Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([C:14]#[C:15]/[CH:16]=[CH:17]\[C:18]#[C:19][Si](C)(C)C)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>CO>[C:10]([Si:7]([C:14]#[C:15]/[CH:16]=[CH:17]\[C:18]#[CH:19])([CH3:9])[CH3:8])([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)C#C/C=C\C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#C/C=C\C#C[Si](C)(C)C(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Solid potassium carbonate (5.36 g, 38.9 mmol, 1.10 equiv) was added to a solution of (Z)-1-(tert-butyldimethylsilyl)-6-trimethylsilyl-3-hexen-1,5-diyne (9.26 g, 35.3 mmol, 1 equiv) in methanol (100 mL) at 23° C. and the resulting suspension was stirred at 23° C. for 1 h. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (200 mL) and hexanes (200 mL). The aqueous layer was separated and extracted further with hexanes (200 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The product was purified by flash column chromatography (hexanes) to furnish tert-butyl[(Z)-3-hexene-1,5-diynyl]dimethylsilane (18) as a brown oil (6.35 g, 95%). ##STR30##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.N1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)C=C1.C([O-])([O-])=[O:35].[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:30]3[CH:25]=[CH:26][C:27]([OH:35])=[CH:28][CH:29]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(O)cc3)c3cc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred suspension of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.30 g, 0.62 mmol) and 1H-indol-5-ylboronic acid (0.12 mg, 0.75 mmol) in CH3CN (3 mL) was added 1 M Na2CO3 (3 mL) followed by bis(triphenylphosphine)palladium(II) dichloride (0.004 g, 0.062 mmol). The resulting mixture was stirred overnight at 60° C. After the mixture was evaporated to dryness in vacuo, it was dissolved in DMF (3 mL), absorbed onto Celite, and dried. The residue was purified via silica gel chromatography using CH2Cl2 as the eluent to obtain the title compound (0.26 g, 76%). 1H NMR (CDCl3, 300 MHz): δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (bs, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.1 Hz), 7.85 (s, 1H), 7.81 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (dd, J=1.8, 8.4 Hz), 7.30 (m, 3H), 6.63 (m, 1H), 2.39 (s, 3H); MS ESI (m/z): 466.2/468.2 (M+1)+, calc. 465.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].CC1C=C(C)[N:29]([C:33](N)=[NH:34])N=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:33](=[NH:29])[NH2:34])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: N#Cc1cccc(N(C(=O)NC2CCNCC2)C2CCCCCC2)c1
Solvent: c1ccncc1
Product: N#Cc1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Temperature: 110 °C

Procedure:
N-(3-Cyanophenyl)-N′-(piperidin-4-yl)cycloheptylurea (0.05 g, 0.126 mmol) was dissolved in pyridine (2 ml) and 3,5-dimethylpyrazole-1-carboxamidine (0.037 g, 0.188 mmol) was added under a nitrogen atmosphere. The reaction was heated to 110° C. for 6 h, then was allowed to cool and was concentrated to give a viscous amber oil. The product was purfied by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The product eluted at 13.8 minutes was concentrated to give N-(3-cyanophenyl)-N′-(1-amidinopiperidin-4-yl)cycloeptylurea as an amorphous solid (0.036 g); LRMS (M+H)+ m/z 341.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5](=O)[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO.O>[CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[CH:5]([NH2:33])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(N)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.3 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2 ) in 5 ml of MeOH was added 922 mg (12 mmol) of ammonium acetate and then 188 mg (3 mmol) of sodium cyanoborohydride. The reaction mixture was refluxed for 1 hour, stirred at ambient temperature for 12 hours and then diluted with water (10 ml) and extracted with Et20 (3×30 ml). The organic layer was washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo to an oil. Recrystallization from EtOAc-hexane yielded the title compound as a white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][CH2:24][C:25]([OH:27])=O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].FC(F)(F)C(O)=O.[NH2:35][C@@H:36]1[C:43](=[O:44])[N:42]2[C@@H:37]1[S:38][CH2:39][C:40](/[CH:48]=[C:49]1/[C:50](=[O:62])[N:51]([CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([OH:61])[CH:56]=3)[CH2:52][CH2:53]/1)=[C:41]2[C:45]([OH:47])=[O:46]>CN(C)C(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][CH2:24][C:25]([NH:35][C@@H:36]2[C:43](=[O:44])[N:42]3[C@@H:37]2[S:38][CH2:39][C:40](/[CH:48]=[C:49]2/[C:50](=[O:62])[N:51]([CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[C:57]([OH:61])[CH:56]=4)[CH2:52][CH2:53]/2)=[C:41]3[C:45]([OH:47])=[O:46])=[O:27])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cccc(O)c4)C3=O)CS[C@H]12
Reactant: COc1ccc(SCC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COc1ccc(SCC(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN(Cc5cccc(O)c5)C4=O)CS[C@H]23)cc1OC

