Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[C-:25]#[N:26].[Na+].O>CS(C)=O>[C:25]([CH:6]([CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])#[N:26]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(C#N)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of 2-[(tert-butoxycarbonyl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}ethyl methanesulfonate (10 g) in dimethyl sulfoxide (100 ml) was added sodium cyanide (2 g) at room temperature and the whole mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residual oil was purified by column chromatography on silica gel (ethyl acetate:hexane=1:5) to give di-tert-butyl (2-cyano-1,3-propanediyl)biscarbamate (4.04 g).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:16]([O:18]C)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Li+].[OH-]>CO>[CH3:15][O:14][C:12]([C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][O:9][C:10]=1[C:16]([OH:18])=[O:17])=[O:13]
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)noc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of dimethyl 3-phenylisoxazole-4,5-dicarboxylate (770 mg, 2.95 mmol) in MeOH (15 mL)/water (5.00 mL) at rt was added LiOH, hydrate (124 mg, 2.95 mmol) and the reaction mixture was allowed to stir at rt for 1 hr. The MeOH was removed in vacuo and the remaining aqueous solution was diluted with water (5 mL). The pH was adjusted to <1 with 1N HCl and the mixture was extracted with EtOAc (40 mL). The organic layer was washed with brine (25 mL), dried (MgSO4) and concentrated to afford 4-(methoxycarbonyl)-3-phenylisoxazole-5-carboxylic acid (709 mg, 2.87 mmol, 97% yield) as a colorless oil. HPLC retention time=1.99 minutes (YMC Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=248.13. 1H NMR (400 MHz, chloroform-d) δ ppm 3.89 (s, 3H) 7.51 (m, 5H).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:16]([O:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[O:31][CH3:32])[C:17]#[CH:18]>C(OCC)(=O)C>[CH:1]1([CH2:7][NH:8][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([O:31][CH3:32])[C:20]([O:19][CH2:16][C:17]#[CH:18])=[C:28]([O:29][CH3:30])[CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1c(OC)cc(C(=O)NCC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of 3.6 g of cyclohexylmethylamine, 3.5 g of triethylamine and 10 ml of ethyl acetate was added dropwise under ice cooling to a mixture of 75 ml of ethyl acetate and 7.4 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and it was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.7 g of N-cyclohexylmethyl-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 1 of the present invention) represented by the formula:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[F-:25].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([F:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Solvent: O
Product: F[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of (R)-1-benzyl-3-pyrrolidinol-tosylate (3.06 g, 9.24 mmol) in THF (30 ml) was added 1.0M solution of tetrabutylammonium fluoride in THF (37.0 ml, 37.0 mmol) at room temperature. After 1.5 h stirring at reflux temperature, water (150 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 ml×2). The combined extract was washed with water, brine, dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel: 80 g, CH2Cl2/MeOH: 50/1) to afford 1.18 g (71%) of brown oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][CH:19]([C:21](O)=[O:22])[CH3:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C@H:19]([C:21]([NH:9][C:7](=[O:8])[C@@H:2]([NH2:1])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:22])[CH3:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: CCCC[C@H](N)C(N)=O
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Product: CCCC[C@H](N)C(=O)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-norleucine amide (prepared from BOC-L-norleucine amide (from Example F above) using General Procedure F) and N-(3,4-dichlorophenyl)-D,L-alanine, the title compound was prepared as a solid (mp=156-161° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([CH3:10])[C:6]([NH:8][CH3:9])=[O:7])=[O:4].[CH2:11]=O.Cl>>[O:7]=[C:6]1[N:5]([CH3:10])[C:3](=[O:4])[N:2]([CH3:11])[CH2:1][N:8]1[CH3:9]
Reactant: C=O
Reactant: CNC(=O)N(C)C(=O)NC
Agent: Cl
Product: CN1CN(C)C(=O)N(C)C1=O

Procedure:
