Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(C(C=C(N[CH2:12][CH:13]([OH:29])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]CCOCCC)=[CH:18][CH:17]=2)C)=O)=CN=1.[C:32]1([CH:39]=CC(O)=[CH:35][CH:34]=1)O.[CH2:40]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51]C=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1OC1>>[CH2:13]([OH:29])[CH2:14][OH:15].[CH2:14]([O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:53]2[CH:54]=[CH:49][C:48]([O:47][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:51][CH:52]=2)=[CH:20][CH:21]=1)[C:13]1[CH:12]=[CH:35][CH:34]=[CH:32][CH:39]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCCOCCOc1ccc(OCC(O)CNC(C)=CC(=O)c2ccc(C)nc2)cc1
Reactant: c1ccc(COCc2ccccc2)cc1
Solvent: C1CO1
Product: OCCO
Product: c1ccc(COc2ccc(Oc3ccc(OCc4ccccc4)cc3)cc2)cc1

Procedure:
The 1-(2-[6-methyl-nicotinoyl]-1-methyl-vinylamino)-3-(p-[2-n-propoxy-ethoxy]-phenoxy)-propan-2-ol of the formula ##STR146## required as reactant can be prepared as follows: a. 450.0 g. of hydroquinone-monobenzylether and 20.0 g. of potassium tertiary butylate are heated to 105° C. in an autoclave holding 700 ml. 19.4 g. of ethylene oxide each are pressed, while stirring, into the autoclave five times at half-hour's intervals. After a further one-hour stirring at 105° C. the reaction is complete. By recrystallizing the reaction product from isopropanol, 477.5 g. of ethyleneglycol-mono-(4-benzyloxy-phenyl)-ether of the formula ##STR147## are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])=[O:4].[O:13]=[CH:14][C@H:15]([C@@H:17]([C@H:19]([C@H:21]([CH2:23]O)[OH:22])[OH:20])[OH:18])[OH:16]>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH2:14][C:15]([C@@H:17]([C@H:19]([C@H:21]([CH3:23])[OH:22])[OH:20])[OH:18])=[O:16]
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C(CO)[C@H](O)[C@@H](O)[C@@H](O)CO
Product: C[C@H](O)[C@H](O)[C@@H](O)C(=O)CO
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@H](O)C=O

Procedure:
The present inventors already publicly report that K. pneumonia 40bXX catalyzes the conversion from L-fructose to L-glucose. By the same method, attempts were made to produce 6-deoxy L-glucose from 6-deoxy L-fructose (the product at the previous step). K. pneumonia 40bXX was cultured in a culture medium containing 0.5 w/v % polypeptone, 0.5 w/v % yeast extract, and 0.5 w/v % salt as supplemented with MnCl2 (1 mM). After 24-hour incubation, the culture was centrifuged at 1200×g for 10 minutes, to recover the bacterial cells. The recovered bacterial cells were washed twice with 50 mM glycine-NaOH buffer (pH 9.0), and then centrifuged at 1200×g for 10 minutes. The washed bacterial cells were disrupted with a motor, to which activated alumina was added for grinding the bacterial cells to recover a crude enzyme. The partially purified enzyme D-AI (400 U) is preliminarily adjusted with 50 mM glycine-NaOH, and then immobilized on 30 g (wet weight) of Chitopearl BCW 2510 for use in the reaction. The rearrangement reaction was progressed in an L-tube containing 1% 6-deoxy L-fructose, the immobilized D-AI (40 U), 50 mM Tris-HCl buffer (pH 9.0) and MnCl2 (to a final concentration: 1 mM) at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[CH2:10](Cl)Cl.[OH2:13]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][CH2:6][CH:10]=[O:13]
Reactant: C=Cc1cccc(Cl)c1
Reactant: O
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CCCc1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
To a 25° C. solution of 3-chlorostyrene in anhydrous CH2Cl2 ( 10.0 g, 72.15 mmol) was added a well-stirred solution of Pb(OAc)4 (35.2 g, 79.4 mmol) in trifluoroacetic acid (150 mL), dropwise. Reaction was completed within 30 minutes of the addition and after being stirred for a further 30 minutes, the mixture was poured into water, extracted with ether (3×), the combined organic layers were washed with saturated NaHCO3 solution, water, dried (MgSO4), and concentrated to a volume of about 15 mL and immediately used for the following reaction described below.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([C:7]([O:9]C)=O)[NH:4][N:3]=1.CO.[NH3:13]>>[Br:1][C:2]1[N:6]=[C:5]([C:7]([NH2:13])=[O:9])[NH:4][N:3]=1
