Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([CH3:21])=[N:19][CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1>[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([CH3:21])=[N:19][CH:20]=1
Reactant: Cc1ncc(N=C(c2ccccc2)c2ccccc2)cc1NS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ncc(N)cc1NS(C)(=O)=O
Temperature: 25 °C
Yield: 29.6 %

Procedure:
To a solution of N-(5-(diphenylmethyleneamino)-2-methylpyridin-3-yl)methanesulfonamide (0.430 g, 1.177 mmol) in THF (10 mL) was added hydrochloric acid (JT Baker) (1.765 mL, 1.765 mmol) (1N). The reaction was stirred at rt in closed system for min. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 5% to 10% MeOH in DCM) to afford the desired product as a brown solid (70.0 mg). MS (ESI pos. ion) m/z: 202.1. 1H NMR (300 MHz, CDCl3) δ ppm 2.42 (s, 3H) 3.03 (s, 3H) 3.70 (br. s., 2H) 6.15 (br. s., 1H) 7.20 (d, J=2.34 Hz, 1H) 7.87 (d, J=2.34 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[C:14]([C:18]#[N:19])=[CH:15][NH:16][CH:17]=1)=O.[OH-].[NH4+]>[Ni].C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]2[C:13]3[C:14](=[CH:15][NH:16][CH:17]=3)[CH2:18][N:19]=[C:4]([C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[F:1])[C:6]=2[CH:11]=1
Reactant: N#Cc1c[nH]cc1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Reaction time: 6 h

Procedure:
A mixture of 3.0 g (9 mmole) of 4-[2-(2-fluorobenzoyl)-4-chlorophenyl]-1H-pyrrole-3-carbonitrile, ca 3 g of Raney nickel and 150 ml of glacial acetic acid was hydrogenated on a Parr apparatus at 50 psi for 6 hr. The Raney nickel was removed by filtration, and the acetic acid was removed at reduced pressure to give a yellow oil. The yellow oil was poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give tan crystals. Recrystallization from a mixture of ether and methylene chloride gave cream prisms, mp 197°-199°.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.O>C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[N:8][CH:9]=1
Reactant: O=C1CCC(c2ccc(Br)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O[C@H]1CC[C@@H](c2ccc(Br)cn2)CC1
Product: O[C@H]1CC[C@H](c2ccc(Br)cn2)CC1

Procedure:
Sodium borohydride (4.58 g) was added under ice cooling to a solution of 4-(5-bromopyridin-2-yl)cyclohexanone (7.9 g) in ethanol (120 ml), and stirred at the same temperature for an hour. After completion of the reaction, water was added under ice cooling, the organic solvent was evaporated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give trans-4-(5-bromopyridin-2-yl)cyclohexanol (4.94 g) as a white solid, and cis-4-(5-bromopyridin-2-yl)cyclohexanol (1.16 g) as a colorless oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)=[N:14][C:13]=1[CH:27]=C.O.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.[Os](=O)(=O)(=O)=O.O>[CH:27]([C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=2)[S:16][C:12]=1[C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:29])[CH3:30])[CH:11]=[CH:10][N:9]=1)=[O:33]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1nccn1COCC[Si](C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(C=O)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
N-{4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-4-vinyl-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.650 g, 1.47 mmol) was dissolved in tetrahydrofuran (20 mL) and water (10 mL) at ambient temperature and 0.157 M osmium tetraoxide in water (93 uL, 0.014 mmol) was added. The mixture was stirred at room temperature for 5 minutes. Sodium metaperiodate (0.661 g, 3.09 mmol) was then added in portions over 20 minutes and the mixture was stirred at room temperature overnight. Solids were removed by filtration and washed with THF (2×50 mL) and ethyl acetate (2×5 mL). The filtrate was extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Crude material was purified by silica gel chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.25 g, 38%). LCMS: (FA) ES+, 444. 1H NMR (400 MHz, CDCl3) δ: 8.75 (s, 1H), 10.21 (s, 1H), 8.41 (d, J=5.18 Hz, 1H), 8.20-8.07 (m, 1H), 7.76 (dd, J=5.21, 1.58 Hz, 1H), 7.30 (dd, J=2.87, 1.21 Hz, 2H), 5.32 (s, 2H), 3.50-3.33 (m, 2H), 2.26 (s, 3H), 0.93-0.78 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O>[Pd].C(OCC)(=O)C>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(O)ccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(O)ccc1F
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A mixture of 4-fluoro-3-nitrophenol (2.70 g, 17.2 mmol) and palladium on charcoal (10%, 0.31 g) in 60 mL ethyl acetate is hydrogenated under 50 psi of H2 using a Parr hydrogenation reactor. After shaking for 1 hour, the reaction mixture is filtered using a diatomaceous earth pad to remove catalyst. The filtrate is concentrated in vacuo, and the residue is sublimed to yield 2.18 g (100%) of Compound 24 as a white solid. MP: 142-144° C. 1H-NMR (d6 -DMSO) 8.82 (s, 1H); 6.70 (dd, 1H); 6.17 (dd, 1H); 5.85 (m, 1H); 4.92 (s, 2H). 19F-NMR (d6 -DMSO) 142.78 (t, 13.0 Hz). Anal. calc. for C6H6FNO: C, 56.69; H, 4.76; N, 11.02. Found: C, 57.28; H, 4.86; N, 10.65.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH3:14])[CH:7]=1>CO.O1CCCC1>[CH3:14][O:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([OH:15])=[O:4]
Reactant: COCc1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cccc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
1 N Sodium hydroxide (3.6 ml, 3.6 mmol) was added to a 3-methoxymethyl-benzoic acid methyl ester (436 mg, 2.4 mmol) in methanol (5 ml) and tetrahydrofuran (5 ml). The reaction was stirred at 70° C. for 30 min. and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH about 2) by the addition of 1 N HCl (aq.). Following extraction of the aqueous layer with ethyl acetate, the organic layer was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 395 mg (98%) of 3-methoxymethyl-benzoic acid as a white solid. 1H NMR (DMSO), δ (ppm): 7.90 (s, 1H), 7.87 (d, 1H), 7.56 (d, 1H), 7.48 (t, 1H), 4.48 (s, 2H), 3.31 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][C:7]#[N:8])[CH:3]=O.[NH3:10].[H][H]>>[CH3:1][C:2]1([CH3:9])[CH2:5][CH2:6][CH2:7][NH:8][CH2:3]1.[CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH2:7][NH2:8])[CH2:3][NH2:10]
Reactant: N
Reactant: CC(C)(C=O)CCC#N
Reactant: [H][H]
Product: CC(C)(CN)CCCN
Product: CC1(C)CCCNC1

