Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:7]=[CH:6]2.C(Cl)(=O)C(Cl)=O.[S:24]1[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[NH:26][CH2:25]1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1.CN(C)C=O.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([N:26]1[CH:27]([C:29]([OH:31])=[O:30])[CH2:28][S:24][CH2:25]1)=[O:16])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reactant: O=C(O)C1CSCN1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(C)C(=O)N3CSCC3C(=O)O)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of 6-methoxy-α-methyl-2-naphthalenacetic acid (4.02 g, 17.5 mmoles) in toluene (30 ml) and N,N-dimethylformamide (0.3 ml) cooled at 0° C., oxalylchloride (2.92 ml, 34.06 mmoles) is added. After 2 hours at room temperature, the solution is evaporated at reduced pressure. The obtained residue is dissolved in acetone (50 ml) and the solution is added to a solution of 4-thiazolidincarboxylic acid (2.33 g, 17.5 mmoles) and triethylamine (6.34 ml, 45.5 mmoles) in acetone (50 ml) cooled at 0° C. After 2 hours the solution is acidified with HCl 4 N, concentrated under vacuum, the residue is treated with ethyl acetate and the organic phase is washed first with HCl 2 N, then with water. The organic phase is anhydrified with sodium sulphate and evaporated at reduced pressure. 4.43 g of the expected product are obtained in the form of a white solid having m.p. 165° C.-168° C.
Reaction SMILES: C([O:14][C:15](=[O:73])[C@H:16]([CH2:35][S:36][CH2:37][CH:38]([O:55][C:56](=[O:72])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[NH:17]C(=O)CCCCCCCCCCCCCCC)(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(Cl)Cl>[C:56]([O:72][NH:17][C@H:16]([C:15]([OH:14])=[O:73])[CH2:35][S:36][CH2:37][CH:38]([O:55][C:56](=[O:72])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])(=[O:55])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71]
Reactant: CCCCCCCCCCCCCCCCC(CSC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(=O)OC(c1ccccc1)c1ccccc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCC(CSC[C@H](NOC(=O)CCCCCCCCCCCCCCC)C(=O)O)OC(=O)CCCCCCCCCCCCCCC

Procedure:
0.2 g of N-palmitoyl-S-[2-(R,S)-palmitoyloxyoctadecyl]-(L)-cysteine benzhydryl ester is dissolved at room temperature in a mixture of 0.4 ml of trifluoroacetic acid and 1.6 ml of methylene chloride and the mixture is allowed to react for 2 hours. The mixture is evaporated to dryness under reduced pressure, the residue is dissolved in chloroform and the chloroform layer is extracted several times with water. After drying with sodium sulfate and evaporation of the solvent there is obtained a crystalline residue, which is dissolved in 2 ml of hot petroleum ether. After addition of 2 ml of ligroin the solution is cooled to -10° and there are obtained crystals of the N-palmitoyloxy-S-[2(R,S)-palmitoyloxyoctadecyl]-(L)-cysteine of melting point 80°-83°.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH:19]([CH3:21])[N:18]2[CH:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:26])[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=O)(C)(C)C.[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][O:26][CH:22]([C:15]2[N:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH2:11][C@H:10]2[N:18]3[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]2)[CH2:23][CH2:24][CH3:25])[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: CCCC(O)c1ccc2c(n1)N1C(C)CN(C(=O)OC(C)(C)C)CC1C2
Product: CCCC(OCC1CC1)c1ccc2c(n1)N1[C@@H](CNC[C@H]1C)C2

Procedure:
(4R,9aR)-6-(1-(RS)-Cyclopropylmethoxy-butyl)-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene di-trifluoroacetate (53 mg) was made from 6-(1-hydroxy-butyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (54 mg), using cyclopropylmethyl bromide (29 μl) in place of methyl iodide, according to the procedure described in Example 63 to afford the product as a colorless oil: HPLC [Xterra; 50/80; 255 nm] 99.6%, 2.29 min; MS (ES) 316.4 (MH+).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:20][CH:21]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34](=[O:58])[NH:35][C:36]4[CH:41]=[CH:40][C:39]([S:42]([CH:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])=[C:38]([CH2:48][N:49](C(OC(C)(C)C)=O)[CH3:50])[CH:37]=4)=[CH:27][CH:26]=3)[C:22]([OH:24])=[O:23])=[CH:16][C:17]=2[F:19])[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.Cl>>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:20][CH:21]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34](=[O:58])[NH:35][C:36]4[CH:41]=[CH:40][C:39]([S:42]([CH:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])=[C:38]([CH2:48][NH:49][CH3:50])[CH:37]=4)=[CH:27][CH:26]=3)[C:22]([OH:24])=[O:23])=[CH:16][C:17]=2[F:19])[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3cc(F)c4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCc1cc(NC(=O)OCCc2ccc(C(Nc3cc(F)c4c(N)nccc4c3)C(=O)O)cc2)ccc1S(=O)(=O)C(C)C
Yield: 132.3 %

