Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42]O)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:20]([O:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:33]([CH3:35])([CH3:36])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](OCCSCCO)(c1ccccc1)c1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCSCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 94.9 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (900 mg, 2.97 mmol) obtained in Example 5 and 2-[2-(t-butyldiphenylsilyloxy)ethylthio]ethanol (1.64 g, 4.55 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (1.26 g, 5.22 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 9 hours. After the reaction mixture was allowed to cool down, 2-[2-(t-butyldiphenylsilyloxy)ethylthio]ethanol (500 mg, 1.39 mmol) and cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) were added thereto. Under an argon atmosphere, the mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, it was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=10:1 eluate was concentrated under reduced pressure, whereby the title compound (1.82 g, 2.82 mmol, 95%) was obtained as a pale yellowish brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[O:27]1CC(O)O[CH2:29][CH:28]1O.ClCCCl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCOC(C)=O.O.CO>[CH3:1][C:2]1([CH3:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][N:17]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:29][CH2:28][OH:27])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: OC1COC(O)CO1
Reactant: Cc1nc(CNC2CCOCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CO
Product: Cc1nc(CN(CCO)C2CCOCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a mixture of N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}tetrahydro-2H-pyran-4-amine (100 mg), 1,4-dioxane-2,5-diol (64 mg), DCE (2 mL), and MeOH (1 mL) was added NaBH(OAc)3 (170 mg) under ice-cooling, followed by stirring at 0° C. for 1 hour. To the reaction mixture were added water and EtOAc, followed by extraction with EtOAc. The organic layer was washed with brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain 2-[{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}(tetrahydro-2H-pyran-4-yl)amino]ethanol (51 mg).
Reaction SMILES: O.[ClH:2].C(N1CCOC(C2C=CC(F)=C(F)C=2)(CCN2CCC(NC(N(C)C)=O)(C3C=CC=CC=3)CC2)C1)(=[O:10])C1C=CC=CC=1.[C:45]([N:53]1[CH2:58][CH2:57][O:56][C:55]([CH2:67][CH2:68]N2CCC(C3C=CC=CC=3)(NC(N(C)C)=O)CC2)([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[C:61]([F:66])[CH:60]=2)[CH2:54]1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:99][O:100][C:101]([NH:103][C:104]1([C:110]2[CH:115]=[CH:114][CH:113]=[CH:112][CH:111]=2)[CH2:109][CH2:108][NH:107][CH2:106][CH2:105]1)=[O:102].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:10].[ClH:2].[C:45]([N:53]1[CH2:58][CH2:57][O:56][C:55]([C:59]2[CH:64]=[CH:63][C:62]([F:65])=[C:61]([F:66])[CH:60]=2)([CH2:67][CH2:68][N:107]2[CH2:106][CH2:105][C:104]([NH:103][C:101]([O:100][CH3:99])=[O:102])([C:110]3[CH:115]=[CH:114][CH:113]=[CH:112][CH:111]=3)[CH2:109][CH2:108]2)[CH2:54]1)(=[O:52])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: COC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CN(C)C(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: COC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Temperature: 90 °C
Yield: 134.2 %

Procedure:
A mixture of 1.2 g of the compound obtained in step C of EXAMPLE 37, 1.3 g of 4-(methoxycarbonylamino)-4-phenylpiperidine p-toluenesulfonate and 1.2 g of K2CO3 in 3 ml of DMF is heated at 80-100° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and the precipitate formed is wrung and dried under vacuum. The precipitate is chromatographed on silica H using a DCM/MeOH mixture (from 100/1.5; v/v to 100/3; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of hydrochloric acid in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.8 g of the expected product. M.p.=170° C.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ncnc(O)c1C
Product: CCOC(=O)c1ncnc(Cl)c1C
Temperature: 100 °C

