Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=CC=1)([O-])=O>>[N:51]1([C:48]2[CH:47]=[CH:46][C:45]([NH:44][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([N:26]6[CH2:31][CH2:30][O:29][CH2:28][CH2:27]6)=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:50][CH:49]=2)[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1
Reactant: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1N1CCOCC1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1cc2c(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)ncnc2cc1N1CCOCC1

Procedure:
The title compound was prepared from 4-(6-methoxy-7-morpholin-4-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester, prepared in Example 211a, and (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 66a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 7.37 (s, 1H), 7.28 (m, 2H), 7.25 (s, 1H), 6.89 (m, 2H), 6.35 (s, 1H), 4.27 (m, 2H), 4.06 (s, 3H), 3.94 (m, 4H), 3.86 (m, 4H), 3.59 (tt, 1H), 3.29 (m, 4H), 3.16 (td, 2H), 3.11 (m, 4H), 2.21-2.08 (m, 2H), 2.03-1.95 (m, 2H). LC/MS (ESI): calcd mass, 532.3, found 533.3 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[C:20]([CH2:22]Cl)[N:21]=1.O>O1CCCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[C:20]([CH2:22][N:3]2[C:2]([CH3:1])=[CH:6][N:5]=[CH:4]2)[N:21]=1
Reactant: COc1ccccc1-c1nc(CCl)cs1
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1nc(Cn2cncc2C)cs1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
To a solution of 82 mg of 4-methylimidazole in 10 ml of tetrahydrofuran at 5° C. was added 50 mg of sodium hydride in 50% oil and the resulting mixture stirred at 5° C. for 20 minutes. 2-(o-Methoxyphenyl)-4-chloromethylthiazole (240 mg) in 5 ml of the same solvent was added and the reation mixture heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and treated with 1 ml of water. The water and solvent were removed in vacuo and the residue dissolved in chloroform. The chloroform solution was washed with a brine solution, dried over sodium sulfate and concentrated to give 250 mg of crude product. The product was obtained by chromatography on 7 g of silica gel (chloroform-methanol), 40:1-v:v), 100 mg.
Reaction SMILES: BrC1C=C2C(C=C(C)C(C(OCC3C=CC(OC)=CC=3)C(OCC)=O)=C2[O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14])=CC=1.[C:37]([O:41][CH:42]([C:48]1[C:57]([CH3:58])=[CH:56][C:55]2[C:50](=[CH:51][C:52]([Cl:59])=[CH:53][CH:54]=2)[C:49]=1[OH:60])[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][CH:42]([C:48]1[C:57]([CH3:58])=[CH:56][C:55]2[C:50](=[CH:51][C:52]([Cl:59])=[CH:53][CH:54]=2)[C:49]=1[O:60][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12])[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:38])([CH3:40])[CH3:39]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1O
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2ccc(Br)cc2c1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Cl)cc2c1OS(=O)(=O)C(F)(F)F

Procedure:
Ethyl 2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar manner to ethyl 2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)-naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate of Example 67, except using ethyl 2-tert-butoxy-2-(7-chloro-1-hydroxy-3-methylnaphthalen-2-yl)acetate. 1H-NMR: (400 MHz, CDCl3): δ 8.00 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.65 (s, 1H), 7.49 (dd, J=8.6, 2.0 Hz, 1H), 5.72 (s, 1H), 4.26-4.08 (m, 2H), 2.54 (s, 3H), 1.20 (s, 9H), 1.17 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH:5]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:23]/[CH:24]=[O:25])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: O=Cc1ccc(-n2cccn2)c(F)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-n2cccn2)c(F)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-fluoro-4-(1H-pyrazol-1-yl)benzaldehyde (prepared as described in Reference Example 6) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][C:12](=[O:31])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]34[CH2:30][CH:25]5[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]5)[CH2:22]3)[CH2:28]4)=[CH:17][CH:16]=2)[CH:5]=1.[OH-].[K+].Cl>O1CCOCC1.O>[C:21]12([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]([NH:11][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=4[OH:10])[C:3]([OH:32])=[O:2])=[O:31])=[CH:16][CH:17]=3)[CH2:28][CH:27]3[CH2:29][CH:23]([CH2:24][CH:25]([CH2:26]3)[CH2:30]1)[CH2:22]2
Reactant: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccc1O
Yield: 74.8 %