Procedure:
Using a procedure analogous to that used in the final step of Example 1, 20A (0.152 g, 0.16 mmol) was deprotected using hydrogen chloride to give 20B (0.132 g, 100%). MS (ESI) m/z 623.97 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](F)=[CH:11][N:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].[CH3:14][O-:15].[Na+].CO>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([O:15][CH3:14])=[CH:11][N:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[O-]
Reactant: CCOC(=O)c1cc(Br)ncc1F
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)ncc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Ethyl 2-bromo-5-fluoroisonicotinate (434 mg, 1.75 mmol) obtained in step 1 was dissolved in methanol (3.50 mL), and the solution was stirred at room temperature for 30 minutes after adding a 28% sodium methoxide-methanol solution (1.69 g, 8.75 mmol). The reaction mixture was extracted with ethyl acetate after adding water. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2-bromo-5-methoxyisonicotinate (154 mg, yield 36%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([O:18][N:17]=[C:7]([C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Product: CC(=O)ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1N
Yield: 54 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (0.1 g, 0.37 mmol) in acetic anhydride was stirred for 2 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (625 mg, 54%). LCMS for C11H10ClFN5O3 (M+H)+: m/z=314.1.
Reaction SMILES: [Na].[Mg].[Br-].[CH:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[CH2:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CCOCC.Cl[Ni]Cl.O>[CH:4]([C:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[CH2:5]
Reactant: C=Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: Cl[Ni]Cl
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cccc(Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a 2 liter three-neck flask equipped with a reflux condenser and a stirrer was added 50 ml of tetrahydrofuran which was dried with metallic sodium and 28 g (1.15 mole) of metallic magnesium and it was maintained with starring at room temperature. Then, a solution of 183 g (1.02 mole) of 3-vinylbenzene bromide in 500 ml of dry tetrahydrofuran was added dropwise over 2 hours to the above contents. The reaction temperature was maintained at 80° C. After the dropping of the solution, the stirring was continued for further 1 hour at 80° C. The thus obtained Grignard reagent solution was added dropwise over 2 hours to the solution of 171 g (1.0 mole) of benzyl bromide and 5.5 g of NiCl2 (Ph2P(CH)3PPh2) in 500 ml of dry ether Stirring was continued for further 1 hour at 35° C. This reaction mixture was poured into iced water and an oily layer was separated. Ether and tetrahydrofuran were evaporated off under reduced pressure to obtain (3-vinylphenyl)phenylmethane of the formula (I) in a yield of 60%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[N+:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:17]2[CH2:18][CH2:19][O:15][C:16]2=[O:20])[CH:11]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1N1CCOC1=O
Yield: 46.9 %

Procedure:
To a mixture of methyl 2-bromo-4-nitrobenzoate (2 g), oxazolidin-2-one (0.67 g), potassium carbonate (2.06 g), copper(I) iodide (0.73 g) and N,N′-dimethylethylenediamine (0.83 mL) was added toluene (16 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give methyl 4-nitro-2-(2-oxo-oxazolidin-3-yl)benzoate (960 mg). To a solution of ethanol (24 mL) and water (5 mL) were added ammonium chloride (0.11 g) and iron (0.79 g), and a solution of the obtained methyl 4-nitro-2-(2-oxooxazolidin-3-yl)benzoate (960 mg) in ethanol (19 mL) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg). Using the obtained methyl 4-amino-2-(2-oxooxazolidin-3-yl)benzoate (730 mg) and 3-chloropropane-1-sulfonyl chloride (0.49 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (495 mg) was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])#[N:8].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[CH2:7][NH2:8]
Reactant: N#Cc1ccccc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccccc1CO
Yield: 99.6 %

