Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[C:7]([C:9](=[N:11]O)[CH3:10])[CH:6]=[CH:5][N:4]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[O-]CC.[K+].[S-:28][C:29]#[N:30].[K+]>C(O)C.C(OCC)C>[NH2:2][C:3]1[CH:8]=[C:7]([C:9]2[N:11]=[C:29]([SH:28])[NH:30][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: N#C[S-]
Reactant: CC(=NO)c1ccnc(N)c1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: Nc1cc(-c2c[nH]c(S)n2)ccn1
Reaction time: 0.08 h

Procedure:
To 720 mg. (31 mmoles) of sodium dissolved in 60 ml. of absolute ethanol at room temperature was added 4.59 g. (30.4 mmoles) of 1-(2-amino-4-pyridyl)-1-ethanone oxime, and the resulting mixture allowed to stir for about 5 minutes. To the resulting solution was added 6.10 g. (32 mmoles) of p-toluenesulfonyl chloride and the reaction mixture allowed to stir for 1 hour under a nitrogen atmosphere. The mixture was then added directly to a solution of potassium ethoxide (prepared by dissolving 1.41 g. of potassium in 30 ml. of ethanol) in ethanol and the reaction mixture allowed to stir under a nitrogen atmosphere at room temperature for 0.5 hour. The resulting gelatinous suspension was diluted with 800 ml. of diethyl ether, stirred at room temperature for 0.5 hour and filtered through celite. The filtrate was concentrated, and the residue taken up in 100 ml. of ether which was then extracted with 2 N hydrochloric acid (4×25 ml.). The combined acid extracts were concentrated to a yellow solid, which was dissolved in 60 ml. of water containing 5.83 g. (60 mmoles) of potassium thiocyanate. The resulting solution was heated at steam bath temperatures for 2 hours. On cooling a solid precipitated which was filtered and stirred in 40 ml. of a saturated sodium bicarbonate solution for 0.5 hour. The solids were filtered, washed with water and dried in vacuo to give 3.21 g. (55%) of the product as a yellow solid, m.p. 262°-264° C. The analytical sample was recrystallized from water.
Reaction SMILES: [Si:1]([O:8][CH2:9]/[C:10](/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:11](/[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)\[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([NH:37][CH2:38][C:39](O)=[O:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCN=C=NCCCN(C)C.Cl.[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:33]([O:32][C:30]([NH:37][CH2:38][C:39]([O:13][CH2:12]/[C:11](/[C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1)=[C:10](/[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)\[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[O:40])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\CO)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)OC/C(=C(\CO[Si](C)(C)C(C)(C)C)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a solution of 16.4 g of (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methyl-sulfonyl)phenyl]-3-phenylbut-2-en-1-ol, 1.92 g of DMAP and 7.30 g of Boc-Glycine in 125 mL of CH2Cl2 at 0° C. was added 8.0 g of EDCl. The reaction mixture was stirred for 4 h. Then saturated ammonium chloride solution was added and extracted with EtOAc. The organic layer was combined, washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography over silica gel (5–55% EtOAc/hexane) to afford 22 g of the titled compound as a colorless oil. 1H (500 MHz, acetone-d6): δ 7.67 (d, 2H), 7.34 (d, 2H), 7.13–7.04 (m, 5H), 6.26 (br s, NH), 5.23 (s, 2H), 4.76 (s, 2H), 3.73 (d, 2H), 3.02 (s, 3H), 1.40 (s, 9H), 0.81 (s, 9H), −0.01 (s, 6H).
