Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1I)([CH3:6])[CH3:5].[CH2:37]([Sn](CCCC)(CCCC)CCCC)[CH:38]=[CH2:39]>>[CH3:1][O:2][C:3](=[O:36])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH2:39][CH:38]=[CH2:37])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1I
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Product: C=CCc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OC

Procedure:
The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl-propionic acid methyl ester (0.200 g, 0.330 mmole) and allyl tributyltin (0.218, 0.659 mmole) to produce a colorless oil (0.102 g, 59%). Mass [EI+] 521 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10][CH2:11][CH:12]([OH:22])[C:13]#[C:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:9]([CH2:10][CH2:11][CH:12]([OH:22])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C#CC(O)CC[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCC(O)CC[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A 25-mL round bottom (RB) flask was purged with nitrogen and charged with (7S)-di-tert-butyl 7-(bis(tert-butoxycarbonyl)amino)-4-hydroxyoct-2-ynedioate (0.04 g, 0.08 mmol), ethyl acetate (5 mL) and 5% palladium on carbon (˜2.0 mg dry weight). The RB flask was evacuated, charged with hydrogen gas in a balloon (to a pressure of 13 psi or approximately 1.0 atmosphere pressure) and stirred for an overnight at room temperature. After this time, the hydrogen was evacuated and nitrogen charged into the RB flask. The catalyst was removed by filtration through a pad of Celite 545 and the filter cake washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure to afford (2S)-di-tert-butyl 2-(bis(tert-butoxycarbonyl)amino)-5-hydroxyoctanedioate (diastereomeric mixture, 0.04 g, 99.3% yield) as an oil. 1H NMR (CDCl3) δ ppm: 4.73 (m, 1H), 3.63 (m, 1H), 2.37 (m, 2H), 2.27-1.56 (m, 6H), 1.51 (s, 18H), 1.45 (2s, 18H). 13C NMR (CDCl3) d ppm: 173.60, 173.58, 170.01, 169.75, 152.58, 152.48, 82.86, 82.82, 81.28, 81.25, 80.42, 80.40, 71.19, 70.65, 58.92, 58.68, 34.37, 34.15, 32.30, 32.22, 32.15, 32.05, 28.07, 28.02, 27.94, 25.69 and 25.55. MS (ESI+): 540 (M+Na)+.
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:22])=O>>[Cl:22][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)c1ccc(C2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(Cl)c1ccc(C2CCCCC2)cc1
Yield: 89 %

Procedure:
To ethyl 2-hydroxy-2-(4-cyclohexylphenyl)acetate (52 g) was added thionyl chloride (100 ml) and the mixture was refluxed for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residual oil was diluted with water and extracted with ether. The ether layer was washed with water, dried (MgSO4) and subjected to vacuum distillation to give ethyl 2-chloro-2-(4-cyclohexylphenyl)acetate (50 g, yield 89%).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CCC(Br)CC
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OC(CC)CC)c2)n1

