Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N+:19]([O-])=O)[C:12]([OH:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl>CO.[Rh]>[NH2:19][C:11]1[C:12]([OH:18])=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1O
Agent: [Rh]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cc(OCc2ccccc2)cc(N)c1O

Procedure:
69.5 g (242 mmol) 1-(5-benzyloxy-2-hydroxy-3-nitrophenyl)-ethanone are dissolved in 1.4 L methanol and hydrogenated in the presence of 14 g rhodium on charcoal (10%) as catalyst at 3 bar and ambient temperature. Then the catalyst is filtered off and the filtrate is evaporated down. The residue is reacted further without additional purification. Yield: 60.0 g (96%), Rf value=0.45 (dichloromethane on silica gel).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][C:11]([OH:13])=[O:12])[C:5](=[O:14])[C:4]=1[N+:15]([O-:17])=[O:16].[CH3:18]O>>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][C:11]([O:13][CH3:18])=[O:12])[C:5](=[O:14])[C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: CO
Reactant: Cc1cc(O)c([N+](=O)[O-])c(=O)n1CC(=O)O
Agent: Cl
Product: COC(=O)Cn1c(C)cc(O)c([N+](=O)[O-])c1=O
Yield: 85 %

Procedure:
250 ml of methanol are saturated with a gaseous hydrochloric acid stream and 25 g (0.11 mol) of 4-hydroxy-6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-1-acetic acid are introduced in portions. The mixture is heated at reflux temperature for 4 hours and then the precipitate is filtered and it is dried in an oven. 23 g of product are obtained in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:16]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:17])(=[O:11])=[O:10].Cl[C:36]1C=CC(Cl)=C[C:37]=1S(Cl)(=O)=O>>[CH2:36]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:37]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2cc(Cl)ccc2Cl)c1OC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cc(Cl)ccc3Cl)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(2,5-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=523.1 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 2,5-dichloro-benzenesulfonyl chloride and yielded 4-[3-(2,5-dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[C:15]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]([OH:38])([CH3:37])[C:33]([F:36])([F:35])[F:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[F:36][C:33]([F:34])([F:35])[C:32]([OH:38])([CH3:37])/[CH:31]=[CH:30]/[C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:23])=[O:22])=[CH:29][CH:28]=1
Reactant: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)(/C=C/c1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of sodium bis(2-methoxyethoxy)aluminum hydride (1.5 mL, 3.4M in toluene) in freshly distilled diethyl ether (6 mL) was added a solution of 1-(4-phenylsulfonylphenyl)-3-hydroxy-3-methyl-4,4,4-trifluorobut-1-yne in diethyl ether (6 mL) dropwise. The rate of addition was controlled so that the reaction temperature did not exceed 8° C. The mixture was stirred for 15 minutes and was quenched at 0° C. with 3N sulfuric acid (15 mL). Water (10 mL) was added and the product was extracted into diethyl ether. The combined organic extracts were washed (brine) and dried. The solvent was evaporated and the material was purified by chromatography, with chloroform:diethyl ether (25:1) as the eluent, to give the title compound (848 mg, 79%).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH:26]=1)[CH2:17][CH:18]([C:23](=O)[CH3:24])[C:19](OC)=[O:20])#[N:10]>CO>[NH2:7][C:6]1[N:8]=[C:19]([OH:20])[C:18]([CH2:17][C:16]2[CH:26]=[C:12]([CH2:11][C:9]#[N:10])[CH:13]=[CH:14][C:15]=2[O:27][CH3:28])=[C:23]([CH3:24])[N:5]=1
Reactant: N=C(N)N
Reactant: COC(=O)C(Cc1cc(CC#N)ccc1OC)C(C)=O
Agent: O=C(O)O
Solvent: CO
Product: COc1ccc(CC#N)cc1Cc1c(C)nc(N)nc1O
Temperature: 50 °C

