Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].[F:11][C:12]([F:16])=[C:13]([F:15])[Cl:14].[OH-].[Na+]>O.CC(C)=O>[F:11][C:12]([F:16])([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH:13]([F:15])[Cl:14]
Reactant: Cc1ccc(S)cc1
Reactant: FC(F)=C(F)Cl
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(SC(F)(F)C(F)Cl)cc1

Procedure:
A hot solution (60° C.) of 248 g (2 moles) of 4-methylthiophenol, 44.8 g of 85% potassium hydroxide, and 280 ml of acetone were placed in an autoclave. An amount of 256 g (2.2 moles) of trifluorochloroethylene was introduced in 1 h under pressure with agitation at 50°-55° C. After 1 h the reaction mixture was poured out in a solution of 1200 ml of water and 80 g (2 moles) of sodium hydroxide. The final product was extracted with ether, the ether solution was dried, and the solvent was evaporated. The residual oil was distilled at 120° C./1 mm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]#N)[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1.C(O)=[O:26]>[Ni].[NH4+]>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([CH:19]=[O:26])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(C#N)cc32)CC1
Reactant: O=CO
Agent: [Ni]
Agent: [NH4+]
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(C=O)cc32)CC1

Procedure:
A mixture of 1.70 g of 1-methyl-4-(3-cyano-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine (prepared as described in U.S. Pat. No. 3,988,342 (1976)), 1.70 g of Raney nickel-ammonium alloy, and 25 ml of 75% aqueous formic acid was stirred under reflux for 1.5 hours. The cooled mixture was filtered and the filtrate was made basic by the additional of solid sodium bicarbonate. Extraction of the neutralized mixture with chloroform and evaporation of the solvent gave 1.30 g of 1-methyl-4-(3-formyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[C:17]2C=O)=[CH:12][CH:11]=1.[C:23](=O)([O-])[O-:24].[K+].[K+]>ClCCl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH:17]=[CH:18][C:19]([CH:23]=[O:24])=[CH:20]2)=[CH:14][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccn1-c1ccc(F)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: O=Cc1ccn(-c2ccc(F)cc2)c1
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic acid (100 g) was added dropwise at room temperature into a dichloromethane solution (680 ml) containing 1-(4-fluorophenyl)-2-formylpyrrole (50.4 g), and stirred at reflux temperature for 13 hours. The reaction solution was poured into ice water, made alkaline with the addition of potassium carbonate and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(4-fluorophenyl)-3-formylpyrrole (34.5 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:28][NH:29][CH3:30]>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:29]([CH3:30])[CH3:28])=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(S(C)(=O)=O)cc2)nn(CC2CC2)c1=O
Product: CN(C)Cc1cc(-c2ccc(S(C)(=O)=O)cc2)nn(CC2CC2)c1=O
Yield: 65.6 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 65.6%).
Reaction SMILES: C(O[C@H:5]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C:7]3[C@:8]4([O:27][C:6]1=3)[O:26][C@H:9]4[C@@H:10]1[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:25])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[CH2:15][CH3:16])(=O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C[C:46](C)=[O:47]>>[O:27]1[C:6]2=[C:7]3[C@:21]([CH3:24])([CH2:22][CH2:23][CH2:5]2)[C@@H:20]2[C@H:10]([C@H:11]4[C@:17]([CH3:25])([CH2:18][CH2:19]2)[C@@H:14]([CH:15]([CH:46]=[O:47])[CH3:16])[CH2:13][CH2:12]4)[C@@H:9]2[O:26][C@:8]123
Reactant: CC(C)=O
Reactant: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4OC(C)=O)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 48 %