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]3[C:21]([C:24]4[S:25][C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=4)=[N:22][N:23]=[C:17]3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.O.[OH-].[Li+]>O1CCCC1.CO.O>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[C:21]1[N:18]2[CH2:19][CH2:20][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=3)[CH2:16][C:17]2=[N:23][N:22]=1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCn3c(nnc3-c3nc4ccccc4s3)C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nccc(N2CCn3c(nnc3-c3nc4ccccc4s3)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (R)-1-[4-(3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 259, Step D, 220 mg, 0.49 mmol) in a 3:1:1 mixture of tetrahydrofuran/methanol/water (5 mL) was added lithium hydroxide hydrate (62 mg, 1.47 mmol). This mixture was stirred at room temperature for 3 h, concentrated, and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (5% methanol/chloroform) to give 192 mg (100%) of the title compound as a colorless solid. mp: 216.5-218.5° C.; 1H NMR (CDCl3, 300 MHz) δ 8.37 (d, 1H), 8.06 (d, 1H), 7.97 (d, 1H), 7.56-7.45 (c, 2H), 6.56 (d, 1H), 5.11 (s, 2H), 4.83 (t, 2H), 4.77 (m, 1H), 4.35-4.25 (c, 2H), 4.16 (s, 1H), 1.54 (d, 3H); MS (APCI) 380 (MH+), [α]D+14.2 (c 1.0, CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:25][CH2:26]1)(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCC(NC(=O)c3ccccc3)CC2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 31.4 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), N-(piperidin-4-yl)benzamide (0.191 g; 0.937 mmol) and triethyl amine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated at 110° C. in a sealed tube for 5 h. The reaction mixture was diluted with a saturated solution of sodium hydrogen carbonate, extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (15-80%) in heptane furnished 0.049 g (34%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][CH2:18][N:19]1[C:28](=[O:29])[CH2:27][C:22]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]1=[O:30]>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][N:19]2[C:20](=[O:30])[CH2:21][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:27][C:28]2=[O:29])[CH2:14][CH2:15]1
Reactant: Fc1cc(F)c(N2CCNCC2)cc1F
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Solvent: CCOCC
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2cc(F)c(F)cc2F)CC1
Temperature: 160 °C
Reaction time: 7 h

Procedure:
A mixture of 1-(2,4,5-trifluorophenyl)piperazine (0.94 g, 4.35 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione (1.00 g, 4.35 mmol) was heated with stirring at 160° C. for 7 hours. The residue was partitioned between ethyl acetate (40 mL) and saturated aqueous sodium carbonate (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL) and the combined ethyl acetate fractions dried over sodium sulfate. The solvent was removed and the residue was purified by flash chromatography over silica gel, eluting with a gradient of hexane to hexane/ethyl acetate (1:1). The solvent was removed from the desired product [Rf=0.7, hexane/ethyl acetate (1:1)], leaving a pale tan oil which slowly solidified (0.652 g, 1.60 mmol, 37%, mp 230-234° C.). 1H NMR (300 MHz, CDCl3) δ6.89 (ddd, 1H, J=11.7, 10.2, 7.5 Hz), 6.74 (dt, 1H, J=12.0, 8.1 Hz), 3.95 (t, 2H, J=6.6 Hz), 2.97 (t, 4H, J=4.7 Hz), 2.65 (t, 4H, J=4.7 Hz), 2.60 (s, 4H), 2.54 (t, 2H, J=6.5 Hz), 1.74-1.70 (m, 4H), 1.55-1.51 (m, 4H); 13C NMR (75 MHz, CDCl3) δ172.7, 151.0 (ddd, J=243.8, 8.5, 1.7 Hz), 146.9 (ddd, J=241.6, 12.2, 3.2 Hz), 144.7 (ddd, J=242.3, 13.9, 12.4 Hz), 137.4 (ddd, J=9.6, 6.1, 2.9 Hz), 107.9 (dd, J=20.7, 4.1 Hz), 106.4 (dd, J=26.6, 21.5 Hz), 55.9, 53.6 (2C), 51.3 (d, 2C, J=3.0 Hz), 45.4 (2C), 40.1, 38.0 (2C), 36.9, 24.7 (2C); ESI-MS m/z 410 (MH+). The title compound was dissolved in ether and precipitated by addition of 1N HCl in ether, giving a white solid. The solid was recrystallized from hot methanol/chloroform (4:1) (with hexane added to cloudiness), giving white flakes (0.43 g, 0.96 mmol, 22%): mp 234-236.5° C., Anal. Calcd. For C21H26N3F3O2·1.2 HCl: C, 55.66; H, 6.05; N, 9.31; F, 12.58. Found: C, 56.06; H, 6.09; N, 9.21; F, 12.20.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[O:9])=[C:6]([CH3:21])[CH:5]=1)[CH3:2].[CH3:24][N:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)[CH3:26]>>[CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:20]=[CH:19][C:7]([C:8]2([N:33]([C:34]3[CH:35]=[CH:36][C:37]([N:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=3)[C:30]3[CH:29]=[CH:28][C:27]([N:25]([CH3:24])[CH3:26])=[CH:32][CH:31]=3)[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=[O:13])[O:9]2)=[C:6]([CH3:21])[CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: CN(C)c1ccc(Nc2ccc(N(C)C)cc2)cc1
Product: CCN(CC)c1ccc(C2(N(c3ccc(N(C)C)cc3)c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)c(C)c1
Yield: 54 %

Procedure:
Following a procedure similar to that described in Example 4 but employing 3.1 g of 2-[4-(diethylamino)-2-methylbenzoyl]benzoic acid and 3.0 g of 4,4'-bis(dimethylamino)diphenylamine there was obtained 2.95 g of 3-[4-(diethylamino)-2-methylphenyl]-3-{bis[4-(dimethylamino)phenyl]amino}phthalide, m.p. 67°-83° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a black-colored image.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CI.[C:36]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][N:21]([CH3:36])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(C[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A mixture of the crude 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{[(2-nitrophenyl)sulfonyl]amino}butanoate from the previous step, MeI (18.2 g, 128 mmol) and K2CO3 (325 mesh, 17.7 g, 128 mmol) in DMF (100 mL) was stirred at room temperature for 70 min. The reaction was diluted with H2O (200 mL) and extracted with Et2O (3×). The organic extracts were washed with H2O (2×), dried over CaCl2, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([NH:17][CH3:18])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([N:17]([CH3:18])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: CNc1ccc(C)cc1
Reactant: Clc1ncnc2ccccc12
Product: Cc1ccc(N(C)c2ncnc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloroquinazoline and 4-methyl-N-methylaniline by a procedure similar to example 28 (80% yield). 1H NMR (CDCl3): 8.23 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.57 (ddd, J=8.4, 6.3 and 1.8 Hz, 1H), 7.17-7.20 (m, 2H), 7.00-7.10 (m, 4H), 3.61 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10](Cl)[C:9]([N:13]([CH2:15][CH3:16])[CH3:14])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:18]N1C(=O)CCC1.C[Mg]Br>C1COCC1.CC(=O)OCC>[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([CH3:18])[C:9]([N:13]([CH2:15][CH3:16])[CH3:14])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCN(C)c1ncc(C(=O)OC(C)C)cc1Cl
Reactant: CN1CCCC1=O
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(C)c1ncc(C(=O)OC(C)C)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
A solution of 5-chloro-6-(ethyl-methyl-amino)-nicotinic acid isopropyl ester (5.18 g, 20.1 mmol), NMP (3.0 g, 30.2 mmol) and Fe(acac)3 (498 mg, 1.41 mmol) in THF (150 mL) is put under argon before a methylmagnesium bromide (3.0 g, 25.2 mmol, solution in diethyl ether) is added dropwise. The dark red-brown solution turns yellow, then dark brown again. The mixture is stirred at rt for 2 h before another portion of methylmagnesium bromide (1.44 g, 12.1 mmol) is added. The dark mixture is stirred at rt for 16 h. Another portion of NMP (3.0 g, 30.2 mmol), Fe(acac)3 (498 mg, 1.41 mmol) and methylmagnesium bromide (1.44 g, 12.1 mmol) is added and stirring is continued at rt for one more hour. The reaction mixture is diluted with EA (200 mL) and carefully quenched with ice-water (100 mL). The suspension is basified by adding 1 N aq. NaOH solution (10 mL) and filtered over a small pad of Hyflo and silica gel. The org. phase of the filtrate is separated and collected and the aq. phase is extracted with DCM (3×100 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. MPLC on silica gel eluting with a gradient of EA in heptane to give 6-(ethyl-methyl-amino)-5-methyl-nicotinic acid isopropyl ester (2.19 g) as a beige oil; LC-MS: tR=0.76 min, [M+1]+=237.20.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Na+].[Cl-].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:23]([O:25][C:26](=[O:38])[CH:27]([CH3:37])[C:28](=[O:36])[C:29](=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:24]>C(OCC)(=O)C.OCC(CO)O.CS(C)=O>[CH2:23]([O:25][C:26](=[O:38])[CH:27]([CH3:37])[C:28](=[O:36])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:24]
Reactant: CCOC(=O)C(=O)C(=O)C(C)C(=O)OCC
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: OCC(O)CO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)CC(=O)C(C)C(=O)OCC
Reaction time: 48 h

Procedure:
To 40 mL of 300 mM potassium phosphate buffer, pH=6.5, containing NaCl (100 mM), DMSO (3% v:v), glucose (200 mM), and glycerol (10% v:v), 40 mM of 2-methyl-3-ketoketoglutarate diethyl ester was added along with 100 mg of lyophilized KRED 1008 and 30 mg of glucose dehydrogenase. The reaction mixture was incubated for 48 hours at 37° C. Gas chromatographic analysis showed that the yield of hydroxy diester product was greater than 80%. The product was isolated by extraction of the reaction mixture with ethyl acetate and purification using silica gel chromatography. Isolated yield was in the range of 85–95%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[S:18][CH:19]=2)[C:12]([OH:14])=O)[CH2:8][CH2:7]1.[NH2:27][C@@H:28]1[C:45](=[O:46])[N:30]2[C:31]([C:42]([OH:44])=[O:43])=[C:32]([CH2:35][S:36][C:37]3[S:38][CH:39]=[N:40][N:41]=3)[CH2:33][S:34][C@H:29]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[S:18][CH:19]=2)[C:12]([NH:27][C@@H:28]2[C:45](=[O:46])[N:30]3[C:31]([C:42]([OH:44])=[O:43])=[C:32]([CH2:35][S:36][C:37]4[S:38][CH:39]=[N:40][N:41]=4)[CH2:33][S:34][C@H:29]23)=[O:14])[CH2:7][CH2:8]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: O=C(O)C(=NOC1CC1)c1csc(NC(=O)C(F)(F)F)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2[C@H](NC(=O)C(=NOC3CC3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
Phosphorus oxychloride (0.24 ml) was dropwise added to a mixture of N,N-dimethylformamide (0.2 ml) and tetrahydrofuran (0.4 ml) under ice-cooling. After being stirred for 10 minutes at the same temperature, the mixture was cooled until a precipitate appeared. To the suspension was added 2-cyclopropyloxyimino-2-(2-trifluoroacetamidothiazol-4-yl) acetic acid (syn isomer) (647 mg) and additional tetrahydrofuran (4 ml). The mixture was stirred at the same temperature for 30 minutes to give an activated acid solution. On the other hand, a mixture of 7β-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (793 mg) and bis(trimethylsilyl)acetamide (2 ml) in tetrahydrofuran (20 ml) was stirred at 30° C. for 30 minutes to give a clear solution. To the clear solution was added the activated acid solution prepared above at -30° C. The mixture was stirred for 30 minutes at -20° C. to -15° C. The mixture was poured into ice-water, adjusted to pH 7.2 with saturated aqueous solution of sodium bicarbonate, and washed with ethyl acetate. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 7β-[2-cyclopropyloxyimino-2-(2-trifluoroacetamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.21 g) as a solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]1([CH2:11][CH2:12][C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl-].[Na+]>>[CH:6]1([CH2:11][CH2:12][C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(-c2cnc(CCC3CCCC3)o2)cc1
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(-c2cnc(CCC3CCCC3)o2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Neat chlorosulfonic acid (2 mL) was added to 2-(2-cyclopentylethyl)-5-phenyloxazole from Step B (500 mg, 2.07 mmol) at room temperature under nitrogen with stirring. To this brown solution was added sodium chloride (100 mg) in portions and then the mixture was heated at 50° C. in an oil bath. After 2 h at 50° C., the mixture was poured onto ice-water and extracted with ethyl acetate (3×10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and evaparated. The brown residue was chromatogaphed on silica gel (eluent: 2:3 ethyl acetate:hexanes) to give 500 mg (76.9%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 2H, J=8.2 Hz), 7.81 (d, 2H, J=8.2 Hz), 7.45 (s, 1H), 2.85 (t, 2H, 7.5 Hz), 1.90-1.75 (m, 5H), 1.70-1.48 (m, H), 1.12 (m, 2H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([OH:12])([C:10]#[CH:11])[CH3:9].[CH3:13][C:14]([C:16](Cl)=[O:17])=[CH2:15]>N1C=CC=CC=1>[C:16]([O:12][C:8]([CH3:9])([C:10]#[CH:11])[CH3:7])(=[O:17])[C:14]([CH3:15])=[CH2:13]
Reactant: C=C(C)C(=O)Cl
Reactant: C#CC(C)(C)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C#CC(C)(C)OC(=O)C(=C)C
Reaction time: 6 h
Yield: 62 %

Procedure:
A reactor was charged with 550 parts of benzene, 74 parts of pyridine and 65.5 parts of 2-methyl-3-butyn-2-ol. To this were added 90 parts of methacryl chloride dropwise over one hour while keeping the inner temperature at 20° C. Then the reaction mixture was kept at 50° C. for 6 hours, suction filtered, evaporated and distilled in vacuo. 2-Methyl-3-butyn-2-yl methacrylate boiling at 56°-58° C./12 mmHg was obtained in a yield of 62% of theory. The product was identified by the IR spectrum thereof.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-].[Na+].[CH3:14][C:15]([CH3:17])=[O:16]>>[CH3:14][C:15](/[CH:17]=[CH:2]/[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:16]
Reactant: CC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(/C=C/C(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 85 %

Procedure:
To a solution of vanillin (5 g) in acetone (20 mL) was added 10% sodium hydroxide solution (20 mL). The reaction mixture was stirred at room temperature for 4 days (Normura, 1917). After acidification the product was extracted with EtOAc twice and washed with water. Evaporation of solvent left a dark brown liquid which on crystallisation from EtOAc-petroleum afforded the title compound (85%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].S1(CCCC1)(=O)=O.[OH-].[Na+]>O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 160 °C
Yield: 50.6 %

Procedure:
A mixture of 9.54 g (0.0500 mole) of 4-chlorophenyl methyl sulfone, 13.0 g (0.0750 mole) of 4-bromophenol, 10.37 g (0.0750 mole) of K2CO3 and 150 ml of sulfolane was heated at 150° C. for 5.5 hrs and at 160° C. for 3.5 hrs. The reaction mixture was cooled and poured into a solution of 200 ml of 20% aqueous NaOH and 400 ml of water. The crystalline product was collected by filtration, washed well with water and dried, which gave 8.27 g (50.6% yield) of product. Recrystallization from ethanol afforded purified 1-bromo-4-(4-(methylsulfonyl)phenoxy)benzene, mp 127.5°-129° C.
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([C@H:23]([NH:25][C@H:26]2[CH2:30][CH2:29][C@@H:28]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[CH2:27]2)[CH3:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][O:37][C:34]1[CH:33]=[CH:32][C:31]([C@@H:28]2[CH2:29][CH2:30][C@H:26]([NH:25][C@@H:23]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH3:24])[CH2:27]2)=[CH:36][CH:35]=1)[CH3:12]
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc(O)cc2)C1)c1cccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (5 mL) and ethyl bromoacetate (0.13 mL, 1.2 mmol) were added to 4-[(1R,3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}cyclopentyl]phenol (331 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. After the extracted solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (NH silica; ethyl acetate/hexane: 5/95-8/92) to give the title compound (298 mg, 71%).