Procedure:
A solution of ethyl 6-hydroxy-5-methylpyrimidine-4-carboxylate 40 (100 g, 549 mmol) in POCl3 (1000 ml) was heated to reflux for 5 h at 100° C. in sealed tube. After cooling to RT, the excess POCl3 was removed under reduced pressure, then quenched with ice water and extracted with EtOAc. The combined organic phase is washed with water, brine and concentrated under reduced pressure to afford ethyl 6-chloro-5-methylpyrimidine-4-carboxylate 41 as a black liquid. Yield: 80 (72%). This material was used as such for next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH2:16])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>C(Cl)Cl>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH:16][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: NC1CC2CCC(C1)N2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(=O)NC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of amine 100 (2.70 g, 12.48 mmol) in CH2Cl2 (13 mL), was added 1M Na2CO3 (19 mL, 18.72 mmol, 1.5 equiv). The mixture was cooled to 0° C. and isobutyryl chloride (1.6 mL, 14.98 mmol, 1.2 equiv) was added dropwise with stirring over 30 min. The resulting mixture was warmed to room temperature and allowed to stir for 2 h after which time the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with 1N NaOH (2×20 mL), then with H2O (2×20 mL), then dried over MgSO4, filtered, and concentrated in vacuo to yield amide 101 (3.3 g, 93%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]=1.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:10]([CH2:9][N:1]1[CH:2]=[CH:3][C:4](=[O:7])[CH:5]=[CH:6]1)=[O:11])[CH3:14]
Reactant: O=C1C=CN=CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(=O)cc1

Procedure:
14.25 g of 4-pyridone was dissolved in 250 ml of DMF, and 25 ml of ethyl bromoacetate and 31.1 g of potassium carbonate were added thereto and reacted for 2.5 hours at 60° C. After the reaction, the insoluble part was filtrated out, and the remaining filtrate solution was concentrated. The formed residue was purified with silicagel-column chromatography (chloroform/methanol=10/1-5/1), to obtain 22.8 g of 1-ethoxycarbonylmethyl-4-pyridone. This was dissolved in 400 ml of dimethoxyethane and 30 g of Lawesson's reagent was added thereto and reacted for 30 minutes, while heated under reflux. After the reaction, the reaction solution was concentrated, and the residue formed was purified with silicagel-column chromatography (chloroform/methanol=20/1) and then crystallized with dichloromethane/ether, to obtain 13.6 g of 1-ethoxycarbonylmethyl-4-thiopyridone.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]=1.[CH2:18]([N:20]([CH2:32][CH3:33])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)=[O:22])[CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH2:32]([N:20]([CH2:18][CH3:19])[C:21](=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]=1)[CH3:33]
Reactant: COc1ccc(Cl)nc1
Reactant: CCN(CC)C(=O)c1ccccc1B(O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccccc1-c1ccc(OC)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
Under an argon atmosphere, a mixture of tripotassium phosphate (6.24 g) and water (15 ml) was added to a mixture of 2-chloro-5-methoxy-pyridine (2.05 g), 2-(diethylcarbamoyl)benzeneboronic acid (4.65 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (0.584 g) and toluene (30 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, water (20 ml), citric acid (2.2 g) and ethyl acetate were added and the mixture was stirred and filtered through celite. The filtrate was partitioned in a separatory funnel. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/2) to give a roughly purified product (1.144 g) of the title compound. This product was directly used for the next reaction without further purification.
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:26])([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SCC(N1CC(O)(CC2C=CC=CC=2)C[C@H]1C(O)=O)=O)(=O)C>>[OH:26][C:17]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccccc2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)SCC(=O)N1CC(O)(Cc2ccccc2)C[C@H]1C(=O)O
Product: O=C(O)[C@@H]1CC(O)(Cc2ccccc2)CN1

