Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[N:7][NH:8][C:9]=1[CH:10]([OH:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>ClCCl>[C:10]([C:9]1[NH:8][N:7]=[C:6]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)Oc2n[nH]c(C(C)O)c2C(C)(C)C)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
4-tert-Butyl-5-(1-hydroxyethyl)-3-(4-methylphenyl)sulfonyloxypyrazole (3.8 g, 11.3 mmol) was dissolved in dichloromethane (100 ml) and PDC (4.26 g, 11.3 mmol) was added After stirring at ambient temperature for 2 h, the reaction mixture was poured directly onto a silica gel column and eluted with dichloromethane then 20% ethyl acetate/dichloromethane to give the required product (2.71 g) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.26 (9H, s), 2.46 (3H, s), 2.56 (3H, s), 7.36 (2H, d, J=8.2 Hz), 7.82 (2H, d, J=8.2 Hz), 10.70 (1H, br s); MS (ES+) m/e 337 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:14]4[O:22][CH:21]=[CH:20][C:15]=4[CH:16]=[N:17][C:18]=3[NH2:19])=[N:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:14]5[O:22][CH:21]=[CH:20][C:15]=5[CH:16]=[N:17][C:18]=4[NH2:19])=[N:9][N:10]=3)[N:7]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc2ccoc2c1OCc1nnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc3nnc(COc4c(N)ncc5ccoc45)n3n2)cn1

Procedure:
A mixture of 7-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy]furo[3,2-c]pyridin-6-amine (15.0 mg, 0.047 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.7 mg, 0.095 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (19.6 mg, 0.142 mmol) and 4:1 dioxane:water (2 mL) was microwaved at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z 363.06 (100) [MH+]. HPLC: tR=1.89 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40].[CH3:41][N:42]([CH3:47])[CH2:43][CH2:44][CH2:45][NH2:46]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:46][CH2:45][CH2:44][CH2:43][N:42]([CH3:47])[CH3:41])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:40]
Reactant: CN(C)CCCN
Reactant: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(NCCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.056 g, 0.1 mmol) was dissolved in THF (5 mL) and N,N-dimethyl-1,3-propanediamine (0.035 g, 0.3 mmol) was added. The reaction was carried out and worked up as in Example 148 to give the title compound as a white amorphous solid. mp 141-144° C. LC-MS m/z 586 (M+H)+, 1.52 min (ret time).
Reaction SMILES: [H-].[C:2]([O:6][C:7]([NH:9][CH2:10][C:11](OC)=[O:12])=[O:8])([CH3:5])([CH3:4])[CH3:3].CO>C1(C)C=CC=CC=1>[C:2]([O:6][C:7](=[O:8])[NH:9][CH2:10][CH:11]=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC=O
Reaction time: 1 h
Yield: 53.2 %

Procedure:
A 1.02M solution of diisobutylalminium hydride in toluene (27 ml) was added dropwise to a solution of methyl tert-butoxycarbonylaminoacetate (2.00 g) in toluene (40 ml) at −70° C., and the mixture was stirred for 1 hour. The reaction solution, to which methanol (10 ml) was added at −70° C., was quenched and then left to room temperature. After the reaction solution was diluted with ethyl acetate, this solution was washed with a 1N aqueous hydrochloric acid solution. The organic layer was washed with a brine filtered through celite, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40→30:70) to yield tert-butyl(2-oxoethyl)carbamate (895 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([CH3:21])[NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][N:33]=[C:34]=[O:35])[CH3:29]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:20][C:34]([NH:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])=[O:35])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN=C=O
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.1 %