Procedure:
3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester (151.8 mg, 0.35 mmol) in 1,4-dioxane/H2O (10 ml) was treated with KOH (290.7 mg, 5.18 mmol) at 60° C. for 3 h. The reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH 4:1) to give 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid as a white solid (110.4 mg, 75.10% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(-c3ccncc3)ccc21
Product: CC1c2ccc(-c3ccncc3)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[F:19][C:20]([F:31])([F:30])[S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:26][CH2:25][N:24]([S:21]([C:20]([F:30])([F:31])[F:19])(=[O:22])=[O:23])[CH2:29][CH2:28]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=S(=O)(N1CCNCC1)C(F)(F)F
Product: O=S(=O)(N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1)C(F)(F)F

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and 1-trifluoromethanesulfonyl-piperazine using procedure C yielded 2-chloro-4-morpholin-4-yl-6-(4-trifluoromethanesulfonyl-piperazin-1-ylmethyl)-thieno[3,2-d]pyrimidine. This compound was subjected to procedure A to yield the desired final compound which was purified using flash chromatography
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH3:15])[CH2:3][C:4]1[N:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:7][N:8]=1.C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C>[Br:24][C:7]1[N:8]=[C:4]([CH2:3][C:2]([CH3:1])([OH:16])[CH3:15])[N:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=1
Reactant: CC(C)(O)Cc1nccn1C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)(O)Cc1nc(Br)cn1C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
To a solution of 2-methyl-1-[1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-propan-2-ol (1.12 g, 5 mmol) in DMF (10 mL) at −78° C. was added NBS (0.72 g, 4 mmol) in DMF (pre-cooled to −78° C.). The reaction mixture was warmed to r.t. slowly and stirred at r.t. overnight. The solvent was removed under vacuum and purified by neutral Al2O3 column chromatography (CH2Cl2: MeOH=100:1) to give 0.5 gm of 1-[4-bromo-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-ol (34%). 1H NMR (CDCl3, 400 MHz): δ 7.03 (s, 1H), 5.13 (dd, J=2.6, 9.6 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.82 (d, J=12.0 Hz, 2H), 2.01-1.89 (m, 4H), 1.92 (m, 1H), 1.69-1.60 (m, 3H), 1.24 (m, 6H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([F:27])[CH:23]=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:17][CH2:18]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Reactant: CC1(C)OB(c2cc(F)ccc2OCC2CC2)OC1(C)C
Product: CCOC(=O)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-5-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A39) the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH3:26])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: NCC(O)c1cccc(F)c1
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2cccc(F)c2)cc1
Yield: 39.2 %

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(3-fluorophenyl) ethanamine (1.55 g) and 4{(E)-2-carbomethoxyethenyl}phenylpropan-2-one (2.18 g). Elution with 1% methanolchloroform on Kieselgel 60 gave the title compound (1.4 g) m.p. 75°-110° C. (benzene-heptane) as an ~45:55 mixture of diastereoisomers. τ(CDCl3) 8.9 (3H, d, J=6 Hz), 6.9-7.8 (7H, m, 2H disappears with D2O), 6.25 (3H, s), 5.45 (1H, m), 3.6 (1H, d, J=16 Hz), 2.55-3.2 (8H, m), 2.35 (1H, d, J=16 Hz).
Reaction SMILES: CC[O-].[Na+].C([O:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](OCC)=O)C.O.[NH2:21][NH2:22].Cl>CCO>[OH:7][C:8]1[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][NH:22][N:21]=1
Reactant: NN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]nc1O
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To a solution of NaOEt in EtOH (60 mL, 21 w %) were added diethyl 2-(ethoxymethylene)malonate (10.4 mL, 52.0 mmol) and hydrazine monohydrate (5.04 mL, 104 mmol) with cooling in an ice-water bath. The resulting mixture was then heated at 80° C. for 4 h. After cooling to rt, HCl (1 N, 180 mL) was added to the reaction mixture and then extracted with EtOAc three time. The combined organic layers were washed with brine and dried over Na2SO4. A solid obtained after evaporation was washed with ether and dried under high vacuum to afford the titled compound as an off-white solid (4.42 g), which was used without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[S:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](O)[C:10]=2[CH:9]=1)[CH3:7]>O1CCOCC1>[Cl:3][C:15]1[C:10]2[CH:9]=[C:8]([CH2:6][CH3:7])[S:17][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc2c(O)ncnc2s1
Solvent: C1COCCO1
Product: CCc1cc2c(Cl)ncnc2s1
Temperature: 25 °C
Yield: 42 %