Procedure:
The N-carbobenzyloxy-4-hydroxy-4-(phenylmethyl)-L-proline from part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-hydroxy-4-(phenylmethyl)-L-proline. This amino acid is then reacted with 2-acetylthioacetyl chloride according to the procedure of Example 1 (c) to yield 1-[2-(acetylthio)-1-oxoethyl]-4-hydroxy-4-(phenylmethyl)-L-proline.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH2:16][C:15](=[O:17])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[NH2:2].P(Cl)(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.C[O-].[Li+].[Li].FC(F)(F)[C:40](O)=[O:41]>O1CCCC1.CO>[CH3:40][O:41][C@H:16]1[C:15](=[O:17])[N:10]2[C:11]([C:12]([OH:14])=[O:13])=[C:6]([CH2:5][O:4][C:1](=[O:3])[NH2:2])[CH2:7][S:8][C@H:9]12
Reactant: NC(=O)OCC1=C(C(=O)[O-])N2C(=O)C[C@H]2SC1
Reactant: O=C(O)C(F)(F)F
Agent: C[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Li+]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Solvent: C1CCOC1
Product: CO[C@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Benzhydryl 7-(1',2'-dichloro-2'-α-thienylethylidenimino)-3-carbamoyloxymethyl-3-cephem-4-carboxylate was prepared from benzhydryl 7β-)α-thienylchloroacetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylate(597 mg), phosphorus pentachloride(220 mg) and quinoline(0.15 ml) according to the same procedure as in Example 23 - (1) and dissolved in tetrahydrofuran(40 ml). To the solution was added a methanol solution of lithium methoxide prepared from lithium(12 mg) and methanol(4 ml) at -70°C. The reaction mixture was stirred at -70°C. for 30 minutes. After the addition of trifluoroacetic acid (5 ml) the solution was stirred at room temperature for 40 minutes. The solution was evaporated under reduced pressure to dryness and the residue was extracted with ethyl acetate, which was re-extracted with a pH 7.5 buffer (disodium hydrogen phosphate-potassium dihydrogen phosphate). The aqueous extracts were acidified to pH 2.0 with diluted hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and evaporated to give 60 mg of 7β-)α-thienylacetamido)-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. IR νmaxNujol cm-1 : 3420, 3330, 3230, 1783, 1715, 1680, 1665. NMR(CD3CN) δ ppm: 3.53(3H, singlet), 3.38(1H, doublet, J=18 Hz), 3.60(1H, doublet, J=18 Hz), 3.90(2H, singlet), 4.88(2H, singlet), 5.07(1H, singlet), 6.95-7.40(3H, multiplet).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7]1.[C:19](=[O:21])=[O:20]>C1COCC1.C(OCC)C.O>[C:14]([O:13][C:12]([NH:11][C:8]1[CH:9]=[CH:10][O:6][C:7]=1[C:19]([OH:21])=[O:20])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccoc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccoc1C(=O)O
Temperature: -40 °C
Reaction time: 4 h

Procedure:
Butyl lithium (as 1.6 M in hexanes, 45 mL) was added slowly to a solution of tert-butyl 3-furylcarbamate (Intermediate 80) (5.49 g) in THF (60 mL) at −40° C., keeping the internal reaction temperature less than −35° C. The reaction was stirred at −40° C. for 4 hours, then poured onto solid CO2 (100 mL) under a blanket of diethyl ether (300 mL). After warming to ambient temperature, the mixture was poured into water (300 mL) with stirring and an additional 100 mL diethyl ether added. The phases were separated and the organic phase was further extracted into water (2×100 mL). The combined organic phases were washed with ether, acidified by addition of aqueous HCl, and extracted into EtOAc (4×250 mL). The combined extracts were dried and evaporated to give a pale yellow solid (7.5 g). This was triturated with cyclohexane to afford the title compound as a white solid (4.80 g, 70%);
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])=[CH:15][CH:14]=1.[O:28]([C@H:36]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:37][CH:38]=[O:39])[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].S([O-])(O)(=O)=O.[K+]>C1COCC1.CCCCCC>[CH2:19]([O:20][C:21]([NH:23][CH:24]([CH:38]([OH:39])[CH2:37][C@H:36]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:25]([OH:27])=[O:26])=[O:22])[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCC[C@H](CC=O)O[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@H](CC(O)C(NC(=O)OCc1ccccc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: -75 °C
Yield: 47.9 %