Procedure:
Guanidine carbonate (5 g) was added to a stirred solution of the product from step (i) (5.01 g) in MeOH (80 mL). The suspension was heated at 50° C. for 15 h and then the solvent evaporated under reduced pressure. The residue was diluted with water (20 mL) and diethyl ether (20 mL). The resulting precipitate was collected by filtration and the solid was dried under vacuum to give the subtitle compound as an orange solid, 2.8 g.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO.C(O)=O>[F:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:34][CH2:33][N:32]([C:7]([C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:31][CH2:30]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Fc1cc(C(F)(F)F)ccc1N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.05 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (Compound 1.2), 0.06 mmol 1-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine, 0.055 mmol TBTU and 0.25 mmol DIPEA in 1 ml DMF was stirred at RT for 16 h. 0.5 ml MeOH/HCOOH 1/1 was added and the mixture was subjected to reversed phase preparative HPLC separation eluting with an acetonitrile/water gradient yielding the title compound. MS (m/e): 489.2 (MH+, 100%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](OC)(=O)C(OC)=O.CC(C)([O-])C.[K+]>CN(C=O)C.O>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)C(=O)OC
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of indole product from Example 38, Step F (182 mg, 0.694 mmol) and dimethyl oxalate (90 mg, 0.76 mmol) in DMF (5 mL), potassium tert-butoxide (86 mg, 0.76 mmol) was added in one portion at room temperature under nitrogen. The reaction mixture was warmed to reflux under nitrogen for 30 min and then was cooled to room temperature. The mixture was diluted with water (50 mL) and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/hexanes, 1:1) to afford the N-methyl indole product, Example 37, as a white solid (180 mg, 92%): mp 106-108° C.; 1H NMR (500 MHz, CDCl3) δ7.19-7.28 (m, 5H), 7.05 (d, J=8.5 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 6.41 (dd, J=3.0, <1 Hz, 1H), 4.37 (t, J=6.3 Hz, 1H), 4.00 (d, J=15.1 Hz, 1H), 3.85 (d, J=15.1 Hz, 1H), 3.75 (s, 3H), 3.08 (dd, J=11.4, 5.4 Hz, 1H), 2.66 (dd, J=11.4, 8.1 Hz, 1H), 2.50 (S, 3H); CI MS m/z=277 [C19H20N2+H]+; IR (KBr) 3050, 2939, 2783, 1487, 1451 cm−1; Anal. Calcd for C19H20N2-0.1 H2O: C, 82.04; H, 7.32; N, 10.07. Found: C, 82.06; H, 7.50; N, 9.85.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5]2.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH:6]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH2:7]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: O=S(=O)(NC1CNc2ccc(Br)cc2C1)c1ccccc1
Product: O=S(=O)(NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1

Procedure:
The title compound was prepared from 87A and benzaldehyde by procedures analogous to those described in Example 22A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:20][CH:19]=1)([OH:25])[CH:22]([CH3:24])[CH3:23]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: CC(C)C(=O)c1ccc(C(C)C)cc1
Product: COc1ccc(C(O)(c2ccc(C(C)C)cc2)C(C)C)c(OC)c1
Yield: 56 %

Procedure:
Using 1-bromo-2,4-dimethoxybenzene and 1-(4-isopropylphenyl)-2-methylpropan-1-one the title compound was obtained in the same manner as in Reference Example 6. Yield 56%.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][C:8]1[C:9](=[O:33])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]CC)=[O:26])=[CH:21][C:20]=2[N+:30]([O-:32])=[O:31])[O:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCOCC1>O>[Cl:6][CH2:7][C:8]1[C:9](=[O:33])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][C:20]=2[N+:30]([O-:32])=[O:31])[O:11][C:12]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(-n2oc(-c3ccccc3)c(CCl)c2=O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-n2oc(-c3ccccc3)c(CCl)c2=O)c([N+](=O)[O-])c1
Yield: 83.7 %