Procedure:
(αS,βR)-β-{[1-(4-Fluorophenyl)-1H-indazole-5-yl]oxy}-α-methylbenzeneethanamine (80 mg, 0.22 mmol), as described in Example 1, is dissolved in 1.42 mL dichloromethane and ethylisocyanatoacetate (28.6 mg, 0.22 mmol) is dropwise added. After stirring for 45 min at r.t. the solvent is removed and the residue purified by chromatography (silicagel, eluents: hexane/ethylacetate). 85.4 mg (78.6%) of the title compound are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[C:20]([I:22])[C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].O[Li].O.CO.Cl>O1CCCC1.O>[C:1]([C:4]1[CH:21]=[C:20]([I:22])[C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc(I)c1OCc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(O)c(C(C)=O)cc(I)c1OCc1ccc(C(=O)O)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution of 245 mg (0.523 mmoles) of methyl 4(-4-acetyl-3-hydroxy-6-iodo-2-propylphenoxy)methylbenzoate in 3 ml of tetrahydrofuran and 0.8 ml of water was treated with 110 mg (2.62 mmoles) of LiOH.H2O and stirred at 22° C. for one hour. The temperature was brought to 55° C. and 3 ml of MeOH was added after 2 hours of reaction. After a total reaction time of 31/2 hours, the mixture was allowed to cool, diluted with water, acidified by addition of concentrated HCl and extracted with dichloromethane. The combined extracts were washed with water, dried over MgSO4 and evaporated to give 217 mg of white powder mp 167°-168.5° C.
Reaction SMILES: O=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1C=CC=CC=1>[S:23]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=S)N1
Yield: 191.1 %

Procedure:
To a solution of t-butyl pyroglutamate (1a) (10.12 g, 54.6 mmol) in benzene (250 mL), was added Lawesson's reagent (11.05 g, 27.3 mmol). The mixture was stirred at reflux for 15.5 h, then concentrated. The resultant residue was purified by flash chromatography (0 to 2 to 3 to 4% MeOH/CHCl3) to afford 10.50 g (95%) of the title compound, 1b. 1H NMR (300 MHz, CDCl3) δ 7.27 (br s, 1H), 4.46–4.39 (m, 1H), 3.03–2.84 (m, 2H), 2.58–2.46 (m, 1H), 2.37–2.23 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:65][CH2:66][CH2:67][NH:68]C(=O)C(F)(F)F)[CH2:10][CH2:11][CH2:12][N:13](C(=O)C(F)(F)F)[CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:23][O:22][CH:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]([N:30]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:29])[O:20]1)=[O:16])=O.[OH-].[Na+]>O1CCCC1>[NH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:65][CH2:66][CH2:67][NH2:68])[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:23][O:22][CH:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]([N:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:29])[O:20]1)=[O:16]
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCCOC1OCC(CNC(=O)CN(CCCN(CCCNC(=O)C(F)(F)F)CCCNC(=O)C(F)(F)F)C(=O)C(F)(F)F)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCCOC1OCC(CNC(=O)CNCCCN(CCCN)CCCN)O1
Reaction time: 8 h

Procedure:
2.1 g of 4-[4-({2-[(3-{bis[3-(2,2,2-trifluoroacetylamino)propyl]amino}propyl)trifluoro-acetylamino]acetylamino}methyl)-[1,3]dioxolan-2-yloxy]-N,N-ditetradecylbutyramide (1.88 mmol) were dissolved in 30 ml of tetrahydrofuran, and 30 ml of molar sodium hydroxide at 4% were added, with vigorous stirring. The reaction was left overnight at room temperature.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: O=C=Nc1ccccc1Br
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Br)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-bromophenyl isocyanate (0.150 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 241 mg (66.8%) of the desired product as a solid.
Reaction SMILES: [CH:1]1([N:4]([CH:13]2[CH2:16][O:15][CH2:14]2)[CH:5]2[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[H-].[Na+].[Cl:19][C:20]1[CH:21]=[C:22]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:23]=[N:24][C:25]=1Cl.[NH4+].[Cl-]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:23]=[N:24][C:25]=1[O:12][CH2:11][CH:8]1[CH2:7][CH2:6][CH:5]([N:4]([CH:1]2[CH2:2][CH2:3]2)[CH:13]2[CH2:16][O:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: OCC1CCC(N(C2CC2)C2COC2)CC1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cnc(OCC2CCC(N(C3CC3)C3COC3)CC2)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 329C (706 mg) in N,N-dimethylformamide (6 mL) was added NaH (60% in mineral oil, 300 mg). The mixture was stirred for 30 minutes, and then 5,6-dichloropyridine-3-sulfonamide (706 mg) was added. The mixture was stirred overnight. The mixture was poured over aqueous NH4Cl and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. After filtration and evaporation of the solvent the residue was loaded on a silica gel cartridge and eluted with 5 to 10% 7N NH3 in methanol in dichloromethane to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[OH-].[Na+].[Cl:13]Cl>>[Cl:13][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1]
Reactant: ClCl
Reactant: CC1(C)CCCC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCCC(C)(C)N1Cl
Temperature: 7.5 °C
Reaction time: 1.5 h