Procedure:
Lithium aluminium hydride (17.4 g, 458 mmol) was suspended in dried tetrahydrofuran (300 ml), followed by stirring under ice-cooling in an argon atmosphere. A solution of 2-cyanobenzaldehyde (20.0 g, 153 mmol) dissolved in dried tetrahydrofuran (100 ml) was dropwise and portionwise added thereto and the reaction solution was stirred for 3 hours under heating at reflux. After the reaction, the solution was ice-cooled and sodium sulfate 10 hydrate was portionwise added thereto until foaming and fever ceased. The reaction solution was filtered and the filtrate was concentrated to give the title compound (20.9 g, quantitative) as oily substances. This compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH:11]=O)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[N+:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]#[C-:11])#[C-:1]
Reactant: O=CNCCCCCCNC=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: [C-]#[N+]CCCCCC[N+]#[C-]

Procedure:
1,6-diisocyanohexane was prepared by dehydration of N,N'-diformyl-(1,6-diaminohexane) with p-toluene sulfonyl chloride, essentially as described by Heztler and Covey (N. R. Heztler and E. J. Corey (1918), J. Org. Chem. 23 1222).
Reaction SMILES: [C:1]1([CH:7]2[S:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]1([CH:7]2[S:16](=[O:31])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][C:9]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(C2CC3(CC(c4ccccc4)S2)OCCO3)cc1
Solvent: ClCCl
Product: O=S1C(c2ccccc2)CC2(CC1c1ccccc1)OCCO2
Reaction time: 16 h

Procedure:
23.4 g of 7,9-diphenyl-1,4-dioxa-8-thiaspiro[4.5]-decane are dissolved in 50 ml of methylene chloride and the solution is cooled to -10°. A solution of 16.0 g of m-chloroperbenzoic acid in 200 ml of methylene chloride is added dropwise in the course of about 7 hours, it being ensured that the temperature does not exceed -5°. The reaction mixture is then stirred at 0° for 16 hours and filtered and the residue is washed with 100 ml of methylene chloride. The combined methylene chloride solutions are washed three times with 150 ml of water each time, dried over sodium sulfate and evaporated. The colourless residue is stirred with 100 ml of 2N sodium hydroxide solution for 1 hour, filtered off, washed neutral, dried and crystallized from toluene. 7,9-Diphenyl-1,4-dioxa-8-thiaspiro[4.5]-decane 8-oxide is obtained as colourless crystals of melting point 230°-32°.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.ClCCl>C(Cl)(Cl)(Cl)Cl>[CH3:7][C:6]1([CH3:8])[CH2:5][C:4]2([CH3:10])[CH:3]([CH:13]3[CH:12]2[O:11][CH2:16][CH2:15][CH2:14]3)[C:2](=[O:1])[CH2:9]1
Reactant: C1=COCCC1
Reactant: CC1=CC(=O)CC(C)(C)C1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(=O)C2C3CCCOC3C2(C)C1

Procedure:
To a 5-liter round bottomed flask equipped with a quartz immersion well and nitrogen bubbler was added, under nitrogen, 138 g. (1.0 mol.) of isophorone and 498 g. (5.93 mol.) of 3,4-dihydropyran. Enough dichloromethane was added to fill the flask. The solution was bubbled with nitrogen for 1.5 hours and was irradiated with a 450 watt Hanovia medium pressure mercury arc through a Corning 9700 glass filter for 20.5 hours. When the photolysis was completed, the solution was concentrated in vacuo to yield 107.9 g. (0.486 mol.) of a crystalline solid and 80.6 g. of a liquid (0.363 mol.) (Total yield 0.849 mol., 85%). The solid after sublimation and recrystallization had m.p. 111°-112.2° C. IR: 1690 cm-1NMR: (CCl4) 0.92δ (S-3H), 1.12δ (S-3H); 1.32δ (S-3H); 1.35-2.15δ (multiplets 8H); 2.35δ (triplet-2H, J=14Hz); 2.65-2.93δ (M-1H); 3.38-4.20δ (M-2H). The liquid, which had b.p. 101° C./0.3 mm.Hg. was found by glpc to consist of a lower boiling minor component, the solid and a higher boiling product. Redistillation of this fraction gave a fraction, b.p. 85°-90° C./0.1 mm.Hg. which had a NMR (CCl4) spectrum which had methyl singlets at 0.92δ, 1.03δ, 1.10δ and 1.30δ. The singlet at 1.30δ belonged to the solid component, which made up 34% of the mixture. IR: 1695 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.[CH3:19][NH2:20]>O1CCOCC1.C(O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:5]=[C:4]([Br:18])[N:3]=[C:2]([NH:20][CH3:19])[CH:7]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CN
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69 %