Procedure:
34.0 g per hour of 2,2-dimethyl-4-cyanobutanal (purity 93.4%, 31.8 g, 0.254 mol) and 1450 ml (870 g, 51.1 mol) per hour of liquid ammonia were pumped at 250 bar and 60° C. through a tubular reactor (diameter 16 mm, fill level 50 cm, oil-heated twin jacket) upstream of the hydrogenation reactor and filled with 63.5 g (100 ml) of TiO2 (anatase) in the form of 1.5 mm pellets. The discharge from the reactor was subsequently passed through the hydrogenation reactor from bottom to top at 250 bar and 120° C. while simultaneously passing 100 l (S.T.P.)/h (4.5 mol) of hydrogen through the reactor. The product stream was decompressed to atmospheric pressure and NH3 was removed by distillation. The product from 32.4 hours was separated by fractional distillation on a 30 cm packed column (3 mm glass rings), giving 344.8 g of 3,3-dimethylpiperidine (b.p. 50°-52° C./210 mmHg) and 753.6 g of 2,2-dimethylpentane-1,5-diamine (b.p.=72° C./8 mmHg). The diamine yield was 70.5% of theory.
Reaction SMILES: ClCCOC(=O)N[C:7]1[S:8][C:9]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:11]=1.[CH3:27][C:28](C)([O-:30])C.[K+].C(=O)([O-])O.[Na+].C[N:39](C)[CH:40]=[O:41]>>[CH3:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]([N:39]3[CH2:27][CH2:28][O:30][C:40]3=[O:41])([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[S:8][CH2:7][N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[O-]
Reactant: Cc1cccc(-c2nc(NC(=O)OCCCl)sc2-c2ccnc(C)c2)c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Product: Cc1cccc(C2=NCSC2(c2ccnc(C)c2)N2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 2-chloroethyl[4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]carbamate (0.30 g, 0.80 mmol) in N,N-dimethylformamide (3 mL) was added potassium tert-butoxide (0.12 g, 1.1 mmol), and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to obtain a crystal. This crystal was recrystallized from hexane-ethyl acetate, to obtain a title compound (0.20 g, yield 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10](C(OCC)=O)([CH2:24][C:25]([OH:27])=[O:26])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][C:25]([OH:27])=[O:26])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(CC(=O)O)N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(CC(=O)O)c1nnc(C)n1-2
Temperature: 25 °C
Yield: 54.9 %

