Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([CH3:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br-:1].[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[O:6][N:5]=[C:4]([CH3:15])[C:3]=2[CH2:2][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CBr
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 75 °C

Procedure:
4-Bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole (0.8066 g, 2.44 mmol) and triphenylphosphine (0.7026 g, 2.68 mmol) were combined in toluene (8 mL) and heated to 75° C. for 75 minutes. Analytical LCMS indicated complete conversion so the reaction was cooled, filtered (rinsing with toluene) and concentrated to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1C=CC(C2C=CC(NC3C=CC=CC=3)=CC=2)=CC=1.[OH:20]/[N:21]=[C:22](/Cl)\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+].[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>O>[C:23]1([C:22]2[CH:1]=[C:36]([C:35]([O:38][CH2:39][CH3:40])=[O:37])[O:20][N:21]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O/N=C(/Cl)c1ccccc1
Reactant: CCOC(C)=O
Reactant: c1ccc(Nc2ccc(-c3ccccc3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of ethyl propriolate (0.657 mL; 6.43 mmol), (E)-N-hydroxybenzimidoyl chloride (0.500 g; 3.21 mmol) and sodium bicarbonate (0.818 g; 9.64 mmol) in a mixture of ethyl acetate (16 mL) and water (1 mL) was stirred at room temperature. overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 5 to 80% dichloromethane in heptane) to furnish 0.295 g (42%) of ethyl 3-phenylisoxazole-5-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+].Cl>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2nnnc2S(C)(=O)=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C(=O)O
Reaction time: 18 h

Procedure:
Combine methyl 2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoate (5 mmol), methanol (10 mL), and a 1 M aqueous sodium hydroxide solution (6 mL, 6.0 mmol). After 18 hours, evaporate in vacuo to give a residue. Combine the residue, water (5 mL) and acidify by dropwise addition of a 1 M aqueous hydrochloric acid solution (6.5 mL). Evaporate in vacuo to give a residue. Combine the residue and dichloromethane and stir. Decant and add dichloromethane and stir. Decant and combine with the first decantate. Dry over Na2SO4, filter, and concentrate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH3:32])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), methyl iodide (0.19 mL), potassium carbonate (0.41 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 67%).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1(CBr)CC1.CN1C(SC2SC(N)=NC=2)=NN=N1>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: Cn1nnnc1Sc1cnc(N)s1
Product: c1ccc2[nH]ccc2c1

Procedure:
6-fluoroindole, R5X=cyclopropyl-methylbromide; NH2A=5-(1-methyl-1-H-tetrazol-5-ylsulfanyl)-thiazole-2-ylamine
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].IC.[CH3:27]N(C)C(=O)C>C1COCC1>[CH3:27][CH:8]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccncc1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)c1ccncc1)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3,3-diphenyl-1-pyridin-4-yl-propan-1-one (200 mg, example 14, step 1) in THF (11 ml) was added NaH (33 mg as a 55% suspension in mineral oil) at room temperature. The mixture was stirred for 1.5 h and placed in an ice bath. Iodomethane (109 mg) was added. The mixture was stirred for 1 h at 0° C. and for 2 h at room temperature. N,N-dimethylacetamide (0.5 ml) was added and the mixture was stirred overnight at room temperature. Ice water was added and the mixture was extracted with ethyl acetate. The organic phase was dried using MgSO4, filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give the title compound (148 mg) as an off-white solid, MS (ESI+): m/z=302.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH3:5])[CH3:3].[C:6](#[N:10])[C:7]([CH3:9])=[CH2:8].S(=O)(=O)(O)[OH:12].O>C(O)(=O)C>[CH3:1][C:2]([NH:10][C:6](=[O:12])[C:7]([CH3:9])=[CH2:8])([CH2:4][CH3:5])[CH3:3]
Reactant: O=S(=O)(O)O
Reactant: C=C(C)C#N
Reactant: CC=C(C)C
Solvent: CC(=O)O
Solvent: O
Product: C=C(C)C(=O)NC(C)(C)CC
Reaction time: 8 h
Yield: 65.2 %