Procedure:
After adding 300 ml of concentrated sulfuric acid to a mixture of 270 g (0.67) of 4-chloromethyl-5-phenyl-2-(4-ethoxycarbonyl-2-nitrophenyl)-4-isoxazolin-3-one (Compound (33)) and 2.5 liters of 1,4-dioxane, the resultant mixture was refluxed for 8 hours. Thereafter, the reaction mixture obtained was cooled and poured into water. Crystals thus deposited were recovered by filtration, washed with water, and dried to provide 210.2 g of the aforesaid compound with a yield of 83.7%. The melting point thereof was 186° C. to 189° C.
Reaction SMILES: [O:1]1[CH2:5]C[CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:18][C:17]([CH2:29][CH2:30][CH3:31])=[C:16]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].[H-].[Na+].ClCOCC>C(O)(=O)C>[CH2:2]([O:1][CH2:5][N:18]1[C:17]([CH2:29][CH2:30][CH3:31])=[C:16]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=2)[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]1[CH2:26][CH2:27][CH3:28])[CH3:3]
Reactant: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(CCC)N1
Reactant: C1CCOC1
Agent: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(CCC)N1COCC
Temperature: -20 °C

Procedure:
In 10 ml. of tetrahydrofuran was dissolved 0.5 g. of diethyl 4-(3-nitrophenyl)-2,6-dipropyl-1,4-dihydropyridine-3,5-dicarboxylate and after adding to the solution 0.2 g. of a 50% oil dispersion of sodium hydride, the mixture was stirred for 2 hours at room temperature. After cooling the mixture to -20° C., 0.5 ml. of chloromethoxyethane was added thereto and the mixture reacted for 1.5 hours at temperatures of from -20° C. to -10° C. After adding to the reaction product 0.5 ml. of glacial acetic acid and 20 ml. of water, the product was extracted three times each time with 5 ml. of ether at room temperature. The extracts were combined, washed with 5 ml. of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the ether was distilled away. The residue was subjected to a silica gel column chromatography, using a 10:1 benzene-acetone mixed solvent as an eluant, the effluent thus recovered was examined by a thin layer chromatography, and the effluent of the main fraction recovered was concentrated. By recrystallizing the residue formed from hexane, 0.4 g. of colorless acicular crystals of diethyl 1-ethoxymethyl-4-(3-nitrophenyl)-2,6-dipropyl-1,4-dihydropyridine-3,5-dicarboxylate melting at 109°-110° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:38][CH2:37][CH2:35][OH:36])=[O:27])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: NCCO
Product: CC1Cc2ccc(-c3ccc(C(=O)NCCO)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and ethanolamine (Aldrich, Cat. No. 411000). LCMS (M+H)+: m/z=503.2.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S-:12][C:13]#[N:14].[K+].O>CN(C)C=O>[CH3:10][C:4]([CH3:11])([CH2:3][CH2:2][S:12][C:13]#[N:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C)(C)CCCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCSC#N
Temperature: 100 °C
Reaction time: 7 h
Yield: 65.9 %

Procedure:
22.1 g of ethyl 4-chloro-2,2-dimethylbutyrate and 14.5 g of potassium thiocyanate were dissolved in 100 ml of dimethylformamide, followed by stirring at 100° C. for 7 hours. The reaction mixture was added to 500 ml of water and extracted with ethyl ether. After the extract was washed with water and dried over MgSO4, the solvent was distilled off. The residue was distilled under reduced pressure to yield 16.4 g of the title compound in the form of a colorless oily substance.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[I:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.Cl>O1CCCC1.C1(C)C=CC=CC=1.CN1CCCC1=O.O1CCCC1.CN1CCCC1=O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:22]#[N:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:17][CH:16]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#CC1(c2ccc(I)cc2)CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Methylpyrrolidinone (NMP) (197 mL, Sigma-Aldrich) was added to a suspension of sodium tert-butoxide (124.0 g, Alfa-Aesar) in tetrahydrofuran (THF) (197 mL, Univar) under argon. The mixture was cooled to 0° C. and a solution of 1,5-dibromopentane (87.9 mL, Sigma-Aldrich) and 4-iodophenylacetonitrile (78.4 g) in a 50:50 mixture of NMP/THF (173 mL) was added dropwise keeping the internal temperature below 10° C. The mixture was warmed to room temperature and stirred overnight. 2M hydrochloric acid (930 mL) and toluene (930 mL) were added then the aqueous layer was separated and extracted with toluene (2×465 mL). The combined organics were washed with saturated sodium bicarbonate (930 mL), brine (930 mL), 2M sodium thiosulfate (930 mL), dried (magnesium sulphate) and concentrated in vacuo to a yellow/orange solid. Dichloromethane was added and the solid was filtered and washed with dichloromethane to give the product as a white solid. Yield: 22.55 g. 1H NMR (400 MHz, CDCl3): δ 7.70-7.72 (2H, m, ArH), 7.22-7.25 (2H, m, ArH), 2.10-2.13 (2H, m, —CH2—), 1.67-1.89 (7H, m, —CH—), 1.22-1.32 (1H, m, —CH—).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[C:8]([O:11]C)[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])([O-:3])=[O:2].B(Br)(Br)Br>>[OH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:6]([N+:13]([O-:15])=[O:14])=[CH:7][C:8]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])c(CCCCC(=O)O)c([N+](=O)[O-])c1O
Agent: BrB(Br)Br
Product: O=C(O)CCCCc1c([N+](=O)[O-])cc(O)c(O)c1[N+](=O)[O-]