Reactant: N
Reactant: COC(=O)c1nc(Br)n[nH]1
Solvent: CO
Product: NC(=O)c1nc(Br)n[nH]1

Procedure:
A solution of methyl 3-bromo-1H-1,2,4-triazole-5-carboxylate from Step 1 (250 mg, 1.21 mmol) in 7M ammonia in methanol (4 mL, 28 mmol) was heated at 125° C. under microwave conditions for 40 minutes. The reaction solution was concentrated under vacuum to give the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]([CH2:15][OH:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C@@H:9]1[CH2:10][CH2:11][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[CH:13]([CH2:15][OH:16])[NH:14][C:25]1=[O:27])[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(N)CO)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)C(CO)NC1=O
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution (5S)-N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-(hydroxymethyl)-D-lysine (180 mg, 0.37 mmol) in DCM (5 mL) were added EDC (106 mg, 0.55 mmol) and HOAT (50 mg, 0.37 mmol). After 30 min, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (0%→10% MeOH/DCM) to give the title compound (100 mg). MS 471.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4][CH:3]=1.C[O-].[Na+].[CH2:16]([CH:18]1O[CH2:19]1)Br.CC(C)=[O:23]>CO.C(Cl)(Cl)Cl>[O:23]1[C:3]2[N:4]1[C:5]([C:7]1[C:12]([C:2]=2[O:1][CH2:16][CH2:18][CH3:19])=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: BrCC1CO1
Reactant: O=c1[nH]cc(O)c2ccccc12
Reactant: CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCOc1c2n(c(=O)c3ccccc13)O2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
16.1 g of 4 -hydroxyisocarbostyril was suspended in 160 ml of methanol, 21.1 g of 28% sodium methylate was added thereto to dissolve, and then 68.5 g of epibromohydrin was added and stirred for 1 hour at inner temperature of 60° C. The resulting reaction mixture was then concentrated under reduced pressure, and the residue obtained was extracted by adding water and chloroform. The chloroform layer thus obtained was washed with a saturated saline solution, dried over anhydrous sodium sulfate, then concentrated under reduced pressure. 11.8 g of the residue was dissolved in a mixed solvent of chloroform and methanol (19:1), purified over a column packed with 100 g of silica gel to obtain 5.0 g of the main fraction. The fraction was then dissolved in a mixed solvent of methanol and chloroform (1:1), then cooled after addition of acetone to separate a crystal. The crystal was taken out by filtration and then dried in vacuo to obtain 4.0 g of 4-(2,3-epoxy)propoxyisocarbostyril. m.p. 145°-149° C.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1.Cl.C1C[O:23][CH2:22][CH2:21]1>CC(N(C)C)=O>[CH2:18]([C:16]1[O:15][N:14]=[C:13]([CH3:12])[CH:17]=1)[C:22]([CH3:21])=[O:23]
Reactant: C1CCOC1
Reactant: Cc1cc(C)on1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(=O)N(C)C
Solvent: CCCCCC
Product: CC(=O)Cc1cc(C)no1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 2 L flask filled with nitrogen were placed 1000 ml of anhydrous THF and 500 ml of a 1.6M n-hexane solution of n-butyl lithium. The flask was placed in a dry ice-acetone bath to set the inside temperature to −70° C., and 68.0 g of 3,5-dimethylisoxazole was slowly dropped in the flask. After the resulting solution was stirred for 30 minutes at the same temperature, a solution of 120.0 g of dimethylacetamide in 300 ml of THF was slowly dropped. After the completion of the dropping, the solution was further stirred for an hour at −60° C. to −65° C. The reaction solution was poured into 1 L of ice water acidified with hydrochloric acid. The organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined and concentrated under reduced pressure. The obtained concentrate was dissolved in 500 ml of ethyl acetate, washed with water and then with saturated salt water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by distillation under reduced pressure to give 68.5 g of the title compound as a colorless liquid. Boiling point: 85° C./1.0 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>C1(C)C=CC=CC=1>[F:15][C:16]([F:24])([F:23])[C:17]([C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([OH:10])=[C:3]([O:2][CH3:1])[CH:8]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: COc1cccc(C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O

Procedure:
To 2-methoxy-6-methylphenol (27.6 g=0.20 mol) in 300 ml toluene, add aluminum chloride (4.0 g=30 mmol). Bubble in hexafluoroacetone (47 g=0.28 mol) over 7 hours. Heat the reaction mixture in a steel bomb 16 hours at 120° C. Cool, and pour the contents onto 1.0 N HCl. Extract with ether. Wash the ether layer with 1.0N NaOH. Acidify the basic aqueous layer with concentrated HCl, extract with ether, dry, concentrate and distill to obtain a fraction boiling at 71°-74° C./0.1 mm. Crystallize from cold hexane to obtain, as a solid m.p. 44°-45° C., 4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylphenol.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29].[BH4-].[Na+].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]([CH3:26])[C:4](=[O:25])[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=2)([C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([CH2:20][NH:30][CH2:27][CH2:28][CH3:29])[CH:18]=2)[N:6]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(C=O)c2)N=C1N
Reactant: CCCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNCc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Yield: 79.2 %

Procedure:
A small vial (2 ml) was charged with 3-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-benzaldehyde (32.7 mg, 91.0 μmol). To this was added one-fifth of a solution of propylamine (31 mg, 0.524 mmol) in methanol (2.50 ml). After stirring for two hours sodium borohydride (8.7 mg) was added, then after another hour 1N sodium hydroxide (1 ml) was added and the mixture extracted with diethyl ether. The ethereal layer was concentrated by rotary evaporation, diluted with methanol and re-concentrated (repeated three times). Finally the oily residue was redissolved in diethylether/hexanes and concentrated, twice then placed under vacuum to give a white foam 29 mg (78%) 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79 (t, J=7.3 Hz, 3H) 1.29-1.39 (m, 2H) 2.36 (t, J=7.1 Hz, 2H) 2.93 (s, 3H) 3.57 (s, 2H) 6.62 (br. s., 2H) 6.67 (br. s., 1H) 7.06 (d, J=8.8 Hz, 2H) 7.13 (t, J=74.12 Hz, 1H) 7.14-7.25 (m, 3H) 7.35 (s, 1H) 7.43 (d, J=8.8 Hz, 2H); MS (APPI) m/z 403 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[N:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH:4]=1>CO.[Pd]>[CH3:1][O:2][CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1
Reactant: COc1cnc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1
Agent: [Pd]
Solvent: CO
Product: COC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
7-Methoxy-2,3-dip-tolylpyrido[2,3-b]pyrazine (94 mg, 0.275 mmol) in dry MeOH (4 ml), under nitrogen was treated with 10% Pd on Carbon (58.6 mg, 0.056 mmol). The suspension was stirred at RT under an atmosphere of hydrogen for 32 hours. The resulting mixture was loaded onto a 2.5 g Celite® column using MeOH and was flushed with 1:1 MeOH:DCM. The filtrate was concentrated in vacuo and the residue was dissolved in DCM (30 ml) and washed with water (×2). The organic portion was isolated and the solvent was removed in vacuo to afford the title compound;
