Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]2[C:3]=1[CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Solvent: O
Product: O=C1CCc2c(Cl)cc(Cl)cc21
Yield: 4.5 %

Procedure:
3-(2,4-dichlorophenyl)propanoic acid (0.44 g, 2 mmol) in polyphosphoric acid (7 g) was heated to 100° C. under argon. After 90 min the mixture was cooled and treated with water (20 ml) and extracted with hexane (40 ml). The hexane layer was dried (MgSO4), and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-30% dichloromethane in hexane to give the title product as a yellow solid, (0.018 g, 4.5%), δH (CDCl3) 2.8 (2H, m), 3.1 (2H, m), 7.6 (1H, d), 7.65 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.C(OC([N:33]1[C:37]2=[CH:38][N:39]=[CH:40][CH:41]=[C:36]2[C:35](B(O)O)=[CH:34]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9]([C:35]3[C:36]4[C:37](=[CH:38][N:39]=[CH:40][CH:41]=4)[NH:33][CH:34]=3)[O:8][C:7]=12
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)c2ccncc21
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: [Na+]
Solvent: C1COCCO1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5c[nH]c6cnccc56)cc34)cn2)CC1
Temperature: 120 °C
Yield: 27.9 %

Procedure:
A mixture of 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (45 mg, 0.13 mmol), [1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]boronic acid (65 mg, 0.26 mmol), Na2CO3 (55 mg, 0.52 mmol) and Pd(PPh3)4 (10 mg, 0.0087 mmol) in 4:1 dioxane:water (5 mL) was degassed with N2 for 1 min, and then heated to 120° C. in a microwave reactor for 30 min. The mixture was filtered and the filtrate was purified by preparative TLC (5:1 DCM:MeOH) to afford 16 mg (29%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.79 (s, 1H), 8.28-8.27 (m, 3H), 8.16 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.25 (s, 1H), 4.71-4.68 (m, 1H), 4.57-4.54 (m, 1H), 4.13-4.09 (m, 1H), 3.37 (m, 1H), 2.85 (m, 1H), 2.21 (m, 1H), 2.13 (s, 3H), 1.95 (m, 1H); MS (ESI): 442.1 [M+H]+; HPLC tR=2.08 min (ZQ3: polar—4 min).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].O>CN(C)C(=O)C>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2cccs2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2cccs2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.50 g, 3.1 mmol) in N,N-dimethylacetamide (7 mL) was added thionyl chloride (0.37 g, 3.1 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-(2-Thienylsulfonyl)benzenamine (0.50 g, 2.1 mmol) was added in one portion to the orange solution and the mixture stirred at room temperature overnight. The brown solution was poured into water and the aqueous solution extracted with ethyl acetate (2×50 mL). The organics were combined, dried (MgSO4), filtered and the solvent distilled to yield a tan solid. Flash chromatography of the solid (eluted with 5% v/v ethyl acetate in methylene chloride) and evaporation of the eluent yielded the title propanamide (0.61 g, 77%) as an off-white solid; mp 158°-161° C. 1H-NMR (250 MHz, d6 -DMSO): 1.57 (s, 3H, CH3), 7.21 (dd, 1H, J=4.9, 4.0 Hz, aromatic), 7.56 (s, 1H, OH), 7.81 (dd, 1H, J=3.8, 1.5 Hz, aromatic), 8.00 (m, 5H, aromatic), 10.43 (s, 1H, NH). MS (CI, CH4): 380(M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]1([C:35]2[C:36]([O:41]C)=[N:37][CH:38]=[CH:39][CH:40]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])(=[O:23])=[O:22])[C:12]1=[O:34])=[O:4].[I-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:43][N:2]([CH3:1])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]1([C:35]2[C:36](=[O:41])[NH:37][CH:38]=[CH:39][CH:40]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=2[O:32][CH3:33])(=[O:22])=[O:23])[C:12]1=[O:34])=[O:4]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cccnc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccc[nH]c3=O)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC)c1
Yield: 59.8 %

Procedure:
A solution of example 5 (0.16 mmol, 100 mg) and sodium iodide (0.32 mmol, 109 mg) in acetic acid (1 mL) was heated overnight at 40° C. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium dithionate solution, water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Chromatographic purification over silica gel (gradient from 4% to 12% MeOH in dichloromethane) yielded 59 mg (60%) of a white crystalline solid.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:11]([NH2:13])=[O:12])[N:6]=[N:5][N:4]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:11]([NH2:13])=[O:12])[N:6]=[N:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1cc(-n2nnnc2CO)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-n2nnnc2CCl)cc(C(F)(F)F)c1
Yield: 67.7 %

