Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.C(OC)(OC)OC.[CH2:24]([NH2:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+]>CO>[CH2:24]([NH:32][CH2:1][C:3]1[S:7][C:6]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1ccc(Oc2ccc(C=O)s2)cc1
Reactant: NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: N#Cc1ccc(Oc2ccc(CNCCc3ccccc3)s2)cc1
Reaction time: 3 h
Yield: 48 %

Procedure:
Combine 4-(5-formyl-thiophen-2-yloxy)-benzonitrile (200 mg, 0.87 mmol), (MeO)3CH (1.2 mL), phenethyl amine (0.142 mL, 130 mol %) and methanol (1.7 mL). Stir the resulting mixture for 3 hours, and then add sodium borohydride in portions. Stir for few hours. Then, concentrate to remove the methanol. Partition the resulting residue between H2O (5 mL) and CH2Cl2 (7 ml). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the product through flash chromatography [CH2Cl2/Ammonia (2.0 M in methanol) 20/1] to provide the title compound (139 mg, 48%).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[H-].[Na+].[CH2:14]([N:21]1[C:25]2[N:26]=[C:27]([NH2:31])[N:28]=[C:29](Cl)[C:24]=2[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:31][C:27]1[N:28]=[C:29]([O:1][C:2]2[C:3]([CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=2[CH3:10])[C:24]2[CH:23]=[CH:22][N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:25]=2[N:26]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(N)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (1.62 mg, 11.0 mmol) in 1-methyl-2-pyrridone (5 mL) in a sealed tube was added NaH (441 mg, 11.0 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (950 mg, 3.67 mmol) in 1-methyl-2-pyrridone (5 mL) was added to the mixture. The mixture was heated at 150° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2×50 mL). The combined organic solution was washed with H2O (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 1.12 mg (83%) of 4-(2-amino-7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:35]=[CH:34][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][Si](C)(C)C)=[CH2:20])=[C:15]([O:26][Si](C)(C)C)[C:14]=2[CH2:31][CH2:32][CH3:33])=[CH:9][CH:8]=1.[H-].[Na+].[O:38]=[C:39]1[O:43][N:42]=[C:41]([C:44]2[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=2)[CH:47]=[O:48])[NH:40]1>O1CCCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:34]=[CH:35][C:7]([CH:47]([OH:48])[C:46]3[CH:45]=[C:44]([C:41]4[NH:40][C:39](=[O:38])[O:43][N:42]=4)[CH:51]=[CH:50][CH:49]=3)=[CH:8][CH:9]=2)=[C:14]([CH2:31][CH2:32][CH3:33])[C:15]=1[OH:26])(=[O:21])[CH3:20]
Reactant: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Reactant: C=C(O[Si](C)(C)C)c1ccc(OCc2ccc(I)cc2)c(CCC)c1O[Si](C)(C)C
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(O)c3cccc(-c4noc(=O)[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 0.496 ml, 0.992 mmol) to a solution of 1-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene (500 mg, 0.901 mmol) in tetrahydrofuran (0.1M) at 0° C. After 15 minutes, warm to room temperature. After 1 hour, cool to −78° C. Add sodium hydride (60% dispersion, 24 mg, 0.992 mmol) to a solution of 3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde (189 mg, 0.992 mmol) in tetrahydrofuran (0.1M). Sonicate the solution for 5 minutes, then add it via syringe to the gringard reagent. After 30 minutes warm the reaction to room temperature. Quench with 10% aq hydrochloric acid (3 mL). Pour the reaction into brine and extract with 25% isopropyl alcohol:75% dichloromethane. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes:acetic acid 50%:50%:0.1% to yield the title product as a off white solid (110 mg, 26%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.47 (sextet, 2H), 2.56 (m, 5H), 5.21 (s, 2H), 5.79 (d, 1H), 6.11 (d, 1H), 6.70 (d, 1H), 7.41 (q, 4H), 7.51 (t, 1H), 7.63 (t, 2H), 7.78 (d, 1H), 7.90 (s, 1H), 12.83 (s, 1H), 12.97 (bs, 1H); MS (esi negative) m/z (rel intensity) 473 (100).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)[CH3:2].C(O)C=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:1]([O:4][CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OCC=Cc1ccccc1
Reactant: OCC=Cc1ccccc1
Solvent: O
Product: C(=Cc1ccccc1)COCC=Cc1ccccc1

