Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33](=O)[NH2:34])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([O:5][C:6](=[O:36])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C(N)=O)cc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
2-[(4-{2-[(5-Carbamoyl-3-chloropyridin-2-yl)(heptyl)amino)ethyl)-1,3-thiazol-2-yl)thio)-2-methylpropionic acid tert-butyl ester (0.85 g) synthesized in Example 281-2 was dissolved in dichloromethane (10 mL), triethylamine (0.26 mL), trifluoroacetic acid anhydride (0.24 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=9:1) to give the title compound (0.37 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[S:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[N:15]=1.C(O)(C(F)(F)F)=O.CO>C([SiH](CC)CC)C.C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:17][NH:16][C:4]1[S:5][C:6]([C:7]2[S:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:14]=3[N:15]=2)=[C:2]([Br:1])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1nc(Br)c(-c2nc3ccncc3s2)s1)Cc1ccc(C(F)(F)F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nc(Br)c(-c2nc3ccncc3s2)s1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
To a 150 mL round-bottomed flask was added tert-butyl (S)-1-(4-bromo-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.157 g, 0.26 mmol), DCM (25.00 mL, 389 mmol) and TFA (5.00 mL, 65 mmol) with a few drops of triethylsilane, and the resulting solution was stirred for about 15 minutes and followed by LCMS. LCMS showed conversion to product so the solvent was removed, and the oil was dissolved in 2 N ammonia in MeOH and adsorbed on to a plug of silica gel. Chromatography through a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 10% 2 M ammonia.MeOH in DCM, provided N—((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-4-bromo-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine (0.086 g, 65% yield).
Reaction SMILES: C(N1[C:12](=[O:13])C2=CC=CC=C2C1=S)C1C=CC=CC=1.CN1CCN([C:26]2[N:30]3[C:31]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:32]=4[CH:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:42])[O:34][CH2:35][C:29]3=[N:28][N:27]=2)CC1>C1C=CC=CC=1.ClCCl>[OH:13][CH2:12][C:26]1[N:30]2[C:31]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:32]=3[CH:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[O:34][CH2:35][C:29]2=[N:28][N:27]=1
Reactant: O=C1c2ccccc2C(=S)N1Cc1ccccc1
Reactant: CN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccc2Cl)OC3)CC1
Solvent: c1ccccc1
Solvent: ClCCl
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Yield: 73.6 %

Procedure:
N-Benzylthiophthalimide (1.62 g) is dissolved in benzene (74 ml) under heating. To the resulting solution is added a solution of Compound 18 (1.13 g) prepared in Example 10 in dichloromethane (10 ml), and the mixture is refluxed under heating for 15 hours, and concentrated. The residue is extracted with ethyl acetate and the extract is dried and concentrated. The residue is treated on column chromatography (silica gel/ethyl acetate) to give Compound 23 (0.7 g), which is recrystallized from ethyl acetate. Yield 47%
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([O:12][CH3:13])=[O:11])=[C:5]1[CH2:14][C:15]([O:17][CH3:18])=[O:16].[CH:19](OC)=[O:20].CO>O1CCCC1>[CH:19]([CH:14]([C:5]1[N:4]([CH3:3])[C:8]([CH3:9])=[CH:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])[C:15]([O:17][CH3:18])=[O:16])=[O:20]
Reactant: COC=O
Reactant: COC(=O)Cc1c(C(=O)OC)cc(C)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)n(C)c1C(C=O)C(=O)OC
Temperature: 10 °C

Procedure:
Sodium hydride (2.29 g, 60% dispersion in mineral oil) was added portionwise to a stirred solution of methyl 1,5-dimethyl-2-[2-(methyloxy)-2-oxoethyl]-1H-pyrrole-3-carboxylate (2.37 g) in tetrahydrofuran (30 ml) at 20° C. After fifteen minutes the reaction mixture was cooled to 10° C. and methyl formate (1.0 ml) added. After ten minutes a mixture of methanol (0.05 ml) and tetrahydrofuran (1 ml) was added. The reaction mixture was stirred at room temperature for sixteen hours. After cooling to 10° C., methanol (0.1 ml) was added, the mixture was stirred at room temperature for two hours. After cooling in an ice bath, methanol (8.4 ml) was added dropwise, the mixture was stirred for a further fifteen minutes, then evaporated. The residue was partitioned between ethyl acetate and aqueous ammonium chloride, and then acidified by addition of 5N hydrochloric acid. The aqueous phase was extracted with a second portion of ethyl acetate. The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The solid residue washed with hexane and then dried to give the title compound 2.59 g as a tautomeric mixture.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(N)cc1
Solvent: C1CCOC1
Product: Nc1ccc(N2C(=O)C=CC2=O)cc1
Temperature: 23 °C
Reaction time: 22 h
Yield: 98.6 %