Procedure:
The product from example 5 (0.5 g) was reacted with boron tribromide according to the procedure described in example 10. Yield: 0.13 g, melting point 135-139° C.
Reaction SMILES: O.[Na].[CH2:3]([N:10]1[CH2:16][C:15]2(Cl)[C:17]([O:20][CH3:21])([O:18][CH3:19])[C:12](Cl)([C:13](Cl)=[C:14]2Cl)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(C)(C)C>O1CCOCC1>[CH2:3]([N:10]1[CH2:16][CH:15]2[C:17]([O:20][CH3:21])([O:18][CH3:19])[CH:12]([CH:13]=[CH:14]2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC1(OC)C2(Cl)CN(Cc3ccccc3)CC1(Cl)C(Cl)=C2Cl
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: O
Product: COC1(OC)C2C=CC1CN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a 3 L 3NRB equipped with a thermometer, addition funnel and water condenser was added dioxane (1000 mL) then sodium (44.7 g, 1.94 mol). Upon heating under reflux (T ˜100° C.), the sodium became a dispersed immiscible liquid. While maintaining this gentle reflux, a solution of 3-benzyl-1,5,6,7-tetrachloro-8,8-dimethoxy-3-aza-bicyclo[3.2.1]oct-6-ene (52.5 g, 0.132 mol), t-butanol (160 mL, 1.67 mol) and dioxane (150 mL) was added dropwise via the addition funnel over 30 min and heat continued overnight. Upon cooling to 70° C., the residual unreacted sodium was quenched with MeOH (150 mL) then water (1 L). The dioxane and MeOH were then removed in vacuo. The product was extracted from the aqueous layer with EtOAc (3×300 mL), washed with saturated aqueous NaCl solution (1×300 mL), dried over Na2SO4, filtered and concentrated to yield a dark brown oil (29.2 g, 85%). (TLC 40% EtOAc/hexanes Rf 0.35); 1H NMR (400 MHz, CDCl3) δ 7.28–7.20 (5H), 6.01 (t, J=1.6 Hz, 2H), 3.65 (s, 2H), 3.23 (s, 3H), 3.17 (s, 3H), 2.63 (s, 2H), 2.57 (AB d, J=10.1 Hz, 2H), 2.44 (AB d, J=10.1 Hz, 2H); GCMS m/z 259 (M)+; APCI MS m/z 260.2 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]([CH3:41])[CH3:40])=[CH:35][C:34]=2[O:42][CH3:43])[C:29]([Cl:44])=[CH:28][N:27]=1>>[Cl:44][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]([CH3:40])[CH3:41])=[CH:35][C:34]=2[O:42][CH3:43])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: COc1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(N)c2OC
Product: CCN1C(=O)C(NC(=O)C(F)(F)F)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(N(C)C)cc3OC)n1)c2OC
Yield: 42 %