Procedure:
As apparent from Table 4, it is found that the carboxylic acid esters, each of which produces a water-soluble carboxylic acid by hydrolysis, are hydrolyzed with a high efficiency, and alcohols can be obtained with a high yield. In addition, in a hydrolysis reaction shown in the bottom portion of Table 4 in which cinnamyl acetate is used as the carboxylic acid ester, since cinnamyl alcohol, which is a reaction product, may be dimerized to form dicinnamyl ether as a by-product in some cases, a reaction was taken place at a low temperature of 40° C.; however, an alcohol could be obtained with a high yield of 93%. In the above table, the yield shown in the parentheses indicates the yield of dicinnamyl ether.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][C:12]([CH3:19])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:22])=[N:13][C:12]([CH3:19])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(c(=O)[nH]1)CCN(Cc1ccccc1)C2
Product: Cc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 25 °C

Procedure:
7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (prepared according to the method of Example 86, Step A, 17.1 g, 67.0 mmol) was suspended in phosphorus oxychloride (66 mL, 335 mmol). This mixture was stirred at reflux for 1 h, cooled to room temperature, evaporated, then chased with toluene. The residue was carefully diluted with ice/water/chloroform and the layers were separated. The aqueous phase was extracted with chloroform (3×) and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (1×) and water (1×), dried over sodium sulfate, filtered, and evaporated to give the title compound of Example 86, Step B as a brown oil that was used without purification in the next step. 1H NMR (CDCl3, 250 MHz) δ7.36-7.23 (c, 5H), 3.73 (s, 2H), 3.63 (s, 2H), 2.63 (app s, 4H), 2.36 (s, 3H); MS (APCI) 274, 276 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(=O)(O)[O-].[Na+].Cl[C:47]([O:49][CH:50]([CH3:52])[CH3:51])=[O:48]>ClCCl.C1(C)C=CC=CC=1>[CH:50]([O:49][C:47](=[O:48])[NH:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4](=[O:5])[N:6]([CH3:8])[CH3:7])([CH3:52])[CH3:51]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC(=O)OC(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 0 °C

Procedure:
45 mg (0.08 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 1.0 mL dichloromethane and 1.0 mL of a saturated aqueous solution of sodium bicarbonate was added. The biphasic solution was cooled to 0° C. in an ice bath and, while stirring vigorously, 161 μL (0.161 mmol) of 1 M isopropyl chloroformate in toluene was added. The reaction was allowed to stir in the ice bath and allowed to warm to room temperature overnight (16 hours). The layers were separated and the organic layer was washed twice with water. The organic layer was then dried over sodium sulfate and concentrated. MS: m/z 645.1 (M+H+).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]([N:19]=1)=[N:8][C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:10]([OH:12])[N:11]=2)[NH2:2].C1C=CC2N(O)N=NC=2C=1.[C:30](O)(=O)[C:31]([NH2:33])=[O:32].C(Cl)CCl.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.O>[OH:12][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]3=[N:1][N:2]=[C:30]([C:31]([NH2:33])=[O:32])[N:19]3[C:7]2=[N:8][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)C(=O)O
Reactant: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nnc2ccc3nc(O)c(-c4ccccc4)nc3n12
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-hydrazinyl-3-phenylpyrido[2,3-b]pyrazin-2(1H)-one (3-3) (300 mg, 1.19 mmol), HOBt (218 mg, 1.42 mmol) and oxamic acid (130 mg, 1.42 mmol) in NMP (12 mL) was added EDC (272 mg, 1.42 mmol) at room temperature and the mixture was stirred for 30 min. After addition of TFA (0.091 mL, 1.19 mmol), the mixture was heated under microwave irradiation at 150° C. for 30 minutes. To a mixture was added water (60 mL) and the precipitate was collected by filtration to give 3-hydroxy-2-phenyl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-9-carboxamide (9-1) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Cl-].[Al+3].[Cl-].[Cl-].[Br:17]Br.Cl>ClCCCl.[Cl-].[Zn+2].[Cl-]>[Br:17][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2
Reactant: BrBr
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc2c(Br)c(F)ccc2n1
Yield: 75.2 %