Procedure:
Ethanol (500 ml) is added to (±)-4-(4-chlorophenyl)-6-ethoxycarbonyl-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine-6-acetic acid (43 g), and the mixture is stirred at room temperature. 2N Sodium hydroxide (182 ml) is added and the mixture is stirred at 50° C. overnight. After the completion of the reaction, ethanol is distilled away, and the residue is adjusted to pH 4-5 with acetic acid. Then, the resulting mixture is stirred at 60° C. for 30 minutes and cooled to room temperature. The mixture is extracted with chloroform, and the organic layer is washed with saturated brine. The layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals are recrystallized from chloroform-methanol to give 20 g of (±)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepine-6-acetic acid, melting point 287°-290° C.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[OH:17].[OH-].[K+]>C(O)C>[C:11]1([C:9]2[CH:8]=[CH:7][C:6]3[O:17][C:1](=[S:3])[NH:4][C:5]=3[CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=c1[nH]c2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Carbon disulfide (7.7 mL) was added to a mixture of 2-amino-4-phenylphenol (1.0 g, 5.4 mmol), potassium hydroxide (0.36 g, 6.5 mmol) and ethanol (11.7 mL). The flask was fitted with a reflux condenser and the resulting mixture was placed in an oil bath at 60° C. for 16 h. After cooling to RT, the mixture was concentrated and ethyl acetate (20 mL) and 1 M hydrochloric acid (10 mL) were added to the residue. The layers were partitioned and the organic layer was washed successively with 1 M HCl, water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford 1.20 g (98%) which was used without further purification: 1H NMR (d6-DMSO, 400 MHz) δ 13.98 (s, 1H), 7.64-7.62 (m, 2H), 7.58-7.49 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.33 (m, 2H); 13C (d6-DMSO, 400 MHz) δ 181.2, 148.2, 140.1, 138.5, 132.7, 129.7, 128.3, 127.7, 123.4, 111.0, 109.1; MS (Cl) m/z 228.1 (M+1); HPLC retention time=3.09 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])[CH:4]=[N:3]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:4]=[N:3]1
Reactant: CCOC(=O)/C=C/c1cnn(C)c1-c1cccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ncc(/C=C/C(=O)O)c1-c1cccnc1
Temperature: 40 °C
Reaction time: 14 h
Yield: 47.5 %

Procedure:
To a mixture of ethyl (2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazol-4-yl]acrylate (700 mg) and methanol (5 ml) was added a 2N aqueous sodium hydroxide solution (2.7 ml) and the mixture was stirred at 40° C. for 14 hrs. A saturated aqueous citric acid solution was poured into the reaction mixture to adjust pH to 5, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from ethyl acetate-isopropyl ether to give (2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazol-4-yl]acrylic acid (296 mg, 47%) as pale-yellow prism crystals. melting point: 236-237° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:36])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:30]1[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:36])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1-c1cccc(C2=Nc3ccc(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M14) (280 mg, 0.545 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pink solid (163 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](=[O:12])[C:5]2=O.[CH:14]1[C:19]([NH:20][NH2:21])=[CH:18][CH:17]=[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:15]=1.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](=[O:12])[C:5]2=[N:21][NH:20][C:19]1[CH:18]=[CH:17][C:16]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:15][CH:14]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc2c(cc1C)C(=O)C(=O)N2
Agent: Cl
Product: Cc1cc2c(cc1C)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 32 %

