Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:13].[CH:14]([NH2:17])([CH3:16])[CH3:15]>O>[NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9]([NH:17][CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Br:13]
Reactant: Nc1c(Br)cc(S(=O)(=O)Cl)cc1Br
Reactant: CC(C)N
Solvent: O
Product: CC(C)NS(=O)(=O)c1cc(Br)c(N)c(Br)c1
Temperature: 0 °C

Procedure:
4.0 G. of 4-amino-3,5-dibromobenzenesulfonyl chloride is added to a solution of 34 ml. of isopropylamine in 30 ml. of water. The resultant solution is stirred overnight at room temperature and poured onto 250 ml. of an ice/water mixture. The precipitate is filtered, washed with water and dried. The dried filtrate is recrystallized from isopropanol affording pure 4-amino-3,5-dibromo-N-isopropylbenzenesulfonamide, m.p. 181° to 183° C.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:26]([NH2:28])[CH3:27]>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:28][CH2:26][CH3:27])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 37 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone and 5.0 g of anhydrous sodium sulfate were added. The mixture was heated at 60° C. for 6 hours. Subsequently, sodium sulfate was filtrated off. To the filtrate, 20 g (310 mmol) of 70% ethylamine was added and the same procedure as in Example 1 was performed to obtain 2.0 g of theanine (yield: 37.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]2[O:22][NH:29][C:17](=[O:18])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2Cl)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(Cl)cc1Cl
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Methyl 2-(2,4-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.55 g, 3.85 mmol) was dissolved in MeOH (15.79 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.014 mL, 3.85 mmol) in water (1.579 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.236 mL, 3.85 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (19.91 mL, 119.45 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM and water were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 25-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.870 g, 60.8%) was isolated as a white solid. MS m/z 371 (M+H)+
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23][C:24]1[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(C(=O)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 34 %

Procedure:
To a solution of p-dodecylbenzenesulfonyl chloride (260 mg, 0.75 mmol) in pyridine (3 mL) was added ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (100 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl was added to quench the reaction. The mixture was extracted with ethyl acetate (3×40 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 49:1 to give the product as a solid, mp 96-97° C., in 34% yield (95 mg, 0.20 mmol); 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H, J=6.6 Hz), 1.20-1.35 (m, 21H), 1.57 (m, 2H), 2.60 (t, 2H, J=7.0 Hz), 4.43 (q, 2H, J=7.2 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.77 (d, 2H, J=7.7 Hz); 13C NMR (300 MHz, CDCl3) δ 14.1, 22.7, 29.3, 29.4, 29.6, 29.6, 31.1, 31.9, 35.9, 63.4, 126.6, 128.9, 136.9, 145.8, 159.9, 163.7, 167.9; MS (LCQ, ESI+) Calcd for C23H36N3O4S2 482.2. found 482.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C23H36N3O4S2 482.2140. found 482.2134 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.CCN(CC)CC.Cl[C:42]([O:44][CH3:45])=[O:43].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:42](=[O:43])[O:44][CH3:45])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: COC(=O)Cl
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 22.2 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (40 mg, 0.088 mmol) and DMAP (4 mg, 10%) in dry CH2Cl2 (3 mL), was added Et3N (27 mg, 0.264 mmol). The resulting mixture was cooled to 0-5° C. under ice-water bath, and a solution of methyl chloroformate (41 mg, 0.44 mmol) in dry CH2Cl2 (1 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0˜5° C. After the starting material was disappeared, water (5 mL) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with 10% citric acid (2×10 mL) and brine, dried over Na2SO4, filtered and concentrated to give the residue, which was purified by preparative HPLC to afford methyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylcarbamate (10 mg, 22%). 1H NMR (CDCl3): 1.50 (m, 3H), 2.06 (m, 2H), 2.10-2.32 (m, 4H), 3.10 (m, 1H), 3.05-3.20 (m, 2H), 3.55 (s, 3H), 4.88 (s, 1H), 5.63 (m, 1H), 6.80-6.90 (m, 2H), 6.92-7.01 (m, 4H), 7.21 (m, 1H), 7.25 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CCNCC1