Procedure:
With 121.1 mg (0.75 mmol) 1,1,-carbonyldiimidazole, 170.6 mg (0.75 mmol) 2-(3,4-dimethoxyphenylthio)acetic acid and 250.0 mg (0.62 mmol) (E)-(6R,7R)-7-amino-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia- 1-aza-bicyclo[4.2.0]oct-2-ene2-carboxylic acid trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[N:11]([O:20][CH3:21])[CH2:12][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:21][O:20][N:11]1[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH2:12]1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CON1CC2=C(C=C1NC(=O)Oc1ccccc1)CCCC2
Product: CON1CC2=C(C=C1NC(=O)N1CCN(c3cccc(Cl)c3)CC1)CCCC2
Yield: 69 %

Procedure:
Phenyl-N-(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2([CH3:14])[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:7]=1>C(O)C.ClCCl.CCCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C@:8]2([CH3:14])[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:7]=1
Reactant: CC1(c2cc(Br)ccc2F)COC(=O)N1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCO
Product: C[C@@]1(c2cc(Br)ccc2F)COC(=O)N1

Procedure:
A solution of the (RS)-4-(5-bromo-2-fluoro-phenyl)-4-methyl-oxazolidin-2-one (20.2 g) in ethanol/dichloromethane/heptane (4/2/2) was divided in 1 g aliquots which were separated on chiral HPLC (Chiralpak AD) using a 90:10-mixture of ethanol and heptane as the eluent. The first eluting enantiomer (retention time: 7.98 min), the (R)-(−)-4-(5-bromo-2-fluoro-phenyl)-4-methyl-oxazolidin-2-one (intermediate C5A), was obtained as a brownish crystalline solid (9.154 g, 45.3% of theory), and the second eluting enantiomer (retention time: 12.19 min), the (S)-(+)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide, was also obtained as a light brown crystalline solid (9.25 g, 45.8% of theory), with e.e. >99.5% each.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:13].CO>>[I:11][C:10]1[C:3]2[C:2]([NH2:13])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH3:12])[CH:9]=1
Reactant: N
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Solvent: CO
Product: Cn1cc(I)c2c(N)ncnc21
Temperature: 110 °C

Procedure:
4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 0.31 mmol) was taken up in 7N NH3/MeOH and heated in a sealed tube at 110° C. overnight. Reaction was concentrated in vacuo to give a brown/off-white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([OH:21])=O)=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:21])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: C1CCNCC1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetic acid i103 (0.5 g, 1.41 mmol, 1 eq), triethylamine (0.2 ml, 1.41 mmol, 1 eq), and piperidine (0.15 ml, 1.45 mmol, 1.03 eq) in dichloromethane (30 ml) is cooled (ice bath) and treated with 1-hydroxybenzotriazole (38 mg, 0.28 mmol, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.271 g, 1.41 mmol, 1 eq). The mixture is stirred at room temperature overnight, then diluted with 70 ml of dichloromethane. The organic layer is washed with water (2×50 ml), brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to obtain an orange solid. The solid is triturated in acetonitrile, filtered and rinsed with cold diethyl ether to give 0.18 g of 1-({2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetyl)piperidine i104 as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[C:4]([NH:8]C(=O)C)[CH:5]=[CH:6][CH:7]=1.Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:20]
Reactant: CC(=O)Nc1cccc(F)c1C(=O)c1ccccc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)c1c(N)cccc1F
Temperature: 70 °C
Reaction time: 4 h

Procedure:
142 mg (0.52 mmol) N-[3-fluoro-2-(2-methyl-benzoyl)-phenyl]-acetamide are dissolved in 2 ml of ethanol, combined with 2 ml of conc. hydrochloric acid and stirred for 4 h at 70° C. Then the reaction mixture is stirred into 30 ml dist. water, adjusted to pH 7 with sodium carbonate and extracted three times with 10 ml of ethyl acetate. Then the organic phase is dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([NH:15][CH2:16][C:17]([O:19]C)=O)=[O:14])[CH:11]=2)[NH:6][CH:5]=1)#[N:2].[NH3:21]>>[NH2:21][C:17](=[O:19])[CH2:16][NH:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][C:1]#[N:2])=[O:14]
Reactant: N
Reactant: COC(=O)CNC(=O)c1ccc2[nH]cc(CC#N)c2c1
Product: N#CCc1c[nH]c2ccc(C(=O)NCC(N)=O)cc12
Reaction time: 8 h