Procedure:
A solution of 20.13 g (0.125 mole) of 6-fluoro-2-methylquinoline in 25 ml of 1,2-dichloroethane was added slowly to a mixture of 25.3 g (0.189 mole) of aluminum chloride and 25 ml of 1,2-dichloroethane. The resulting solution was heated to 70° C.-80° C., and 19.98 g (0.125 mole) of bromine was added dropwise thereto. The reaction mixture was heated at 80° C.-85° C. for about 16 hours and was poured onto ice and acidified by adding 100 ml concentrated hydrochloric acid. 17.04 g (0.125 mole) of zinc chloride was added, and the resulting suspension was heated on a steam bath for 15 minutes. After cooling in an ice bath, the complex was collected by filtration and washed sequentially with 100 ml of cold 3N hydrochloric acid and 100 ml of methylene chloride. The complex was slurried in 100 ml of water, and the pH was adjusted to pH 11 with ammonium hydroxide. The product was collected by filtration, washed with water and dissolved in 150 ml of toluene. The toluene solution was treated with magnesium sulfate and decolorizing charcoal, and was then evaporated to give 22.5 g (0.094 mole) of 5-bromo-6-fluoro-2-methylquinoline, a known compound. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[C:8](\[CH2:11][CH3:12])/[CH2:9][OH:10])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[C:8](\[CH2:11][CH3:12])/[CH:9]=[O:10])=[CH:5][CH:4]=1
Reactant: CC/C(=C\c1ccc(OC)cc1)CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC/C(C=O)=C\c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
A mixture of 2-((E)-4-methoxybenzylidene)butan-1-ol (31 g) and manganese dioxide (130 g) in chloroform (600 ml) was stirred at room temperature for 20 hours. Manganese dioxide was filtered off by filtration and the filtrate was condensed to give 2-((E)-4-methoxybenzylidene)butan-1-al (9.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH2:21])=[CH:16][CH:15]=1.P(Cl)(Cl)Cl>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([Br:11])[CH:10]=[C:2]([Br:1])[C:3]=3[OH:12])=[CH:19][CH:18]=2)=[CH2:21])=[CH:27][CH:26]=1
Reactant: C=C(c1ccc(N)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Br)cc(Br)c1O
Solvent: ClP(Cl)Cl
Product: C=C(c1ccc(Cl)cc1)c1ccc(NC(=O)c2cc(Br)cc(Br)c2O)cc1

Procedure:
Using the reaction conditions of Example 2, 5.92 g (0.02 mole) of 3,5-dibromosalicylic acid and 5.32 g (0.02 mole) of 1-(4-aminophenyl)-1-(4-chlorophenyl)ethylene in the presence of phosphorus trichloride were reacted to give 4.26 of purified N-[4-[1-(4-chlorophenyl)ethenyl]phenyl]-2-hydroxy-3,5-dibromobenzamide, m.p. 181°-183°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8]O.O=S(Cl)[Cl:12]>C(Cl)Cl>[Cl:12][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCc1ccccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCCc1ccccn1

Procedure:
2-(Pyridin-2-yl)ethanol (1 g, 8.12 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (10 ml) at rt for 3 hrs. The solvent was removed to get a crude 2-(2-chloroethyl)pyridine. Then following General Procedure A, the title compound (1.69 g, 79%) was prepared from 2-amino-4-chlorobenzenethiol (1.6 g, 9.74 mmol), K2CO3 (3.36 g, 24.36 mmol) in DMF (20 ml).
Reaction SMILES: [CH2:1]([N:5]([CH2:13][C:14](=[O:17])[CH:15]=[CH2:16])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]C=C>C(Cl)Cl>[O:17]=[C:14]1[CH2:13][N:5]([C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])[CH2:1][CH2:2][CH:16]=[CH:15]1
Reactant: C=CCCN(CC(=O)C=C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Temperature: 18 °C
Reaction time: 10 h
Yield: 64.1 %