Procedure:
A solution of 3.0 ml of diisopropylamine in 50 ml of THF was treated at 0° C. with 12.0 ml of a solution of 1.6M n-butyllithium in hexane and, after stirring, cooled to -75° C. A solution of 1.26 g of Z-glycine in 10 ml of THF was then added dropwise. The reaction mixture was left to warm to room temperature and again cooled to -75° C. 0.7 g of (R)-3-(t-butyldimethylsiloxy)tetradecanal in 5 ml of THF was then added dropwise at -75° C. The reaction mixture was stirred at -75° C. for 1 hour and at -40° to -50° C. for 1/2 hour, then warmed to 5° C., again cooled to -75° C., poured into dilute potassium hydrogen sulphate solution and extracted with ether. The ether phase was dried, concentrated and chromatographed on silica gel with methylene chloride/methanol. There were obtained 540 mg of (2R/S,3R/S,5R)-2-[1-(benzyloxy)formamido]-5-(t-butyldimethylsiloxy)-3-hydroxyhexadecanoic acid as a mixture of 4 diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@:9]([C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=2)(O)[C@@H:8]([OH:25])[CH2:7]1)=[O:5])[CH3:2]>CCO.[Ni]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[C@@H:8]([OH:25])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@](O)(c2cccc(-c3ccccc3)c2)[C@@H](O)C1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)N1CC[C@H](c2cccc(-c3ccccc3)c2)[C@@H](O)C1
Temperature: 25 °C

Procedure:
To a vigorously stirred solution of the title B compound, (3S,4S)-4-biphenyl-3-yl-3,4-dihydroxy-piperidine-1-carboxylic acid ethyl ester (4.2 g, 12.05 mmol) in EtOH (250 mL) is added 6.5 g Raney-Nickel. The stirred suspension is heated to reflux for 4 h, then allowed to cool to room temperature, filtered over a celite pad and rinsed with EtOH. The solvent is removed under reduced pressure and purification by flash column chromatography (hexane/EtOAc 4/1 to ½) affords the desired product: (3R,4R)-4-Biphenyl-3-yl-3-hydroxy-piperidine-1-carboxylic acid ethyl ester. TLC, Rf (Hexane/EtOAc 2/1)=0.65. MS 326.1 [M+H]. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 5.62 min.
Reaction SMILES: ClC1C=CC=CC=1[C:8]1[S:9][C:10](C2C=CC(SC)=CC=2)=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:12]=1.C(O)C.OOS([O-])=O.[K+]>O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[CH:8][S:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccc(C)cc2)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cscn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 225.9 %

Procedure:
A 100 mL one-neck round-bottom flask, equipped with provisions for magnetic stirring, was charged with 2-(2-chlorophenyl)-4-(4-methylphenyl)-5-(4-methylthiophenyl)thiazole from Step 4 (0.243 g, 0.596 mmol) and aqueous ethanol (25 mL). Oxone®(1.10 g, 1.787 mmol) was added, and the suspension was stirred at room temperature for 16 hours. Water (25 mL) was added, and the product precipitated. The suspension was cooled to 0° C. and held for one hour. The product was filtered, washed with water (25 mL), and dried to yield 2-(2-chlorophenyl)-5-methylsulfonylphenyl)-4-(4-methylphenyl)thiazole (0.236 g, 90%) as a white solid: mp 185°-187 ° C. 1H NMR (CDCl3) 300 MHz 8.40(m, 1H), 7.89(d, J=8.26 Hz, 2H), 7.61 (d, J=8.46 Hz, 2H), 7.54-7.37 (m, 5H), 7.16 (d, J=7.85 Hz, 2H), 3.09(s, 3H), 2.38(s, 3H). Mass spectrum: MH+ =439.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4c(C)cccc4C)CC3)nc2c1
Yield: 87 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 2.33-2.36 (m, 6H), 3.14-3.22 (m, 4H), 3.70-3.90 (m, 6H), 4.09-4.15 (m, 4H), 6.67-7.32 (m, 6H), 7.50-7.65 (m, 1H).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[C:12]#[N:13])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:6]1[CH:7]=[C:8]([CH:11]([CH3:14])[C:12]#[N:13])[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: COc1ccc(C(C)C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(C)C#N)cc1Br
Reaction time: 0.5 h