Procedure:
In 5 ml of acetone was dissolved 24.3 mg (0.05 mmole ) of 20-(5,5-dimethyl-1,3 -dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3β-yl acetate, followed by addition of 2.5 mg (0.01 mmole) of pyridinium p-toluenesulfonate. The mixture was refluxed for 2 hours. The reaction mixture thus obtained was cooled to room temperature and the solvent was distilled off under reduced pressure. To the residue was added methylene chloride and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:5, v/v) to recover 9.6 mg of 3β-acetoxy-1α,2α;6α,7α-diepoxypregn-4-ene-20-carbaldehyde (yield: 48%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: Sc1cccs1
Reactant: O=C(O)CCCCBr
Product: O=C(O)CCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with 5-bromo valeric acid to obtain 5-(2-thienylsulfanyl) valeric acid represented by Chemical Formula [4].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[C:12]([N:19]1[CH2:23][CH2:22][C@H:21](O)[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:22]1[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:23]1)[N:6]=[C:5]2[I:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(I)c3cc(F)ccc32)C1
Yield: 32 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and BOC—(S)-3-pyrrolidinol in 32% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.43 (9H, s), 2.38-2.40 (1H, m), 2.56-2.66 (1H, m), 3.51-3.57 (1H, m), 3.74-3.78 (2H, m), 3.85-3.94 (1H, m), 5.12-5.15 (1H, m), 7.13 (1H, d, J=8.0 Hz), 7.23-7.27 (1H, m), 7.35-7.37 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:19][CH:18]=2)[NH:9][C:10]([CH:12]2[CH2:15][C:14](=[CH2:16])[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:15][C:14](=[CH2:16])[CH2:13]3)=[N:9][C:8]=2[C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:19][CH:18]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: C=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Temperature: 55 °C

Procedure:
N-[(3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methyl]-3 methylenecyclobutanecarboxamide (0.02 mmol, 10 g) was dissolved in 150 mL POCl3 in a 250 mL rbf, charged with 0.1 mL DMF and heated to 55° C. under a consistent N2 flow for 1 h (the reaction was vented with a needle). The excess POCl3 was removed under reduced pressure and the residue was quenched with 2 N NH3 in isopropanol (250 mL) at 0° C. and water. The aqueous layer was washed with DCM (100 mL×2) and the combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (flash column) eluting with 20-50% EtOAc in hexane. Concentration in vacuo of the product-rich fractions afforded the desired product as yellow solid; MS (ES, Pos.): m/z 423 (100) [MH+]; 1H NMR (CDCl3, 400 MHz) δ 3.28-3.31 (m, 2H), 3.39-3.42 (m, 2H), 3.85-3.93 (m, 1H), 4.94 (p, J=2.4 Hz, 2H), 7.38 (d, J=4.9 Hz, 1H), 7.42-7.57 (m, 4H), 7.89-7.92 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (dd, J=8.6 Hz, 0.8 Hz, 1H), 8.53 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([C@H:14]([OH:23])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[Li].O>C1COCC1.O>[OH:23][C@@H:14]([C@@H:4]([CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:24])=[O:2])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.2 %

Procedure:
A solution of (R)-2-((S)-1-hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (230 mg, 0.69 mmol) and LiOH.H2O (57.5 mg, 1.37 mmol) in a mixture of THF and water (2:1, 6 ml) was stirred at room temperature for 2.5 hrs. The reaction was diluted with water and THF removed under reduced pressure. The pH of the aqueous solution was adjusted to pH5 with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and evaporated under reduced pressure to give the title compound as white solid (180 mg); 1H NMR (CDCl3) δ 1.92–1.60 (m, 4H), 2.75–2.60 (m, 3H), 3.78–3.45 (m, 9H), 4.5 (d, J=8 Hz, 1H), 7.35–7.18 (m, 5H); MS: 322(MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:38]=1[O:39][CH2:40][O:41][CH3:42])[C:33](Cl)=O)([CH3:29])([CH3:28])[CH3:27]>>[CH2:10]([N:5]1[C:6]2[C:7](=[O:8])[NH:9][C:33]([C:32]3[CH:36]=[C:37]([C:43]([CH3:46])([CH3:44])[CH3:45])[C:38]([O:39][CH2:40][O:41][CH3:42])=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:31]=3)=[N:1][C:2]=2[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: COCOc1c(C(C)(C)C)cc(C(=O)Cl)cc1C(C)(C)C
Solvent: O=C(Cl)c1ccccc1
Product: COCOc1c(C(C)(C)C)cc(-c2nc3ncn(Cc4ccccc4)c3c(=O)[nH]2)cc1C(C)(C)C
Yield: 45 %

