Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([N:33]1[CH2:37][CH:36]([CH2:38]O)[CH2:35][S:34]1(=[O:41])=[O:40])[CH3:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:31]([N:33]1[CH2:37][CH:36]([CH2:38][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:35][S:34]1(=[O:41])=[O:40])[CH3:32]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCN1CC(CO)CS1(=O)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1CC(CN2C(=O)c3ccccc3C2=O)CS1(=O)=O
Temperature: 25 °C

Procedure:
To a stirred solution of phthalimide (133 mg, 1 equiv) in tetrahydrofuran (4.5 ml) was added triphenylphosphine (237 mg, 1 equiv) and (2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methanol (0.905 mmol). This solution was cooled down to 0° C. for the dropwise addition of diisopropylazodicarboxylate (0.18 ml, 1 equiv). The reaction mixture was stirred at room temperature over the weekend. It was then concentrated, and stirred in diethyl ether for 5 hours. Volatiles were removed in vacuo. Flash chromatography eluting with cyclohexane/ethyl acetate (7/3) afforded 261 mg (0.85 mmol, 94%). LCMS (Method E) 1.40 min, M+H 309. 1H-NMR (CDCl3, 400 MHz): 7.93-7.84 (m, 2H), 7.83-7.72 (m, 2H), 3.89 (dd, 2H), 3.41-3.23 (m, 2H), 3.17-2.98 (m, 5H), 1.22 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15]>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccc1)c1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of aniline (178 mg, 1.9 mmol) in 20 mL CH2Cl2 at room temperature was added NaOH (76.2 mg, 2.9 mmol) in 6 mL water. This mixture was stirred vigorously for 5 minutes after which 3-chlorobenzoyl chloride (500 mg, 2.9 mmol) was added drop-wise while stirring over a period of 30 minutes. This reaction mixture was stirred for an additional 2 hours followed by an acid work-up and extraction with CH2Cl2 (3×20 mL). The organic layers were combined, dried over anhydrous MgSO4. The product was purified via column chromatography on silica gel and eluted with a CHCl3/MeOH/Et3N (9.8:0.1:0.1) to give white crystals in 81% yield.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[Cl-].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[N:28]3[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)=[C:22]([C:29](O)=[O:30])[CH:21]=2)[CH:15]=1.Cl>C(#N)C.O.C(N(CC)CC)C>[CH3:9][O:8][C:6]([CH:5]([C:29](=[O:30])[C:22]1[CH:21]=[C:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[N:28]2[C:23]=1[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:4]([O:11][CH3:12])=[O:10])=[O:7]
Reactant: O=C(O)c1cc(-c2cccnc2)n2c1CCCC2
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C(=O)OC)C(=O)c1cc(-c2cccnc2)n2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.8 cm3 of triethylamine are added dropwise to a suspension of 1.4 g of magnesium chloride in 16 cm3 of acetonitrile under argon, followed, after 5 minutes, by 2.9 cm3 of dimethyl malonate. The resulting white suspension is then stirred at ambient temperature under argon for 1 hour. To this suspension is then added, via a cannula, a suspension, prepared beforehand from 6.3 g of the chloride of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxylic acid in 36 cm3 of acetonitrile under argon, to which 2.8 cm3 of triethylamine has been added. The resulting brick-red suspension is stirred at ambient temperature under argon for 18 hours and is then cooled to 0° C. and treated dropwise with 7 cm3 of concentrated hydrochloric acid. The resulting mixture is diluted with 15 cm3 of distilled water and separated and then the aqueous phase is extracted 6 times with 50 cm3 of dichloromethane. The organic extracts are combined and dried over magnesium sulphate and then concentrated at reduced pressure (2.7 kPa). 8.1 g of methyl 2-(methoxycarbonyl)-3-oxo-3-[3-(3-pyridyl)-5,6,7,8-tetrahydro-1-indolizinyl]propionate are thus obtained in the form of a beige crystalline solid melting at 146-150° C. (Rf=0.65; thin layer chromatography on silica gel; eluent: 10/90 by volume mixture of methanol and of dichloromethane).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:32])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].ON1[C:38](=O)[CH2:37][CH2:36][C:35]1=O.CC(N=C=NC(C)C)C>CS(C)=O>[CH2:27]([CH:26]([CH2:35][CH2:36][CH2:37][CH3:38])[C:25]([OH:32])=[O:31])[CH2:28][CH2:29][CH2:30][CH2:1][CH3:2].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CS(C)=O
Solvent: OCC(O)CO