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[C:8]1([C@H:14]([CH3:26])[C:15]([NH:17][NH:18]C(OC(C)(C)C)=O)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)C>C(OCC)(=O)C>[ClH:7].[C:8]1([C@H:14]([CH3:26])[C:15]([NH:17][NH2:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H](C(=O)NNC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)NN)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 N hydrogen chloride-ethyl acetate (2 mL) was added to a suspension of tert-butyl N′-((S)-2-phenylpropionyl)hydrazinecarboxylate (470 mg) in ethyl acetate (4 mL), and the reaction solution was stirred at room temperature overnight. Diethyl ether (6 mL) was added to the reaction solution, and the precipitated powder was collected by filtration. The resulting solid was dried under reduced pressure to obtain 280 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1cn(S(=O)(=O)c2c(Cl)cccc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 2,6-dichlorophenylsulfonyl chloride (0.589 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(2,6-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.658 g, 93%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CN(C=O)C.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+]>O>[N:30]1[NH:38][N:39]=[N:40][C:29]=1[CH2:28][CH:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[N:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:26]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ccc(-c3ccc(C4CCC(Cc5nn[nH]n5)CC4)cc3)nn2)cn1
Temperature: 140 °C

Procedure:
To a mixture of (4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile (0.12 g, 0.29 mmol, 1.0 equiv) in 3 Ml DMF was added sodium azide (0.057 g, 0.88 mmol, 3.0 equiv), followed by solid ammonium chloride (0.062 g, 4.0 equiv). The reaction was heated to 140° C. over the weekend. The cooled reaction mixture was diluted with 10 Ml water and then acidified to Ph 4-5. The precipitate was filtered to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 103-1.16 (m, 2 H) 1.33-1.45 (m, 2 H) 1.73 (t, J=14.27 Hz, 5 H) 2.60-2.68 (m, 3 H) 7.27 (dd, J=17.94, 8.84 Hz, 3 H) 7.79 (d,J=8.84 Hz, 1 H) 7.86-7.95 (m, 2 H) 8.01 (d, J=9.09 Hz, 1 H) 8.63 (dd, J=8.59, 1.77 Hz, 1 H) 8.87 (d, J=2.27 Hz, 1 H) 9.99 (s, 1 H); (M+H)+ 481.7.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].CN(C)P(N(C)C)(N(C)C)=O.[CH3:32]/[C:33](/[CH2:37][CH2:38]/[CH:39]=[C:40](\[CH3:47])/[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])=[CH:34]\[CH2:35]Br>O1CCCC1>[CH3:32]/[C:33](/[CH2:37][CH2:38]/[CH:39]=[C:40](\[CH3:47])/[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])=[CH:34]\[CH2:35][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 9.60 mL (68.5 mmol, 1.5 eq.) of diisopropylamine in 100 mL of tetrahydrofuran (THF) at -78° C. under argon was added 28.2 mL (45.0 mmol, 1.0 eq.) of 1.6M n-butyllithium in hexanes over 20 minutes. After warming to 0° C. for 15 minutes, the solution was recooled to -78° C. and 6.05 mL (45 mmol, 1.0 eq.) of t-butyl acetate was added over 20 minutes. After an additional 15 minutes, 16.0 mL (92 mmol, 2.05 eq.) of hexamethylphosphoramide (HMPA) was added, followed by a solution of 12.53 g (45.0 mmol) of Part A(1) farnesyl bromide in 100 mL of THF over 20 minutes. The reaction was stirred at -78° C. for 2.5 hours, quenched with saturated NH4Cl and allowed to warm to room temperature. After diluting with 400 mL of ethyl acetate, the mixture was washed with four 100 mL portions of water, and 200 mL of brine, dried over MgSO4 and evaporated to provide 12.96 g of crude product as a yellow oil. Purification by flash chromatography on 1 kg of silica gel, eluted with 1:9 ethyl acetate:petroleum ether afforded 9.39 g (65%) of title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([OH:29])[CH2:25]2)[C:21](=[O:30])[NH:20][C:19]2([C:31]([O:33]CC)=[O:32])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)[CH2:25]2)[C:21](=[O:30])[NH:20][C:19]2([C:31]([OH:33])=[O:32])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O)CC1C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3ccc([N+](=O)[O-])cc3)CN2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.7 %