Procedure:
An amidation reaction was performed following the same conditions as in Example 1 using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazole carboxamide obtained in Reference Example 2 and using, instead of benzoyl chloride, 3,5-di-t-butyl-4-methoxymethoxybenzoyl chloride which was separately prepared by a conventional method. After a post-treatment, a crude amide product was obtained. The crude amide was subjected to a cyclization reaction for 12 hours according to the same conditions as in Example 1. 2.17 g of 7-benzyl-2-(3,5-di-t-butyl-4-methoxymethoxyphenyl)hypoxanthine was obtained after a post-treatment. Yield 45% (2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:25])=[O:24])=[C:6]([CH2:8][C:9](=[O:10])[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: C1CCNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)N2CCCC2)c1
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and pyrrolidine (0.5 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (28 mg, yield 7%). MS calcd for (C19H22BN3O5S): 415.1. MS found (ESI negative): (M−H)−=414.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.77 (s, 1H), 9.17 (bs, 1H), 7.44 (m, 2H), 7.23 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.37 (m, 2H)), 4.87 (s, 2H), 3.82 (s, 2H), 3.32 (m, 4H), 1.81 (m, 4H).
Reaction SMILES: [CH3:1]OC1C=C(OC)C=CC=1C(Cl)=O.[Cl:14][C:15]1[CH:21]=[C:20]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25]N=2)[CH:19]=[CH:18][C:16]=1[NH2:17].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48].[Cl:14][C:15]1[CH:21]=[C:20]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:1]=2)[CH:19]=[CH:18][C:16]=1[NH:17][C:50]([NH:49][C:47](=[O:48])[C:40]1[CH:41]=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:39]=1[O:38][CH3:37])=[S:51]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 48%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O:10][CH:11](O)[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[N:7]=[C:6]([CH:11]([OH:10])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cn1
Reactant: COC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(O)c(C(O)C(F)(F)F)n1
Temperature: 180 °C
Yield: 66.1 %

Procedure:
A mixture of commercially available 6-methylpyridin-3-ol (500 mg), trifluoroacetaldehyde methylhemiacetal (715 mg) and potassium carbonate (69 mg) was heated in a microwave reactor at 180° C. for 3 min. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using 1:1 hexane:ethyl acetate and recrystallized from ethyl acetate and hexane to give 627 mg of 6-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][NH:27][CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C([BH3-])#N.[Na+].[C:49]1(=O)[CH2:52][CH2:51][CH2:50]1.C([O-])(O)=O.[Na+]>CO.CC(O)=O>[CH:49]1([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH:28]2[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31]2)[CH2:52][CH2:51][CH2:50]1
Reactant: O=C1CCC1
Reactant: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C2CCC2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.84 g, 1.4 mmol) was taken up in methanol (10 ml) and Sodium cyanoborohydride (0.087 g, 1.4 mmol) was added. The pH was adjusted to ca. 6 using a 10% solution of AcOH in MeOH, then Cyclobutanone (0.15 ml, 2.1 mmol) added in one portion. The reaction was stirred at RT for 3 days. NaHCO3 (sat'd) added to the reaction mixture which was then extracted (3×) with DCM. The combined organics were dried with MgSO4, filtered and concentrated. The material was used without further purification.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7](=[CH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C.FC(F)(F)C(O)=O>C(OCC)(=O)C.CCCCCCC>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[NH:6][CH:5]=[CH:4][C:16]=2[S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:9][CH:10]=1
Reactant: CCOC(CNC(=CS(=O)(=O)C(F)(F)F)c1ccc(OC)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2[nH]ccc2S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
The oil obtained in Example 3 is treated with trifluoroacetic acid (20 mL), stirred for several hours at room temperature, concentrated in vacuo and chased with ethyl acetate to obtain an oil. Flash chromatography of the oil using silica gel and a 1:4 ethyl acetate/heptane solution gives a yellow semi-solid. Recrystallization of the semi-solid gives the title product as a yellow solid (0.88 g, mp 138.5°-140.5° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[N:17]1.[I-].[K+].[OH-].[Na+]>CC(O)(CC)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:16]3[CH:20]=[CH:19][N:18]=[N:17]3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2nc(CCl)cs2)cc1
Reactant: c1c[nH]nn1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: COc1ccc(-c2nc(Cn3ccnn3)cs2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
A suspension of 1.50 g (6.3 mmol) 4-chloromethyl-2-(4-methoxy-phenyl)-thiazole, 0.65 g (9.4 mmol) 1H-[1,2,3]triazole, 0.11 g (0.63 mmol) potassium iodide and 0.37 g (9.4 mmol) sodium hydroxide in 20 ml 2-methyl-2-butanol was stirred at 120° C. for 5 h. After evaporation, the residue was quenched with water and extracted with ethyl acetate. The extract was dried and concentrated to yield 1.4 g (82%) 1-[2-(4-methoxy-phenyl)-thiazol-4-ylmethyl]-1H-[1,2,3]triazole as beige crystals, melting at 89-94° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][C:6]=2[CH:16]=1>CO.C1COCC1.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(Br)ccc2CCC1
Yield: 100 %