Product: CCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous DMSO (50 mL). Hexanoic acid (11.96 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was dialyzed in SpectraPor7 MWCO 1000 dialysis tubing to remove the DMSO and unreacted monomer. The polymer crashed out in water into a thick white liquid. After 3 days of dialysis, the solution was placed into a separatory funnel and the organic portion was dissolved into chloroform. The water layer was removed and the organic layer was dried with sodium sulfate. The solvent was stripped via rotoevaporation to leave a clear thick liquid product. NMR analysis supported full conversion of hydroxyl groups to the hexanoic esters.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[CH:34]([NH2:37])([CH3:36])[CH3:35].[BH4-].[Na+].Cl.C(O)(C(F)(F)F)=O>C(O)C.C(Cl)Cl.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH:34]([NH:37][CH2:14][C:13]1[CH:16]=[C:17]([C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[C:10]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:11][CH:12]=1)([CH3:36])[CH3:35]
Reactant: CC(C)N
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Nc2ncc(CNC(C)C)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 96.8 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (90.6 mg, 0.203 mmol) was suspended in ethanol (1.2 mL) and DCM (1.2 mL), and isopropylamine (0.060 mL, 0.70 mmol) and tetraisopropoxytitanium (0.20 mL, 0.68 mmol) were added. The reaction was stirred at room temperature for 75 min, and then sodium borohydride (26.8 mg, 0.708 mmol) was added, along with MeOH (1 mL), and stirring was continued at room temperature. After 2 h, more MeOH and 5 N HCl (0.50 mL) were added, and stirring was continued overnight. The suspension was diluted with DCM and MeOH and filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and purified by prep HPLC to give 5-((isopropylamino)methyl)-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (79.5 mg, 97.1% purity, 76% yield) as a TFA salt. 1H NMR (d6-DMSO, 400 MHz) δ 12.71 (br s, 1H), 9.80 (br s, 1H), 8.69 (s, 1H), 8.65 (br s, 2H), 8.58 (d, J=2.74 Hz, 1H), 8.42 (d, J=2.15 Hz, 1H), 8.14 (dd, J=9.00 Hz, 2.74 Hz, 1H), 6.89 (d, J=9.00 Hz, 1H), 4.24-4.18 (m, 2H), 3.86 (s, 3H), 3.48-3.38 (m, 1H), 2.87 (s, 3H), 1.31 (d, J=6.46 Hz, 6H). m/z (ESI, +ve ion) 405 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])([CH3:26])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:23]([O-])=O>[Pt].C(#N)C>[NH2:23][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[NH:4][CH2:3][C:2]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])([CH3:26])[CH3:1])=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:10]=2
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12)NS(C)(=O)=O
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NS(C)(=O)=O
Reaction time: 2 h
Yield: 91.3 %

Procedure:
N-[1,1-Dimethyl-2-(3-nitro-7-benzyloxyquinolin-4-ylamino)ethyl]methanesulfonamide (14.8 g, 33.3 mmol) was mixed with acetonitrile (300 mL) and added to a Parr flask; 5% platinum on carbon (2 g) was added. The reaction was flushed with nitrogen and placed under hydrogen pressure (40 psi, 2.8×105 Pa) for 5.5 hours with the hydrogen replaced after two hours. An analysis by TLC indicated the presence of starting material. Additional acetonitrile (200 mL) and 5% platinum on carbon (2 g) were added, and the reaction was placed under hydrogen pressure overnight. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. Toluene and dichloromethane were added and removed under reduced pressure twice to yield 12.6 g of N-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][C:12]([CH3:14])=O.C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)=O>O1CCCC1.O>[CH3:1][C:2]1[CH:8]=[C:7]([I:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH:4][CH:12]([CH3:14])[CH3:11]
Reactant: CC(C)=O
Reactant: Cc1cc(I)c(C)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(C)C)c(C)cc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.1 g (0.017 mol) of 2,5-dimethyl-4-iodo-aniline, 1.4 ml of (0.019 mol) of acetone, 1.4 ml of (0,024 mol) of glacial acetic acid and 0.1 g (0.001 mol) of p-toluenesulphonic acid are dissolved in 30 ml of tetrahydrofuran and stirred for 30 minutes at ambient temperature. Then 4.7 g (0.022 mol) of sodium triacetoxyborohydride are added and the mixture is stirred for another 20 hours at ambient temperature. After the addition of 150 ml of water, sodium carbonate is added until no further development of CO2 can be detected. The mixture is then extracted with ethyl acetate, the combined organic extracts are dried over sodium sulphate and evaporated down. The residue is chromatographed on silica gel, eluting with ethyl acetate/petroleum ether (2:98).
