Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Li+].[CH3:3][S:4][C:5]1[CH:28]=[CH:27][C:8](/[CH:9]=[C:10]2/[C:11]([CH3:26])=[C:12]([CH2:22][C:23](Cl)=[O:24])[C:13]3[C:18]/2=[CH:17][CH:16]=[C:15]([N:19]([CH3:21])[CH3:20])[CH:14]=3)=[CH:7][CH:6]=1>C1COCC1>[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[C:10]2/[C:11]([CH3:26])=[C:12]([CH2:22][CH2:23][OH:24])[C:13]3[C:18]/2=[CH:17][CH:16]=[C:15]([N:19]([CH3:20])[CH3:21])[CH:14]=3)=[CH:27][CH:28]=1
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)Cl)c3cc(N(C)C)ccc32)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(CCO)c3cc(N(C)C)ccc32)cc1

Procedure:
Lithium borohydride (1.38 mmol) in THF (2 ml) is added to the suspension of (Z)-1-(4-methylthiobenzylidene)-5-dimethylamino-2-methyl-3-indenylacetyl chloride (2.78 mmol) in THF (20 ml) at 0° C. The reaction is quenched after 5 minutes with HCl (10%, aqueous, 30 ml). Ethyl acetate (50 ml) is added to extract the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(Br)c(C)c1
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: CC(=N[S@](=O)C(C)(C)C)c1ccc(Br)c(C)c1

Procedure:
The title compound was prepared from 1-(4-bromo-3-methyl-phenyl)-ethanone and (R)-2-methyl-2-propanesulfinamide following a procedure analogous to that described in Step 1 of Intermediate 1. Mass spectrum (ESI+): m/z=316/318 (Br) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:26])[CH3:25]>>[CH:24]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: CC(C)N1CCC(N)CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCN(C(C)C)CC2)cn1
Yield: 73 %

Procedure:
As described for example 34, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using N-isopropyl-4-aminopiperidine instead of 1-methylpiperidin-4-amine, to the title compound (110 mg, 73%) which was obtained as a white foam. MS: m/e=435.4 [M+H]+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13]OC2CCCCC2)[C:10]([OH:12])=O)[N:8]=1)=[O:2].CN(C)C=O.P(Cl)(Cl)(Cl)=O.[NH2:31][CH:32]1[C:52](=[O:53])[N:34]2[C:35]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=3)=[O:40])=[CH:36][CH2:37][S:38][C@H:33]12>O.CC(C)=O.O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[C:10]([NH:31][CH:32]2[C:52](=[O:53])[N:34]3[C:35]([C:39]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][CH:48]=4)=[O:40])=[CH:36][CH2:37][S:38][C@H:33]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: O=CNc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CNc1nc(C(=NC2CCCCC2)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Yield: 180.3 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 0.9 g.), N,N-dimethylformamide (266 mg.), phosphoryl chloride (557 mg.), tetrahydrofuran (20 ml.), 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (1.05 g.), acetone (3 ml.) and water (3 ml.) were treated in a similar manner to that of Example 15-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexyliminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.69 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[S]Cl.[C:11](=[S:13])=[S:12]>C(O)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:11]([SH:13])[S:12][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: S=C=S
Agent: [S]Cl
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Sc1nc2ccc(Cl)cc2s1
Temperature: 60 °C