Procedure:
A mixture of methyl 2-bromo-6,7-dihydro-5H-benzocyclohepten-8-carboxylate (1.0 g) in methanol (25 ml), THF (25 ml) and 1N NaOH (18 ml) was refluxed for 1 hour. The solvent was concentrated, acidified using 1N HCl, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo to give 2-bromo-6,7-dihydro-5H-benzocyclohepten-8-carboxylic acid (0.95 g) as colorless prisms.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[NH2:17][C:18]1[CH:30]=[CH:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH3:32])([CH3:31])[C:20]=2[CH:19]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][C:5]1([CH3:16])[C:4]2[CH:3]=[C:2]([NH:17][C:18]3[CH:30]=[CH:29][C:28]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([CH3:32])([CH3:31])[C:20]=4[CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CC1(C)c2ccccc2-c2ccc(N)cc21
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(Nc3ccc4c(c3)C(C)(C)c3ccccc3-4)cc21

Procedure:
81 g of 2-bromo-9,9-dimethyl-9H-fluorene (300 mmol), 93 g of 2-amino-9,9-dimethyl-9H-fluorene (444 mmol), 5 g of DPPF (9 mmol), 2 g of palladium(II) acetate and 86 g of sodium tert-butoxide (486 mmol) are heated at the boil for 18 h in 1.5 l of toluene under a protective-gas atmosphere. The mixture is subsequently partitioned between toluene and water, the organic phase is washed three times with water, dried over Na2SO4 and evaporated in a rotary evaporator. The residue which remains is recrystallised from heptane/ethyl acetate. The yield is 93 g (231 mmol, 77%).
Reaction SMILES: [Si:1]([CH:5]=[N+:6]=[N-:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:29]=[N:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>CCOCC>[F:13][C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:29]=[N:28][CH:27]=[CH:26][C:23]=1[C:24]1[N:25]=[N:7][NH:6][C:5]=1[Si:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccncc1Nc1ccc(I)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1[nH]nnc1-c1ccncc1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of TMSdiazomethane (2 M, 90 μL, 0.18 mmol) in ether (2 mL) at 0° C., was added butyl lithium (2.5 M, 72 μL, 0.18 mmol) dropwise. The mixture was stirred for 20 min at 0° C. 3-[(2-fluoro-4-iodophenyl)amino]isonicotinonitrile (50 mg, 0.15 mmol) was then added into the solution. The reaction was allowed to warm to room temperature and proceed for three days. The mixture was diluted with ether and washed with saturated ammonium chloride solution, water, and dried over solid Na2SO4. The organic phase was concentrated, and the resulting residue was applied to chromatography in silica gel to give the desired product in 40% yield (27 mg). LC/MS [Method A: rt: 0.40 min; m/z: 454 (M+1)].
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[O:4][N:3]=1.[NH2:11][CH:12]1[C:26](=[O:27])[N:14]2[C:15]([C:23]([OH:25])=[O:24])=[C:16]([CH2:19][N:20]=[N+:21]=[N-:22])[CH2:17][S:18][C@H:13]12>C(#N)C>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:8]([NH:11][CH:12]2[C:26](=[O:27])[N:14]3[C:15]([C:23]([OH:25])=[O:24])=[C:16]([CH2:19][N:20]=[N+:21]=[N-:22])[CH2:17][S:18][C@H:13]23)=[O:10])[O:4][N:3]=1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Cc1noc(CC(=O)O)n1
Solvent: CC#N
Product: Cc1noc(CC(=O)NC2C(=O)N3C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]23)n1
Yield: 35 %

Procedure:
Using the same procedure, 5.51 mmol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 5.51 mmol of 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid (90% purity) in 55 ml of dry acetonitrile were reacted for one hour at room temperature and 11/2 hours at 50° C. to obtain a 35% yield of pure 7-[3-methyl-1,2,4-oxadiazol-5-yl-acetamido]-3-azidomethyl-3-cephem-4-carboxylic acid with a recovery of 45% of 7-amino-3-azidomethyl-cephalosporanic acid.