Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:36][CH2:35][CH2:33][OH:34])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNS(C)(=O)=O)c1=O
Reactant: NCCO
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-{2-[(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (t, J=5.2 Hz, 1 H), 8.55 (s, 1 H), 8.10 (s, 1 H), 7.40 (dd, J=8.2, 5.7 Hz, 2 H), 7.27 (t, J=6.1 Hz, 1 H), 7.13 (t, J=8.8 Hz, 2 H), 4.95 (t, J=5.0 Hz, 1 H), 4.34 (t, J=6.3 Hz, 2 H), 4.14 (s, 2 H), 3.57 (m, 2 H), 3.45 (m, 2 H), 3.24 (m, 2 H), 2.89 (s, 3 H); HRMS C21H23FN4O6S (M+H)+ calcd 479.1322, found 479.1400.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: O.[N+:2]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][S:10][N:11]=[C:7]2[CH:6]=1)([O-])=O>C1COCC1.[Zn]>[N:9]1[S:10][N:11]=[C:7]2[CH:6]=[C:5]([NH2:2])[CH:13]=[CH:12][C:8]=12
Reactant: O=[N+]([O-])c1ccc2nsnc2c1
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2nsnc2c1
Yield: 47.9 %

Procedure:
To a suspension of MOCl5 (8 g) in 50 ml of THF was added 10 ml of H2O and followed by the addition of Zn dust (3 g) 5 minutes later. 5-Nitrobenzo-2,1,3-thiadiazole (1.0 g) was then added to this mixture and the resulting reaction mixture was kept under reflux for 20 minutes. Benzo[1,2,5]thiadiazol-5-ylamine (0.4 g) was isolated by filtration and purified by column chromatography to be used in the next step.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH3:30])[CH:15]=[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:17](=[O:19])[CH3:18].[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].P([O-])(O)(O)=O.[K+]>CCCCCC.O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:18][C:17](=[O:19])[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=1)=[CH:15][N:14]([CH3:13])[CH3:30]
Reactant: CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CN(C)C=C(C(=O)CC(=O)C(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In 175 ml. of dry tetrahydrofuran was dissolved 3.9 g. of diisopropylamine with stirring under nitrogen. The solution was cooled to -65°, and 16 ml. of 2.4 molar n-butyllithium in hexane was added dropwise. The solution was stirred at constant temperature for 40 minutes, and to it was added dropwise 10 g. of 1-dimethylamino-2-(3-trifluoromethylphenyl)-1-butene-3-one dissolved in 50 ml. of tetrahydrofuran, and 25 ml. of hexamethylphosphoramide. The temperature at the end of the addition was -70°. The mixture was stirred for 1 hour at constant temperature and then 4.7 g. of pivaloyl chloride dissolved in 25 ml. of tetrahydrofuran was added dropwise. The mixture was stirred overnight and allowed to warm to ambient temperature. To the mixture was then added saturated potassium dihydrogen phosphate solution to bring its pH to 6, and the quenched reaction mixture was then partitioned between water and diethyl ether. The organic layer was dried over magnesium sulfate and evaporated under vacuum to obtain a dark oil, which was chromatographed on 300 g. of silica gel, eluting with 20% ethyl acetate in dichloromethane. The yield was 3.6 g. of the desired intermediate product.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@H:7]1[CH2:12][N:11](CC2C=CC(OC)=CC=2)[CH2:10][C@@H:9]([OH:22])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C@H:7]1[CH2:12][NH:11][CH2:10][C@H:9]([OH:22])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc(CN2C[C@@H](O)C[C@@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A suspension of 329 (25.5 mmol) and 10% Pd/C (1 mol %) in MeOH (250 mL) was fitted with a balloon of hydrogen and allowed to stir at room temperature for 4 h. At that time, a vacuum was applied to remove any remaining hydrogen, the vessel was purged with nitrogen, diluted with MeOH (100 mL) and filtered through a pad of Celite on a fritted funnel. The resulting solution was concentrated to give 5-(R)-(tert-Butyl-dimethyl-silanyloxy)-piperidin-3-(R)-ol (330) as a colorless oil (25.0 mmol, 98% yield). 1H NMR (400 MHz, CD3OD) δ=0.13 ppm (s, 3H), 0.14 (s, 3H), 0.929 (s, 9H), 1.84 (br t, 2H, J=5 Hz), 2.71–2.78 (m, 2H), 2.97–3.05 (m, 2H), 4.04–4.09 (m, 1H), 4.19–4.24 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:24]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[CH2:20][Br:24])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2CO)c1
Reactant: BrP(Br)Br
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To [3-(4-fluoro-2-hydroxymethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.35 g, 1.15 mmol) in 1,4-dioxane was added phosphorus tribromide (0.14 mL, 1.49 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up, 0.3 g of the desired product was obtained.