Procedure:
To a mixture of (14-tert-butoxycarbonylamino-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid, ethyl ester (192 mg, 0.39 mmol; prepared in Ex. 25, step 3) in 3 mL of THF was added sodium hydride (50 mg, 60% in oil, 1.25 mmol). The mixture was stirred at rt for 5 min. then 1-fluoro-4-nitrobenzene (60 mg, 0.42 mmol) was added and stirring was continued at rt overnight. The reaction was quenched by adding 10 mL of water, and then 0.1 N hydrochloric acid was used bring the pH to 4. This acidic solution was then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo to obtain 14-tert-butoxycarbonylamino-18-(4-nitrophenoxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid as a white solid (100 mg, 44%). LC-MS (YMC Xterra MS C18 S7 column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 4 min. Hold time: 1 min. Flow rate: 4 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2/90% MeOH/0.1% TFA.) (Retention time: 3. 17 min), MS m/z 587(M++1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH2:18][OH:19])=[C:6]([C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:20][C:21]1[C:22](Cl)=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27].O>C1COCC1>[CH3:17][O:16][N:15]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[CH2:18][O:19][C:22]1[C:21]([Cl:20])=[CH:29][C:25]([C:26]([O:28][C:5]([CH3:18])([CH3:6])[CH3:4])=[O:27])=[CH:24][N:23]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)C(=NOC)c1cccc(Cl)c1CO
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1cccc(Cl)c1COc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%, 0.12 g, 3.0 mmol) was added to a solution of 3-chloro-2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (0.43 g, 1.68 mmol) in dry THF (10 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. 5,6-Dichloronicotinic acid; t-butyl ester (0.44 g, 1.87 mmol) in 2-3 mL THF was added to this reaction mixture and stirred at 25° C. for about two hours. Water (40 mL) was added and the resulting mixture was extracted with ether (2×), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield 0.72 g crude oil. The oil was chromatographed with dry pack silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 pet ether/ethyl acetate as mobile phase. Elution and concentration gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(t-butoxycarbonyl)-2-pyridinyl]oxy]methyl]-3-chloro-benzeneacetamide (430 mg) as an oil. (95% E isomer; 5% Z isomer).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11])([O-])=O.[C-:14]#[N:15].[K+].[OH2:17]>CS(C)=O>[F:11][C:10]([F:13])([F:12])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:14]#[N:15])[C:4]=1[OH:17]
Reactant: O=[N+]([O-])c1ccccc1C(F)(F)F
Reactant: [C-]#N
Reactant: O
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cccc(C(F)(F)F)c1O

Procedure:
2-Nitro-α,α,α-trifluorotoluene (3.82 g.) was heated at 100°C for 3 hours with potassium cyanide (7.8 g.) in dimethyl sulphoxide (40 ml.). After pouring into water, the mixture was brought to pH 7 and filtered. Acidification, ether extraction, and removal of the ether gave a solid which was sublimed or crystallised from aqueous ethanol to give 3-trifluoromethyl-salicylonitrile, m.p. 134°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17](F)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Cl:20]
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc(N)c(Cl)c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc(N)c(Cl)c1
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 318C (8.90 g) and piperazine (10.34 g) in dimethylsulfoxide (100 mL) was heated to 85° C. After stirring for 3 hours, the reaction mixture was cooled, diluted with ethyl acetate (400 mL), washed with water (2×250 mL) and brine (250 mL), dried over magnesium sulfate, filtered, and concentrated to provide the title compound.