Procedure:
Using the compound obtained in Example 347 and 3-bromopentane, white powdery N-{2-[4-difluoromethoxy-3-(1-ethylpropoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CN(C=O)C.Cl[CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[C:18]1[CH2:30][CH3:31]>>[CH2:30]([C:18]1[N:17]([CH2:16][CH2:15][S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[C:22](=[O:23])[CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)[CH3:31]
Reactant: CCc1nc(-c2ccccc2)cc(=O)n1CCCl
Reactant: Oc1ccc(S)cc1
Solvent: CN(C)C=O
Product: CCc1nc(-c2ccccc2)cc(=O)n1CCSc1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
To 4-hydroxy thiophenol (2.016 g, 0.016 mol) in DMF (50 ml) K2CO3 (4.416 g, 0.032 mol) was added and stirred for 30 min. and then added 1-(2-chloroethyl)-2-ethyl-4-phenyl-1,6-dihydropyrimidin-6-one (4.3 g, 0.016 mol). The resulting mixture was stirred at room temperature for 15 h, filtered, washed with EtOAc and the combined filtrates were partitioned between water and EtOAc. The EtOAc layer was washed with water, brine, dried over Na2SO4 and evaporated the solvent to get the title compound as a gummy mass (1.25 g, 26%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:32][CH2:33]C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:76])([C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50]CCC(CCCCCC=C)C(OCC)=O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:32][CH2:33][CH2:50][CH2:49][C:48]([F:47])([F:76])[C:66]([F:74])([F:75])[C:67]([F:72])([F:73])[C:68]([F:71])([F:70])[F:69])[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 8 and the ethyl 2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)-8-nonenoate prepared in Example 5, a procedure analogous to that as shown in Example 8 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)decanoic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][C:4]([C:6]1[CH:25]=[CH:24][C:9]2[O:10][C:11]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:12]=3[CH2:13][O:14][C:15](=[O:16])[C:8]=2[C:7]=1[O:26][CH3:27])=[O:5].[BH4-].[Na+]>O1CCCC1.O>[OH:5][CH:4]([C:6]1[CH:25]=[CH:24][C:9]2[O:10][C:11]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[CH:17][C:12]=3[CH2:13][O:14][C:15](=[O:16])[C:8]=2[C:7]=1[O:26][CH3:27])[CH2:3][CH:2]([CH3:28])[CH3:1]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(=O)CC(C)C)c(OC)c1C(=O)OC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)cc2c1Oc1ccc(C(O)CC(C)C)c(OC)c1C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
158 g (0.41 mmol) of 3-(3-methyl-1-butanonyl)-4,11-dimethoxy-9-methyl-7H-dibenzo[b,g][1,5]dioxocin-5-one are dissolved in 2 ml of tetrahydrofuran and 0.1 ml of water. 23 mg (0.61 mmol) of sodium borohydride are added to the solution and the mixture is stirred overnight at room temperature. Excess sodium borohydride is destroyed by addition of a few drops of acetic acid. The mixture is concentrated in vacuo, the residue is taken up in dichloromethane and the solution is washed with water. The organic phase is dried over magnesium sulphate, concentrated and purified by column chromatography on silica gel using petroleum ether/diethyl ether 1:1.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:18].[Na+]>O1CCOCC1>[CH3:17][N:8]1[C:4]2[N:5]=[CH:6][NH:7][C:2](=[O:18])[C:3]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9]1
Reactant: [OH-]
Reactant: Cn1cc(-c2ccccc2)c2c(Cl)ncnc21
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccccc2)c2c(=O)[nH]cnc21
Temperature: 100 °C
Yield: 71 %

Procedure:
To a stirred solution of 4-chloro-7-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine (1.32 g, 5.42 mmol) in 1,4-dioxane (40 ml) was added 2M sodium hydroxide (aq) solution (40 ml, 80 mmol). The solution was heated to 100° C. for 16 h. The solution was cooled and the organic solvent removed in vacuo. The aqueous mixture was extracted using ethyl acetate (3×40 ml) and the organic extract was discarded. The solid was collected and dried using a sintered funnel under vacuum to afford the title compound (0.86 g, 71%) which was used in the next step without further purification. LCMS RT=0.87 min, M+H+=226.1.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>[OH-].[K+].C1COCC1>[O:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(-c2cnco2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cnco2)cc1

Procedure:
The above ester was heated at reflux for 2 hours in a mixture of 1 M aqueous potassium hydroxide and 50 ml THF. The THF was removed in vacuo and the solution cooled, then acidified with 50% HCl to give 4-(l,3-oxazol-5-yl)benzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[C:13]([CH3:20])[C:14]([F:19])=[C:15]([F:18])[CH:16]=3)[C:11](=[O:21])[C:10]([C:22]([O:24]CC)=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[C:13]([CH3:20])[C:14]([F:19])=[C:15]([F:18])[CH:16]=3)[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1
Yield: 94.9 %

Procedure:
Employing ethyl 1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.56 g), conc. hydrochloric acid (1.5 ml), and 90 % acetic acid (6 ml), the procedure of Reference Example 10 is repeated to give 1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.49 g), as white crystals, m.p. 255°-257° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].ClCC#CC[N:32]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[C:33](=[O:35])[O-:34]>>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:7][CH2:8][N:9]([CH2:4][C:6]#[C:7][CH2:8][O:34][C:33]([NH:32][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[O:35])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: O=C([O-])N(CC#CCCl)c1cccc(Cl)c1
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(CC#CCOC(=O)Nc3cccc(Cl)c3)CC2)cc1
Yield: 128.3 %