Reaction SMILES: C(NC1C=CN([C@@H]2O[C@H](CO)[C@@H](O)C2)C(=O)N=1)(=O)C1C=CC=CC=1.C(NC1C=CN([C@@H]2O[C@H](CO)[C@@H](OC(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)C2)C(=O)N=1)(=O)C1C=CC=CC=1.[C:72]([NH:80][C:81]1[CH:140]=[CH:139][N:84]([C@@H:85]2[O:115][C@H:89]([CH2:90][O:91][C:92]([C:109]3[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=3)([C:101]3[CH:106]=[CH:105][C:104]([O:107][CH3:108])=[CH:103][CH:102]=3)[C:93]3[CH:98]=[CH:97][C:96]([O:99][CH3:100])=[CH:95][CH:94]=3)[C@@:87](C(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)([OH:88])[CH2:86]2)[C:83](=[O:141])[N:82]=1)(=[O:79])[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.O>C(#N)C>[C:72]([NH:80][C:81]1[CH:140]=[CH:139][N:84]([C@@H:85]2[O:115][C@H:89]([CH2:90][O:91][C:92]([C:109]3[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=3)([C:93]3[CH:98]=[CH:97][C:96]([O:99][CH3:100])=[CH:95][CH:94]=3)[C:101]3[CH:106]=[CH:105][C:104]([O:107][CH3:108])=[CH:103][CH:102]=3)[C@@H:87]([OH:88])[CH2:86]2)[C:83](=[O:141])[N:82]=1)(=[O:79])[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@]2(O)C(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: COc1ccc(C(O[C@H]2C[C@H](n3ccc(NC(=O)c4ccccc4)nc3=O)O[C@@H]2CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
Referring to PCT Publication No. WO00/75154, the non-hydrated N4-benzoyl-5′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine (2.00 g), including N4-benzoyl-2′-deoxycytidine, N4-benzoyl-3′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine, and N4-benzoyl-3′, 5′-O-bis(4, 4′-dimethoxytrityl)-2′-deoxycytidine with rates by peak areas of 1.0%, 0.15%, and 2.2%, respectively, was dissolved in acetonitrile (2.3 mL). The solution was added dropwise to water (41 mL) with vigorous stirring and the resultant mixture was stirred for one hour. A white precipitate was recovered by filtration, was washed twice with water and was dried at 50° C. in a vacuum to yield N4-benzoyl-5′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine (1.82 g). The XRD pattern and the DSC thermogram showed neither an absorption peak nor an endothermic peak due to the crystallization, which indicates the resultant components was not crystallized. Moreover, the component contained N4-benzoyl-2′-deoxycytidine, N4-benzoyl-3′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine, and N4-benzoyl-3′, 5′-O-bis(4, 4′-dimethoxytrityl)-2′-deoxycytidine and the respective peak areas were 0.9%, 0.13%, and 1.8%, respectively, which indicates that the above procedure had no substantial effect on the purification.
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[CH3:13])(O)O.[C:14]([N:17]1[C:26]2[C:21](=[CH:22][C:23](OS(C(F)(F)F)(=O)=O)=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC>[C:14]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([C:4]3[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=3[CH3:13])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)N1CCCc2cc(-c3ccc(C(=O)O)cc3C)ccc21
Yield: 104 %

Procedure:
4-Borono-3-methylbenzoic acid (D29) (220 mg, 1.2 mmol), 1-acetyl-1,2,3,4-tetrahydro-6-trifluoromethanesulphonyloxyquinoline (D41, 410 mg, 1.25 mmol), lithium chloride (150 mg, 3.6 mmol) and sodium carbonate (505 mg, 4.7 mmol) were dissolved in a mixture of water (10 ml) and dimethoxyethane (10 ml). The suspension was degassed with argon for 15 mins and then treated with tetrakis (triphenylphosphine)palladium (O) (68 mg). The reaction mixture was heated at reflux for 28 hrs, then concentrated in vacuo. The residue was treated with 10% aqueous Na2CO3 solution and washed with ethyl acetate. The aqueous layer was acidified with 5M HCl and the resultant precipitate was filtered off and dried to afford the title compound as a light brown solid (386 mg, 100%).
