Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([CH2:27][CH3:28])[CH2:19][C:20]([O:22][C:23](C)(C)C)=[O:21])=O)(C)(C)C.Cl.CO>>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([CH2:27][CH3:28])[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: CCC(CC(=O)OC(C)(C)C)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: Cl
Solvent: CO
Product: CCC(CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of Step F (120 mg, 0.24 mmol) and 4 N HCl/MeOH (2 mL) was stirred at room temperature for 2 h. The volatile was removed in vacuo to give the title compound as colorless oil. LC/MS m/z=357.1[M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][N:6]=1)=[O:4].BrC1C(C(O)=S)=NC(C)=NC=1>[Ni]>[N:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccncn1
Agent: [Ni]
Agent: Cc1ncc(Br)c(C(O)=S)n1
Product: O=C(O)c1ccncn1

Procedure:
While J. Org. Chem., 30, 2398 (1965) describes that methylpyrimidine-4-carboxylate can be synthesized by treating 5-bromo-2-methylthiopyrimidine-4-carboxylic acid with Raney-nickel, as described in J. Chem. Soc., 1953, 3129, to give pyrimidine-4-carboxylic acid, and heating the obtained compound in methanol in the presence of concentrated hydrochloric acid. This method is problematic in the availability of the starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Yield: 96.3 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and morpholine (1.89 g, 22 mmol) to give the title compound (5.9 g, 98%) as a white solid. MS (ISP) 306.1 [(M+H)+].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([NH:30][C@H:31]([C:33](O)=[O:34])[CH3:32])(OCC1C=CC=CC=1)=O.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[NH2:44][C@H:45]([C:51]([OH:53])=[O:52])[CH2:46][CH2:47][C:48](=[O:50])[NH2:49].[OH-].[K+].S(=O)(=O)(O)O>ClCCl.O.O1CCCC1>[NH2:30][C@H:31]([C:33]([NH:44][C@H:45]([C:51]([OH:53])=[O:52])[CH2:46][CH2:47][C:48](=[O:50])[NH2:49])=[O:34])[CH3:32]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Dissolve 15 mmol of triphenylphosphine with 10 ml of tetrahydrofuran, drop it into a mixed system composed of 10 mmol of carbobenzoxy-alanine (Z-Ala), 20 mmol of hexachloroethane and 10 ml of tetrahydrofuran. After reacting at 0° C. for 1.5 hours, drop it into a liquid mixture containing 18 mmol of glutamine, 20 ml of water and 40 ml of dichloromethane. While reacting, regulate pH to 13 with potassium hydroxide, the reaction temperature is 0° C., the reaction time after dropping is 2 hours. And then acidify it to regulate pH=2.0 with dilute sulfuric acid. The aqueous phase, after concentrated, reacts with hydrogen in methanol at room temperature for 15 hours. The product L-Ala-L-Gln with a yield of 65% is obtained.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].I[CH2:14][CH3:15].O>CCO>[CH2:14]([S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)[CH3:15]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])cc1
Yield: 59.7 %

Procedure:
To a solution of NaOH (0.13 g, 3.2 mmol) in EtOH (10 mL) was added 4-nitrothiophenol (0.50 g, 3.2 mmol) and iodoethane (0.26 mL, 3.2 mmol). After stirring 2h the reaction mixture was added to water (30 mL) and extracted with Et2O (3×25 mL). The combined extracts were washed with satd NH4Cl (3×25 mL) and brine, dried (MgSO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex 0:100 to 30:70) to yield 1-ethylthio-4-nitrobenzene (0.35 g, 59%) as a yellow crystalline solid. 1H-NMR (CDCl3) δ 8.13 (2H, d, J=8.8), 7.32 (2H, d, J=8.8), 3.06 (2H, q, J=7.3), 1.41 (3H, t, J=7.3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][S:32]1(=[O:38])=[O:37]>>[O:37]=[S:32]1(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][N:31]1[C:26]1[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: O=S1(=O)CCCCN1c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3N3CCCCS3(=O)=O)cc2F)cn1

Procedure:
Title compound was prepared using conditions analogous to those described in Example 1 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-(2-bromophenyl)-1,2-thiazinane 1,1-dioxide. MS (ESI): mass calcd. for C20H19FN4O2S, 398.12; m/z found, 399.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.48-8.43 (m, 1H), 8.38-8.33 (m, 1H), 8.08-8.02 (m, 1H), 7.62 (m, 1H), 7.45-7.39 (m, 4H), 7.34 (dd, J=12.5, 1.7, 1H), 3.76-3.65 (m, 2H), 3.24-3.10 (m, 2H), 3.00-2.89 (m, 2H), 2.35-2.23 (m, 2H), 2.22-2.10 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH:11]2[CH2:13][CH2:12]2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Br)nc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(Br)nc1