Procedure:
The product of Stage (i) (0.05 g) dissolved in methanolic ammonia (2 ml) was stirred overnight, further 2 ml portions of methanolic ammonia being added after 3.5 h and 5.5 h. The solution was evaporated to dryness and the residual solid triturated with anhydrous ether to present the product as a powder (0.036 g) m.p. 206°-209°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:20][C:21]1[N:26]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH2:20][C:21]1[N:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(CN(CC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(Cc1cccc(C(=O)O)n1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a solution of ethyl 6-({[(benzyloxy)carbonyl](2-tert-butoxy-2-oxoethyl)amino}methyl)pyridine-2-carboxylate (3.26 g) in tetrahydrofuran (10.0 mL) were added a 1 M aqueous sodium hydroxide solution (8.00 mL), followed by stirring at room temperature overnight. To the reaction mixture was added 1 M hydrochloric acid (8.00 mL), followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 6-({[(benzyloxy)carbonyl](2-tert-butoxy-2-oxoethyl)amino}methyl)pyridine-2-carboxylic acid (2.08 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18]
Reactant: [H][H]
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Agent: [Pd]
Solvent: CO
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Reaction time: 2.25 h
Yield: 89.1 %

Procedure:
Palladium on carbon (10 wt. %, 25 mg) was added to a solution of [(Z)4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester (318 mg, 1.17 mmol) in MeOH (5.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 2.25 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30% EtOAc/CH2Cl2→50% EtOAc/CH2Cl2, gradient, then 2% MeOH(CH2Cl2→5% MeOH/CH2Cl2) afforded 285 mg (89%) of [4-((R)-2-hydroxymethyl-6-oxo -piperidin-1-yl)-butoxy]-acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](/[N:19]=[N:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][OH:30])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH:7]=[C:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1>[CH2:31]([N:27]([CH2:28][CH2:29][OH:30])[C:24]1[CH:25]=[CH:26][C:21](/[N:20]=[N:19]/[C:4]2[S:5][C:6]([CH:7]=[C:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])=[C:2]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[N:3]=2)=[CH:22][CH:23]=1)[CH3:32]
Reactant: C1CCNCC1
Reactant: CCN(CCO)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Solvent: C1CCOC1
Product: CCN(CCO)c1ccc(/N=N/c2nc(N3CCCCC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g (1.07 mmol) 2-{[4-chloro-2-((E)-{4-[ethyl(2-hydroxyethyl)amino]phenyl}-diazenyl)-1,3-thiazol-5-yl]methylene}-1H-indene-1,3(2H)-dione were dissolved in 20 ml THF. Then 0.2 g (2.14 mmol) piperidine were added dropwise and the mixture was stirred under reflux for 6 hours. After cooling to room temperature, stirring was continued overnight. The formed piperidine hydrochloric salt was separated by filtration and the solvent removed with a rotary evaporator. The resulting precipitate containing the crude product was recrystallized with toluene to obtain a dark powder.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C@@:21]12(O)[N:28](C)[C@@H:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]=[CH:22]2>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:20][CH:19]=2)([OH:11])[C:7]([O:9][C@@:10]23[N:28]([CH3:21])[C@@H:25]([CH2:26][CH2:27]2)[CH2:24][CH:23]=[CH:22]3)=[O:8])=[CH:17][CH:16]=1
Reactant: COC(=O)C(O)(c1ccc(C)cc1)c1ccc(C)cc1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Product: Cc1ccc(C(O)(C(=O)O[C@]23C=CC[C@H](CC2)N3C)c2ccc(C)cc2)cc1