Procedure:
Phosphoryl trichloride (2.3 mL, 3.00 equiv) was added to a solution of 6-ethylthieno[2,3-d]pyrimidin-4-ol (1.5 g, 8.32 mmol, 1.00 equiv) in dioxane (15 mL) dropwise with stirring at room temperature. The resulting solution was stirred overnight at 110° C. in an oil bath. The resulting solution was cooled and quenched by the addition of 100 mL of water and ice mixture. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10) to yield 700 mg (42%) of 4-chloro-6-ethylthieno[2,3-d]pyrimidine as a yellow solid. MS: m/z 199 (M+H)+.
Reaction SMILES: Br.Cl[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]3[CH:22]=2)=[CH:9][C:8]=1[O:23][CH3:24].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]4[CH:22]=3)=[CH:9][C:8]=2[O:23][CH3:24])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: COc1cc(-c2cn3ccc(C)cc3n2)ccc1OCCCCl
Agent: Br
Product: COc1cc(-c2cn3ccc(C)cc3n2)ccc1OCCCN1CCCCC1
Temperature: 25 °C

Procedure:
The product of Step C (184 mg) and piperidine (1.5 mL) were heated at 100° C. for 4 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted twice with additional ethyl acetate (10 mL) and once with dichloromethane (10 mL). The organic portions were combined, washed with brine, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/2M ammonia in methanol) to give the title compound (150 mg). 1H-NMR (CD3OD) δ8.17 (d, J=7.0 Hz, 1H), 7.93 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.26 (s, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.68 (dd, J=7.0 Hz, J=1.5 Hz, 1H), 4.00 (t, J=6.0 Hz, 2H), 3.91 (s, 3H), 2.56 (m, 3H), 2.48 (br. s, 3 H), 2.38 (s, 3H), 1.98 (m, 2H), 1.60 (m, 4H), 1.47 (m, 2H)
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccc(OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1ccc(OC)c(Cl)c1
Yield: 101.8 %

Procedure:
Methyl 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetate (syn isomer) (2.7 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar manner to that of Preparation (5-3) (c) to give crystals of 2-methoxyimino-2-(3-chloro-4-methoxyphenyl)acetic acid (syn isomer) (2.6 g. ), mp 133° to 135° (dec.).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][CH:39]1[C:58](=[O:59])[N:41]2[C:42]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[C:43]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[CH2:44][S:45][C@H:40]12.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:27]([NH:38][CH:39]2[C:58](=[O:59])[N:41]3[C:42]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])=[C:43]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[CH2:44][S:45][C@H:40]23)=[O:29])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=NOC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC3CCCCO3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.362 g of the product of Step C, 0.244 g of tert.-butyl 7-amino-3-acetoxymethyl-ceph-3-eme-4-carboxylate, 0.280 g of dicyclohexylcarbodiimide and 4 ml of dry chloroform was stirred for 2 hours at room temperature and the mixture was vacuum filtered to remove dicyclohexylurea which was rinsed with chloroform. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in 1 ml of ether. The solution was chromatographed over silica gel and was eluted with ether. The fractions with an Rf=0.38 were combined and evaporated to dryness under reduced pressure. The residue was taken up in isopropyl ether and effloresced. The mixture was vacuum filtered and the recovered product was rinsed with isopropyl ether to obtain 0.184 g of the syn isomer of tert.-butyl 7-[2-(2-tritylamino-4-thiazolyl)-2-tetrahydropyranyloxyimino-acetamido]-3-acetoxymethyl-ceph-3-eme-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16]([C:18]1[C:19]([Cl:27])=[N:20][CH:21]=[C:22]([C:24](O)=[O:25])[CH:23]=1)=[O:17])[CH3:14].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:15][C:16](=[O:17])[C:18]1[CH:23]=[C:22]([C:24](=[O:25])[NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[CH:21]=[N:20][C:19]=1[Cl:27])[CH3:14]
Reactant: CCOC(=O)c1cc(C(=O)O)cnc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Reaction time: 2 h