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][C:8]#[C:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH:22]=[CH:23][C:24]2[C:32]3[C:27](=[CH:28][C:29]([NH:33][C:34]4[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=4[C:36](O)=[O:37])=[CH:30][CH:31]=3)[N:26]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[N:25]=2)[CH:16]=1>O>[C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][C:8]#[C:9][CH2:10][NH:11][C:36](=[O:37])[C:35]1[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=1[NH:33][C:29]1[CH:28]=[C:27]2[C:32]([C:24]([CH:23]=[CH:22][C:17]3[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[N:18]=3)=[N:25][N:26]2[CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)=[CH:31][CH:30]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCN
Solvent: O
Product: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCC#CCO[Si](C)(C)C(C)(C)C)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 33(a) step (v), in U.S. Pat. No. 6,531,491, issued Mar. 11, 2003, herein incorporated by reference in its entirety for all purposes, except using 4-(tert-Butyl-dimethyl-silanyloxy)-but-2-ynylamine and 2-[3-[2-(4,6-Dimethyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid. 1H NMR (DMSO-d6) δ 9.56 (1H, s), 9.01 (1H, t, J=5.7 Hz), 8.06 (1H, d, J=8.7 Hz), 7.81 (1H, d, J=16.4 Hz), 7.66 (1H, d, J=7.5 Hz), 7.41 (4H, m), 7.32 (1H, s), 7.09 (1H, dd, J=1.8, 8.7 Hz), 6.98 (1H, s), 6.89 (1H, t, J=8.0 Hz), 5.79 (1H, dd, J=2.4, 9.2 Hz), 4.28 (2H, s), 4.09 (2H, m), 3.86(1H,m), 3.72 (1H, m), 2.46 (3H, s), 2.42 (1H, m), 2.30 (3H, s), 2.08 (2H, m), 1.74 (1H, m), 1.57 (2H, m), 0.80 (9H, s), 0.03 (6H, s). Anal. Calcd for C38H47N5O3Si. 0.7 H2O: C, 68.89; H, 7.36; N, 10.57. Found: C, 68.99; H, 7.36; N, 10.21.
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1.Cl[Si:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1.C(O)(=O)C>[Br:12][C:13]1[N:14]=[C:15]([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[Si](C)(C)Cl
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C[Si](C)(C)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
n-Butylmagnesium chloride (4.00 mmol) in 2.00M tetrahydrofuran solution (2.00 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.55M hexane (5.20 mL). The mixture was stirred at 0° C. for 15 minutes, and 2,6-dibromopyridine (2.37 g, 10.0 mmol) in toluene (25 mL) was added thereto below 10° C. over a period of 10 minutes or more. The resultant suspension was stirred at 0° C. for one hour, and chlorotrimethylsilane (13 mmol, 1.65 mL)) was added thereto. After the mixture was stirred at 0° C. for one hour and at room temperature for 1.5 hours, an aqueous solution (20 mL) of 1M acetic acid was added thereto. The reaction mixture was extracted twice with ethyl acetate (50 mL). The organic phase was separated, washed with water (10 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (20:1, v/v) to give the title compound (881 mg, about 38% yield) as colorless powder.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11]([O:14][C:15]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:16]=1[C:17](O)=[O:18])([CH3:13])[CH3:12]>>[N:1]1([C:17]([C:16]2[CH:20]=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:22]=[CH:23][C:15]=2[O:14][CH:11]([CH3:13])[CH3:12])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCCc2ccccc21

Procedure:
Prepared in analogy to example 1.1 from 1,2,3,4-tetrahydro-quinoline (CA [635-46-1]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 373.3 (M+).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:8]1[CH:9]=[C:10]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=O)([CH3:7])([CH3:6])[CH3:5].C([O-])(=O)C.[Na+]>C(O)C>[C:4]([C:8]1[CH:9]=[C:10]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=[N:2][OH:3])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=NO)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
Following the patent procedure of C. G. Luca (US 20050137168), hydroxylamine hydrochloride (355 mg, 5.11 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (from Example 47, Step 1) (1.5 g, 4.64 mmol) and sodium acetate (419 mg, 5.11 mmol) in ethanol (15 mL). The reaction was stirred at room temperature for 16 hours. The mixture was partitioned between water and ethyl acetate and the organic phase separated, dried (Na2SO4), filtered and the solvent removed under reduced pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde oxime (1.3 g, 83% yield).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[OH:2][CH2:3][CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7]1
Reactant: COC(=O)CC1COc2ccccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