Procedure:
Ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-(4-{[(3-chloroanilino)carbonyl]oxy}-2-butynyl)-4-piperidinecarboxylate was prepared according to the general method as outlined in Example 37 (step 1). Starting from 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.291 g, 0.7 mmol) and 4-chloro-2-butynyl-(3-chlorophenyl)carbamate (0.19 g, 0.735), 0.27 g (64%) of the desired product was isolated as pale yellow oil. Electrospray Mass Spec: 601.3 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)=[N:16][CH:17]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:21]1[CH2:22][CH:23]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:7]3[N:6]=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:17][N:16]=2)[CH2:19][CH2:20]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: C1=C(c2ccc(-c3ncccn3)cn2)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CC=C(c2ccc(-c3ncccn3)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Added chloroacetyl chloride (0.35 g, 4.39 mmol) in MeCl2 (15 ml) to a solution of 5-Pyrimidin-2-yl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl (3Q) (0.4 g, 1.68 mmol) and triethylamine (0.4 g, 2.87 mmol) in MeCl2 (10 ml) at 0° C., then stirred 2 hours at 0° C. Added saturated NaHCO3 solution and stirred an additional hour at 0° C. MeCl2 (100 ml) was added, organic layer separated, dried over Na2SO4, filtered and solvent evaporated yielding 4Q as a pale yellow solid (0.53 g, 100%) ESMS (MH 315).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7].[CH3:19][Mg]Br>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH3:19])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: C[Mg]Br
Reactant: COc1cc(C(=O)N(C)OC)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: COc1cc(C(C)=O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3,N-Dimethoxy-N-methyl-5-trifluoromethylbenzamide (O3.014, 460 mg) was initially charged in THF (15 ml) under at RT Ar dissolved. Thereafter, the mixture was cooled to 0° C., and methylmagnesium bromide (1.5 ml; 3 M in diethyl ether) was added dropwise. Subsequently, the ice bath was removed and the mixture was stirred at RT for 2 h. Then the mixture was admixed with 1 N hydrochloric acid while cooling with ice, diluted with water and extracted three times with EA. The combined EA phases were dried over sodium sulfate, filtered and concentrated. 349 mg of the title compound were isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:17][C:18]1[C:19]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=2)=[O:5])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccccc1C(=O)c1cccc(Cl)c1
Reactant: Nc1cccnc1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Nc1cccnc1Nc1ccccc1C(=O)c1cccc(Cl)c1
Temperature: 180 °C

Procedure:
A stirred mixture of 35 g (0.152 mole) of 2-amino-3'-chlorobenzophenone and 23.4 g (0.182 mole) of 3-amino-2-chloropyridine was heated at 180° C. for 2 hr. The hot melt was allowed to cool to 110° C., after which 100 ml of hot toluene was added dropwise with vigorous stirring. The mixture was allowed to cool while stirring to 30° C. and 50 ml of methylene chloride was added. After stirring for an additional 1/2 hour, the mixture was filtered and the filter cake suspended in methylene chloride with stirring for 1/2 hr and methylene chloride was separated by filtration. The filter cake containing the product (25.4 g) was partially dissolved in hot methanol (total volume 150 ml) and 50% aqueous sodium hydroxide was added until the mixture was basic. Ice water was added and the solution was extracted with methylene chloride. This methylene chloride extract was washed with water and dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in isopropyl alcohol and boiled with charcoal. The mixture was filtered, reduced in volume to give a first crop of crystals weighing 16 g (33%). A portion of the crystals was recrystallized from isopropyl alcohol to give a brick red solid melting 119°-120° C.
Reaction SMILES: O=[CH:2][C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[K+].[K+].C(=O)([O-])[O-].[Ca+2].S([O-])([O-])(=O)=O.[Mg+2].[NH2:44][C@H:45]([C:50]([OH:52])=[O:51])[CH2:46][CH:47]([CH3:49])C>S([O-])([O-])(=O)=O.[Fe+2].S([O-])([O-])(=O)=O.[Mn+2].S([O-])([O-])(=O)=O.[Zn+2].S([O-])([O-])(=O)=O.[Cu+2]>[NH2:44][C@H:45]([C:50]([OH:52])=[O:51])[C@H:46]([CH2:47][CH3:49])[CH3:2]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Cu+2]
Agent: [Fe+2]
Agent: [Mn+2]
Product: CC[C@H](C)[C@H](N)C(=O)O
Temperature: 33 °C
Reaction time: 16 h

Procedure:
In each case, 10 ml of Caso broth containing 0.5% glucose were inoculated with 100 μl of a bacterial culture from example 10 (ATCC 14310 derivatives) in a conical flask with baffles (volume: 100 ml) and shaken at 200 rpm by way of a preculture at 33° C. for 16 h (amplitude: 5 cm). From the preculture, 10 ml of main culture in each of three 100 ml conical flasks with baffles were inoculated with an inoculation volume of 1%. A medium containing 40 g of glucose, 20 g of ammonium sulphate, 0.5 g of potassium dihydrogen phosphate, 0.5 g of dipotassium hydrogen phosphate, 20 g of calcium carbonate, 0.25 g of magnesium sulphate (heptahydrate), 10 mg of iron sulphate (heptahydrate), 10 mg of manganese sulphate (×4H2O), 1 mg of zinc sulphate (heptahydrate), 0.2 mg of copper sulphate and 300 mg/l of L-leucine was used for the main culture. The main culture was incubated at 33° C. and a shaker speed of 200 rpm (amplitude: 5 cm) for 48 h. The culture fluid obtained was removed by centrifugation and the concentration of isoleucine was subsequently determined in the supernatant. Table 4 depicts the results.
Reaction SMILES: C(CN)O.[OH-].[Na+].[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.[N+:19]([C:22]1[CH:44]=[CH:43][C:25]([C:26]([N:28](C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:29][CH2:30][OH:31])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:44]=[CH:43][C:25]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N(CCO)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: NCCO
Product: O=C(NCCO)c1ccc([N+](=O)[O-])cc1
Reaction time: 24 h