145 g (1 mol) of 1,3,5-trimethyl-biuret and 30 g of paraformaldehyde are heated together with 5 ml of concentrated hydrochloric acid to 70° C for 5 hours. The liquid contents of the flask are then poured onto a dry metal sheet and, after solidification, recrystallised from cyclohexane. This gives 154 g (98%) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-s-triazine of melting point 88° C to 90° C.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19]I>CCO>[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19][S:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCI
Reactant: O=C(O)c1ccc(S)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(SCCC(F)(F)F)nc1
Yield: 56.7 %

Procedure:
To a stirred solution of 6-sulfanylpyridine-3-carboxylic acid (0.5 g, 3.22 mmol) in EtOH (50 mL) at 0 C was added sodium acetate (0.26 g, 3.22 mmol) and 1,1,1-trifluoro-3-iodopropane (0.72 g, 3.22 mmol) and the mixture was heated at 80 C for 24 h. The mixture was concentrated under vacuum, water was added and the mixture was acidified to pH 4 using acetic acid. The resultant yellow precipitate was collected by filtration and purified by FCC, eluting with 2% MeOH in DCM to afford the title compound (0.459 g, 57%). Method B HPLC-MS: MH+ requires m/z=252 Found: m/z=252, Rt=1.84 min (91%).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.N.O>O1CCCC1>[C:1]([C:3]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:5]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:25])=[O:20])=[CH:21][CH:22]=2)[CH:4]=1)#[N:2]
Reactant: N#Cc1cn(-c2ccc(C(=O)O)cc2)cc1-c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cn(-c2ccc(C(N)=O)cc2)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 4-(3-cyano-4-phenylpyrrole-1-yl)benzoic acid (0.14 g) in tetrahydrofuran (2 5 mL) was added 1,1′-carbonyldiimidazole (0.16 g). After stirring for 30 minutes, to this reaction mixture was added aqueous ammonia (28% solution 0.75 mL), and this mixture was stirred 2 hours. To this reaction mixture was added water (10 mL), the precipitated white solid was collected by filtration, and wash with methanol, dried to give the title compound (0.13 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:23])CC.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:15][F:23])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(CO)(c2cccc(Br)c2)N1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1COCC(CF)(c2cccc(Br)c2)N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 5-(3-bromo-phenyl)-5-hydroxymethyl-morpholin-3-one (2.6 g, 9.09 mmol) and 120 ml of dichloromethane was cooled to 0° C. DAST (1.26 ml) was added dropwise. The mixture was stirred overnight, poured onto 50 ml of 10% aqueous Na2CO3 solution and ice and extracted with dichloromethane. The extract was dried with sodium sulfate and evaporated. Chromatography on silica gel (EtOAc/hexane=1:1) gave the title compound in the form of a colourless solid. TLC (hexane/EtOAc=1:1): Rf=0.31; HPLC: RtH2=3.13 min; 1H-NMR (400 MHz, CD3OD): 7.71 (s, 1H), 7.56 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 4.77 (d, 2H), 4.20 (s, 2H), 4.11 (d, 1H), 3.95 (d, 1H); MS: 289, 291 [(M+H)+].
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].Cl.[C:18]1([CH:24]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@H:25]([NH2:48])[CH:26]=[CH:27][S:28]([CH:31]=[CH:32][C@@H:33]([NH2:47])[CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:30])=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:49]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:25]([NH:48][C:4](=[O:5])[C@H:2]([CH3:3])[NH:1][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:26]=[CH:27][S:28]([CH:31]=[CH:32][C@@H:33]([NH:47][C:4](=[O:5])[C@H:2]([CH3:3])[NH:1][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)(=[O:30])=[O:29])[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: N[C@H](C=CS(=O)(=O)C=C[C@@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
Cbz-Ala-Phe-VS-Ph was prepared from Cbz-Ala-OH and Phe-VS-Ph.HCl using standard mixed anhydride coupling method, yield 88%. 1H-NMR (CDCl3) δ 1.25 (d, 3H, Ala-CH3), 2.91 (dq, 2H, CH2-Phe), 4.10 (m, 1H, α-H), 4.80-4.90 (m, 1H, α-H), 5.10 (s, 2H, Cbz), 6.34 (b, 1H, NH), 6.39 (d, 1H, CH═), 6.90-6.98 (dd, 1H, CH═), 7.10-7.39 (m, 10H, 2×Ph), 7.55 (t, 2H, SO2-Ph), 7.65 (t, 1H, SO2-Ph), 7.91 (d, 2H, SO2-Ph). 13C NMR (400 MHz, CDCl3) δ 172.1, 156.3, 144.4, 140.8, 135.7, 134.2, 133.6, 131.2, 129.5, 129.4×3, 129.3, 128.8×2, 128.7, 128.6, 128.4, 128.3, 127.8, 127.3, 126.9, 67.6, 51.7, 51.6, 40.2, 19.4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[BH4-].