Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.N1C(C)=CC=CC=1C.[N+:22]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34](Cl)(=[O:36])=[O:35])([O-:24])=[O:23].Cl>ClCCl.O>[N+:22]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:36])=[O:35])([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)N1CC[C@H](NS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (5 g, 27 mmol) was added to a solution of 2,6-lutidine (6.2 mL, 54 mmol) in dichloromethane (150 ml) under nitrogen. The reaction mixture was cooled down to 0° C. and a solution of 2,4-dinitrobenzenesulphonyl chloride (7.15 g, 27 mmol) in dichloromethane (100 ml) was slowly added over 15 minutes at 0° C. The reaction mixture was then stirred at room temperature for 48 hours under nitrogen. Water (100 ml) was added followed by 2N aqueous hydrogen chloride until the aqueous layer reached pH 2. The layers were then separated and the aqueous layer extracted with more dichloromethane (100 ml). The organic phases were combined, washed twice with water (100 ml), dried over magnesium sulfate and concentrated in vacuo to provide the title compound as a gum, 10 g (89%).
Reaction SMILES: [C:1](=[O:40])([O:36][CH:37](I)[CH3:38])[O:2][CH:3]([CH2:20][O:21][C:22](=[O:35])[C@H:23]([CH:32]([CH3:34])[CH3:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4][O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:41][C:42]([O:44][CH2:45][C:46]1[CH2:67][S:66][C@@H:49]2[C@H:50]([NH:53][C:54](/[C:56](/[C:60]3[N:64]=[C:63]([NH2:65])[S:62][CH:61]=3)=[N:57]\[O:58][CH3:59])=[O:55])[C:51](=[O:52])[N:48]2[C:47]=1[C:68]([O-:70])=[O:69])=[O:43].[Na+]>CN(C=O)C>[C:42]([O:44][CH2:45][C:46]1[CH2:67][S:66][C@@H:49]2[C@H:50]([NH:53][C:54](=[O:55])/[C:56](/[C:60]3[N:64]=[C:63]([NH2:65])[S:62][CH:61]=3)=[N:57]\[O:58][CH3:59])[C:51](=[O:52])[N:48]2[C:47]=1[C:68]([O:70][CH:37]([O:36][C:1]([O:2][CH:3]([CH2:20][O:21][C:22](=[O:35])[C@H:23]([CH:32]([CH3:34])[CH3:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4][O:5][C:6](=[O:19])[C@H:7]([CH:16]([CH3:18])[CH3:17])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:40])[CH3:38])=[O:69])(=[O:43])[CH3:41]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: CC(I)OC(=O)OC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(=O)OC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1

Procedure:
A solution of 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-iodoethyl carbonate (0.156 mmol) and cefotaxime sodium (67.8 mg, 0.142 mmol) in 3.2 mL dry N,N′-dimethylformamide was stirred under argon for 22 h. The reaction mixture was concentrated and subjected to column chromatography (silica, 2/1 petroleum ether-ethyl acetate, and then 20/1 CH2Cl2-methanol) to yield an oil enriched in the desired product. The oil was dissolved in 10 mL ethyl acetate, washed with water, dried, and concentrated. A second chromatography (silica, 40/1 CH2Cl2-methanol) gave the title compound (59.7 mg) as cream-colored solids.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][CH2:20][C:19]3=[O:25])[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][CH2:20][C:19]3=[O:25])[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)C(=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)C(=O)CC2
Yield: 1.4 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-(3-oxo-2,3-dihydro-1H-inden-5-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.177 g; 0.282 mmol), sodium hydroxide 10N (0.282 mL; 2.82 mmol) in methanol (2.8 mL). Purification by preparative HPLC (HPLC method 1) furnished 0.0016 g (1.4%) of the title compound as a brown solid.
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([C:29]([O:32][C:33]([C:39]([O:42]C(C(OC(C(C(F)(F)F)(F)F)(F)F)(C(F)(F)F)F)=O)(F)[F:40])([C:35]([F:38])([F:37])[F:36])[F:34])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[F-].[Na+]>>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([C:26]([C:29]([O:32][C:33]([C:39]([F:40])=[O:42])([C:35]([F:36])([F:37])[F:38])[F:34])([F:30])[F:31])([F:27])[F:28])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: O=C(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [F-]
Agent: [Na+]
Product: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Temperature: 150 °C
Yield: 63.8 %