Procedure:
To a suspension of 3-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-5-(trifluoromethyl)benzamide (500 mg, 1.741 mmol) in toluene (5 mL) was added thionyl chloride (0.140 mL, 1.92 mmol) and the reaction heated to reflux for 4 hours. The reaction was allowed to cool and the solvent removed under vacuum. The residue was partitioned between DCM (20 mL) and water (10 mL). The organic layer collected via a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 10% EtOAc in iso-hexane (5 column volumes) then a gradient from 10-100% EtOAc in iso-hexane (over 10 column volumes)) to yield the title compound as a pale yellow gum (360 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[C:17](O)=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([N:9]=[C:16]([C:12]3[S:11][CH:15]=[CH:14][CH:13]=3)[C:17](=[O:18])[NH:10]2)=[CH:7][CH:8]=1
Reactant: O=C(O)C(=O)c1cccs1
Reactant: COc1ccc(N)c(N)c1
Product: COc1ccc2nc(-c3cccs3)c(=O)[nH]c2c1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4-Methoxy-benzene-1,2-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 7-Methoxy-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[SH:34]>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)[O:4][C:3](=[O:25])[C:2]([S:34][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=3[Cl:26])=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1cccc(Cl)c1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3cccc(Cl)c3Cl)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2,3-dichlorothiophenol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:30])[CH2:22][CH2:21]2)([OH:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[BH4-].[K+]>CO.O>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[OH:30])[CH2:24][CH2:25]2)([OH:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(O)(c2ccccc2)C2CCN(CCCC(=O)c3ccccc3)CC2)cc1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(C(O)(c2ccccc2)C2CCN(CCCC(O)c3ccccc3)CC2)cc1
Reaction time: 8 h

Procedure:
To a mixture of 4.2 g (0.0083 mole) of 4-[4-[α-(p tert-butylphenyl)-α-hydroxybenzyl]piperidino]butyrophenone hydrochloride and 0.54 g (0.01 mole) of sodium methoxide in 25 ml of methanol is added 2.16 g (0.04 mole) of potassium borohydride. The reaction mixture is stirred overnight, diluted with water and the methanol removed under reduced pressure. The remaining material is extracted with chloroform, washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated, and the residue is recrystallized from acetone-water to give 4-[α-(p-tert-butylphenyl)-α-hydroxybenzyl]-α-phenyl-1-piperidinebutanol, M.P. 161°-163°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([F:15])[N:12]=[CH:11][C:10]=2[NH2:16])[C:5](F)=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[NH:16][C:10]3[CH:11]=[N:12][C:13]([F:15])=[CH:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: Nc1cnc(F)cc1-c1cc(Br)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cc2c(cn1)[nH]c1ncc(Br)cc12
Reaction time: 0.33 h

Procedure:
A solution of 5-bromo-2,6′-difluoro-[3,4′]bipyridinyl-3′-ylamine (0.79 g, 2.76 mmol) in THF (15 mL) was added dropwise over 10 minutes to sodium bis(trimethylsilyl)amide (1N solution in THF, 5.5 mL, 5.52 mmol). The reaction mixture was left to stir for 20 minutes then quenched by the addition of water (2 mL). The resultant black solution was partitioned between ethyl acetate (75 mL) and water (50 mL) and the layers separated. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give an off white solid. The resultant solid was triturated with ethyl acetate (30 mL), collected by filtration, washed with diethyl ether (5 mL) and left to air dry to afford the title compound as an off white solid (0.51 g, 65%). 1H NMR (DMSO-D6, 300 MHz): 9.00 (d, J=2.3 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H), 8.51 (dd, J=1.7, 0.9 Hz, 1H), 7.95 (dd, J=2.4, 0.9 Hz, 1H). LCMS (Method B): RT=3.10 min, M+H+=266/268.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(Cc1ccccc1)c1ccccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccccc1C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
Methyl 2-(2-methoxyphenyl)-3-phenylpropanoate (4.433 g, 16 mmol, 1 eq) is dissolved in 100 mL of a 1:1 (v:v) mixture of THF and methanol. Sodium hydroxide (3.28 g, 82 mmol, 5 eq) is added and the reaction mixture is stirred 18 hours at room temperature. The reaction is then poured into H2O and the pH is adjusted to 2 via addition of 1N HCl. A white precipitate forms which is removed by filtration. The resulting solution is extracted with 3 portion of diethyl ether. The extracts are pooled, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue is purified over silica to afford 2.107 g (51%) of the desired compound. ESI−MS 255 (M−1), 211 (M-CO2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:25]=[CH:24][C:19]2[CH:20]([NH2:23])[CH2:21][O:22][C:18]=2[CH:17]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[F:15][C:16]1[CH:25]=[CH:24][C:19]2[CH:20]([NH:23][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:21][O:22][C:18]=2[CH:17]=1
Reactant: NC1COc2cc(F)ccc21
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2nc(NC3COc4cc(F)ccc43)ccc2c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (1.6 g, 7.67 mmol) in N-methyl-2-pyrrolidinone (15 ml) with the above described rac-6-fluoro-2,3-dihydro-benzofuran-3-ylamine (1.3 g, 8.43 mmol) and N-ethyldiisopropylamine (1.96 ml, 11.5 mmol) was stirred at 140° C. for 2 h. Cooled to room temperature, poured onto water and extracted twice with Ethyl acetate, dried over sodium sulfate and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (1.0 g, 40%); MS (ISP) m/e=326.2 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([NH2:8])=[O:7])[C:3]1([CH3:10])[CH3:9].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[C:18]([C:17]1[C:12]([NH:1][C@@H:2]2[CH2:5][C@H:4]([C:6]([NH2:8])=[O:7])[C:3]2([CH3:10])[CH3:9])=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=1)#[N:19]
Reactant: CC1(C)[C@H](N)C[C@@H]1C(N)=O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2C[C@H](C(N)=O)C2(C)C)n1
Yield: 78 %