Procedure:
2-Methyl-2-butene (7.0 g) was added to a stirred mixture of methacrylonitrile (6.7 g) in acetic acid (50 ml) and concentrated sulfuric acid (10 g) at 10° to 20° C. The mixture was allowed to stand overnight at room temperature, and then poured into 200 g of water and extracted with methylene chloride (2×100 ml). The methylene chloride solution was dried over sodium sulfate, the solid filtered off and the methylene chloride evaporated to afford an oily product. Distillation of the product at 10 mm yielded N-(2-methyl-2-butyl)methacrylamide (10.1 g, 65%); bp 84° C.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.C(Br)(Br)(Br)[Br:20]>>[Br:20][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(OCc1ccccc1)N1CCCC(CO)C1
Product: O=C(OCc1ccccc1)N1CCCC(CBr)C1

Procedure:
The title compound was prepared by the method of Preparation 9 from benzyl 3-(hydroxymethyl)-1-piperidinecarboxylate [Preparation 59] and carbon tetrabromide. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 80:20, by volume ethyl acetate:hexane, in 10% increments, to afford benzyl 3-(bromomethyl)-1-piperidinecarboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][CH2:20][O-:21].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:21][CH2:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reaction time: 20 h
Yield: 72.8 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and sodium ethylate (262 mg, 3.85 mmol) were dissolved in ethanol (20 ml) and then the solution was refluxed on heating under stirring for 20 hours. The reaction mixture was evaporated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (151 mg, yield 73%).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])=[CH:10][C:9]=1[O:20][CH3:21])[CH2:4][CH2:5][CH3:6]>CO.O>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:10][C:9]=1[O:20][CH3:21])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc(/C=C/C(=O)OC)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOc1ccc(/C=C/C(=O)O)cc1OC
Temperature: 60 °C
Yield: 92.3 %

Procedure:
10 g (0.15 mol) potassium hydroxide were dissolved in a mixture of 200 ml methyl alcohol and 5 ml water. 4.85 g (18.35 mmol) methyl (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoate was added. The reaction mixture was subsequently heated to 60° C. After 2.5 h the mixture was concentrated by evaporation. The residue was dissolved in 100 ml cold water and acidified to pH=1 with 13.5 ml hydrochloric acid 37 wt. %. The product was filtered off, washed with water and dried at 50° C. under vacuum to give 4.24 g (92%) (2E)-3-(4-butoxy-3-methoxyphenyl)-2-propenoic acid as white crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH3:9]I>C1COCC1>[CH3:9][O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](N)CO
Reactant: CI
Solvent: C1CCOC1
Product: COC[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-2-amino-4-methylpentan-1-ol (0.276 ml, 2.133 mmol) was added to a stirred, ice-bath cooled suspension of KH (267 mg, 2.327 mmol) in THF (10 ml) under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for ˜10 minutes and then treated with MeI (0.121 ml, 1.93 mmol). After stirring for 30 minutes the reaction mixture was quenched by addition of saturated NH4Cl(aq) (˜20 ml) and extracted with EtOAc (25 ml×2). The combined organic phases were dried over MgSO4, filtered under vacuum and the filtrate was evaporated to afford an orange oil. The oil was purified by chromatography on silica eluting with 10% (2M NH3 in MeOH)/DCM to afford the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][C:4](=[O:8])[CH:5]=[CH:6][CH3:7].CC(C(C)CC=C(C)C)=CC=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]([C:4](=[O:8])/[CH:5]=[CH:6]/[CH3:7])[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]=1
Reactant: CC=CC(=O)C=C(C)CCC=C(C)C
Agent: CC(C)=CCC(C)C(C)=CC=O
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: C/C=C/C(=O)C1C(C)=CCCC1(C)C
Temperature: 0 °C
Yield: 50 %