Procedure:
6-bromo-N-cyclopropylnicotinamide was prepared from 6-bromonicotinoyl chloride and cyclopropylamine.
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([F:19])=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:4])=[O:3].[CH3:20][NH:21][CH3:22]>C(Cl)Cl>[CH3:20][N:21]([CH3:22])[S:2]([C:5]1[C:6]([F:19])=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:4])=[O:3]
Reactant: CNC
Reactant: CCOC(=O)c1cc(S(=O)(=O)Cl)c(F)cc1OCC
Solvent: ClCCl
Product: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(F)cc1OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Ethyl 5-chlorosulfonyl-2-ethoxy-4-fluorobenzoate (1.5 g, 4.84 mmol; prepared as described in example 2) was taken up in 36 mL of anhydrous methylene chloride and cooled to 0° C. Dimethylamine (7.3 mL, 14.5 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20-40% ethyl acetate in hexanes) gave ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate as a white solid (1.02 g, 68%). LC-MS: 320.2 [(M+H)+].
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1>[Br:25][C:26]1[O:30][C:29]([CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:27]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)o1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(Br)o1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
4.58 g (13.7 mmol, 1.2 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 2.0 g (11.4 mmol, 1.0 eq) of 5-bromofuran-2-carbaldehyde in 15 mL of toluene. The reaction mixture is stirred for 1 hour at 80° C. The reaction is stopped by adding 20 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (80/20 heptane/ethyl acetate). 2.0 g of methyl 3-(5-bromofuran-2-yl)acrylate are obtained. Yield=77%.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([CH2:13][SH:14])[C@H:11]([C:15](O)=[O:16])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[O:16])[C@@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1[C@H](CS)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1SC[C@H]2[C@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
In 160 ml of chloroform was dissolved 20 g of (4R,5R)-1,3-dibenzyl-2-oxo-5-(mercaptomethyl)imidazolidin-4-carboxylic acid, 6.2 g of pyridine was added to the solution, and under ice-cooling, 40 ml of a chloroform solution containing 12.7 g of dicyclohexylcarbodiimide was added to the mixture at 15° C. or lower. The mixture was stirred at room temperature for 1 hour, ethyl acetate was added to the reaction mixture and the resulting mixture was filtered. The filtrate was washed successively with 2M hydrochloric acid, water, a saturated sodium bicarbonate solution, and saturated brine. The organic layer was dried and then concentrated. The residue was recrystallized from ethyl acetate to give 8.0 g of (3aR,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16]O)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:16][N:29]4[C:25](=[O:35])[C:26]5=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]5[C:28]4=[O:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: OCCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Reactant: O=C1NC(=O)c2ccccc21
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1CCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 2, 8-fluoro-1-(2-hydroxyethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dioxane is treated with phthalimide, triphenylphosphine and subsequently with dimethyl azodicarboxylate to give 8-fluoro-1-(2-phthalimidoethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Si:7]([O:14][CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:18]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C(=O)(O)[O-].[Na+]>C(OCC)C>[Si:7]([O:14][CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:18]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(CCC(=O)O)c2ccccc21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCn1cc(CCCO)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
To a solution of lithium aluminium hydride (0.44 g, 0.011 mol) in diethyl ether (10 mL) was added dropwise at 0° C. solution of 3-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-indol-3-yl]propanoic acid (Intermediate 40; 2 g, 0.011 mol) in ethyl ether (10 mL). The reaction mixture was stirred at room temperature for 45 minutes. Saturated sodium bicarbonate was added into the mixture at 0° C. The organic phase was extracted and the solvent was removed under reduced pressure giving the title compound (3.2 g, 83%), which was used in the next step without further purification.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([F:19])[F:18])=[C:13]([F:20])[CH:12]=2)[O:4][C:3]1=[O:26].[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([SH:38])[N:37]=[C:30]2[N:29]=1.C(N(CC)CC)C>CN(C=O)C>[CH:21]1([C:5]2([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]([F:19])[F:18])=[C:13]([F:20])[CH:12]=3)[O:4][C:3](=[O:26])[C:2]([S:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: O=C1CC(CCc2ccc(C(F)F)c(F)c2)(C2CCCC2)OC(=O)C1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)n2nc(SC3=C(O)CC(CCc4ccc(C(F)F)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Temperature: 55 °C
Yield: 67.9 %