Procedure:
CF3(CF2)9OCF(CF3)CF2OCOCF(CF3)OCF2CF2CF3 (2.0 g) obtained in Example 23 was charged into a flask together with a NaF powder (0.05 g) and heated at 150° C. for 24 hours in an oil bath with vigorous stirring. At an upper part of the flask, a reflux condenser adjusted to a temperature of 20° C., was installed. After cooling, the liquid sample (1.9 g) was recovered. By GC-MS, it was confirmed that CF3CF(OCF2CF2CF3)COF and the above-identified compound were the main products. The yield was 63.8%.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[N:6]1([CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=O)=[CH:15][CH:14]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>O1CCCC1>[N:6]1([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17](=[O:19])[CH2:2][C:1]#[N:3])=[CH:21][CH:22]=2)[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: CC#N
Reactant: COC(=O)c1ccc(CN2CCOCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 70 °C

Procedure:
To a solution of acetonitrile (1.35 ml) in tetrahydrofuran (80 ml), cooled to 5° C., was added sodium hydride (0.94 g, 60% dispersion in oil). The mixture was stirred for 30 minutes before the addition of a solution of methyl 4-(morpholin-4-ylmethyl)benzoate (5.53 g) in tetrahydrofuran (20 ml). The resulting mixture was heated to 70° C. for 5 h. The mixture was cooled, quenched with saturated ammonium chloride (20 ml) and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give a gum which was purified by column chromatography eluting with a 20–100% ethyl acetate/iso-hexane gradient to give 3-[4-(morpholin-4-ylmethyl)phenyl]-3-oxopropanenitrile (0.97 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH2:18][CH2:19][OH:20])=[CH:5][CH:4]=1.Br.[OH-].[Na+]>>[OH:20][CH2:19][CH2:18][C:14]1[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(CCCCn2ccnc2CCO)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: OCCc1nccn1CCCCc1ccc(O)cc1
Temperature: 0 °C

Procedure:
2.40 g (8.75 mmol) 2-{1-[4-(4-methoxy-phenyl)-butyl]-1H-imidazol-2-yl}-ethanol and 9 ml (81 mmol) 48% aqueous hydrobromic acid were stirred at 80° C. for 12 h. The mixture was cooled to 0° C., 23 ml 4 N NaOH added, extracted with toluene and the aqueous phase adjusted to pH=6.3 by addition of 1 N HCl. The resulting precipitate was isolated, washed twice with water and ethyl acetate and dried. 1.71 g (75%) yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[C:14]([C:18]#[N:19])=[N:15][NH:16][CH:17]=1)=O.[OH-].[NH4+]>[Ni].C(O)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]2[C:13]3[C:14](=[N:15][NH:16][CH:17]=3)[CH2:18][N:19]=[C:4]([C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[F:1])[C:6]=2[CH:11]=1
Reactant: N#Cc1n[nH]cc1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1ccccc1C1=NCc2n[nH]cc2-c2ccc(Cl)cc21

Procedure:
A mixture of 2.0 g (6.1 mmole) of 4-[2-(2-fluorobenzoyl)-4-chlorophenyl]-1H-pyrazole-3-carbonitrile, ca 2 g. of Raney nickel, and 100 ml of acetic acid was hydrogenated on a Parr apparatus for 4 hr. The Raney nickel was removed by filtration and the acetic acid was removed at reduced pressure to give a yellow oil. The yellow oil was poured over ice, basified with ammonium hydroxide, and extracted with methylene chloride. The methylene chloride solution was washed with water, dried with anhydrous sodium sulfate, and concentrated at reduced pressure to give a pale yellow solid. Recrystallization from a mixture of ether and methylene chloride gave cream colored prisms, mp 208°-210°.
Reaction SMILES: [CH2:1]([C:3]1[N:13](CC2C=CC3=C(C=2)OCC2C=CC=CC=2/C/3=C(/C)\C#N)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].OCC1C=CC2=C(C=1)OCC1C=CC=CC=1/C/2=C(/C)\C#N>>[CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)OCc1ccccc1/C2=C(/C)C#N
Agent: C/C(C#N)=C1/c2ccccc2COc2cc(CO)ccc21
Product: CCc1nc2c(C)cc(C)nc2[nH]1
Yield: 369.9 %