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2,2,2-trifluoro-acetamide (78 mgs) and N(1)-(2,5-Dichloro-pyrimidin-4-yl)-2-methoxy-N(4),N(4)-dimethyl-benzene-1,4-diamine (60 mgs) were converted to the title compound as an off-white solid (50 mgs). 1H-NMR (CDCl3, 400 MHz): 8.39 (d, J=8.8 Hz, 1H), 8.05-8.04 (m, 2H), 7.59 (s, 1H), 7.43 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.9 Hz, 1H), 6.41-6.39 (m, 2H), 4.49-4.41 (m, 1H), 4.34-4.28 (m, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.29-3.54 (m, 1H), 3.16-3.11 (m, 1H), 3.01 (s, 6H), 2.76-2.71 (m, 1H), 2.57-2.51 (m, 1H), 2.05-2.98 (m, 1H), 1.20 (t, J=7.3 Hz, 3H); LC/MS: found (M+H)+=622.52, MP: 192-193° C.
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4]([CH3:6])=[O:5].[C:11]1([CH2:17][CH2:18]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[C:11]1([CH2:17][CH2:18][CH2:3][C:4](=[O:5])[CH3:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CC(=O)CCCc1ccccc1
Reaction time: 5 h

Procedure:
According to reference F. C. Montgomery, W. H. Saunders, Jr. J. Org. Chem. 1976, 41, 2368-72, 7.6 g of sodium are added to 200 ml of absolute ethanol. Once the sodium has dissolved, 43 g (0.33 mol) of ethyl acetoacetate are added dropwise within an hour, the mixture refluxed for 1 hour, 65 g of 2-phenylethyl bromide are slowly added dropwise and the mixture is refluxed again (21 hours). After cooling and filtration, the mixture is distilled. The product is first heated for 5 h to 90° C. with 350 ml of 5% sodium hydroxide, then stirred for 5 hours at the same temperature with 150 ml of 50% sulfuric acid. After cooling, the product is left to stand for 48 hours, extracted with diethyl ether, the combined extracts are dried over sodium sulfate and 3a is finally obtained in good yield by distillation (b.p.: 132-134° C., 2.3 103 Pa (17 Torr)).
Reaction SMILES: [N:1]([C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12])[CH3:5])=[N+]=[N-].[NH4+].[Cl-].[In]>CCO.O>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C@@H:4]([NH2:1])[CH3:5]
Reactant: C[C@H](N=[N+]=[N-])c1ccccc1Br
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@H](N)c1ccccc1Br
Yield: 87.5 %

Procedure:
To a solution of (S)-1-(1-azidoethyl)-2-bromobenzene (45 mg, 0.2 mmol) in EtOH/H2O (5 mL/5 mL) was added in NH4Cl (108 mg, 2.0 mmol) and indium (91 mg, 0.8 mmol). The mixture was refluxed overnight. The reaction mixture was filtered, washed with EtOH and evaporated. The residue was triturated with AcOEt and filtered. The filtrate was evaporated to give the title compound (35 mg, 88%).
Reaction SMILES: S([O-])([O-])(=O)=O.[NH4+].[NH4+].OP([O-])(O)=O.[K+].[O-]S([O-])(=O)=O.[Mg+2].CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO.[NH2:38][C@H:39]([C:44]([OH:46])=[O:45])[C@H:40](CC)[CH3:41].[C:47]([O-:50])([O-:49])=O.[Ca+2]>OCC(CO)O>[NH2:38][C@H:39]([C:44]([OH:46])=[O:45])[CH2:40][CH2:41][C:47]([OH:50])=[O:49]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: O=P([O-])(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: OCC(O)CO
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 21 h

Procedure:
coli strains, VL334thrC+, VL334thrC+glpK*-231, VL334thrC+glpK*-234, VL334thrC+glpK*-random, and VL334thrC+glpK*-ΔglpR, can be grown for 18-24 hours at 37° C. on L-agar plates. Then, one loop of the cells can be transferred into test tubes containing 2 ml of fermentation medium. The fermentation medium contains glycerol (60 μl), ammonium sulfate (25 μl), KH2PO4 (2 g/l), MgSO4 (1 μl), thiamine (0.1 mg/ml), L-isoleucine (70 μg/ml), and CaCO3 (25 μl). The pH is adjusted to 7.2. Glyserol and CaCO3 are sterilized separately. Cultivation can be carried out at 30° C. for 3 days with shaking. After the cultivation, the amount of L-glutamic acid which is produced can be determined by paper chromatography (liquid phase composition of butanol-acetic acid-water=4:1:1) with subsequent staining by ninhydrin (1% solution in acetone) and further elution of the compounds in 50% ethanol with 0.5% CdCl2.