Procedure:
The solution of 21.6 g (200 mmol) of 1,4-phenylenediamine in 200 ml of tetrahydrofuran is mixed over 1.5 hours with the solution of 19.6 g of maleic acid anhydride, and it is stirred for 22 hours at 23° C. It is filtered, rewashed with tetrahydrofuran, and the filtrate is dried. 37.1 g (197 mmol, 98%) of the title compound is isolated as a crystalline solid.
Reaction SMILES: O[CH:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([C:10]1[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=1)[CH2:6]2.CC1(C)[O:35][C:33](=[O:34])[CH2:32][C:30](=[O:31])[O:29]1.N1CCCCC1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([CH:5]3[CH2:4][CH:3]4[CH:2]([CH:32]([C:33]([OH:35])=[O:34])[C:30]([OH:31])=[O:29])[CH:7]([CH2:8][CH2:9]4)[CH2:6]3)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4O)nc2n(CCC)c1=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4C(C(=O)O)C(=O)O)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8-(8-Hydroxy-bicyclo[3.2.1]oct-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (30 mg) taken in CHCl3 (5 ml). To this solution Meldrum's acid (58 mg), piperidine (10 mg) were added and heated to reflux overnight. The next day, after cooling to room temperature, diluted with ethyl acetate, washed with 1N HCl, sat NaHCO3, brine, and dried. The solvent was removed under reduced pressure, the crude residue was taken up in MeOH, cooled to 0° C., NaBH4 (30 mg) was added, the mixture was stirred for 15 min. The reaction was diluted with 1N HCl, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was taken up in THF (5 ml) and 4N HCl (5 ml) was added and stirred for 1 day. The reaction mixture was extracted with ethyl acetate, washed with brine, and concentrated. The crude product was purified by HPLC. Yield (6 mg). Mass (ES+ 447).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[OH:12])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1C(O)c1cnc2c(F)cccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1C(=O)c1cnc2c(F)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
After 0.32 g of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3-yl)-methanol was dissolved in 3 ml of dichloromethane, 0.51 g of Dess-Martin reagent was added and the mixture was stirred for 1 hour at room temperature. After water was added and then the liquid was separated with ethyl acetate, the organic layer was concentrated and purified by silica gel column chromatography to obtain 0.21 g of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3-yl)-methanone (Compound Number 57).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:22]([F:25])([F:24])[F:23])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[N:26]([O-])=[O:27].[Na+]>Cl.O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:22]([F:24])([F:23])[F:25])[CH:11]=[CH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([N:26]=[O:27])[CH2:17][CH2:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: Fc1c(Cl)cc(C(/C=C/c2ccc3c(c2)CCN3)C(F)(F)F)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=NN1CCc2cc(C=CC(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (E)-5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)indoline (0.2 g, 0.5 mmol) in concentrated HCl (5.0 ml) at 5° C., was added slowly NaNO2 in water and the reaction was allowed to stir at RT for 2 h. The reaction mixture was diluted with DCM, and the DCM layer washed with water and brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product as a pale yellow solid that was used in the next step without further purification (0.2 g): 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.4 Hz, 1H), 7.39 (m, 4H), 6.61 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.4 Hz, 1H), 4.07 (m, 3H), 3.23 (t, J=8.4 Hz, 2H); ESIMS m/z 418.82 ([M+H]+); IR (thin film) 1488, 1112, 860 cm−1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]=[N:16][C:17]2[C:22]([Br:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Br:24])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH2:15][NH:16][C:17]2[C:22]([Br:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Br:24])[C:6]=1[OH:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C=Nc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(CNc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
To a suspension of 2,4-bis(tert-butyl)-6-[[(2,6-dibromophenyl)imino]methyl]phenol (0.91 g, 2.41 mmol) in methanol (20 ml) was added NaBH4 (1.2 g), in small portions. The yellow suspension was stirred for 2 hours during which the yellow solution turned clear. Water (10 ml) was then slowly added, the organic phase separated and the aqueous phase extracted with dichloromethane (3×10 ml). The organic fractions were combined, dried (NaSO4), and the solvent removed under reduced pressure. The crude product was purified by recrystallisation from hot hexane to afford the product as large colourless crystals. Yield 0.48 g, 95%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C@@H:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:37][CH2:38]I>>[C:1]([C:3]1[CH:4]=[C:5]([C@H:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:38][F:37])=[CH:32][CH:31]=2)[C@@H:10]([NH:12][C:13](=[O:28])[C:14]([O:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)([CH3:16])[CH3:15])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@H](NC(=O)C(C)(C)Oc1cc(C(F)(F)F)ccn1)[C@@H](Cc1ccc(O)cc1)c1cccc(C#N)c1
Reactant: FCI
Product: C[C@H](NC(=O)C(C)(C)Oc1cc(C(F)(F)F)ccn1)[C@@H](Cc1ccc(OCF)cc1)c1cccc(C#N)c1