Procedure:
A solution of 10 ml. ethanolamine in 120 ml. 10% aqueous sodium hydroxide solution was cooled to 5° C. and 30 g. finely powdered 4-nitrobenzoyl chloride added thereto portionwise. The reaction mixture was stirred for 24 hours and filtered. The solid obtained, which mainly consisted of bis-(4-nitrobenzoyl)-ethanolamine, was hydrolysed with 200 ml. of 4% aqueous ethanolic sodium hydroxide at ambient temperature for 24 hours. The reaction mixture was added to the above filtrate, acidified and the precipitated 4-nitrobenzoic acid was filtered off. The filtrate was concentrated and the 13 g. of precipitated N-4-nitrobenzoylethanolamine isolated. The mother liquor was distilled to dryness and the residue was boiled with ethanol. Concentration of the ethanolic extract gave a further 5.3 g. of product; m.p. 134°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12]S(C)(=O)=O)=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.FC(F)(F)C([O-])=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:9][CH2:8][CH:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)=[O:19])[C:6]1=[O:30]
Reactant: COC(=O)CN1CC(CS(C)(=O)=O)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: NCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To the crude product from the previous reaction, {6-[(methanesulfonyl)methyl]-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 23, (0.147 g, 0.32 mmol) in CH2Cl2 (1 mL), is added benzylamine (1 mL). The reaction is stirred at room temperature for 10 minutes, then the reaction is diluted with CH2Cl2. The organic layer is washed with saturated NaHCO3, saturated NaCl, and dried (Na2SO4). The solvent is removed in vacuo and the resulting crude material is purified by HPLC to afford 82 mg (44% yield) of the desired product as the trifluoroacetate salt. 1H (CDCl3) δ 8.82–8.79 (d, J=6.1 Hz, 1H), 8.61–8.59 (d, J=8.6 Hz, 1H), 8.33–8.31, (d, J=5.8 Hz, 1H), 8.01–7.99 (d, J=5.94 Hz, 1H), 7.95–7.82 (m, 2H), 7.77–7.72 (d, d, J=7.98, 7.98 Hz, 1H), 7.36–7.18 (m, 5H), 5.91 (bs, 1H), 5.40–5.39 (m, 1H), 4.67–4.61 (d, J=17.4 Hz, 1H), 4.55–4.49 (d, J=17.8 Hz, 1H), 4.19–4.05 (m, 1H), 3.88–3.83 (d, J=14.7 Hz, 1H), 3.77–3.57 (m, 3H), 3.50 (s, 3H), 2.84–2.78 (d, J=17.8 Hz, 1H), 2.50–2.40 (d, d, J=15.8, 14.5 Hz, 1H); 13C (CDCl3) 171.9, 171.5, 161.9, 161.4, 160.9, 160.6, 149.1, 139.1, 135.2, 134.7, 134.2, 131.3, 130.3, 130.2, 130.1, 129.6, 128.2, 127.9, 127.8, 127.4, 125.8, 121.5, 117.7, 113.8, 110.0, 53.5, 52.9, 51.6, 49.8, 48.3, 37.9, 31.6; MS 473 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]CC(C1C=C(Cl)C=CC=1Cl)=O>>[Br:12][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])=[O:11]
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Reactant: CC(=O)c1ccc(F)cc1Br
Product: O=C(CBr)c1ccc(F)cc1Br
Yield: 63 %

Procedure:
This compound was prepared from 1-(2-bromo-4-fluoro-phenyl)-ethanone (2.5 g, 11.52 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)-ethanone (Method I-2), affording 2.14 g (63%) of 2-bromo-1-(2-bromo-4-fluoro-phenyl)-ethanone as a clear oil. 1H-NMR (CD2Cl2) δ 7.57 (dd, J=9, 6 Hz, 1H), 7.44 (dd, J=8, 2 Hz, 1H), 7.21 ((m, 7.21–7.14, 1H), 4.51 (s, 2H); TLC Rf=0.38, 15% ethyl acetate-hexanes.