmol): MS (ES) 356.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][OH:10])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:2].[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15].[Na+].[Cl-]>C(Cl)(Cl)Cl>[CH3:11][C:12]([CH3:17])=[CH:13][C:14]([O:10][CH2:9][C:3]1([CH2:1][CH3:2])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)=[O:15]
Reactant: CCC1(CO)COC(=O)N1
Reactant: CC(C)=CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC1(COC(=O)C=C(C)C)COC(=O)N1

Procedure:
3.1 grams (0.021 mole) 4-ethyl-4-hydroxymethyl-2-oxazolidinone, prepared identically to that discussed in example 1, 2.6 grams (0.022 mole) 3,3-dimethylacryloyl chloride, and 25 milliliters chloroform were mixed in a one-necked round-bottom flask. The procedure employed was identical to that discussed in example 4. 4.10 grams (90% of the yield theoretically expected) of pure product was obtained as a yellow oil. The product exhibited the following spectral data: 1H NMR (CDCl3) δ0.98(t, 3H J=1.2 Hz), 1.65-1.71(m, 2H), 1.92(s, 3H), 2.17(s, 3H), 4.04-4.23(m. 4H), 5.71(s, 1H), 6.43(s, 1H); 13C NMR(CDCl3) δ7.6, 20.6, 27.7, 28.7, 60.3, 66.1, 71.3, 115.2, 159.0, 159.5, 166.2; IR (NaCl) 3215, 3020, 2970, 1785 cm-1 ; MS m/z 227. This monomer can be chlorinated or brominated by the same procedure as in example 1.