Product: Brc1ccc(-c2nsc3cc(OCCCN4CCCCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Piperidine were converted to yield 3-(4-Bromo-phenyl)-6-(3-piperidin-1-yl-propoxy)-benzo[d]isothiazole as pink oil, MS: 431 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)Nc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCNc2ccccc2)c1
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-N-phenylacetamide (2.0 g, 8.3 mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was added lithium aluminum hydride (1.59 g, 42 mmol) in small portions over a 1 hour period. After 16 hours, the reaction was poured over ice and the crude product extracted with ethyl acetate (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (1.3 g, 69% yield): EI-MS (m/z) 227.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17](O)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:23]=1)([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:34][CH:33]=2)=[C:27]([NH:46][C:47]2[C:48]3[CH:56]=[CH:55][C:54]([CH:57]([CH3:59])[CH3:58])=[N:53][C:49]=3[N:50]=[CH:51][N:52]=2)[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:57]([C:54]1[CH:55]=[CH:56][C:48]2[C:47]([NH:46][C:27]3[CH:26]=[C:25]([NH:24][C:17](=[O:18])[C:16]4[CH:20]=[CH:21][CH:22]=[C:14]([NH:13][C:12]5[C:7]6[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[N:23][C:8]=6[N:9]=[CH:10][N:11]=5)[CH:15]=4)[CH:30]=[CH:29][C:28]=3[S:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:34][CH:33]=3)=[N:52][CH:51]=[N:50][C:49]=2[N:53]=1)([CH3:59])[CH3:58]
Reactant: CC(C)c1ccc2c(Nc3cc(N)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(C)c1ccc2c(Nc3cccc(C(=O)O)c3)ncnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc2c(Nc3cccc(C(=O)Nc4ccc(Sc5ccc(NC(=O)OC(C)(C)C)cc5)c(Nc5ncnc6nc(C(C)C)ccc56)c4)c3)ncnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
To a solution of the product from Example 7B (25.8 mg, 0.084 mmol) in DMSO (2.0 mL) were added the product from Example 2A (40 mg, 0.084 mmol), HATU (31.8 mg, 0.084 mmol), and Hunigs base (56 μL, 0.318 mmol), and the mixture was stirred at room temperature for 24 hours. Additional HATU (39.5 mg, 0.104 mmol), and Hunigs base (50 μL, 0.282 mmol) were added and the reaction was stirred for 48 hours. Added more HATU (39.5 mg, 0.104 mmol) and heated at 45° C. for 8 hours. Added more HATU (39.5 mg, 0.104 mmol) and stirred overnight at room temperature. Water was added and the product was collected by filtration. Purification by chromatography on silica gel eluting with (0% to 5% methanol in dichloromethane) gave the title compound (40 mg, 63% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[CH3:43][O:44][C:45](=[O:60])[C@@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:47][NH2:48].C[Si](C)(C)NC(=O)C>O1CCCC1>[CH3:43][O:44][C:45](=[O:60])[C@@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])[CH2:47][NH:48][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:19]1)=[O:25]
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CC(=O)N[Si](C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a stirred solution of (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidine carboxylic acid (1.0 g) in tetrahydrofuran (20 ml) was added dropwise isobutyl chloroformate (356 μl) and 4-methylmorpholine (300 μl) at −15° C. under a nitrogen atmosphere. To an ice cooled solution of 2(S)-benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (783 mg) and N-(trimethylsilyl)acetamide (1.78 g) in tetrahydrofuran (30 ml) was added dropwise the above solution with stirring under a nitrogen atmosphere. The reaction mixture was allowed to warm to ambient temperature, and stirred for 2 hours, which was partitioned between ethyl acetate and water. The organic layer was separated, washed in turn with water, aqueous 5% KHSO4, aqueous 5% NaHCO3 and brine, and dried over MgSO4. Evaporation of the solvent gave a residue, which was purified by silica-gel column chromatography eluting with n-hexane-ethyl acetate (from 1:6 to ethyl acetate only) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-benzyloxycarbonylamino-β-alanine methyl ester (1.36 g) as a foam, which is the same compound obtained in Preparation 7.