Procedure:
[step 1] (E)-2-[3-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (168 mg, 27%) was obtained in the same manner as in step 1 of Example 104, using (E)-2-(3-hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (264 mg, 0.952 mmol) obtained in Reference Example 30 and 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (250 mg, 1.43 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Dissolve aniline (930 mg, 10 mmol) in anhydrous pyridine (25 mL) and cool to 5° C. Add, by dropwise addition, p-toluenesulfonyl chloride (2.1 g, 11 mmol) and stir overnight. Partition between water and ethyl acetate and separate the organic phase. Wash the organic phase with cold 1N hydrochloric acid, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [CH3:1][N:2]([C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.O.[NH2:24][NH2:25]>CCO>[NH:24]([C:7]([C:6]1[CH:11]=[CH:12][C:3]([N:2]([CH3:1])[C:13](=[O:22])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=1)=[O:8])[NH2:25]
Reactant: COC(=O)c1ccc(N(C)C(=O)CCc2ccccc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(C(=O)CCc1ccccc1)c1ccc(C(=O)NN)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of methyl 4-[methyl(3-phenylpropanoyl)amino]benzoate (1600 mg, 5.38 mmol) in EtOH (14 mL) was added hydrazine hydrate (4.0 mL). The resulting mixture was stirred for 16 h at reflux and evaporated under vacuo to give the title compound (1600 mg, 100%) as a gummy colorless oil, which was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24]C)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:30]#[N:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:30]#[N:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OC)cc3N2C)C(=O)N1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 72 h
Yield: 58.4 %

Procedure:
To a suspension of the product of Example 56 (1.06 g, 2 mmol) in DCM (10 mL) was added BBr3 (1.0 M in DCM, 2 mL) dropwise at −78° C. It was warmed to 20° C. slowly and the suspension was stirred for 72 h at 20° C. under N2. MeOH was added to decompose BBr3 at 0° C. Solvent was removed to give a crude, which was purified by chromatography on silica gel eluting with MeOH-DCM (2.5:97.5) to afford the title compound (0.6 g). 1H-NMR indicated one isomer. 1H-NMR (DMSO-d6): δ 9.66 (1H, s), 7.35 (1H, d), 7.13–7.24 (5H, m), 6.99 (1H, d), 6.60 (1H, d), 6.53 (1H, dd), 6.46 (1H, d), 4.96 (2H, s), 4.82(1H, t), 3.58 (3H, s), 2.89 (2H, m), 0.84 (3H, t); MS (ESI): 514 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].C(OCC)(OCC)[O:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)Cl.C(O)CO>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:14][CH2:15][CH2:16][O:3]1
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: ClCCl
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
P-Nitroacetophenone (1.65 g, 10 m mol), ethylene glycol (5 ml, 89 m mol), triethyl orthoformate (2.96 g, 20 m mol), and p-toluenesulfonic acid (0.086 g, 0.5 m mol) were combined in methylene chloride (4 ml). The solution was heated with an oil bath (50°-70° C., 6 hrs), cooled to room temperature, and poured into excess 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phase was washed three times with water and dried with anhydrous sodium sulphate. Evaporation of the solvent left a light yellow product (1.78 g) with mp. 69°-71° C., (lit. 73°-75° C., see J. Pharm. Sci. 57, 784 (1968)).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=O)[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OP([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:46]/[C:47]([O:49][CH2:50][CH3:51])=[O:48])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a mixture of 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (1.50 g), ethyl diethylphosphonoacetate (0.74 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.14 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (2E)-3-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoate as colorless crystals (1.50 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 147-148° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:22])([F:21])[CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1.[OH-].[Na+].Cl.[NH2:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=1)[C:28]([OH:30])=[O:29]>CN(C=O)C.C1COCC1.O.C(Cl)Cl>[F:40][C:39]([F:41])([F:42])[O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][CH:27]([NH:26][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][C:8]([F:7])([F:22])[F:21])=[CH:20][CH:19]=2)[C:28]([OH:30])=[O:29])=[CH:37][CH:36]=1
Reactant: NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1
Yield: 94 %

Procedure:
DMF (three drops) and oxalyl chloride (3.50 mL, 40.0 mmol) were added to a methylene chloride (35 mL) solution of 4-(3,3,3-trifluoropropoxy)benzoic acid (4.68 g, 20.0 mmol) obtained in preparation process of Example 33 (33a), under ice-cooling with stirring. The mixture was stirred at room temperature for 3.5 hours, and then the solvent was evaporated. The obtained residue was dissolved in THF (20 mL). This solution and a 1 M sodium hydroxide aqueous solution (20 mL) were added dropwise simultaneously under ice-cooling with stirring to a solution mixture of a 1 M sodium hydroxide aqueous solution (40 mL) of 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride (5.71 g, 20.0 mmol) prepared in Reference Example 2, water (20 mL), and THF (15 mL). The resulting mixture was stirred under ice-cooling for 70 minutes, and then the solvents (mainly THF) were evaporated. Water was added to the residue, and the resulting mixture was changed to acidic by adding 2 M hydrochloric acid thereto. The precipitated crystalline solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to give 8.75 g of the title compound (white powder, yield: 94%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].Cl.[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][NH2:22])=[N:16]1.C(=O)(O)[O-].[Na+]>O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:22][O:21][CH2:20][C:17]2[CH:18]=[CH:19][O:15][N:16]=2)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: NOCc1ccon1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=CNc1nc(C(=NOCc2ccon2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.8 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)glyoxylic acid (5 g.), (3-isoxazolyl)methoxyamine hydrochloride (4.53 g.), sodium bicarbonate (4.2 g.) and water (200 ml.) was stirred at room temperature for 4 hours, while keeping at pH 5.0. After removing the insoluble substance from the resultant mixture by filtration, the filtrate was adjusted to pH 1.5 with 10% hydrochloric acid and stirred at 5° C. for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-[(3-isoxazolyl)methoxyimino]acetic acid (syn isomer, 5.68 g.), mp 110° C. (dec.).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[OH2:10]>O1CCOCC1>[O:3]1[CH2:8][CH2:7][CH:6]([O:9][C:4](=[O:3])[C@@H:5]([CH3:6])[OH:10])[CH2:5][CH2:4]1
Reactant: OC1CCOCC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](O)C(=O)OC1CCOCC1
Reaction time: 14 h