Reaction SMILES: C(O[CH:6]([N:10]([CH3:12])C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]1[N:17]2[C:18]3[CH2:29][C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:19]=3[NH:20][C:21](=[O:22])[C:16]2=NC=1.O>CN(C)C=O.CO>[CH3:16][N:17](/[CH:18]=[C:29]1\[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]2[NH:20][C:21](=[O:22])[C:6]3[N:7]([CH:8]=[CH:12][N:10]=3)[C:9]\1=2)[CH3:13]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)/C=c1\c2ccccc2c2[nH]c(=O)c3nccn3c12
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
6.3 g of t-butoxybis(dimethylamino)methane are added dropwise over 5 minutes at a temperature in the region of 25° C. to a suspension of 5.5 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 100 ml of dimethylformamide. After stirring for 30 minutes at the same temperature, the mixture is poured into 500 ml of distilled water and extracted 5 times with 1.5 litres in total of chloroform. The organic extracts are combined, washed with 250 ml of distilled water, dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained (4.5 g) is suspended in 25 ml of methanol, filtered, washed twice with 20 ml in total of methanol and dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (4.5 g) is dissolved in 45 ml of boiling dimethylformamide and, after cooling, the solution is stored for 4 hours at a temperature in the region of 5° C. The crystals are separated out by filtration, washed successively with 10 ml of dimethylformamide, 10 ml of acetone and dried to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 4 g of 10-[(E)-dimethylaminomethylene]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, melting at 293° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 3.35 (s, 6H: --N(CH3)2); 7.18 and 7.28 (2t, J=7.5 Hz, 2H: --H7 and --H8); 7.48 and 7.92 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 7.63 and 8.50 (2s broad, 1H each: --H of the imidazole); 8.09 (s, 1H: =CH--N); 12.30 (cplx, 1H: --NH--)].
Reaction SMILES: Cl[Sn]Cl.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1)([O-])=O>C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Yield: 99.8 %

Procedure:
SnCl2 (5.798 g, 30.58 mmol) was added to 2-(4-nitrophenyl)-6-methoxybenzothiazole (41, 1.459 g, 5.10 mmol) obtained in step 2 dissolved in ethanol (300 mL). The resulting reaction mixture was refluxed for 4 hours under a nitrogen atmosphere and the solvent was removed under reduced pressure. Then, the remaining mixture was dissolved in ethyl acetate and, after washing with 1N NaOH aqueous solution (50 mL) and water (100 mL), water was removed using sodium sulfate. After removing the solvent by distilling under reduced pressure, 2-(4-aminophenyl)-6-methoxybenzothiazole (43, 1.305 g, 99%) was yielded as a yellow solid without further purification.
Reaction SMILES: [CH3:1][CH:2]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[N:23]=3)[N:20]=2)[N:15](COCC[Si](C)(C)C)[CH:14]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][CH:2]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[N:23]=3)[N:20]=2)[NH:15][CH:14]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCCC4)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: CC(Cc1ccccn1)NC(=O)c1c[nH]c2ncc(-c3nn(CCN4CCCC4)c4cc(F)ccc34)nc12
Reaction time: 2 h
Yield: 43.4 %

Procedure:
2-[6-Fluoro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)amide (75 mg, 0.117 mmol) was combined with dichloromethane (1 mL) then trifluoroacetic acid (0.26 ml, 3.50 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL) and ethylenediamine (0.23 ml, 3.50 mmol) was added and the reaction was stirred at room temperature for 20 min. The reaction mixture was concentrated in vacuo and the residue was triturated with water (2 mL). The precipitate was filtered, washed with water and dried to afford 26 mg (41%) of 2-[6-fluoro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide (26 mg, 41%) as a yellow solid. MS: (M+H)+=513; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.32-8.44 (m, 2H), 8.22 (d, J=8.3 Hz, 1H), 7.73 (d, J=9.8 Hz, 1H), 7.50-7.66 (m, 2H), 7.27 (d, J=7.8 Hz, 1H), 7.03-7.16 (m, 2H), 4.53-4.67 (m, 4H), 4.46 (s, 1H), 3.02-3.25 (m, 2H), 2.98 (t, J=6.5 Hz, 3H), 1.64 (br. s., 5H), 1.29 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Cl-].[Li+].[CH3:3][C:4]1([CH3:26])S[C@@H:7]2[C@H:9]([NH:12][C:13]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[C:10](=[O:11])[N:6]2[C@H:5]1[C:23]([OH:25])=[O:24].[CH3:27]O>C(O)(C)(C)C.[Pt]>[CH3:27][O:25][C:23]([C:5]([N:6]1[C:10](=[O:11])[C@@H:9]2[C@H:7]1[O:14][C:13]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:12]2)=[C:4]([CH3:26])[CH3:3])=[O:24]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CO