Procedure:
A mixture of 10 g. of 6,10-dimethyl-4-oxo-2,5,9-undecatriene prepared according to the method of paragraph (c) herebelow, 100 ml. of benzene and 1 g. of boron trifluoride etherate was heated to the reflux until the vapour phase chromatographic analysis of a sample showed that practically all the starting material had disappeared. The solution was cooled and stirred with ice-water. The organic layer was removed and treated as usual. Distillation of the residue of evaporation gave a 50% yield of trans-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene of about 60% purity as shown by the vapour phase chromatographic analysis.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14](Cl)(Cl)=[O:15].Cl.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[C:30]([C:32]3[CH:41]=[C:40]4[C:35]([CH2:36][CH2:37][NH:38][CH2:39]4)=[CH:34][CH:33]=3)[N:29]=[C:28]([NH2:42])[N:27]=2)[CH2:22][CH2:21]1>>[NH2:42][C:28]1[N:29]=[C:30]([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][N:38]([C:14]([NH:2][C@H:3]4[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]4[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:15])[CH2:39]3)=[CH:34][CH:33]=2)[CH:31]=[C:26]([N:23]2[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]2)[N:27]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: O=C(Cl)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from ethyl cis-2-aminocyclohexanecarboxylate hydrochloride (Acros Organics, Cat. #26564), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=522.3.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CN1C(=O)OC[C@@H]1c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of Example 2A (1 g, 4.25 mmol) in 10 mL of anhydrous THF at −78° C. was treated with 4.68 mL (4.68 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred for 1 h. at about −70° C. before adding MeI (1.59 mL, 25.51 mmol). Upon complete conversion of the azetidinone, the reaction was quenched with saturated aqueous NH4Cl and partitioned between EtOAc and water. The organic layer was washed sequentially with saturated aqueous sodium bisulfite, and saturated aqueous NaCl. The resulting organic layer was dried (MgSO4) and evaporated to afford the title compound (a mixture of diasteromers) as a white solid (1.06 g, 93%); 1H NMR (CDCl3) δ 1.07/1.53 (d/d, J=7.5 Hz, 3H), 3.59/3.74 (s/s, 3H), 3.85/4.48 (q/q, J=7.5 Hz, 1H), 4.10-4.14 (m, 1H), 4.60-4.64/4.65-4.69 (m/m, 1H), 4.88-4.92/4.98-5.02 (m/m, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1.C1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:22])(=[O:1])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCC1CCc2ccccc2O1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 25 h
Yield: 84.5 %

Procedure:
To a stirred and cooled (0° C.) solution of 32.8 g of 3,4-dihydro-2H-1-benzopyran-2-methanol in 71 ml of pyridine and 135 ml of benzene was added dropwise a solution of 41.9 g of 4-methyl-benzenesulfonyl chloride in 72.5 ml of benzene. Upon completion, stirring was continued for 25 hours. The reaction mixture was washed successively with a hydrochloric acid solution (10% ), with water and with a sodium carbonate solution (10% ). The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 100%). The eluent of the desired fraction was evaporated, yielding 28.3 g of 3,4-dihydro-2H-1-benzopyran-2-methanol 4-methylbenzenesulfonate (ester) as a solid residue, mp. 59.4° C. (interm. 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(C(C)C)C(C)C)C.O>CN(C=O)C>[C:16]([Si:13]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:15])[CH3:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
A mixture of 2-methoxy-5-nitrophenol (3.0 g, 17.8 mmol), tert-butyldimethylsilyl chloride (3.2 g, 21.4 mmol), and ethyldiisopropylamine (5.8 g, 44.5 mmol) in DMF (50 mL) was stirred at room temperature for 3 hours. The mixture was poured into water (100 mL) and extracted with methylene chloride (3×100 mL). The combined organic extracts were washed with water (5×100 mL) and dried (MgSO4), and the solvent was evaporated under vacuum. The residue was recrystallized from ethanol-water, providing 3.2 g of the product as white crystals, in 64% yield: 1H NMR (CDCl3) δ 0.19 (s, 6H), 1.01 (s, 9H), 3.91 (s, 3H), 6.89 (d, J=8.9 Hz, 1H), 7.71 (d, J=2.8 Hz, 1H), 7.89 (dd, J=8.9 Hz, J=2.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=O)[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:30](=[N:34][OH:35])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:27])[CH3:28])[CH2:10][CH2:9]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The resulting mixture was stirred overnight at room temperature, diluted with water, filtered, washed and dried to yield the title compound as a colorless solid.
Reaction SMILES: [NH3:1].N.N.N.N.N.[OH2:7].O.O.O.[OH:11][Mo:12](O)(=O)=O.[OH:16][Mo](O)(=O)=O.[OH:21][Mo](O)(=O)=O.[O:26]=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O>[OH-].[NH4+].O>[NH3:1].[NH3:1].[NH3:1].[NH3:1].[NH3:1].[NH3:1].[OH2:11].[OH2:16].[OH2:21].[OH2:26].[OH2:7].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[OH2:11].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12].[Mo:12]
Reactant: O=[Mo](=O)=O
Reactant: O=[Mo](=O)(O)O
Agent: N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: [Mo]