Procedure:
A mixture of (1S,3R)-3-amino-2,2-dimethylcyclobutanecarboxamide. (120 mg, crude), chloro-2-(methylthio)pyrimidine-5-carbonitrile (130 mg, 0.70 mmol) and DIEA (129 mg, 1.0 mmol) in isopropanol (5 mL) was stirred at 80° C. for 2 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (160 mg, 0.55 mmol, 78% yield for two steps). MS (ESI) m/z 292.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:26])([CH3:25])[C:5]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[N:23]O)[CH3:22])=[CH:17][CH:16]=1)([OH:12])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[Cl:27][C:28]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Cl.O>CS(C)=O.C(O)(=O)C>[Cl:27][C:28]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:29]=1[CH2:30][N:23]=[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:5]([OH:12])([C:4]([CH3:26])([CH3:25])[CH3:3])[CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:16][CH:17]=1)[CH3:22]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CC(=NO)c1ccc(OCC(O)(Cn2cncn2)C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=NCc1ccc(Cl)cc1Cl)c1ccc(OCC(O)(Cn2cncn2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
1.44 g (0.06 mol) of sodium hydride (80% strength in paraffin oil) are added to a solution of 14.94 g (0.045 mol) of 3,3-dimethyl-2-[4-(1-hydroximinoethyl)phenoxymethyl]-1-(1,2,4-triazol-1-yl)-2-butanol (Example 2) in 120 ml of absolute dimethylsulphoxide. The reaction mixture is stirred at room temperature for about 1 hour, until a clear solution has formed. 8.33 ml (0.06 mol) of 2,4-dichlorobenzyl chloride are then added and the reaction mixture is subsequently stirred at room temperature for 1.5 hours. Thereafter, water and glacial acetic acid are carefully added and the mixture is concentrated. The residue is taken up in ethyl acetate and the mixture is washed several times with dilute sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed over a silica gel column (methylene chloride/ethyl acetate=4:1) and the product is recrystallized from acetonitrile. 16.2 g (73% of theory) of 2-{4-[1-(2,4-dichlorobenzylimino)-ethyl]phenoxymethyl} -3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 101° C. are obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11]CCCC#CC1C=CC(NC(=O)C(F)(F)F)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:43][CH2:44][CH2:45][C:46]#[C:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][CH2:58][C:59]2[C:60]([NH:72][CH:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[C:61]3[CH:69]=[N:68][N:67]([CH2:70][CH3:71])[C:62]3=[N:63][C:64]=2[CH2:65][CH3:66])=[O:56])=[CH:50][CH:49]=1>>[Si:1]([O:8][C@H:9]([C:30]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34](=[O:41])[NH:35]2)[CH2:10][NH:11][CH2:43][CH2:44][CH2:45][C:46]#[C:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:55]([NH:57][CH2:58][C:59]2[C:60]([NH:72][CH:73]3[CH2:74][CH2:75][O:76][CH2:77][CH2:78]3)=[C:61]3[CH:69]=[N:68][N:67]([CH2:70][CH3:71])[C:62]3=[N:63][C:64]=2[CH2:65][CH3:66])=[O:56])=[CH:50][CH:49]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(C#CCCCBr)cc1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1