Procedure:
4-Trifluoromethoxyaniline (1.79 mL, 13.3 mmol) was added to a stirred solution of 2-chloropyridine-3,5-dicarboxylic acid ethyl ester (Stage 72.6, 3.20 g, 14 mmol), 1-hydroxybenzotriazole (3.20 g, 20.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.94 g, 15.3 mmol) in DMF (50 mL). The mixture was stirred for 2 h and then treated with EtOAc, washed with a sat. aq. solution of NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 50% EtOAc) and recrystallized from n-hexane/EtOAc to afford the title compound as a colorless crystalline solid. m.p. 135-137° C., HPLC (Condition 4) tR=6.59 min, UPLC-MS (Condition 8) tR=1.24 min, m/z=389.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.35 (t, J=7.23 Hz, 3H), 4.39 (q, J=7.04 Hz, 2H), 7.39 (d, J=8.60 Hz, 2H), 7.76-7.92 (m, 2H), 8.69 (d, J=2.35 Hz, 1H), 9.08 (d, J=2.35 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([OH:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([O:26][C:33]1[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Yield: 26 %

Procedure:
To solution of 2,4-dibenzyloxyphenylacetic acid (2.0 g) and para-nitrophenol (920 mg) in N,N-dimethylformamide anhydride (20 ml) is added drop by drop a solution of of dicyclohexylcarbodiimide (1.2 g) in N,N-dimethylformamide anhydride (10 ml) at 0 ° C. and the mixture is left to stand at room temperature (15 ° C.) for 22 hours. The resulting solution is concentrated under reduced pressure to dryness and thereto is added ethyl acetate (70 ml). The precipitate produced is removed by filtration. The filtrate is concentrated under reduced pressure and the residue is separated and purified by use of a silica gel column [silica gel: 350 ml ; developer : hexane-ethyl acetate mixture (4:1)] to yield para-nitrophenyl 2,4-dibenzyloxyphenylacetate (0.70 g; yield 26%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: CCOC(=O)CBr
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CP(=O)(O)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (1.0 g, 0.005 mole) in chloroform (20 ml) was added triethylamine (1.6 ml, 0.011 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (1.4 ml, 0.011 mole) was added to the above solution dropwise, followed by ethyl bromoacetate (0.84 g, 0.56 ml, 0.011 mole). The ice bath was removed and the mixture stirred at room temperature overnight. The mixture was poured into 10% aqueous HCl (10 ml) and crushed ice HCl (10 ml) and crushed ice (10 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (1.42 g) was vacuum dried to get 1.42 g (99%) of title compound in the form of an oil. TLC: silica gel, CH2Cl2 :MeOH:HOAc shows one main spot, but elongated, Rf =0.29.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[CH2:11]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C=O)c(O)c1
Yield: 36.7 %

Procedure:
2,4-Dihydroxybenzaldehyde (3.00 g, 21.7 mmol) and hexyl bromide (7.62 ml, 54.3 mmol) were stirred in the presence of lithium carbonate (4.00 g, 54.3 mmol) in dimethylformamide (5 ml) at 55° C. overnight. After the neutralization with hydrochloric acid followed by the extraction with ethyl acetate, the product was purified by the silica gel column chromatography to obtain 4-hexyloxy-2-hydroxybenzaldehyde (yield: 1.77 g, 37%) in the form of a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)(=[O:3])[CH3:2].O.[Se](=O)=[O:21].C>O1CCOCC1>[F:18][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[O:21])=[CH:9][C:8]=1[C:10]1[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(F)c(-c2ccccc2C#N)c1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1cc(C(=O)C=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5′-Acetyl-2′-fluorobiphenyl-2-carbonitrile (0.31 g, 1.3 mmol) was suspended in 1,4-dioxane (4.75 ml) and water (0.25 ml) and warmed to 60° C. to solubilise the starting material. The solution was then cooled to ambient temperature, selenium dioxide (0.17 g, 1.55 mmol) added and the mixture heated under reflux for 2 h. The mixture was then allowed to cool to 60° C., activated charcoal (1 g) added and the mixture stirred for 30 min. The mixture was then allowed to cool to ambient temperature, filtered through a glass fibre filter paper and the solid washed with 1,4-dioxane (10 ml) and the filtrate evaporated to give crude 2′-fluoro-5′-(2-oxoacetyl)biphenyl-2-carbonitrile which was used without further purification in the next step.