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Cl-].[CH3:12][O:13][C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[CH:16]=[N+:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:16]([C:15]1[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=1[O:13][CH3:12])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Reactant: c1coc(-n2cccc2)c1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1-c1ccco1)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-furan-2-yl-1H-pyrrole and 1-(2-methoxy-benzylidene)-piperidinium chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](O)([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>S(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C(C)(O)c1ccc(-c2ccccc2)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 50 °C

Procedure:
The product of Example I (5 g.) was heated under reflux with methanol (50 ml.) and concentrated sulphuric acid (1 ml.) for 4 hours. The product was poured into water, extracted with ether, the ether extracts dried and evaporated to give methyl 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionate, m.p. 59°-61° C. This ester (1 g.) was dissolved in thionyl chloride (5 ml.) and heated on a water bath at 50° C. for two hours. Thionyl chloride was removed and the product was applied to preparative thin layer chromatography plates, eluted with an ether/petroleum (b.p. 62°-68° C.) mixture (5% 95%) and methyl 2-chloro-2-(2-fluoro-4-biphenylyl)propionate recovered. This was dissolved in ethyl acetate (5 ml.) and hydrogenated at room temperature using a 10% palladium/charcoal catalyst (73 mg.) for 16 hours. The solution was filtered and evaporated to give methyl 2-(2-fluoro-4-biphenylyl)propionate, whose structure was confirmed by n.m.r. This was hydrolysed by heating under reflux with aqueous ethanolic potassium hydroxide. The solution was acidified, extracted with ether and then aqueous potassium carbonate (10%) and this extract acidified and the precipitate collected to give 2-(2-fluoro-4-biphenylyl)propionic acid (m.p t. 105°-106° C.).
Reaction SMILES: N([C@:4]1([CH2:19][OH:20])[O:8][C@@H:7]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@H:6]([OH:17])[C@@H:5]1[OH:18])=[N+]=[N-].CO[C:23](OC)([CH3:25])[CH3:24]>CC(C)=O.C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:20][CH2:19][CH:4]1[CH:5]2[O:18][C:23]([CH3:25])([CH3:24])[O:17][CH:6]2[CH:7]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8]1
Reactant: [N-]=[N+]=N[C@]1(CO)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OC2C(CO)OC(n3ccc(=O)[nH]c3=O)C2O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture containing 3.0 g (10.5 mmol) of 4′-azidouridine, 0.05 g (0.26 mmol) p-toluenesulfonic acid monohydrate and 6 mL (48.8 mmol) 2,2-dimethoxypropane in 20 mL acetone was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give the desired product 2.20 g (64%) of as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]1.Br.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[C:4]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:5]=1
Reactant: COc1ccc(C)cc1C1CC(C)(C)CC(C)(C)C1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c(C2CC(C)(C)CC(C)(C)C2)c1
Yield: 47.6 %

Procedure:
To a solution of 1-methoxy-4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)benzene (1.0 g, 3.84 mmol) produced in Example (104b) in acetic acid (5 mL) was added 48% hydrobromic acid (10 mL, 59.3 mmol), followed by reflux for 12 hours. Saturated aqueous solution of sodium hydrogencarbonate was added to the cooled reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate/heptane) to give 450 mg of the title compound as a light yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)[CH3:18].O>CN(C=O)C>[CH2:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[O:9][CH3:10])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(CCl)cc1