Procedure:
4.8 g (120 mmol) of 60% sodium hydride in oil (Fluka, pract.) are added at 65° to a solution of 3.06 g (2.85 ml, d=1.074; 29.96 mmol) of tetrahydro-2H-pyran-4-ol (Fluka, pract.) in 100 ml of absolute 1,4-dioxane. The resulting grey suspension is stirred under reflux for 2 hours, is allowed to cool to 65° again and then a solution of 3.25 g (2.59 ml, d=1.25; 29.95 mmol) of S(-)-2-chloropropionic acid (Fluka, puriss.) in 60 ml of absolute 1,4-dioxane is added dropwise over a period of 8 minutes. The resulting brown suspension is diluted with 100 ml of absolute 1,4-dioxane and the batch is heated under reflux for 3 hours, with stirring. Stirring is then continued for a further 14 hours at room temperature. 40 ml of water are then added dropwise to the resulting brown suspension over a period of 2 minutes and the yellow solution obtained is concentrated to dryness by evaporation under a high vacuum. The residue is taken up in 200 ml of water and the aqueous solution is extracted once with 250 ml and once with 150 ml of ethyl acetate. The ethyl acetate extracts are then washed once with 100 ml of water. All the aqueous phases are combined and then acidified with 4N hydrochloric acid (pH 1). The resulting solution is saturated with sodium chloride and extracted twice with 300 ml of ethyl acetate each time. The organic phases are then washed three times with 150 ml of saturated sodium chloride solution each time. All the ethyl acetate extracts are then combined, dried over magnesium sulfate, filtered and concentrated to dryness by evaporation under a high vacuum at 30°. The residue (yellow oil) is purified by bulb tube distillation (b.p. approximately 160° at 0.6 mm Hg). O-(tetrahydropyran-4-yl)-D-lactic acid is obtained in the form of a slightly yellowish oil; [α]D20 =+46.7±0.9° (c=1.058; chloroform). The oil crystallises from ethyl acetate/hexane 1:1 in the form of colourless crystals having a melting point of 68.7°-69.5°; [α]D20 =+48.8±0.8° (c=1; chloroform)
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH3:30].[K+].[Br-]>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(Cl)cc3Cl)cc2)cc1C
Agent: [Br-]
Agent: [K+]
Product: Cc1cc(SCc2ccc(OCc3ccc(Cl)cc3Cl)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 32C. mp 143-145° C.; IR (KBr) cm−1: 3062, 2936, 1724, 1492, 1227, 1192; 400 MHz 1H NMR (DMSO-d6): δ 12.97 (br(s), 1H), 7.64 (d, 1H, J=2.0 Hz), 7.54 (d, 1H, J=8.3 Hz), 7.42 (dd, 1H, J=8.3, 2.0 Hz), 7.01-7.20 (m, 4H), 6.84-6.92 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 5.05 (s, 2H), 4.62 (s, 2H), 4.01 (s, 2H), 2.08 (s, 3H); MS m/z 461 (M−1). Anal. Calc'd for C23H20Cl2O4S: C, 59.62; H, 4.35. found: C, 59.33; H, 4.28.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH2:17]([O:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)[CH3:18]
Reactant: CCI
Reactant: CN(CCO)c1ncc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCCN(C)c1ncc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
(2-Hydroxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine (198 mg, 1 mmol) in THF (15 mL) and DMF (3 mL) was stirred with 60% NaH in oil (60 mg, 1.75 mmol) for 1 hr. The mixture was cooled and to this was added ethyl iodide. The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc was filtered, evaporated to dryness and used without further purification. Yield: 75 mg. ES-MS calcd for C9H14N4O3 (m/e) 226.24, obsd 227 (M+H).