Procedure:
To a stirred solution of 4-chloroaniline (2.55 g) in acetic acid (5 cm3) was added sulphur monochloride (10 cm3) causing formation of a thick red slurry. The reaction was heated at 60° C. for 4 hours giving a mixture of green solid and a green solution. The mixture was diluted with hexane and the green solid was filtered off. The solid was taken into water and 2M NaOH was added and the mixture heated for 4 hours at 100° C. and then filtered through celite to give a pale pink filtrate. Carbon disulphide (2 cm3) was added to the filtrate and the reaction was heated at reflux for 15 hours. The mixture was cooled and acidlied to pH 1 causing formation of a thick yellow precipitate. Filtration and recrystallisation from ethanol/acetone/water gave 6-chloro-2-mercaptobenzthiazole as a white solid. 1H NMR (DMSO): d 7.97 (1H, d), 7.58 (1H, dd), 7.41 (1 H, d). Mp 251°-253° C. (dec).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@H:40]([O:50][C@@H:51]2[O:80][C@H:79]([CH3:81])[C@@H:70]([O:71][CH2:72][C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C@H:61]([O:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C@H:52]2[O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@@H:39]([CH2:82][O:83][CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[O:38][CH:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16]([C:20]([O:22][CH2:23]C3C=CC=CC=3)=[O:21])[O:17][CH2:18]2)[CH2:14][C@H:13]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[O-].[Na+].C(OCC)C>CO>[CH2:1]([O:8][C@@H:9]1[C@@H:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@H:40]([O:50][C@@H:51]2[O:80][C@H:79]([CH3:81])[C@@H:70]([O:71][CH2:72][C:73]3[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=3)[C@H:61]([O:62][CH2:63][C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C@H:52]2[O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@@H:39]([CH2:82][O:83][CH2:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[O:38][C@@H:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16]([C:20]([O:22][CH3:23])=[O:21])[O:17][CH2:18]2)[CH2:14][C@H:13]1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)C(O[C@@H]3[C@H]4CON(C(=O)OCc5ccccc5)[C@H]4C[C@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)N1OC[C@@H]2[C@@H](O[C@H]3O[C@H](COCc4ccccc4)[C@@H](O[C@@H]4O[C@H](C)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@H](OCc3ccccc3)C[C@@H]21
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 36.1 %

Procedure:
The compound (516 mg, 0.42 mmol) synthesized in Example 6 (6i) was dissolved in methanol (6 mL) and toluene (6 mL) and sodium methoxide (221 μL, 1.15 mmol) was added thereto, followed by stirring of the mixture at 50° C. for 40 minutes. After cooling to room temperature, Dowex 50W×8 was added thereto until the reaction mixture became neutral and it was filtered, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:diethyl ether, 1.5:1-1:1, v/v) to obtain the desired title compound (173 mg, yield 47%) as colorless amorphous matter.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4].[CH3:11][C:12](O)([C:15]#[N:16])[CH:13]=[CH2:14].P(=O)(O)(O)O.B(F)(F)F>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[OH:4][C:3]1[C:5]([CH3:10])=[C:6]2[C:7](=[CH:8][C:2]=1[CH3:1])[O:9][C:12]([CH3:11])([C:15]#[N:16])[CH2:13][CH2:14]2
Reactant: Cc1cc(O)cc(C)c1O
Reactant: C=CC(C)(O)C#N
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc2c(c(C)c1O)CCC(C)(C#N)O2
Yield: 79 %