Procedure:
20 g of 2,2,6,6-tetramethylpiperidine are mixed with 40.7 g, 1.1 eq, of 15% sodium hydroxide solution and cooled to 5 to 10° C. Over a period of 1.5 hours, 10.8 g, 1.1 eq. of chlorine gas are introduced, then nitrogen gas is used to drive out the excess chlorine and the mixture is warmed to room temperature (RT). After separating the phases, washing the aqueous phase with 25 ml of dichloromethane, drying the combined organic phases with magnesium sulphate and distilling off the dichloromethane in vacuo, 24.2 g, 99%, of 1-chloro-2,2,6,6-tetramethylpiperidine are obtained.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([S:23](=[O:34])(=[O:33])[N:24]([CH2:29][CH2:30][O:31][CH3:32])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=4)[N:11]=3)=[CH:8][N:7]=[C:6]2[CH3:35])[CH2:3][CH2:2]1.C([Li])CCC.[CH3:41][C:42]([CH3:44])=[O:43].O>C1COCC1>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([S:23](=[O:33])(=[O:34])[N:24]([CH2:29][CH2:30][O:31][CH3:32])[C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:21][CH:22]=4)[N:11]=3)=[CH:8][N:7]=[C:6]2[CH2:35][C:42]([OH:43])([CH3:44])[CH3:41])[CH2:3][CH2:2]1
Reactant: CC(C)=O
Reactant: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3CC3CC3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(CC(C)(C)O)n3CC3CC3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
4-(1-Cyclopropylmethyl-2-methylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(t-butyl)sulphamoyl]anilino}pyrimidine (Method 78; 1.15 g, 2.31 mmol) was dissolved in anhydrous THF (80 ml), under nitrogen. The solution was cooled to −78° C. and n-butyl lithium (2.88 ml of a 1.6 N solution in hexanes, 4.62 mmol), was added slowly, maintaining the temperature at less than −65° C. The reaction mixture was then stirred at −78° C. for 30 minutes, then acetone (1187 μl, 2.54 mmol) was added and mixture allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was then poured into water (100 ml), and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with water (50 ml), brine (50 ml), and dried. The volatiles were removed and the residue was purified by chromatography on silica gel eluting with EtOAc to give the title compound (465 mg, 36%) as a yellow solid. NMR: 0.10 (m, 2H) 0.18 (m, 2H) 0.89 (m, H) 1.07 (s, 6H) 1.12 (s, 9H) 2.75 (s, 2H) 3.15 (s, 3H) 3.38 (m, 4H) 4.54 (d, 2H) 7.11 (d, H) 7.58 (m, 3H) 7.75 (d, 2H) 8.34 (d, H) 9.8 (s, H); m/z 557.
Reaction SMILES: [OH-].[K+].[C:3](I)([C:6]([C:9]([C:12]([C:15]([C:18]([F:21])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.C(O)(C)C>[CH:3]([C:6]([C:9]([C:12]([C:15]([C:18]([F:19])([F:20])[F:21])([F:16])[F:17])([F:13])[F:14])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 1 l four-necked flask equipped with a stirrer, a distillation apparatus-equipped reflux condenser, a dropping funnel and a thermometer, 400 cc of isopropyl alcohol, 49.5 g (0.75 mol) of 85% potassium hydroxide and 1 g of tetrabutylphosphonium bromide were charged. The reactor was heated to bring the internal temperature to 60° C. Then, 223 g (0.5 mol) of C6F13I was dropwise added thereto over a period of one hour. After completion of the dropwise addition, heating and refluxing were continued for one hour. The conversion at that time was 100%. A fraction with a boiling point of up to 75° C. was recovered by distillation from the reactor. The recovered liquid was washed five times with 200 g of water, and acetone and isopropyl alcohol were removed. Thus, 152 g of C6F13H having a purity of 99.9%, was obtained.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1[OH:35].[H-].