Procedure:
To a mixture of tert-butyl N-but-3-enyl-N-(2-oxobut-3-enyl)carbamate (1.50 g, 6.27 mmol, 1.00 Eq) in DCM (250 mL), was added Zhan catalyst 1B (150.00 mg, 204.43 umol, 0.03 Eq) in one portion at 18° C. under N2. The mixture was stirred at 18° C. for 10 hr. TLC showed the reaction was completed. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=30/1, 20/1) to afford tert-butyl 6-oxo-3,7-dihydro-2H-azepine-1-carboxylate (850.00 mg, 4.02 mmol, 64.17% yield) as yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) 6.36-6.64 (m, 1H), 5.88-6.14 (m, 1H), 4.23-4.35 (m, 1H), 4.16 (s, 1H), 3.51-3.68 (m, 2H), 2.62-2.78 (m, 2H), 1.46 (d, J=17.32 Hz, 1H)
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:22])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]1[C:12]([C:13]2[C:14]([CH3:22])=[CH:15][CH:16]=[CH:17][C:18]=2[NH2:19])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(N)c1-c1nnnn1Cc1ccccc1
Reaction time: 4 h
Yield: 100.2 %

Procedure:
1-Benzyl-5-(2-methyl-6-nitrophenyl)-1H-tetrazole (Intermediate 17, 0.1 g) was dissolved in ethyl acetate (20 mL) under a nitrogen atmosphere. Palladium on carbon (10%, 0.1 g) was added and the nitrogen atmosphere was replaced by hydrogen. The mixture was stirred for 4 hours and then filtered through celite. The solvent was removed by evaporation under vacuum to give the title compound as a white solid (0.09 g).
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1C=CC=CC=1.[C:18]1(C(=O)CC(=O)C)C=CC=CC=1>>[C:11]1([C:10](=[O:17])[CH:9]([CH3:18])[C:1](=[O:8])[CH3:2])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: CC(=O)CC(=O)c1ccccc1
Product: CC(=O)C(C)C(=O)c1ccccc1

Procedure:
Synthetic procedure was identical with that described in synthetic example 42(1), except that raw material dibenzoyl methane was replaced by 1-phenyl-1,3-butandione.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[CH2:5][C:4](=[O:17])[C:3]=1[C:18](=O)[CH2:19][CH2:20][CH3:21].Cl.[CH2:24]([O:26][NH2:27])[CH3:25].C([O-])(=O)C.[Na+].Cl>C(O)C>[CH2:24]([O:26][N:27]=[C:18]([C:3]1[C:4](=[O:17])[CH2:5][CH:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[CH2:7][C:2]=1[OH:1])[CH2:19][CH2:20][CH3:21])[CH3:25]
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC(c2cc3ccccc3o2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCC(=NOCC)C1=C(O)CC(c2cc3ccccc3o2)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-hydroxy-5-(benzo[b]furan-2-yl)-2-butyryl cyclohex-2-en-1-one (1.0 g), ethoxyamine hydrochloride (0.36 g), sodium acetate (0.3 g) and ethanol (100 ml) were stirred at room temperature for 12 hr. The mixture was poured into a very dilute aqueous hydrochloric acid solution which was then extracted with ether. Evaporation of the dried (MgSO4) organic fraction and purification of the residue by column chromatography over silica with dichloromethane elution gave 2-[1-(ethoxyimino)butyl]-3-hydroxy-5-(benzo[b]furan-2-yl)cyclohex-2-en-1-one as a yellow solid, mp 70° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1.[C:29]1([NH2:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][C:7](=[N:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:6][CH2:5]1)[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(=Nc2ccccc2)CC1