Procedure:
A solution of ammonium paramolybdate was prepared by dissolving 120 gm of (NH4)6Mo7O24. 4H2O in 250 ml of concentrated ammonium hydroxide. The resulting solution was diluted subsequently with distilled water to make 500 ml of solution. A 1-ml portion of the solution contained the equivalent of 0.20 gm of MoO3. An 11-ml portion of the above-prepared solution was diluted to 250 ml with distilled water and the resultant aqueous solution was added to 219 gm (500 cc) of the 14-to-20-mesh alumina. This amount of solution just wetted all of the alumina. The impregnated alumina was then calcined in static air at a temperature of 1,000° F. for a period of 11/2 hours. The finished catalyst, hereinafter identified as Catalyst A, was found to have a surface area of 198 m2 /gm and to contain 1.22 wt.% MoO3, based upon the total catalyst weight.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH:38]([C:42](=[O:50])[NH:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH2:37]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2>>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:38]([C:42](=[O:50])[NH:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH2:37]1)(=[O:34])=[O:35])[CH:27]=[CH:26]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: O=C(NN1CCOCC1)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)NN3CCOCC3)sc2CN1
Product: Cl

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[N-(morpholin-4-yl)carbamoyl]piperazine trifluoroacetate
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][S:6][CH2:7][C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH3:46][NH:47][CH:48]1[CH:55]2[CH2:56][C:51]3([OH:58])[CH2:52][CH:53]([CH2:57][CH:49]1[CH2:50]3)[CH2:54]2>C1COCC1>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][S:6][CH2:7][C:8]([N:47]([CH:48]1[CH:55]2[CH2:54][CH:53]3[CH2:52][C:51]([OH:58])([CH2:50][CH:49]1[CH2:57]3)[CH2:56]2)[CH3:46])=[O:10]
Reactant: O=C(O)CSCOc1ccc(Cl)cc1Cl
Reactant: CNC1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CSCOc1ccc(Cl)cc1Cl)C1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2,4-dichloro-phenoxymethylsulfanyl)-acetic acid (125 mg, 0.47 mmol) in dry THF (20 mL) was added HOBt (76 mg, 0.56 mmol) and EDAC (108 mg, 0.56 mmol). After stirring for 1 hr at room temperature, DIPEA (180 μL) and 4-methylaminoadamantan-1-ol (93 mg, 0.52 mmol) were added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were removed in vacuo and the residue was purified using prep. HPLC/MS affording crude 2-(2,4-dichloro-phenoxymethylsulfanyl)-N-(5-hydroxy-adamantan-2-yl)-N-methyl-acetamide which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+].[Cl:28][C:29]([Cl:33])=[CH:30]CCl>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:25][CH2:22][CH:30]=[C:29]([Cl:33])[Cl:28])=[CH:4][CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=1
Reactant: ClCC=C(Cl)Cl
Reactant: Oc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Br)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc(Oc2c(Cl)ccc(OCC=C(Cl)Cl)c2Cl)c(Br)c1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
To a mixture of 0.83 g of 3,5-dichloro-4-(3-bromo-5-trifluoromethyl-2-pyridyloxy)phenol, 0.31 g of potassium carbonate and 20 ml of N-dimethylformamide, a solution prepared by dissolving 0.33 g of 1,1,3-trichloro-1-propene in 5 ml of N,N-dimethylformamide was added dropwise at room temperature with stirring. After stirring at room temperature for 7 hours, the reaction solution was poured into ice-water, and extracted twice with 50 mi of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 0.79 g of 3,5-dichloro-4-(3-bromo-5-trifluoromethyl-2-pyridyloxy)-2-(3,3-dichloro-2-propenyloxy)benzene, yield 75%; m.p., 90.7° C.