Procedure:
Using the method described in the last paragraph of Example 1, 23.3 g (0.169 mole) of 2,6-dimethylhydroquinone were reacted with 16.6 g (0.169 mole) of methyl vinyl ketone cyanohydrin, stabilized with 1 g of phosphoric acid, in 125 ml of toluene and 17 ml of nitromethane in the presence of 11.5 g (0.169 mole) of BF3. Conventional working up gave 6-hydroxy-2,5,7-trimethyl-2-cyanochromane in the form of colorless crystals, in 79% yield; melting point 135° C.
Reaction SMILES: C[Si](C)(C)[O:3][C@H:4]1[CH2:27][C@@:26]2([CH3:28])[C@@H:15]([CH2:16][CH2:17][C@:18]2([OH:29])[C:19](=[O:25])[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@H:14]2[C@H:5]1[C@:6]1([CH3:31])[C:11]([CH2:12][CH2:13]2)=[CH:10][C:9](=[O:30])[CH:8]=[CH:7]1.[C:34]([O-])(=[O:36])[CH3:35].[Na+].[SiH3]O[SiH3]>C(OC(C)=C)(=O)C>[CH3:23][C:22]([O:21][CH2:20][C:19]([C@:18]1([O:29][C:34]([CH3:35])=[O:36])[C@@:26]2([CH3:28])[CH2:27][C@H:4]([OH:3])[C@@H:5]3[C@:6]4([CH3:31])[C:11](=[CH:10][C:9]([CH:8]=[CH:7]4)=[O:30])[CH2:12][CH2:13][C@H:14]3[C@@H:15]2[CH2:16][CH2:17]1)=[O:25])=[O:24]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O[Si](C)(C)C)C[C@@]21C
Agent: C=C(C)OC(C)=O
Agent: [Na+]
Agent: [SiH3]O[SiH3]
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A mixture of 8 g of 11β -trimethylsiloxy-17α-hydroxy-21-acetoxy-pregna-1,4-diene-3,20 -dione (from Example 29), 8 g of paratoluenesulfonic acid monohydrate and 800 ml of isopropenyl acetate was allowed to stand for one week at room temperature. By this time TLC control indicated that almost all the starting material had reacted. 15 g of anhydrous sodium acetate was added and the mixture left stirring for another day. The supernatant was decanted from the salt crystals and the resulting solution -- after addition of 400 ml methyl-isobutyl ketone -- was washed twice, each time with 500 ml of water, then with 200 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to dryness. This residue was found to be 11β-trimethylsiloxy-17α,21-diacetoxypregna-1,4-diene-3,20-dione, about 90% pure, there was about 10% of a less polar artifact believed to be the result of a slight aromatization side reaction about ring A, followed by acetylation. The identity was proved by hydrolyzing off the silyl ether blocking group to give prednisolone 17,21-diacetate, identified by TLC with a sample obtained by the Ortho ester route.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:9][CH3:10])=[CH:5][C:6]=1[C:7]#[N:8].F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].[H-].[Na+]>O1CCCC1>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]([NH:1][C:2]2[S:3][C:4]([CH2:9][CH3:10])=[CH:5][C:6]=2[C:7]#[N:8])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCc1cc(C#N)c(N)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(C#N)c(Nc2cc(F)ccc2[N+](=O)[O-])s1
Reaction time: 18 h

Procedure:
Dissolve 2-amino-5-ethyl-thiophene-3-carbonitrile (8.2 g, 54 mmol) and 2,4-difluoronitrobenzene (8.6 g, 54 mmol) in tetrahydrofuran (20 ml) and add to a stirring solution of sodium hydride (50% dispersion in mineral oil)(4.1 g, 1.4 equiv) in tetrahydrofuran (50 ml) under a nitrogen atmosphere. Maintain the rate of addition to keep the temperature below 45° C. and gas evolution under control. Stir 18 h. Pour the mixture into a mixture of ice and 2NHCl, extract into ethyl acetate, dry (MgSO4) and concentrate under reduced pressure. Dissolve in ethanol (100 ml) and collect 2-(5-fluoro-2-nitro-phenylamino)-5-ethyl-thiophene-3-carbonitrile by filtration as a yellow solid (7.9 g, 50%): mass spectrum (LCMS) 292 (M+1), 314 (M+Na). NMR (1H, 300 MHz, CDCl3): δ 9.7 (1H broad), 8.25 (1H,m), 6.80 (1H, s), 6.75 (1H,dd), 6.65 (1H, s), 2.80 (2H,q), 1.35(3H,t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH2:16])=O)[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]#[N:16])[C:5]([CH2:11][O:12][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COCc1cc([N+](=O)[O-])c(Cl)cc1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C#N