Procedure:
4.10 is prepared analogously to the method according to II.1. Yield: 3.55 g (81% of theory) starting from 2.87 g (0.01 mol) of 3e and 1.48 g (0.01 mol) of tropenol; to purify it, the hydrochloride was precipitated and recrystallized from acetonitrile. Melting point: 232° C.-233° C. (hydrochloride).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][CH:7]([NH:21][CH3:22])[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][CH:7]([N:21]([C:29](=[O:30])[C:28]1[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=[C:26]([C:25]([F:24])([F:39])[F:40])[CH:27]=1)[CH3:22])[CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(NC)C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 10.6 g (34.3 mmol) of 4-methylamino-5,5-diphenyl-pent-2-enoic acid ethyl ester in 110 ml of methylene chloride is added at 0° C. via a cannula to a solution of 6.7 ml (36.0 mmol) of 3,5-bistrifluoromethyl-benzoyl chloride in 110 ml of methylene chloride. 5.8 ml (41.1 mmol) of triethylamine and 0.4 g (3.4 mmol) of 4-dimethylaminopyridine are then added. After 1 hour the reaction mixture is diluted with ethyl acetate and washed twice with water and once with brine. The aqueous phases are back-extracted once with ethyl acetate. The combined organic phases are then dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride/methanol (100:0 to 98:2). The title compound is obtained in the form of a light-yellow foam. TLC: methylene chloride/methanol (98:2) Rf =0.38; Rt (HPLC)=22.4 min; 1H-NMR (400 MHz, d6 -DMSO, 120° C.) d 8.00 (br, 1H), 7.47-7.29 (m, 10H), 7.26-7.20 (m, 2H), 6.83 (dd, 1H), 5.96 (d, 1H), 5.89 (br, 1H), 4.65 (d, 1H), 4.10 (q, 2H), 2.68 (s, 3H), 1.18 (t, 3H); FAB-MS (M+H)+ =550.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(F)[C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:7]1)=[O:5])[CH3:2].C(OC(C1(F)C(O)CCOC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(F)COCCC1=O
Agent: CCOC(=O)C1(F)COCCC1O
Product: CCOC(=O)C1COCCC1=O

Procedure:
First, 3-ethoxycarbonyl-tetrahydro-4H-pyran4-one was synthesized referring the process described in Japan Laid-Open Patent Publication No. 32080/90. Then this ester was fluorinated in the same manner as in Example 4 to prepare 3-ethoxycarbony-3-fluoro-tetrahydro-4H-pyran-4-one which was then reduced in the same manner as in the same example to prepare 3-ethoxycarbonyl-3-fluoro-4-hydroxytetrahydro-4H-pyran.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(C1C=C(C)C=[C:15]([C:20](C)(C)C)[C:14]=1[OH:24])(C)(C)C.[C:25](Cl)(=[O:35])[C:26]1[CH:34]=[CH:33][CH:32]=[C:28]([C:29](Cl)=[O:30])[CH:27]=1.Cl>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:25](=[O:35])[C:26]1[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([O:5][CH2:6][CH2:7][O:8][C:14](=[O:24])[CH:15]=[CH2:20])=[O:30])[CH:27]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCOC(=O)c1cccc(C(=O)OCCOC(=O)C=C)c1
Temperature: 0 °C

Procedure:
A 500 ml round-bottom flask was initially charged with 64.1 g of hydroxyethyl acrylate in 100 ml of pyridine/toluene (1:1, v/v) together with 0.1 g of 2,6-di-tert-butyl-4-methylphenol at 0° C., and 56.1 g of isophthaloyl chloride were slowly added dropwise. The mixture was stirred at room temperature until the hydroxyethyl acrylate content had fallen below 0.1%. Thereafter, the mixture was poured onto 0.5 l of ice-water and acidified with 1 N aqueous hydrochloric acid. The aqueous phase was extracted three times with 0.5 l each time of tert-butyl methyl ether. The organic phase was washed with 10% sodium hydrogencarbonate solution, dried over sodium sulfate and filtered. Another 0.1 g of 2,6-di-tert-butyl-4-methylphenol was added and the organic solvent was distilled off. The product was obtained as a colorless oil.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH:65]([S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)[CH3:66])=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH:65]([S:67][C:68]4[N:72]=[CH:71][NH:70][N:69]=4)[CH3:66])[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1)Sc1nc[nH]n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: CC(SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1)Sc1nc[nH]n1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(1-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.52 g: 1.47 mMol.) in a mixture of anisole (5 ml) and nitromethane (20 ml) at -40° C. is added a solution of aluminum chloride (1.56 g: 11.7 mMol.) in anisole (5 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is mixed with 1N-hydrochloric acid (12 ml), diluted with water, washed with ethyl acetate, concentrated to remove remaining organic solvents, and passed through a column of styrene-divinylbenzene copolymer adsorbent. The adsorbed product is eluted with water-methanol (1:4). The eluate is concentrated to give powder and washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-(1-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid (628 mg) as yellow powder. Yield: 81%.