At room temperature and while stirring, a solution of 7.22 g (35 mmol) of 3-methoxycarbonylmethylchroman in 50 ml of absolute tetrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 1.33 g (35 mmol) of lithium aluminium hydride in 50 ml of absolute diethyl ether. Stirring is continued at room temperature for a further 16 hours and then the whole is carefully decomposed with 1.33 ml of water, 1.33 ml of sodium hydroxide solution (15% strength) and 4.0 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The solution is washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 6.23 g (100%) of 3-(2-hydroxyethyl)chroman are obtained in the form of a yellow oil.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:62]/[O:63]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([NH:29][C@@H:30]2[C:60](=[O:61])[N:32]3[C:33]([C:44]([O:46]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:45])=[C:34]([S:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:62]/[OH:63])/[C:27]([NH:29][C@@H:30]2[C:60](=[O:61])[N:32]3[C:33]([C:44]([OH:46])=[O:45])=[C:34]([S:37][C:38]4[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccncc2)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(Sc4ccncc4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9 %

Procedure:
To a suspension of diphenylmethyl 7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-(4-pyridylthio)-3-cephem-4-carboxylate (1.37 g, 1.21 m mol) in anisole (2.7 ml) was added trifluoroacetic acid (5.4 ml) at 5° C. and the resulting solution was stirred at room temperature for 4 hours. The mixture was poured into IPE (150 ml) and the precipitates were collected by filtration, washed with IPE and dried in vacuo. The powder was dissolved in water (100 ml) by addition of saturated NaHCO3 aqueous solution. The solution was adjusted to pH 6 by addition of 1N HCl and chromatographed on HP-20 (50 ml) and eluted with 10% aqueous IPA. The eluent was lyophilized and the crude product was purified by preparative HPLC to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-(4-pyridylthio)-3-cephem-4-carboxylic acid (52 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:12]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1oc2cc(O)ccc2s1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1oc2cc(OCc3ccccc3)ccc2s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
Dissolve 6-hydroxy-1,3-benzoxathiol-2-one (16.8 g, 0.1 mol) in THF (1650 mL) and cool to 0° C. Sequentially add benzyl alcohol (16.2 g, 0.15 mol), triphenylphosphine (PPh3, 39.3 g, 0.15 mol), and diisopropylazodicarboxylate (30.3 g, 0.15 mol). Stir the reaction mixture at room temperature overnight. Add water (1500 mL) and extract the aqueous layer with EtOAc (3×1500 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 10-25% of EtOAc/hexane) to give 24.33 g of 6-benzyloxy-benzo[1,3]oxathiol-2-one (94%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li]CCCC>C(Cl)Cl.C1COCC1.CN(C=O)C>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:10])[F:9])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)CCCC(F)(F)F
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCCC(F)(F)F)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 5,5,5-trifluoropentanoic acid (14.76 g, 95 mmol) and DMF (0.146 mL) in DCM (50 mL) was slowly added oxalyl chloride (8.27 mL, 95 mmol). After 2 h, the mixture was concentrated to dryness. A separate flask was changed with (S)-4-benzyloxazolidin-2-one (16.75 g, 95 mmol) in THF (100 mL) and then cooled to −78° C. To the solution was slowly added n-BuLi (2.5M, 37.8 mL, 95 mmol) over 10 min, stirred for 10 min, and then a solution of the above acid chloride in THF (50 mL) was slowly added over 5 min. The mixture was stirred for 30 min, and then warmed to room temperature. The reaction was quenched with sat aq NH4Cl. Next, 10% aq LiCl was then added to the mixture, and the mixture was extracted with Et2O. The organic layer was washed with sat aq NaHCO3 then with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was purified by SiO2 chromatography (ISCO, 330 g column, eluting with a gradient from 100% hexane to 100% EtOAc) to afford the product Intermediate S-1B; (25.25 g, 85%): 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.39 (2 H, m), 7.30 (1 H, d, J=7.05 Hz), 7.18-7.25 (2 H, m), 4.64-4.74 (1 H, m), 4.17-4.27 (2 H, m), 3.31 (1 H, dd, J=13.35, 3.27 Hz), 3.00-3.11 (2 H, m), 2.79 (1 H, dd, J=13.35, 9.57 Hz), 2.16-2.28 (2 H, m), 1.93-2.04 (2 H, m).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1ccc(-c2cc([N+](=O)[O-])ccc2F)cc1

Procedure:
4-Bromobenzonitrile and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled using the procedure described in Example 1 to afford 2′-fluoro-5′-nitrobiphenyl-4-carbonitrile as a brown solid: δH (400 MHz, CDCl3) 7.37 (1H, dd, J 9 and 9), 7.70 (2H, dd, J 8 and 1), 7.80 (1H, dd, J 8 and 1), 8.29-8.33 (1H, m), 8.37-8.40 (1H, m).