[Na+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)CCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of 2,3-dihydrobenzofuran-5-carbaldehyde (30.0 g, 0.202 mol) in methanol (150 mL) was added sodium borohydride (3.83 g, 0.101 mol) under ice-cooling. The mixture was stirred for 15 minutes at ambient temperature and then diluted with water. The product was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the title compound (yield 27.6 g, 91%) as an oily product.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20](O)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31]>>[CH:14]1([N:10]2[C:8]3[N:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:20]([NH:23][CH2:24][C:25]4[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=4[CH3:31])=[O:21])[C:7]=3[C:12]([CH3:13])=[N:11]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1nn(C2CCCCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCCCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 6-cyclopropyl-1-(1-cyclohexyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.501 mmol), and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (123 mg, 0.651 mmol). The product was collected as a solid, 0.190 g (87%). LCMS E-S (M+H)=434.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.07 (m, 4H), 1.15-1.31 (m, 1H), 1.36-1.52 (m, 2H), 1.68 (br. s., 1H), 1.77-1.99 (m, 6H), 2.11 (s, 3H), 2.18-2.29 (m, 4H), 2.35 (s, 3H), 4.33 (d, J=4.80 Hz, 2H), 4.53-4.73 (m, 1H), 5.87 (s, 1H), 6.96 (s, 1H), 8.58 (t, J=4.93 Hz, 1H), 11.51 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[H-].[Na+].[CH2:10]([O:17][C:18](=[O:21])[CH2:19]Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18](=[O:21])[CH2:19][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)C(CC(=O)OCc1ccccc1)C(C)=O
Yield: 51 %

Procedure:
10 grams acetylacetone were reacted with 5 grams of a 50% suspension of sodium hydride in paraffin oil and with 25 grams bromoacetic acid-benzylester in accordance with a procedure analogous to that set out in Example (2b). 3,3-diacetyl-propionic acid-benzylester having a Kp0.005 of 126°-128° C. was obtained. This substance was further reacted with phenylhydrazine by a procedure analogous to that set out in Example (2c). 3,5-dimethyl-1-phenyl-pyrazol-4-acetic acid-benzylester, having a Kp0.001 of 205°-209° C., was obtained in a yield of 51%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])/[C:6](/[NH:18][C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:36])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:22][C:21]=1[Cl:37])=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2>CO.O1CCCC1>[Cl:37][C:21]1[CH:22]=[C:23]([CH:26]([OH:36])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH:24]=[CH:25][C:20]=1[C:19]([NH:18]/[C:6](=[CH:7]\[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)/[C:5]([OH:39])=[O:4])=[O:38]
Reactant: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
An aqueous solution of sodium hydroxide (1N; 0.5 mL, 0.5 mmol) was added to a solution of rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (Example 228; 82 mg, 0.16 mmol) in methanol/tetrahydrofuran (1:1; 2 mL). The solution was stirred at room temperature for 16 h and the solvent was evaporated. Water (3 mL) was added and the mixture was acidified with 1N hydrochloric acid solution (0.25 mL). The precipitated solids were recovered by filtration, washed with water, dried and crystallized from tetrahydrofuran/methanol/water to give rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid (53 mg, 66% yield) as a colorless solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12].[Cl:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:18][CH2:17][O:16][CH2:15][CH2:14][Cl:13]
Reactant: ClCCOCCCl
Reactant: COc1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOCCCl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a suspension of 9.6 g. of 50% sodium hydride in 250 ml. of dry dimethylformamide was added in portions 31.6 g. of 2-chloro-4-methoxyphenol. To this mixture was added 143 g. of bis(2-chloroethyl) ether, and the reaction mixture was heated at reflux with stirring for eight hours. The volatile solvent was removed, the residue partitioned between water and methylene dichloride, and the organic solution washed with water and dried over anhydrous magnesium sulfate. The product was twice distilled to give 2-[2-(2-chloro-4-methoxyphenoxy)ethoxy]ethyl chloride, b.p. 139°-140° C. (0.05 mm.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:32]1[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 96 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 96%). 1H NMR (300 MHz, DMSO-d6): δ 3.57-3.65 (m, 8H), 4.17 (s, 3H), 7.05 (d, J=9.5 Hz, 2H), 7.55 (dd, J=8.9 and 2.2 Hz, 1H), 7.74-7.79 (m, 2H), 8.08 (d, J=9.4 Hz, 2H), 9.40 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[NH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[C:4]([CH2:5][CH2:6][CH2:7][NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22])([O:3][CH2:1][CH3:2])=[O:9]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1cc(OC)c(OC)cc1C(C)=O