Procedure:
A sample of 4-chloro-α-methoxy-5-nitro-o-toluamide (0.8 g) is added to phosphorus oxychloride (10 ml) and the slurry gradually heated to reflux. After about 10 minutes at reflux, all the solid has dissolved giving a clear yellow solution. The solution is concentrated in vacuo and the crude residue is portioned between ether and water. The ether layer is separated and dried. Removal of the drying agent and concentration of the filtrate in vacuo leaves a crude solid (0.7 g.) with mp 57°-59°.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[CH2:40]=[C:41]([CH2:44]O)[CH2:42][OH:43].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:40]=[C:41]1[CH2:42][O:43][C:2]2([CH2:7][CH2:6][CH:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]5[NH:32][C:31](=[O:33])[O:30][N:29]=5)=[CH:20][CH:21]=4)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]4[N:37]=[CH:38][N:39]=[C:9]34)[CH2:4][CH2:3]2)[O:1][CH2:44]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: C=C(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C1COC2(CCC(n3c(=O)c(Cc4ccc(-c5ccccc5-c5noc(=O)[nH]5)cc4)c(CCC)n4ncnc34)CC2)OC1
Yield: 19 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.20 g), 2-methylidenepropane-1,3-diol (0.067 g), 4-methylbenzenesulfonic acid (0.0072 g) and toluene (20 mL) was heated under reflux for 1.5 hr using a Dean-Stark trap. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.043 g, 19%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]1[CH:11]=[C:12]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:13]=[C:14]([F:18])[C:15]=1[S:16][CH3:17]>C(O)C.O>[F:9][C:10]1[CH:11]=[C:12]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:2][OH:3])[CH:13]=[C:14]([F:18])[C:15]=1[S:16][CH3:17]
Reactant: NO
Reactant: CSc1c(F)cc(CC(=O)c2ccccc2)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1c(F)cc(CC(=NO)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
Hydroxylamine hydrochloride (5.5 g, 0.079 mol) and sodium acetate (6.5 g, 0.079 mol) were added to a slurry of 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone in ethanol (120 mL) and water (30 mL). The mixture was heated and held at reflux for 1 hour, then cooled and allowed to stir for 18 hours at room temperature. Additional water (50 mL) was added, and the mixture concentrated to half its volume. Dilute HCl was added, and the mixture extracted with dichloromethane (1×100 mL), 3×50 mL). The combined extracts were washed with dilute sodium bicarbonate, dried with magnesium sulfate, and concentrated to give a light yellow oil, that was crystallized from ethyl acetate/hexanes to afford 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone oxime as white solid (6.2 g, 53%). A second crop (2.3 g, 73% net yield) was also collected. 1H NMR (CDCl3/400 MHz) 7.57-7.60 (m, 2H), 7.35-7.37 (m, 3H), 6.80-6.84 (m, 1.7H), 6.75-6.77 (m, 0.3H), 4.14 (s, 1.7H), 3.83 (s, 0.3H), 2.39 (s, 3H). HRMS m/z 244.0773 (M+H+, calcd 244.0764). Anal. Calcd for C15H13F2NOS: C, 61.42; H, 4.47; N, 4.78. Found: C, 61.44; H, 4.50; N, 4.84.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.Cl[C:16](OC(Cl)(Cl)Cl)=[O:17]>C1(C)C=CC=CC=1>[CH3:12][C:8]1([CH3:11])[CH2:7][C:6]2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=[C:2]([N:1]=[C:16]=[O:17])[C:10]=2[O:9]1
Reactant: COc1ccc(N)c2c1CC(C)(C)O2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(N=C=O)c2c1CC(C)(C)O2

Procedure:
By the method of Example 1, Step F, 3.70 g (0.0191 mole) of 7-amino-2,3-dihydro-2,2-dimethyl-4-methoxybenzofuran and 3.79 g (0.0191 mole) of trichloromethyl chloroformate were reacted in 100 mL of toluene, yielding 2,3-dihydro-2,2-dimethyl-4-methoxybenzofuran-7-yl isocyanate as a brownish-yellow, viscous oil. The IR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Br:13])[C:10]([O:14][C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:24])=[CH:17][C:16]=2[CH2:25][CH3:26])=[C:9]([Br:27])[CH:8]=1)=[O:5].[OH-].[Na+].Cl>CC(C)=O>[CH2:25]([C:16]1[CH:17]=[C:18]([OH:24])[C:19]([CH:21]([CH3:22])[CH3:23])=[CH:20][C:15]=1[O:14][C:10]1[C:9]([Br:27])=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]([OH:28])=[O:2])=[CH:12][C:11]=1[Br:13])[CH3:26]
Reactant: CCc1cc(O)c(C(C)C)cc1Oc1c(Br)cc(NC(=O)C(=O)OC)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCc1cc(O)c(C(C)C)cc1Oc1c(Br)cc(NC(=O)C(=O)O)cc1Br
Reaction time: 1 h
Yield: 718.3 %