Procedure:
N-(1S,2S)-[2-(3-Cyanophenyl)-3-(4-fluoromethoxyphenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide was prepared from N(1S,2S)-[2-(3-cyanophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (Example 12, Step B) and fluoromethyliodide following the procedure described in Example 4.
Reaction SMILES: [O:1]1[C@H:12]2[CH2:13][C@@H:14]([CH3:26])[C@@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:25])[C@H:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]>C(OCC)(=O)C.[Pt]=O>[O:1]1[C@H:12]2[CH2:13][C@@H:14]([CH3:26])[C@H:15]([CH2:16][CH2:17][C@@H:18]([OH:25])[C@H:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCCC[C@@H](F)[C@H](O)/C=C/[C@H]1[C@H]2C[C@H](CCCCC(=O)O)O[C@H]2C[C@H]1C
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCC[C@@H](F)[C@H](O)CC[C@@H]1[C@H]2C[C@H](CCCCC(=O)O)O[C@H]2C[C@H]1C
Reaction time: 8 h

Procedure:
To a solution of 275 mg of [6S,8R,9S,11R,12S,15R,16R]-6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)-enoic acid in 20 ml of ethyl acetate was added 30 mg of platinum oxide. The mixture was sealed under a positive hydrogen atmosphere and vigorously stirred. After eight hours, the reaction mixture was filtered and the volatiles removed by rotary evaporation. The residual oily product was purified by chromatography over 50 g of Sephadex LH-20 using chloroform-hexane (65/35) to yield [6S,8R,9S,11R,12S,15R,16R]-6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprostanoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C([Li:21])CCC>C1C=CC=CC=1.CCCCCC>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Li:21])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: [Li]c1ccc(OCCCCCCCC)cc1

Procedure:
31.38 g (110.0 mmol) of 1-bromo-4-octyloxybenzene in 80 ml of benzene and 81 ml (130.0 mmol) of a 1.6-molar n-butyllithium solution in hexane are stirred at room temperature under argon for 4 hours. The 4-octyloxyphenyllithium formed as a white precipitate is filtered off under argon, washed twice with 20 ml of n-hexane, dried in vacuo and slowly added dropwise as a solution in 60 ml of tetrahydrofuran at 0° C. under argon to a solution of 11.51 g (100.0 mmol) of 2,6-difluoropyridine in 80 ml of tetrahydrofuran. After a reaction time of 1 hour at 0° C., sodium chloride solution is added, the mixture is taken up in ether, the organic phase is washed with sodium chloride solution, dried over sodium sulfate, filtered, the solvent is removed from the filtrate, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate), giving 4.00 g of 2-fluoro-6-(4-octyloxyphenyl)pyridine. ##STR17##
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[N:18]=[C:17]([NH2:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:21][NH:22][C:23]3[CH:45]=[C:44]([O:46][CH3:47])[C:26]([O:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[C:25]([O:48][CH3:49])[CH:24]=3)[C:15]=2[CH3:20])[N:10]=1>O>[NH2:8][C:9]1[N:18]=[C:17]([NH2:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:21][NH:22][C:23]3[CH:45]=[C:44]([O:46][CH3:47])[C:26]([O:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[C:25]([O:48][CH3:49])[CH:24]=3)[C:15]=2[CH3:20])[N:10]=1
Reactant: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OCC(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OCC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
HCl in dioxane (3.22 ml, 12.87 mmol) was added to example (6) (0.03 g, 0.051 mmol) followed by a few drops of water. The solution was allowed to stir at RT. After 3 h, the solvents were evaporated, the residue triturated with Et2O and dried under vacuum to afford the title compound (7) (22 mg, 82%). LCMS purity 96%, m/z 527 [M+H]+, 1H NMR (400 MHz, d6-DMSO) δ: 12.6 (1H, s), 9.0 (1H, s), 8.0 (1H, d, J=8.3 Hz), 7.9 (1H, s), 7.5 (3H, m), 7.2 (1H, d, J=8.8 Hz), 6.0 (2H, s), 4.3 (3H, m), 4.2 (2H, d, J=5.4 Hz), 3.7 (6H, s), 2.7 (3H, s), 1.5 (3H, m), 0.8 (6H, m).
Reaction SMILES: COC1C=CC(COC([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:33])[CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])[CH2:13][CH2:12]2)=O)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:20]([NH:19][CH2:18][C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:33])=[O:21])=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: COc1ccc(COC(=O)N2CCN(C(=O)CNC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Yield: 98.9 %