Procedure:
To a stirred and refluxing mixture of 48 parts of 1-(1-methylethyl)-4-piperidinone, 1 part of 4-methylbenzenesulfonic acid and 540 parts of methylbenzene is added dropwise a solution of 30 parts of benzenamine in 90 parts of methylbenzene. Upon completion, the whole is stirred and refluxed for 3 hours with water-separator. The reaction mixture is evaporated, yielding 72 parts of N-[1-(1-methylethyl)-4-piperidinylidene]benzenamine as a residue.
Reaction SMILES: CC(S([NH:7][C:8]1([C:12]([F:15])([F:14])[F:13])[CH2:11][O:10][CH2:9]1)=O)(C)C.[ClH:16].O1CCOCC1>CO>[ClH:16].[F:13][C:12]([F:15])([F:14])[C:8]1([NH2:7])[CH2:11][O:10][CH2:9]1
Reactant: CC(C)(C)S(=O)NC1(C(F)(F)F)COC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Methyl-N-(3-(trifluoromethyl)oxetan-3-yl)propane-2-sulfinamide (52 mg, 0.212 mmol) was dissolved in methanol (1 mL). The solution was cooled down at ice-water bath and added slowly 4 N HCl in dioxane (240 μL, 0.954 mmol). The mixture was warmed to room temperature, stirred for 5 h, then concentrated. The solid was washed with ether twice then dried in vacuo to give the title compound (27 mg).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[O:18]=[C:19]1[C@@H:22]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:21][N:20]1[S:34]([O-:37])(=[O:36])=[O:35].O.O.O.O.O.O.O.O.O.O.B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Cl:55][O-].[Na+]>C(Cl)Cl.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[O:18]=[C:19]1[CH:22]([N:23]([Cl:55])[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:21][N:20]1[S:34]([O-:37])(=[O:35])=[O:36]
Reactant: [O-]Cl
Reactant: O=C(N[C@H]1CN(S(=O)(=O)[O-])C1=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N(Cl)C1CN(S(=O)(=O)[O-])C1=O
Reaction time: 0.92 h

Procedure:
(S)-2-Oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt (0.9 g; see Example 4) dissolved in 80 ml of methylene chloride is added to a mixture (cooled to 0°-5° C.) of 3.17 g of sodium borate decahydrate and 11.8 ml of a 5.25% sodium hypochlorite solution in 70 ml of water. The reaction mixture is vigorously stirred for 55 minutes while cooling in an ice bath. After diluting the mixture with 0.5M monobasic potassium phosphate solution, the product is extracted with methylene chloride (three 150 ml portions). Combination of the extracts, drying (sodium sulfate), and removal of solvent in vacuo yields the title compound as an oil (0.94 g).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.C([N:35]1[CH:39]=[C:38]([CH2:40][C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[N:37]=[CH:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:37]2[C:38]([CH2:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=3)=[CH:39][N:35]=[CH:36]2)=[CH:10][CH:9]=1
Reactant: O=c1ccccn1-c1ccc(CBr)cc1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: CC#N
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-n3ccccc3=O)cc2)cc1

Procedure:
4-(-2-Oxo-2-H-pyridin-1-yl)benzyl bromide from Step 3 (1.7 mmol, 450 mg ) and 4-(1-trityl-1H-imidazol-4-ylmethyl)benzonitrile (1.7 mmol) were suspended in CH3CN and heated to reflux for 3 hours. The reaction mixture was concentrated and the residue taken up in MeOH and refluxed for 2 hours. The MeOH was removed in-vacuo. The resulting oil was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield an oil which was purified by flash chromatography using 5% IPA/CHCl3 saturated with NH3 as an eluent. Pure fractions were collected and concentrated to give a white solid. The solids were washed with warm 50% EtOAc/Hexane and collected on a frit. The white solid was collected and dried under high vacuum at 50° for 12 hours to give the title compound.
Reaction SMILES: [Cl:1][O-].[Na+].[Cl:4][C:5]1[C:15]([Cl:16])=[C:14]([C:17]([C:19]2[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][CH:20]=2)=[O:18])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.CN(C)C=O.O>[Cl:4][C:5]1[C:15]([Cl:16])=[C:14]([C:17]([C:19]2[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=2[Cl:1])=[O:18])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: [O-]Cl
Reactant: CCn1nccc1C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ncc(Cl)c1C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.7 g of an aqueous 10% sodium hypochlorite solution are added dropwise to a solution of 2.36 g of [2,3-dichloro-4-(1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid in a mixture of 50 ml of acetic acid and 20 ml of dimethylformamide, and the mixture is stirred at room temperature for 30 minutes. A solution of 2.0 g of sodium thiosulfate in 5 ml of water is added to the reaction mixture to decompose excess sodium hypochloride, and the mixture is evaporated to remove solvent. The residue (oil) is dissolved in water, and the solution is adjusted to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is crystallized from a mixture of ethyl acetate and hexane to give 2.19 g of [2,3-dichloro-4-(4-chloro-1-ethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid.