Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:29]=O)=[N:18][CH:19]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])[N:21]=1.[CH2:31]([NH:38][CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:31]([N:38]([CH2:29][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@H:23]2[CH3:28])=[CH:19][N:18]=1)[CH2:39][CH2:40][OH:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@@H]1COCCN1c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: C[C@@H]1COCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
Sodium triacetoxyborohydride (1.37 g) was added to a solution of 3-chloro-5-[(3R)-3-methylmorpholin-4-yl]pyrazine-2-carbaldehyde (1.04 g), N-benzylethanolamine (0.78 g) and acetic acid (0.74 mL) in acetonitrile (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (solvent gradient: 5→40% ethyl acetate/hexane) to give the title compound (1.65 g, quantitative) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[OH-].[K+].[C:13](=S)=[S:14].C>O.C(O)C>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[N:1]=[C:13]([SH:14])[NH:10][C:3]=2[CH:4]=1
Reactant: Nc1cc(F)c(Cl)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1cc2nc(S)[nH]c2cc1Cl
Reaction time: 4 h
Yield: 575.7 %

Procedure:
The procedure of Van Allan and Deacon, Org. Synth. Coll. Vol. IV, 569, was adapted. A mixture of 1,2-diamino-4-chloro-5-fluorobenzene (528 mg, 3.29 mmol, Aldrich), potassium hydroxide (202 mg, 0.36 mmol), carbon disulfide (280 mg, 0.36 mmol), 95% ethanol (3 mL) and water (0.45 mL) was heated under reflux for 3 h. Activated charcoal (120 mg) was then added cautiously, and after the mixture has been heated at the refluxing temperature for 10 min the activated charcoal was removed by filtration. The filtrate was heated to 60°-70° C., warm water (3 mL) was added, and then acetic acid (0.25 mL) in water (0.5 mL) was added with good stirring for 4 h. The mixture was placed in a refrigerator overnight to give a mixture of brown and white crystals. The brown crystals were removed by washing with chloroform (5 mL). Recrystallization from hot EtOH/H2O gave pure title compound (420 mg, 63.5%, purity >99.57% by HPLC) as a white cubic crystals; top: 294°-6° C. (sub. from 250° C.). IR (KBr, cm-1): 3443, 3131, 3075, 1618, 1506, 1487, 1462. 1H NMR (DMSO-d6): δ 7.169 (d, J=9 Hz, 1H); 7.245 (d, J=6.6 Hz, 1H); 12.758 (s, 2H). HRMS: calcd for C7H4ClFN2S (M+) m/z: 201.9766, Found: 201.9779.
Reaction SMILES: C([O:5][C:6](=[O:50])[CH2:7][CH:8]([NH:22][C:23](=[O:49])[C@H:24]([CH3:48])[NH:25][C:26](=[O:47])[C@H:27]([CH:44]([CH3:46])[CH3:45])[NH:28][C:29](=[O:43])[C@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[NH:31][C:32](=[O:34])[CH3:33])[C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.CC(C)=O.CCCCCC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:32]([NH:31][C@H:30]([C:29]([NH:28][C@H:27]([C:26]([NH:25][C@H:24]([C:23]([NH:22][CH:8]([C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:7][C:6]([OH:50])=[O:5])=[O:49])[CH3:48])=[O:47])[CH:44]([CH3:46])[CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CCCCCc1ccccc1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)NC(CC(=O)O)C(=O)CCCCCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
N-(N-AcetylTyrosinyl-Valinyl-Alaninyl)-3-amino-4-oxo-9-phenyl nonanoic acid t-butyl ester (140 mg) was dissolved in a 1:1 mixture of CH2Cl2 /TFA (8 mL). The mixture was stirred at rt for 30 min and the solvent was reduced in vacuo. The residue was recrystilized from acetone/hexane to provide the acid (120 mg, 80%).
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:20](O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[CH3:20][C@@H:6]1[CH:7]=[C:8]2[C@@H:18]([CH2:17][C@H:16]3[C:19]4[C:13](=[CH:12][CH:11]=[CH:10][C:9]2=4)[NH:14][CH2:15]3)[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]1
Reactant: CCCN1CCC[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Product: CCCN1C[C@H](C)C=C2c3cccc4c3[C@@H](CN4)C[C@H]21
Yield: 7 %

Procedure:
A mixture of 1.5 g (6.7 mmol) of 6-desmethyllysergine (prepared by the N-demethylation of lysergine by cyanogen bromide), 1.8 g (13 mmol) of anhydrous potassium carbonate, 2.2 g (13 mmol) of 1-iodopropane and 50 ml of dry dimethylformamide was stirred for 42 hours. The solvent was evaporated in vacuo and the residue was digested with two 75 ml portions of ether and then filtered. The ether extracts were evaporated and the resulting solid residue was suspended in cold ether and collected by filtration to give 0.72 g (40%) of single spot material by thin layer chromatography (methanol:chloroform, 1:9). The NMR of the material was consistent with that expected for 6-propylergoline. Reduction was accomplished as described previously by stirring a mixture of 5 ml TFA, 1.3 g (11.1 mmol) of triethylsilane and 0.72 g (2.7 mmol) of 6-propyllysergine for 6 hours. The resultant was worked up as described above and gave 0.05 g of the title compound (7%) following HPLC and recrystallization from methanol/petane, mp. 135°-137° C.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:79])([F:78])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:93])([O:90]CC)[O:87][CH2:88][CH3:89])=[CH:83][C:82]=4[O:96][CH3:97])[CH:71]=3)=[CH:61][CH:60]=2)[CH:56]=[N:55]1>>[OH:50][CH2:51][CH2:52][CH2:53][N:54]1[CH:58]=[C:57]([C:59]2[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]3[C:75]([C:76]([F:77])([F:78])[F:79])=[CH:74][N:73]=[C:72]([NH:80][C:81]4[CH:95]=[CH:94][C:84]([CH2:85][P:86](=[O:90])([OH:93])[O:87][CH2:88][CH3:89])=[CH:83][C:82]=4[O:96][CH3:97])[CH:71]=3)=[CH:61][CH:60]=2)[CH:56]=[N:55]1
Reactant: CCOP(=O)(Cc1ccc(Nc2cc(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)c(C(F)(F)F)cn2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2cc(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)c(C(F)(F)F)cn2)c(OC)c1

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyridin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 36B). 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.08 (t, J=1.8 Hz, 1H), 6.88 (td, J=2.0, 8.1 Hz, 1H), 6.63 (s, 1H), 4.31 (t, J=6.8 Hz, 2H), 3.88 (s, 3H), 3.74 (quin, J=7 Hz, 2H), 3.57 (t, J=6.1 Hz, 2H), 2.89-2.98 (m, 5H), 2.10 (quin, J=6.5 Hz, 2H), 1.03 (t, J=7.1 Hz, 3H). MS (ESI): m/z 664.21 [M+H]+. UPLC: tR=1.06 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][CH2:22][OH:23]>CN(C)C=O.C[O-].[Na+]>[OH:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: OCCCCl
Reactant: O=C(c1ccc(O)cc1)c1c[nH]c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCCCO)cc1)c1c[nH]c2ccccc12
Temperature: 110 °C
Reaction time: 3 h

Procedure:
5 g of 3-(p-hydroxybenzoyl) indole were dissolved in 50 ml of dimethylformamide containing 2.28 g of sodium methoxide. 4.0 g of 3-chloropropanol was added to the solution followed by stirring at 110° C. in oil bath for 3 hours. After cooling, the solution was concentrated and extracted with 100 ml of ethyl acetate and 50 ml of water. The organic layer obtained was concentrated, and then the residue was purified by column chromatography on silica gel. Crude product was recrystallized from ethyl acetate to give 3-[p-(3-hydroxypropoxy)benzoyl]indole (compound 23) in the form of white needle crystals. (Yield: 30.5%).
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[C:1]([CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)([CH2:4][C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(C)(C)C1CCC(O)CC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)CC(C)(C)C1CC=CCC1
Yield: 93.6 %

Procedure:
A 1 L four-necked flask equipped with a mechanical stirrer, a thermometer, and a Dean-Stark water separator was charged with 4-t-octylcyclohexanol (0.471 mol), sulfuric acid (0.047 mol), sodium sulfate (0.047 mol), distilled water (35 g), and xylene (100 g), and they were heated and refluxed for 3 hours. After completion of the reaction, the reaction mixture was filtered with a glass filter, the solvent was removed by vacuum distillation, and purification was carried out by silica gel column chromatography (silica gel 60 (70-230 mesh), manufactured by Merck Ltd., elution solvent: n-hexane). The reaction product thus obtained was subjected to vacuum distillation using a kugelrohr distillation apparatus at 120° C./666 Pa to give 85.64 g (94% yield) of 4-t-octyl-1-cyclohexene (Formula (14) below). The results of 1H-NMR of this product are shown below.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])[CH2:2][CH3:3].C([O-])=O.[NH4+].C1C2C(=CC=CC=2)CCC1.ClC1C=CC=C2C=1CC(NCCC)CC2>CO.[Pd]>[C:1]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1cnc2ccccc2c1
Agent: [Pd]
Agent: CCCNC1CCc2cccc(Cl)c2C1
Agent: O=C[O-]
Solvent: c1ccc2c(c1)CCCC2
Solvent: CO
Product: CCC(=O)NC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 17.4 g (86.9) 3-(N-propionyl)aminoquinoline and 20.0 g (317 mmol) ammonium formate in 150 ml methanol was added 1.0 g Pd/C cautiously under an inert atmosphere. After stirring at ambient temperature for 2 days the reaction stopped. The ratio between starting material and product was approximately 1:1 (monitored by GLC). The mixture was filtered on Celite and evaporated to a residue from which the product was extracted into diethyl ether. The ether solution was dried (magnesium sulfate), filtered and evaporated. The product/starting material mixture was then recharged in a similar manner using the same amounts of reactants. After additional 4 days the reaction was completed and worked-up as above to yield 9.7 g (55%) of reasonably pure material: MS m/e 204 (M+, 4), 130 (100), 131 (45), 118 (8), 91 (5), 77 (5).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]3[N:10]=[C:11]([NH2:13])[CH:12]=[C:6]3[CH2:5]2)[CH2:3][CH2:2]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:57]1[C:58](=[O:65])[N:59]([CH3:64])[CH:60]=[C:61]([Br:63])[CH:62]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:63][C:61]1[CH:62]=[C:57]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:9][CH2:8][N:7]3[N:10]=2)[C:58](=[O:65])[N:59]([CH3:64])[CH:60]=1
Reactant: Nc1cc2n(n1)CCN(C1CC1)C2
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C2CC2)C3)c1=O
Yield: 35.5 %

Procedure:
A mixture of 128b (1.39 g, 7.8 mmol), XantPhos (450 mg, 0.78 mmol), Pd2dba3 (476 mg, 0.52 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.72 g, 6.5 mmol) and Cs2CO3 (6.3 mg. 19.5 mmol) in 1,4-dioxane (30 mL) was heated at reflux for 1 h. After the completion of the reaction the mixture was filtered off and the solid was washed with methanol (60 mL). The filtrate was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 128c (0.84 g, 30%). MS: [M+H]+ 364.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]#[N:25])[CH:18]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>>[C:24]([CH2:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][C:7]([NH:6][OH:5])=[O:26])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1)#[N:25]
Reactant: CC(C)(C)ONC(=O)CCOc1ccc(-c2cccc(CC#N)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1cccc(-c2ccc(OCCC(=O)NO)cc2)c1
Yield: 45 %

Procedure:
A solution of O-tert-butyl 3-[4-(3-cyanomethylphenyl)phenoxy]propanohydroxamic acid (0.043 g, 0.12 mmol) in 1:1 trifluoroacetic acid-dichloromethane was stirred overnight at ambient temperature. The reaction mixture was filtered, concentrated in vacuo, and azeotroped with dichloromethane and dichloromethane-ethyl ether. Chromatography on silica gel (40:1, then 20:1 dichloromethane-methanol, both containing 0.25% acetic acid) gave 3-[4-(3-cyanomethylphenyl)phenoxy]propanohydroxamic acid (16 mg, 44%). 1H NMR (DMSO-d6) δ 2.45 (t, 2H, J=6.0 Hz), 4.08 (s, 2H), 4.23 (t, 2H, J=6.0 Hz), 7.02 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=7.5 Hz), 7.46 (t, 1H, J=8.0 Hz), 7.57 (d, 1H, J=6 Hz), 7.58 (s, 1H), 7.60 (d, 2H, J=8.8 Hz); 8.84 (br s, 1H), 10.53 (br s, 1H). IR (microscope) 3245 (br), 2924 (m), 2251 (w), 1643 (s), 1608 (s), 1518 (s), i483 (m), 1244 (s), 784 (m) cm-1. MS (DCI/NH3) 314 (M+NH4)+. Anal. Calcd for C17H16N2O3 ·0.70 H2O·0.20 tBuOH: C, 66.04; H, 6.04; N, 8.65. Found: C, 65.93; H, 5.64; N, 8.30.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.[OH:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].O>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:6][CH:7]=1.[CH3:13][C:11]1([CH3:14])[CH2:10][O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]([OH:25])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:23]3[CH:22]=[C:21]([OH:20])[CH:34]=[CH:33][CH:32]=3)=[CH:3][CH:4]=2)=[N:12]1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: CC1(C)COC(c2ccc(Br)cc2)=N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(c2ccc(C(O)(c3ccccc3)c3cccc(O)c3)cc2)=N1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(4-Bromophenyl)-4,4-dimethyl-1,3-oxazoline 1 was prepared as described in Example 4. To a stirred solution of 2-(4-bromophenyl)-4,4-dimethyl-1,3-oxazoline (1.5 g, 6 mM) in anhydrous THF (10 mL) at −78° C. was added slowly n-BuLi (384 mg, 6 mM) in hexane over the period of 20 min. After that the reaction mixture was stirred at −78° C. for another 30 min. To this stirred solution was added 3-hydroxybenzophenone (534 mg, 2.7 mM) dissolved in anhy. THF (10 mL) by dropwise at −78° C. and allowed to stir at room temperature overnight. To this reaction mixture was added 20 mL of water to quench the reaction and extracted with CH2Cl2 (3×50 mL) and the combined extract was dried over anhydrous Mg2SO4. The oily residue obtained on evaporation of the solvent was purified by silica gel column chromatography using hexane/EtOAc (1:1) mixture gave 3-{[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-hydroxy-phenyl-methyl}-phenol (2) as colorless crystalline solid. Yield: 0.855 g (85%). Mass: 374 (MH+), 372 (M-H).
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O.[CH3:20][C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22]>ClC1C=CC=CC=1>[CH:23]1([C:21](=[O:22])[CH2:20][C:8]([C:7]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:6]=2[S:5][CH3:4])=[O:10])[CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1SC
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CSc1cc(C(F)(F)F)ccc1C(=O)CC(=O)C1CC1
Temperature: 75 °C
Yield: 99.3 %

Procedure:
Sodium methoxide (64 g, 1.15M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (200 g, 0.8M) in chlorobenzene (380 g). The mixture was heated to 75° C. and cyclopropyl methyl ketone (75 g, 0.88M) added during 2 hours whilst maintaining stirring at 75° C. After 4 hours methanol was distilled under reduced pressure. the mixture cooled to 50° C., and water followed by sulphuric acid (53 g of 36N) added. The organic phase was distilled under reduced pressure to give 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione as yellow crystals (240 g), m.p. 58-60° C. A yield of 88% was obtained. The purity of the product was 90%.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[NH2:19][N:20]1[C:24]([N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)=[N:23][N:22]=[C:21]1[SH:30].C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O.Cl>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[CH:9]1[S:14][CH2:15][C:6]([CH2:5][S:30][C:21]1[N:20]([NH2:19])[C:24]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[N:23][N:22]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Nn1c(S)nnc1-n1cccn1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(-n4cccn4)n3N)CSC12
Temperature: 60 °C

Procedure:
A solution of 2.72 g. of 7-aminocephalosporanic acid, 1.82 g. of 4-amino-5-(1-pyrazolyl)-4H-1,2,4-triazole-3-thiol and 1.68 g. of sodium bicarbonate in 75 ml. of pH 6.4 phosphate buffer is stirred and heated at 60° C. for 7 hours. The resulting solution is cooled, acidified to pH 3 with 4 N hydrochloric acid and the precipitate is collected by filtration and dried, giving 2.6 g. of the desired product, I.R. 5.60μ (β-lactam carbonyl).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:60][CH2:61][CH3:62])[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[N:40](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:9]=1[C:10]([O:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1)=[O:11])([CH3:4])[CH3:3]>C(O)(=O)C>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:60][CH2:61][CH3:62])[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:9]=1[C:10]([O:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1)=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OC2OC(=O)c3ccccc32)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 79.6 %

Procedure:
Following a procedure similar to that described in Example 61(b), 0.196 g of phthalidyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] was detritylated by heating it with 75% v/v aqueous acetic acid to give 0.110 g of the title compound, melting at 168°-170° C.
Reaction SMILES: C([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:11]([F:23])[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[Si:16]([O:15][CH:12]1[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH:11]1[F:23])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(OCc2ccccc2)CC1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1F
Reaction time: 8 h

Procedure:
To a stirred solution {[4-(benzyloxy)-2-fluorocyclohexyl]oxy}(tert-butyl)dimethylsilane (4.66 g, 13.8 mmol) in MeOH (30 mL) was added Pd(OH)2 in MeOH (20 mL). The flask was evacuated and filled with hydrogen several times, and left to stir overnight under hydrogen atmosphere. The mixture was diluted with DCM, filtered through a pad of Celite, and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]([C:21](=O)[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:3]1[CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33].[BH3-]C#N.[Na+]>ClCCCl.[Zn+2].[I-].[I-]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:3]1[CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OC(=O)c3ccc(Cl)cc3)cc2n1C
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OC(=O)c3ccc(Cl)cc3)cc2n1C
Temperature: 65 °C

Procedure:
To a solution of 500 mg of the benzoyl derivative from Step D of Example 24 in 10 mL of 1,2-dichloroethane were added 1.19 g of ZnI2 and 700 mg of NaBH3CN. The mixture was heated at 65° C. for 5 hours and cooled to R.T. The mixture was quenched with 1N aq. HCl and extracted with CH2Cl2. The extracts were washed with brine, dried over Na2SO4 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (15:85) as eluant to isolate the title compound as a white foam.
Reaction SMILES: [Li+].[OH-].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[N:11]2)=[CH:7][CH:6]=1>O.C1COCC1.CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[N:11]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Temperature: 60 °C
Yield: 96.5 %

Procedure:
According to Scheme 1 Step 2: A solution of LiOH (358 mmol, 15.3 g) in water (2 M) was added at room temperature to a solution of ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (143 mmol, 37.2 g) in THF/MeOH (1:1, 400 mL) and the reaction mixture was heated at 60° C. overnight. After evaporation of THF and MeOH, a solid was filtered, water (150 mL) was added and the aqueous phase was extracted with Et2O. The aqueous phase was then acidified with a solution of HCl 1 M until pH=1-2 and extracted with DCM. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (138 mmol, 32.1 g, 97%) as a pale yellow solid. The crude product was used without further purification.