Temperature: 110 °C
Yield: 62 %

Procedure:
Ethyl-4-bromobutyrate (190.7 g, 978 mM) was added with stirring to 2'-amino-4',5'-dimethoxyacetophenone (31.8 g, 163 mM) in triethylamine (33.9 mM) and the reaction mixture was heated at 110° C. for one hour. After cooling to room temperature 100 mL of 2% NaHCO3 was added and the reaction mixture was stirred for sixteen hours. A yellow solid formed which was dissolved in CHCl3 (250 mL). The aqueous phase was extracted with CHCl3 (4×200 mL), the organic extracts were combined and dried over MgSO4, filtered, and the solvent removed in vacuo to give a semisolid residue. The residue was chromatographed on SilicAR CC-7 and the appropriate fractions were crystallized upon standing from ether to afford the title compound in 62% yield, ,mp 74°-76° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:14]([CH:18]([O:20][C:21](=[O:23])[CH3:22])[CH3:19])[CH2:15][S:16](=O)[C@H:11]12)=[O:8].C(Cl)(=O)C>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:25])=[C:14]([CH:18]([O:20][C:21](=[O:23])[CH3:22])[CH3:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 105.8 %

Procedure:
Similarly, polar isomer B of diphenylmethyl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate 1-oxide (69 mg) is reduced with stannous chloride dihydrate (66 mg) and acetyl chloride (0.28 ml) in N,N-dimethylformamide (2.1 ml) for 15 minutes to give stereoisomer B of diphenylmethyl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate (71 mg). m.p. 72°-80° C. Yield: 83.4%. IR: νmaxCHCl 3 3396, 1787, 1731, 1687, 1508 cm-1. NMR: δCDCl 3 1.27d(6.5Hz) 3H, 1.88s3H, 3.40br-s2H, 3.83s2H, 4.95d(5Hz)1H, 5.72q(9;5Hz) 1H, 6.11q(6.5Hz)1H, 6.48d(9Hz)1H, 6.9-7.5m14H.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].CCOC(C)=O>N1C=CC=CC=1>[C:21]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH:12]=[C:11]([CH2:13][O:14][C:27](=[O:29])[CH3:28])[N:10]=[CH:9]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 48 h

Procedure:
The alcohol from Step B (260 mmol, prepared above) was suspended in pyridine (500 mL). Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into EtOAc, washed sequentially with water, 5% aq. HCl solution, sat. aq. NaHCO3, solution, and brine. The organic extracts were dried, (Na2SO4), and concentrated in vacuo to provide the product as a white powder, which was sufficiently pure for use in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.[CH3:10][O:11][C:12](=[O:32])[C:13]1[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:21]1[CH:22]=[C:13]([C:12]([O:11][CH3:10])=[O:32])[CH:14]=[CH:15][C:16]=1[C:17](=[O:18])[NH:8]2
Reactant: COC(=O)c1ccc(C(=O)OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1nccc(Cl)c1I
Product: COC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine and 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-terephthalic acid dimethyl ester to provide 277. LC-MS (M+H=289, obsd.=289).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[F:15].[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([N:23]=[C:24]=S)[CH:22]=1>CO>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([NH:23][C:24]2[O:8][C:7]3[CH:6]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[C:3]([F:15])[C:2]=3[N:1]=2)[CH:22]=1
Reactant: Cc1ccc(F)cc1N=C=S
Reactant: CCOC(=O)Cc1cc(O)c(N)c(F)c1
Solvent: CO
Product: CCOC(=O)Cc1cc(F)c2nc(Nc3cc(F)ccc3C)oc2c1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
Under stirring at room temperature, ethyl 4-amino-3-fluoro-5-hydroxyphenylacetate (233 mg, 1.10 mmol) was added to a solution of 5-fluoro-2-methylphenyl isothiocyanate (184 mg, 1.10 mmol) in methanol (20 ml). The resulting mixture was stirred at 70° C. for 1 hour. To the reaction mixture was added mercuric oxide (yellow) (262 mg, 1.21 mmol), followed by stirring for further 30 minutes. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was washed with methanol and then, distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/methanol (10/1) eluate fractions, ethyl (2-(5-fluoro-2-methylphenylamino)-4-fluoro-6-benzoxazolyl)acetate (216 mg, 57%) was obtained as a pale yellow solid.