Procedure:
1.45 g (0.0037 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine were dissolved in 40 ml of dioxane and treated with 9.6 ml of 8M methylamine in ethanol. The mixture was stirred at room temperature for 48 hrs., the solvents were removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:3 and 1:2. The product-containing fractions, after concentration, were suspended in 50 ml of diethyl ether, treated in an ultrasound bath for 1 hr., then treated with 75 ml of hexane and the precipitate which thereby resulted was filtered off under suction. After drying in a high vacuum there was obtained 0.87 g (69%) of [4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-methylamine as pale beige crystals; m.p.: 171-173° C.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:21]([OH:23])=O)[N:19]=1)=[O:13].Cl.[NH2:34][CH:35]1[C:60](=[O:61])[N:37]2[C:38]([C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])=[C:39]([CH:42]=[CH2:43])[CH2:40][S:41][C@H:36]12.C[Si](CC(N)=O)(C)C.C(OC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:21]([NH:34][CH:35]2[C:60](=[O:61])[N:37]3[C:38]([C:44]([O:46][CH:47]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:45])=[C:39]([CH:42]=[CH2:43])[CH2:40][S:41][C@H:36]23)=[O:23])[N:19]=1)=[O:13]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCc2ccccn2)C(=O)O)cs1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCc3ccccn3)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a suspension of Vilsmeier reagent, which was prepared from N,N-dimethylformamide (1.8 g) and phosphorus oxychloride (3.7 g), in tetrahydrofuran (60 ml) was added 2-(2-formamidothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetic acid (syn isomer) (6.74 g) under ice-cooling with stirring, and the stirring was continued at the same temperature for 30 minutes to prepare the activated acid solution. This solution was added to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (8.6 g) and trimethylsilylacetamide (15.7 g) in ethyl acetate (100 ml) at -20° C., and the mixture was stirred at -20° to -5° C. for 2 hours. To the reaction mixture were added ethyl acetate and water, followed by separating the ethyl acetate layer. After the ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate and an aqueous sodium chloride, it was dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diisopropyl ether to obtain benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-(2-pyridylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (13.6 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:15]=2[N:16]=1>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: COC(=O)CO
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 54.6 %

Procedure:
To a suspension of 72 mg (3.00 mmol) of sodium hydride in 2 mL of benzene was added 225 mg (2.49 mmol) of methyl glycolate and a solution of 300 mg (0.78 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-[[3-(trifluoromethyl)-phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidine in 2 ml of benzene. The mixture was then heated at 60° C. After 24 hours the reaction was cooled to ambient temperature and an additional 36 mg of sodium hydride and 110 mg of methyl glycolate were added. After 3 days, the reaction was partitioned by the addition of 2 mL of 2 M sodium hydrogen sulfate and 20 mL of ethyl acetate. The organic phase was washed with 10 mL of water, dried with sodium sulfate and concentrated. The product was purified by flash chromatography (30 g silica, methylene chloride-heptane gradient 2:1 to 100:0) to provide 187 mg (54%) of [[2-(methylthio)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.26 (t, J=7.4 Hz, 3H), 2.52 (s, 3H), 2.56 (q, J=7.4 Hz, 2H), 3.79 (s, 3H),5.05 (s, 2H), 5.42 (s, 2H), 6.32 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.44 (s, 1H), 7.51 (d, J=7.8 Hz, 1H)
Reaction SMILES: [C:1]([C@H:4]([C@@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2].[C:11]([NH:15][C:16]([NH2:18])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([NH:15][C:16]([NH2:18])=[O:17])([CH3:14])([CH3:13])[CH3:12].[C:8]([OH:10])(=[O:9])[C@H:6]([C@@H:4]([C:1]([OH:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: CC(C)(C)NC(N)=O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O

Procedure:
The batch 1 D-tartrate of (208), was reconverted to the free base (a necessary part of the chiral assay procedure) using the procedure given above (to give 3.49 g), and the D-tartrate formation procedure was repeated as described to give the batch 2 salt of (208), 4.41 g (92% from D-tartaric acid) (chiral LC: 1.7% at 8.34 min and 96.22% at 8.98 min=96.5% ee after preparative derivatisation as the tert-butylurea (208)).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[N:3]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3ccc(N)nc3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiazol-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.80) (0.30 g, 0.75 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.248 g, 1.13 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.040 g, 11%). MS (ISP) 413.2 [(M+H)+]; mp 191° C.