Procedure:
N-(4-(2-ethyl-4-hydroxy-5-isopropylphenoxy)-3,5-dibromophenyl)oxamic acid methyl ester (50 mg, 0.01 mmol), was dissolved in acetone (2 ml). 1M NaOH (1 ml) was added and the solution was stirred for 1 hour, cooled in an ice bath, acidified with 1M HCl, concentrated, extracted with ethyl acetate, dried over MgSO4, filtered and evaporated to give 36 mg (74%) of N-(4-(2-ethyl-4-hydroxy-5-isopropylphenoxy)-3,5-dibromophenyl)oxamic acid. 1H NMR (CD3COCD3): d 10.24 (s, 1H), 8.33 (s, 2H), 6.77 (s, 1H), 6.12 (s, 1H), 3.16 (m, 1H), 2.74 (q, 2H), 1.27 (t, 3H), 1.04 (d, 6H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.CC(C)([O-])C.[K+]>CC(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([OH:9])[CH2:2]2
Reactant: O=C1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@@H]1CN2CCC1CC2
Temperature: 30 °C
Reaction time: 6 h

Procedure:
To a 100 mL autoclave with a stirrer, 3-quinuclidinone (1.0 g, 8.0 mmol) and trans-RuCl2[(S)-xylbinap][(S)-daiPen] (0.5 mg, 0.40 μmol, 1/20,000 molar fold of 3-quinuclidinone) were added. After the autoclave was purged with nitrogen, 2-propanol (6 mL) and 2-propanol solution of potassium t-butoxide (0.1 mol/L, 0.4 mL, 0.04 mmol) were added. Subsequently, the autoclave was purged with hydrogen, the mixture was stirred at 30° C. for 6 hours under hydrogen pressure of 3 MPa. As a result of analysis of the reaction solution, it was found that the conversion rate is 49.8% and the optical purity is 86.2° Me.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc([N+](=O)[O-])cn2)c1C

Procedure:
5-Nitro-pyridin-2-ylamine (5 mmol, 0.7 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting solid was triturated with chloroform, the filtrate was further purified over silica gel to yield the named product, 1H-NMR (CDCl3, ppm): 1.35 t (3H), 2.54 s (3H), 4.30 q (2H), 6.78 s (1H), 6.96-7.25 bm (6H), 8.33 dd (1H) , 9.39 sd (1H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][C:3]=1[CH3:15].[O:16]=[C:17]([CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:18]>>[CH3:21][C:20]([CH3:22])([CH2:19][C:17](=[O:16])[CH3:18])[CH:8]([C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([F:1])=[C:3]([CH3:15])[CH:4]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)c1ccc(F)c(C)c1
Reactant: CC(=O)C=C(C)C
Product: COC(=O)C(C(=O)c1ccc(F)c(C)c1)C(C)(C)CC(C)=O
Reaction time: 120 h

Procedure:
A mixture of methyl 4-fluoro-3-methylbenzoylacetate (1a) (26.95 g, 0.128 mol) and mesityl oxide (2) (19.3 g, 0.192 mol) was kept at 0°-5° C. for 5 days, poured onto cold saturated NaHC3 and extracted with ether. The combined extracts were washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo furnished 3a which was used without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16]2[N:20]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl>CO>[F:26][C:23]([F:24])([F:25])[CH2:22][CH2:21][N:20]1[C:16]([C:11]2[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:17][CH:18]=[N:19]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccnn1CCC(F)(F)F
Agent: Cl
Solvent: CO
Product: OCc1cccnc1-c1ccnn1CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (1.58 g, 4.1 mmol) in MeOH (20 mL) was added HCl (4 N, 4.0 mL). The mixture was stirred at RT for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, and concentrated to give (2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridin-3-yl)methanol (1.1 g, 99%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.64 (dd, J=4.7, 1.7 Hz, 1H), 8.00 (dd, J=7.9, 1.7 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 4.69 (s, 2H), 4.51-4.43 (m, 2H), 2.85-2.72 (m, 2H), 2.70 (s, 1H). MS (ESD m/z 272.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:31]([C:34]1[CH:35]=[C:36](O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32]>>[C:31]([C:34]1[CH:39]=[C:38]([CH:37]=[CH:36][CH:35]=1)[O:1][CH:2]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:33])[CH3:32]
Reactant: CC(=O)c1cccc(O)c1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2cccc(C(C)=O)c2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-acetylphenol: ESMS m/e: 529.0 (M+H)+.