Procedure:
The title compound was prepared in a manner analogous to that described for Intermediate 37, using Intermediate 35 in place of Intermediate 26. ES/MS calcd. for C45H61N8O5Si+ 821.5. found m/z=821.6 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH:21][C:22]1[S:23][CH:24]=[C:25](/[C:27](=[N:31]/[O:32][CH3:33])/[C:28](O)=[O:29])[N:26]=1)([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)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:48][C@@H:49]1[C:80](=[O:81])[N:51]2[C:52]([C:64]([O:66][CH:67]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])=[C:53]([O:56][CH2:57][C:58]3[CH2:62][O:61][C:60](=[O:63])[CH:59]=3)[CH2:54][S:55][C@H:50]12>CN(C)C=O.O.C(OCC)(=O)C.N1C=CC=CC=1>[O:63]=[C:60]1[CH:59]=[C:58]([CH2:57][O:56][C:53]2[CH2:54][S:55][C@@H:50]3[C@H:49]([NH:48][C:28](=[O:29])/[C:27](/[C:25]4[N:26]=[C:22]([NH:21][C:2]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)[C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[S:23][CH:24]=4)=[N:31]\[O:32][CH3:33])[C:80](=[O:81])[N:51]3[C:52]=2[C:64]([O:66][CH:67]([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[O:65])[CH2:62][O:61]1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OCC3=CC(=O)OC3)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OCC3=CC(=O)OC3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid hydrochloride (300 mg) in dimethylformamide (4 ml) was cooled to -50° C. whilst under an inert atmosphere. N,N-Diisopropylethylamine (218 μl) was added followed by methanesulphonyl chloride (49 μl). The reaction was stirred for 30 min. at -50° C. before treating with pyridine (52 μl) followed by a solution of diphenylmethyl 7β-amino-3-(2,5-dihydro-2-oxofuran-4-ylmethyloxy)ceph-3-em-4-carboxylate (300 mg) in dimethylformamide (4 ml) and the temperature allowed to rise to 0° C. The reaction was stirred for 15 min. and then poured into ethyl acetate and water. The organic phase was washed with water (two times) and brine before drying over anhydrous magnesium sulphate. Chromatography on silica gel (Keiselgel) eluting with 4:1 ethyl acetate/hexane gave the title compound which was finally isolated as a foam (431 mg). υmax (CH2Cl2) 3400, 1785, 1755, and 1730cm-1 ; δH(CDCl3) 3.34 (2H, s), 4.08 (3H, s), 4.64 (2H, s) 4.73 (2H, bs), 5.11 (1H, d, J 4.5Hz), 5.79 (1H, dd, J 8.24Hz, 4.5Hz), 5.95 (1H, bs) 6.77 (1H, s), 6.90 (1H, s), 6.96 (1H, d, J 8.07Hz), 7.02 (1H, s), and 7.26-7.39 (25H, m). [Mass spectrum: FAB +ve ion (3NOBA/Na+)MH+ 904, MNa+ 926].
Reaction SMILES: [C:1]([N:8]([N:14]=[N+:15]=[N-:16])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)(=O)C.CCCCCC>[CH2:17]([O:12][C:11](=[O:13])[C@H:9]([CH3:10])[N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])[N:14]=[N+:15]=[N-:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](C(=O)O)N(N=[N+]=[N-])C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)OCc1ccccc1)N(N=[N+]=[N-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
Boc-azidoalanine 8 (520 mg, 2.26 mmol) was dissolved in dry acetonitrile (8 mL) in glass vial equipped with a magnetic stir bar and capped with a septum. Benzyl bromide (325 μL, 2.71 mmol) and diisopropylethylamine (440 μL, 2.49 mmol) were subsequently added via syringe. The solution was stirred for 18 h at room temperature until TLC indicated the consumption of the starting material. The reaction mixture was concentrated in vacuo and the crude product was loaded onto a silica gel column. The column was eluted first with 10% ethyl acetate/hexane to wash off the residual benzyl bromide and then with 20% ethyl acetate/hexane to elute the product (452 mg, 63% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][C:17]=3[CH2:28][CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[CH2:28][CH3:29])=[CH:30][CH:31]=2)=[O:10])=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reaction time: 3 h
Yield: 21.2 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-ethylphenyl)acetate (10 mg, 0.0215 mmol) was diluted with dioxane (500 μL) followed by the addition of NaOH (0.0429 ml, 0.215 mmol) and 5 drops of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl, and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with 10% MeOH/DCM to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-ethylphenyl)acetic acid (2 mg, 21.3% yield). (400 MHz, CD3Cl3, CD3OD) 7.65 (d, 2H), 7.30 (d, 2H), 7.10-7.25 (m, 4H), 6.90 (m, 3H), 3.62 (m, 2H), 3.40 (s, 1H), 2.90 (t, 2H), 2.55 (q, 2H), 1.15 (t, 3H).