Procedure:
A mixture of 3-chloro-6-cyclopentyl-6-{-[4-(difluoromethyl)-3-fluorophenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (200 mg, 0.514 mmol), from Step 1, below, and 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol (93 mg, 0.514 mmol) in DMF (4 mL) was treated with triethylamine (52 mg, 0.514 mmol, 1 equiv). The mixture stirred and heated at 55° C. for 4 h. The reaction was cooled to room temperature, and the DMF removed in vacuo. Water and ethyl acetate were added to the resinous material, resulting in the precipitation of a solid. This was filtered, washed with ether, and allowed to air dry, affording 186 mg (68%) of the title product. 1H NMR (DMF-d7) δ 1.81-2.00 (m, 8H) 2.56-2.62 (m, 2H) 2.71 (s, 3H) 2.76 (s, 3H) 2.80 (m, 1H) 3.07(m, 2H) 3.14 (d, J=6 Hz, 1H) 3.32 (d, J=18 Hz, 1H) 7.40 (t, J=57 Hz, 1H), 7.24 (s, 1H) 7.66 (m, 2H) 7.84 (m, 1H,). MS (APCI) calcd for C26H27F3O3S: 532.58; MS found; (M+H+) 533.1. Anal. Calc'd for C26H27F3O3S: C, 58.64; H, 5.11; N, 10.52; S, 6.02. Found: C, 58.26, 58.33; H, 5.25, 5.14; N, 10.69, 10.61; S, 5.78, 5.79.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[C:11]([CH3:13])([CH3:12])[C@@H:8]([CH2:9][CH2:10]1)[CH:7]=[C:6]2[C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22](C)([CH2:24][CH2:25][CH2:26][CH2:27]CC)C)=[CH:16][C:15]=1[O:31][CH3:32])=[O:4].COC1C=C(CCCCC)C=C(OC)C=1B1OC(C)(C)C(C)(C)O1.COC([C@@]12C(C)(C)[C@@H](CC1)C=C2OS(C(F)(F)F)(=O)=O)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C@@:5]12[C:11]([CH3:12])([CH3:13])[C@@H:8]([CH2:9][CH2:10]1)[CH:7]=[C:6]2[C:14]1[C:15]([O:31][CH3:32])=[CH:16][C:17]([CH2:22][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:18][C:19]=1[O:20][CH3:21])=[O:4]
Reactant: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCc1cc(OC)c(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: COC(=O)[C@@]12CC[C@@H](C=C1OS(=O)(=O)C(F)(F)F)C2(C)C
Product: CCCCCc1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1

Procedure:
The title compound was prepared by the general procedure described for compound 11a (HU-911), using pinacol arylboronate 4 (mixed with 2) 0.244 g, enol triflate 9a 0.2 g (0.61 mmol), Pd(PPh3)4 0.042 g (0.037 mmol) and t-BuNF 0.91 ml (0.91 mmol, 1M solution in THF) to give colorless oil 170 mg (72%). 1H NMR (300 MHz, CDCl3) δ ppm 6.33 (s, 2H), 6.26 (d, J=3.42 Hz, 1H), 3.71 (s, 6H), 3.47 (s, 3H), 2.55 (t, J=7.70 Hz, 2H), 2.38-2.46 (m, 2H), 1.81-2.03 (m, 2H), 1.56-1.66 (m, 2H), 1.30-1.35 (m, 4H), 1.12 (s, 3H, syn), 1.07-1.16 (m, 1H), 0.97 (s, 3H, anti), 0.90 (t, J=6.84 Hz, 3H). Exact mass calculated for C24H34O4 by the general procedure described for compo4O4: C, 74.58; H, 8.87. Found: C, 74.61; H, 9.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:36][O:37][NH3+:38].[Cl-].Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:38][O:37][CH3:36])=[O:19])=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CO[NH3+]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CONC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a suspension of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol), which had been obtained in Example 338, in dichloromethane (6 ml) were added N-methylmorpholine (77.7 μl, 0.708 mmol), o-methylhydroxylamine hydrochloride (23.6 mg, 0.283 mzmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.3 mg, 0.283 mmol). After stirring at room temperature for 1 hour, tetrahydrofuran (1 ml) was added to the mixture. The reaction mixture was stirred at room temperature for 18 hours. The mixture was then diluted with dichloromethane, and washed with water and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and a fraction obtained from the elution portion with hexane:ethyl acetate=1:1 was concentrated, whereby a white solid was obtained. The solid was washed with ethyl acetate, whereby the title compound (55.1 mg, 0.122 mmol, 52%) was obtained as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14](=[O:17])([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:5][C@@H:6]2[CH2:12][CH2:14][O:17][CH2:7]2)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: O=C([O-])[O-]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Agent: [K+]
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CN[C@@H]1CCOC1
Reaction time: 8 h