Agent: [Pt]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]2N=C(COc3ccccc3)O[C@H]21
Reaction time: 2.67 h
Yield: 80 %

Procedure:
Lithium chloride (6.7 mg) was dissolved in a mixture of 2 ml of methanol and 0.5 ml of tert-butyl alcohol. Thereto was added 72 mg of methyl ester of penicillin V to prepare an electrolyte. Electrolysis was performed at a temperature of less than -70° C. and 10 to 15 V for 160 minutes (5 F) by dipping platinum electrodes (1 cm2) in the electrolyte and passing constant current of 10 mA through the electrolyte. Thereafter, the reaction mixture was stirred at less than -10° C. for about 30 minutes and extracted with ethyl acetate. The extract was treated in the same manner as in Example 1, affording 53 mg of contemplated compound in 80% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3]1.[CH:12]1[CH:17]=[C:16]([C:18](O)=[O:19])[C:15]([OH:21])=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[OH:21][C:15]1[CH:14]=[CH:13][CH:12]=[CH:17][C:16]=1[C:18]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]2[CH3:1])=[O:19]
Reactant: Cn1ccc2c(N)cccc21
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cn1ccc2c(NC(=O)c3ccccc3O)cccc21
Yield: 60.7 %

Procedure:
A solution of 5 g of 1-methyl-1H-indol-4-amine [prepared according to Ley (J. Chem. Soc. Chem. Com. (1982) p. 1356], 4.7 g of salicyclic acid and 7 g of dicyclohexylcarbodiimide in 80 ml of tetrahydrofuran was refluxed for 24 hours and 20% of salicylic acid and of dicyclohexylcarbodiimide were added after 5 hours of refluxing. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography over silica (eluant:methylene chloride) to obtain 5.5 g of 2-hydroxy-N-(1-methyl-1H-indol-4-yl)benzamide melting at 211° C.
Reaction SMILES: [BrH:1].N[C@@H:3]([C@@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH3:9])[C:4]([OH:6])=[O:5].N([O-])=O.[Na+]>Br>[Br:1][C@@H:3]([C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH3:9])[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: CC[C@H](C(=O)OC)[C@H](N)C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Product: CC[C@@H](C(=O)OC)[C@H](Br)C(=O)O
Temperature: -9 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of crude amino acid salt (2S,3S)-2-amino-3-(methoxycarbonyl)pentanoic acid hydrobromide (19.6 g) of Example 7 in aqueous hydrobromic acid (2.5N), cooled to -9° C. with an ice water-salt-acetone bath, was added sodium nitrite (10.0 g, 144.9 mmol) in small portions over a 1.5 h period, keeping the internal temperature (measured by electronic internal temperature probe) below -7° C. The reaction mixture was stirred for 2 h in the cooling bath after the addition was complete, then it was extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated aqueous sodium chloride (2×250 mL), dried (MgSO4), and concentrated in vacuo to give the bromoacid which slowly solidified to a waxy solid (13.0 g).
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]2[N:45]=[C:44]([CH2:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][C:55]([OH:57])=O)[C:43]([C:58]([F:61])([F:60])[F:59])=[CH:42][N:41]=2)=[CH:35][CH:34]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C.C1COCC1>[NH2:7][C:55](=[O:57])[CH2:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[CH2:47][CH2:46][C:44]1[C:43]([C:58]([F:60])([F:59])[F:61])=[CH:42][N:41]=[C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([CH2:32][NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:34][CH:35]=2)[N:45]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(=O)O)n2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HOBt (76 mg, 0.56 mmol) and EDCl.HCl (108 mg, 0.561 mmol) were added to a solution of 2-(2-(2-(2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A15) (251 mg, 0.468 mmol) and DIPEA (326 μL, 1.87 mmol) in DMF (2 mL) and THF (10 mL). The resulting mixture was stirred at room temperature overnight then the volatiles were removed in vacuo and the residue partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (100 mL). The layers were separated and the organic layer was washed with water (100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo and the residue adsorbed onto silica gel and purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A16 as a tan solid (0.22 g, 89%); 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 8.67 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.43 (s, 1H), 7.33 (t, J=6.0 Hz, 1H), 7.27-7.10 (m, 6H), 6.91 (s, 1H), 3.50 (s, 2H), 3.18 (d, J=5.3 Hz, 2H), 3.14-2.99 (m, 4H), 1.40 (s, 9H). LCMS-A: rt 6.086 min; m/z 530 [M+H]+.