Reactant: COc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(COc2ccc(I)cc2OC)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 4-iodo-2-methoxyphenol (90 g) in DMF (450 mL) were added K2CO3 (60 g) and 4-ethylbenzyl chloride (58 g) at RT. The reaction mixture was stirred at 80° C. for 3 hr. Water (900 mL) was added to the reaction mixture. The precipitated solid was collected on a filter and dried under reduced pressure. The suspension of this solid in heptane (520 mL) was stirred at RT. The precipitated solid was collected on a filter and dried under reduced pressure to give the title compound (115 g, 87%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH3:10])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>O.C(O)(=O)C>[CH2:9]([NH:8][C:4]1[CH:3]=[C:2]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[N:7]=[CH:6][N:5]=1)[CH3:10]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCNc1cc(Cl)ncn1
Solvent: CC(=O)O
Solvent: O
Product: CCNc1cc(Nc2ccc(N3CCN(C)CC3)cc2)ncn1
Temperature: 100 °C
Yield: 60.5 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-ethyl-amine (363 mg, 2.30 mmol, 1.1 eq.) and 4-(4-methylpiperazin-1-yl)-aniline (400 mg, 2.09 mmol) in water (0.8 ml) and glacial acetic acid (3.2 ml) is heated to 100° C. 3 h. After solvent evaporation, the residue is taken up in methanol, made alkaline by addition of 25% NH3 in water and concentrated. The residue is purified by MPLC (silica gel) (DCM/MeOH) to afford 395 mg of the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR=1.25 min (purity: ˜90%, gradient J); TLC: Rf=0.12 (DCM/MeOH, 9:1).
Reaction SMILES: C1([NH:7][CH2:8][C:9](O)=[O:10])C=CC=CC=1.C(OC(N([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)CC(O)=O)=O)(C)(C)C.[NH2:31][CH:32]1[C:53](=[O:54])[N:34]2[C:35]([C:50]([OH:52])=[O:51])=[C:36]([CH:39]([S:44][C:45]3[NH:49][N:48]=[N:47][N:46]=3)[CH2:40][C:41]([OH:43])=[O:42])[CH2:37][S:38][C@H:33]12>>[NH2:7][CH:8]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[C:9]([NH:31][CH:32]1[C:53](=[O:54])[N:34]2[C:35]([C:50]([OH:52])=[O:51])=[C:36]([CH:39]([S:44][C:45]3[NH:46][N:47]=[N:48][N:49]=3)[CH2:40][C:41]([OH:43])=[O:42])[CH2:37][S:38][C@H:33]12)=[O:10]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12
Reactant: O=C(O)CNc1ccccc1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(O)cc1
Product: NC(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12)c1ccc(O)cc1
Yield: 5 %

Procedure:
Japanese Patent Application Laid-open No. 54580/1976 discloses a prior art preparation process of a compound represented by the general formula (I) by reacting its corresponding phenylglycine derivative with 7-aminocephem derivative. According to the above prior art process, N-t-butoxycarbonyl-p-hydroxyphenylglycine is reacted with 7-amino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and the protecting group is then removed from the resultant reaction product to give 7-(α-amino-4-hydroxyphenylacetamido)-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid. In other words, the p-hydroxyphenylglycine is caused to undergo a reaction after its amino group has been protected with a t-butoxycarbonyl group. According to the above known literature, the above prior art process provided an extremely low yield, i.e., a yield of as low as about 5%.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1[S:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[Cl:20]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:20][C:5]1[S:6][C:7]([S:8][CH2:9][CH2:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]([CH2:2][Cl:1])[N:4]=1
Reactant: O=S(=O)(CCSc1scnc1CCl)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(CCSc1sc(Cl)nc1CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of 4-chloromethyl-5-(2-phenylsulfonylethyl)thio-1,3-thiazole (400 mg, 1.2 mmol) in N,N-dimethylformamide (3 mL) was added N-chlorosuccinimide (160 mg, 1.2 mmol), and the mixture was stirred at room temperature for 16 h. The resulting mixture was poured into water and extracted with ethyl acetate. The organic solution was washed with water, dried over sodium sulfate, and concentrated; The residue was chromatographed (silica gel, 20% ethyl acetate-hexane), affording 260 mg of the title compound. 1H NMR (CDCl3) δ 3.09 (2H), 3.36 (2H), 4.60 (2H), 7.5-7.9 (5H).