Procedure:
To a stirred solution of Example 8D (0.03 g, 0.153 mmol) and potassium carbonate (0.2 g, 1.53 mmol) in acetonitrile (2 mL), at room temperature under nitrogen was added R(+)-3-aminotetrahydrofuran toluene-4-sulfonate (0.08 g, 0.32 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 248 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2 (2H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m), 5.43-5.9 (4H, m).
Reaction SMILES: C(O)=O.O1CCCC1.O.[CH3:10][O:11][N:12]=[C:13]([C:40]1([O:45][CH2:44][CH2:43][O:42]1)[CH3:41])[C:14]([NH:16][CH:17]1[C:38](=[O:39])[N:19]2[C:20]([C:35]([OH:37])=[O:36])=[C:21]([CH2:24]SC3SC4C=CC=CC=4N=3)[CH2:22][S:23][C@H:18]12)=[O:15]>CN(C)C=O.[Zn]>[CH3:10][O:11][N:12]=[C:13]([C:40]1([O:45][CH2:44][CH2:43][O:42]1)[CH3:41])[C:14]([NH:16][CH:17]1[C:38](=[O:39])[N:19]2[CH:20]([C:35]([OH:37])=[O:36])[C:21](=[CH2:24])[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12)C1(C)OCCO1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=CO
Product: C=C1CS[C@@H]2C(NC(=O)C(=NOC)C3(C)OCCO3)C(=O)N2C1C(=O)O
Reaction time: 1.5 h
Yield: 35.7 %

Procedure:
Formic acid (10 ml.), tetrahydrofuran (40 ml.) and water (10 ml.) were added to a solution of 7-[2-methoxyimino-3,3-ethylenedioxybutyramido]-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2 g.) in N,N-dimethylformamide (10 ml.). Zinc powder (1.4 g.) was added to the stirred mixture at 0° to 2° C., and stirred at the same temperature for 1.5 hours. The reaction mixture was filtered, and the residue was washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated in vacuo. The residue was diluted with water (50 ml.) and extracted with ethyl acetate (150 ml.). The extract was washed with water and extracted with an aqueous solution of sodium bicarbonate. Ethyl acetate (50 ml.) was added to the extract and acidified to pH 2.0 with 6 N hydrochloric acid. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (50 ml.). The ethyl acetate layers were combined, washed with water and saturated aqueous sodium chloride in turn, dried over magnesium sulfate and evaporated in vacuo. n-Hexane was added to the oily residue and the mixture was allowed to stand in a refrigerator overnight, and triturated. The precipitates were collected by filtration to give a mixture (0.5 g.) of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methylenecepham-4-carboxylic acid (syn isomer) and 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methyl-3-cephem-4-carboxylic acid (syn isomer) (5:1).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[CH:30]=[N:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][N:26]=4)[CH:14]=[CH:15][C:16]=3[O:17]CC3C=CC=CC=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br>C(Cl)Cl>[C:1]12([C:11]3[CH:12]=[C:13]([C:25]4[CH:30]=[N:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][N:26]=4)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CCOC(=O)/C=C/c1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)cn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cnc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cn1
Yield: 94.5 %

Procedure:
A solution of ethyl(E)-3-{2-[3-(1-adamantyl)-4-benzyloxyphenyl]-5-pyrazinyl}-2-propenoate (477 mg, 0.96 mmol), 1.0 M boron tribromide (3.86 mmol) in CH2Cl2 (3.86 mL), and CH2Cl2 (13 mL) was stirred at −78° C. under argon for 2 h, quenched with water (50 mL), and extracted with EtOAc (100 mL, 50 mL, and 30 mL). The extracts were washed (brine) and dried. After solvent removal at reduced pressure, the residue was purified on silica gel (20% to 33% EtOAc/hexane) to give 367 mg (94%) of ethyl(E)-3-{2-[3-(1-adamantyl)-4-hydroxyphenyl]-5-pyrazinyl}-2-propenoate as a yellow solid, mp 212-215° C. IR 3352, 2843, 1686 cm−1; 1H NMR (CDCl3) δ 1.35 (t, J=7.3 Hz, 3H, OCH2CH3), 1.79 (bs, 6H, AdCH2), 2.10 (bs, 3H, AdCH), 2.18 (bs, 6H, AdCH2), 4.29 (q, J=7.3 Hz, 2H, OCH2CH3), 5.32 (s, 1H, OH), 6.77 (d, J=8.5 Hz, 1H, 5-ArH), 6.97 (d, J=15.9 Hz, 1H, CH═CHCO), 7.71 (d, J=15.9 Hz, 1H, CH═CHCO), 7.75 (dd, J=8.5 Hz, 2.4 Hz, 1H, 6-ArH), 7.98 (d, J=2.4 Hz, 1H, 2-ArH), 8.62 (d, J=1.2 Hz, 1H, 3-PyrH), 8.97 ppm (d, J=1.2 Hz, 1H, 6-PyrH). HRMS calcd C25H28N2O3 [M+H]+ 405.2173. found 405.2181.