Procedure:
The title compound was prepared from 5,6-dimethyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 32% yield: 1H NMR (DMSO-d6): δ 2.22 (s, 3H), 2.24 (s, 3H), 6.72 (s, 1H), 7.23 (s, 2H), 7.36 (s, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 10.93 (s, 1H), 12.71 (s, 1H). APCI-MS m/z 343 (M−H)−. Anal. Calcd for C16H16N4O3S: C, 55.80, H, 4.68; N, 16.27; S, 9.31. Found C, 55.78, H, 4.74; N, 16.37; S, 9.22.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C([Mg]Br)C.[CH3:12][Si:13]([CH3:20])([CH3:19])[C:14]#[C:15][C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>C(Cl)Cl.C1COCC1>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([C:16]([OH:18])([C:15]#[C:14][Si:13]([CH3:20])([CH3:19])[CH3:12])[CH3:17])=[N:3]1
Reactant: CC(=O)C#C[Si](C)(C)C
Reactant: Cn1ccc(I)n1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ccc(C(C)(O)C#C[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-1-methyl-1H-pyrazole (378 mg, 1.82 mmol) in dry DCM (15 mL) at 0° C. under an atmosphere of nitrogen, was introduced ethylmagnesium bromide (2.0 mL of a 1.0M solution in THF, 2.0 mmol). After 30 minutes at 0° C., the reaction mixture was warmed to RT for 15 minutes, then introduced to a solution of 4-(trimethylsilyl)but-3-yn-2-one (0.37 ml, 2.18 mmol) in dry DCM (5 ml) at 0° C. under an atmosphere of nitrogen. The reaction mixture was warmed to RT for 16 hr. Following addition of saturated aqueous ammonium chloride (5 ml), the reaction mixture was extracted with DCM (3×5 mL extractions). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (heptane/EtOAc gradient) furnished the title compound as an orange-brown oil: 1H NMR (500 MHz, CDCl3) delta 0.15 (9H, d, J=3.5 Hz), 1.82 (3H, s), 3.18 (1H, s), 3.86 (3H, s), 6.28 (1H, d, J=2.2 Hz), 7.26 (1H, d, J=2.2 Hz); LC-MS: m/z=+222.95 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH:5]([CH2:11][CH3:12])C(OCC)=O.[OH-:24].[K+].[CH3:26][OH:27]>>[Cl:23][C:13]1[CH:14]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:21])[Cl:22])[CH:16]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:11][CH2:12][C:26]([OH:27])=[O:24]
Reactant: CO
Reactant: CCOC(=O)C(CC)Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A reaction vessel was charged with 2.54 g of ethyl 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxybutyrate, 4.0 g of 10% aqueous potassium hydroxide solution and 50 ml of methanol. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. Then, 50 ml of diethyl ether was poured into the reaction mixture, and the mixture was extracted twice with 50 ml of 5% aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and made weak acidic by the addition of concentrated hydrochloric acid. The deposited crystals were extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated, which afforded 2.11 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyric acid (90% yield), m.p., 80.9° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][O:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][O:10]2)=[CH:4][CH:3]=1)=[O:28]
Reactant: CC1(C)CON(C(C)(C)c2ccc(Br)cc2)C1
Reactant: O=C(Cl)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CON(C(C)(C)c2ccc(C(=O)CCCCl)cc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene (10.0 g. 0.0338 mole), prepared in accordance with Example 2, in 400 ML THF is cooled to −78° C., n-butyllithium (16 mL, 0.042 mole) is added via syringe, and the mixture is stirred at −78° C. for 30 minutes. While keeping the temperature below −75° C., 4-chlorobutyryl chloride (14.4 g, 0.102 mole) in 30 mL THF is added dropwise, and the mixture is stirred at −78° C. for 30 minutes. The mixture is allowed to warm to −15° C. and is quenched with water. The product is extracted with methylene chloride, washed with saturated NaCl solution, dried over Na2SO4, and concentrated. The residue is cooled to 0° C., treated with minimal acetonitrile, and filtered, to afford 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[C:20]([O:22]C)=[O:21])#[N:2].[OH-].[Na+].Cl>CO>[C:20]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:3]=1[C:1]#[N:2])[O:7][C:8]1[CH:9]=[CH:10][C:11]2[B:15]([OH:16])[O:14][CH2:13][C:12]=2[CH:17]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
A mixture of 5-(4-Cyano-3-methoxycarbonylphenoxy)-1-hydroxy-2,1-benzoxaborole (5.25 g, 17.0 mmol) and 1 M NaOH (50 mL) in methanol (150 mL) was stirred at room temperature for 1 h. The mixture was acidified with 6 M HCl and extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate to 3:1 chloroform/methanol) followed by trituration with ethyl acetate to give 5-(3-carboxy-4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole (810 mg, 16%)
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]4[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=4)=[CH:30][CH:29]=3)[CH2:17][CH2:16]2)=[O:19])=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)OCc3ccc(F)cc3)CC2)cc1
Solvent: O=CO
Product: O=C(OCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 29.3 %

Procedure:
4-Fluorobenzyl 4-[4-(2-aminoethyl)anilino]-1-piperidinecarboxylate formate (0.33 g, 0.792) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.32 g, 0.792 mmol) according to the method described in Procedure G to give the title compound (0.18 g, 0.232 mmol).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH2:15][C@:14]3([CH3:27])[C@@H:16]([CH3:26])[CH2:17][CH2:18][C@H:19]4[C:20]([CH3:25])([CH3:24])[CH:21]=[CH:22][CH2:23][C@@:13]34[O:12][C:4]=2[C:5]2[CH2:6][NH:7][C:8](=[O:11])[C:9]=2[CH:10]=1>CO.[C].[Pd]>[OH:1][C:2]1[C:3]2[CH2:15][C@:14]3([CH3:27])[C@@H:16]([CH3:26])[CH2:17][CH2:18][C@H:19]4[C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][CH2:23][C@@:13]34[O:12][C:4]=2[C:5]2[CH2:6][NH:7][C:8](=[O:11])[C:9]=2[CH:10]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CC[C@H]2C(C)(C)CCC[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 85.5 %

Procedure:
To the above Compound (41a) (35 mg, 0.095 mmol) dissolved in 5 ml of methanol was added 7 mg of 10% palladium-carbon, and the mixture stirred under hydrogen atmosphere for 7.5 hours at room temperature. After removing palladium-carbon by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol 15:1) to give 30 mg (85%) of Compound (42).