[Na+]>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[C:18]([O:35][C:26]3[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:25]=3[F:24])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Cl)c2C2CC2)CC1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(6-Chloro-5-cyclopropyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (200 mg, 0.588 mmol), 2-fluoro-4-methanesulfonyl-phenol (168 mg, 0.883 mmol) and sodium hydride (60% dispersion in mineral oil, 53 mg, 1.325 mmol) were dissolved in DMSO (2 mL) and the mixture stirred under Nitrogen for 10 min at rt. The mixture was then heated under microwave irradiation for 1 h at 150° C. The crude was quenched with water and extracted with EtOAc (3×). The organic layer was concentrated and the residue was purified by HPLC to afford Compound C44 (51 mg, 14.3%) as oil. 1H NMR (CDCl3, 400 MHz) δ 0.90-0.97 (m, 2H), 1.01-1.06 (m, 2H), 1.23-1.27 (d, J=6.06 Hz, 6H), 1.76-1.91 (m, 2H), 1.92-2.02 (m, 2H), 3.08 (s, 3H), 3.46-3.55 (m, 2H), 3.63-3.72 (m, 2H), 4.87-4.98 (m, 1H), 5.32-5.39 (m, 1H), 7.36-7.42 (m, 1H), 7.73-7.80 (m, 2H), 8.17 (s, 1H). Exact mass calculated for C23H28FN3O6S 493.17, found 494.5 (MH+).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][CH2:44][CH2:45][NH:46]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:36]([OH:38])=[O:37])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH2:27][NH:28]C(OC(C)(C)C)=O)=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][CH2:44][CH2:45][NH2:46])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:36]([OH:38])=[O:37])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH2:27][NH2:28])=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CN)s3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (0.8 ml.), methanol (30 ml.) and tetrahydrofuran (30 ml.) was stirred at room temperature for 3 hours. After evaporation, methanol was added to the residue. The solution was evaporated in vacuo again, and the residue was dissolved in water (30 ml.). The solution was adjusted to pH 3.5 with saturated aqueous sodium bicarbonate solution under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (trademark: Mitsubishi Chemical Industries Ltd.) and eluted with 30% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(3-aminopropoxyimino)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.6 g.).
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH2:34]>CC#N.C(Cl)Cl.CC(O)=O>[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1
Reactant: Cn1c(N)nc2ccccc21
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CC=O)c2)c1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCNc3nc4ccccc4n3C)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-(1-(2-oxoethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (157 mg, 0.45 mmol) in MeCN (1 mL) and DCM (0.8 mL) was added 1-methyl-1H-benzo[d]imidazol-2-amine (66 mg, 0.45 mmol) followed by STAB (190 mg, 0.90 mmol) and 1 drop of AcOH. After stirring at rt for 18 h, the reaction mixture was filtered and directly purified by prep. HPLC. LC-MS conditions D: tR=0.77 min, [M+H]+=442.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[CH3:20][C:21]1[C:26]([CH2:27][CH2:28]O)=[CH:25][CH:24]=[C:23]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:15]=[C:14]([O:16][CH2:28][CH2:27][C:26]2[C:21]([CH3:20])=[N:22][C:23]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)=[CH:24][CH:25]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Reactant: COC(=O)C(Cc1cc(O)c2ccccc2c1)OC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1)OC
Temperature: 0 °C
Reaction time: 20 h

Procedure:
0.26 g (1.0 mmol) of the above prepared [rac]-3-(4-hydroxy-naphthalen-2-yl)-2-methoxy-propionic acid methyl ester, 0.30 g (1.05 mmol) of 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (see below example 4K]) and 0.31 g (1.20 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The stirred reaction mixture was cooled down to 0° C. and a solution of 0.27 g (1.15 mmol) of di-tert.-butyl azodicarboxylate in 5 ml of THF was added drop by drop and the reaction warmed up to ambient temperature. After 20 hours, the solvent was evaporated and the residue purified by chromatography (SiO2, heptane/EtOAc=9:1 to 1:1) to give 0.45 g of the title compound as light yellow oil.