Procedure:
Bromine (21.4 ml) is added dropwise over a period of 1 hour to a stirred solution of 4-methoxyphenylpropionitrile (67.5 g) and sodium acetate (68.4 g) in glacial acetic acid (40 ml). The reaction mixture is stirred for an additional 30 minutes and partitioned between water and ether. The ether layer is washed with sodium carbonate solution, 10% aqueous NaOH, saturated salt, dried over Na2SO4 and filtered. The filtrate is evaporated in vacuo yielding the desired product, B.P. 155°-158° C. (4 mm).
Reaction SMILES: O[CH:2]([C:10]1[C:19]([O:20][CH3:21])=[CH:18][C:17]2[C:16]([CH3:23])([CH3:22])[CH2:15][CH2:14][C:13]([CH3:25])([CH3:24])[C:12]=2[CH:11]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[O:9])[O:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][O:20][C:19]1[C:10]([CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[O:9])[O:6][CH:7]=2)=[CH:11][C:12]2[C:13]([CH3:25])([CH3:24])[CH2:14][CH2:15][C:16]([CH3:22])([CH3:23])[C:17]=2[CH:18]=1
Reactant: COc1cc2c(cc1C(O)c1coc(C=O)c1)C(C)(C)CCC2(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Cc1coc(C=O)c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution containing 4-[hydroxy(3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furaldehyde (2.9 g, 8.5 mmol), triethylsilane (2.9 g, 25.4 mmol) and anhydrous methylene chloride (40 mL) was cooled to 0° C. To this mixture was added trifluoroacetic acid (˜1.0 mL, 8.5 mmol) and the reaction was allowed to stir at RT for 16 hours. The reaction was quenched with saturated NaHCO3 and the organics were separated and dried over MgSO4. The resulting oil (2.5 g) was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:17][CH2:18][C:19]([NH2:21])=[O:20])=[N:5][C:6](S(C(F)(F)F)(=O)=O)=[CH:7][C:8]=1[CH3:9])#[N:2].C(OC)(=O)C#CC.[CH3:29][NH:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:4](=[N:5][C:6]([N:30]([CH3:31])[CH3:29])=[CH:7][C:8]=2[CH3:9])[S:17][C:18]=1[C:19]([NH2:21])=[O:20]
Reactant: Cc1cc(S(=O)(=O)C(F)(F)F)nc(SCC(N)=O)c1C#N
Reactant: CNC
Agent: CC#CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1cc(N(C)C)nc2sc(C(N)=O)c(N)c12
Temperature: 80 °C
Yield: 25 %

Procedure:
2-(3-Cyano-4-methyl-6-trifluoromethanesulfonylpyridin-2-ylmercapto)acetamide (30.0 mg, 0.08 mmol) (prepared as described in Example 1 for the n-propyl analog but using methyl 2-butynoate) and dimethylamine (170.0 microL, 0.34 mmol) were mixed in 1,4-dioxane (0.5 mL) in a pressure tube and heated at 80° C. for 1 h. 2.0 M Aqueous sodium carbonate (520 □L, 1.04 mmol) was added, and the reaction heated at 100° C. for 6 h, then cooled to room temperature overnight. The mixture was poured into saturated aqueous ammonium chloride, and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford 23.0 mg of the crude product. This was purified via automated flash silica chromatography (4 g silica gel column, 30-100% EtOAc/hexanes) to afford 9.0 mg (0.02 mmol, 45% yield) of the title compound.