Procedure:
To 3.74 g of 1-(p-methoxybenzyloxycarbonyl)-4-(2-(p-nitrobenzyloxycarbonyl)aminoacetyl)piperazine were added 4.17 ml of anisole and, with cooling on an ice bath, 20 ml of trifluoroacetic acid, followed by 1 hour of reaction at room temperature. After removing trifluoroacetic acid by evaporation under a reduced pressure, the residue was adjusted to basic with a sodium hydroxide aqueous solution and extracted with chloroform, and an organic layer was washed with water and dried over sodium sulfate, followed by removal of the solvent under a reduced pressure and subsequent addition of n-hexane to a residue to collect a solid material by filtration, thereby obtaining 2.45 g of 1-(2-(p-nitrobenzyloxycarbonyl)aminoacetyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:12][CH2:13][CH2:14]Br)(=[O:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[CH2:13]([O:12][C:9](=[O:11])[CH2:10][O:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: CC(=O)OCCBr
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a suspension of 6-chloro-pyridin-3-ol (1000 mg, 7.72 mmol) and bromoethyl acetate (1933 mg, 11.57 mmol) in CH3CN was added Cs2CO3 (3772 mg, 11.57 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with EtOAc, then washed three times with H2O and brine, and then dried. MgSO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield the (6-chloro-pyridin-3-yloxy)-acetic acid ethyl ester (1.5 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C2C=CC=C3C(NC(=O)C=23)=O)=[CH:4][CH:3]=1.O.[NH2:27]N.CCO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:27])=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCCCSc3ccc(Cl)cc3)cccc21
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NCCCCCCSc1ccc(Cl)cc1

Procedure:
2-[6-(4-Chloro-phenylsulfanyl)-hexylphthalimide (7.47 g, 20 mmol) and hydrazine hydrate (6.1 ml, 100 mmol) were dissolved in THF (50 mL) and EtOH (50 mL) and stirred under reflux for 17 h. The solvent was removed under reduced pressure, the residue was suspended in THF (100 mL) and the precipitate was filtered off, washed with THF (1×50 mL) and the filtrate was concentrated under reduced pressure. The residue was resuspended in THF (25 mL), the precipitate was filtered off and the filtrate was concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].O1CCCC1.CO.[OH-].[Li+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:9])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OCC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(C(=O)NC2(C(=O)O)CC2)cc1
Temperature: 55 °C
Yield: 99.1 %

Procedure:
Add ethyl 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylate (478 g, 1.72 mol) to tetrahydrofuran (2 L) and methanol (1 L). Dissolve lithium hydroxide (LiOH) (144.7 g, 3.45 mol) in water (1 L) and add it to the mixture. Stir the reaction mixture while heating to 55° C. Cool the reaction to ambient temperature and concentrate under reduced pressure. After removing 2.5 L of solvent, dilute the mixture with water (2 L) and immerse it in an ice water bath. Adjust to pH 2 with aqueous 5N hydrochloric acid (750 mL). Filter the precipitate, wash the cake with water (2×2 L), and dry to give the title compound (425 g, 99%) as a white powder: MS (m/z): 250 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17]C1C=CC=CC=1>O1CCCC1>[C:1]1([N:7]=[C:8]([C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)[NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cccc(C(=O)NC2CCCCC2)c1
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(C(N)=Nc2ccccc2)c1
Yield: 82.9 %

Procedure:
65.1 g (0.3 mole) of N-cyclohexyl-m-toluamide were dissolved in 500 ml of dried tetrahydrofuran and a benzene solution of 45 g of COCl2 absorbed in 30 ml dried benzene, and 30 ml dried pyridine were added dropwise and under agitation and ice cooling to the above tetrahydrofuran solution. Upon completion of the dropwise addition, the reaction mixture was adjusted in its temperature to room temperature and brought into reaction for 2 hours. The sedimented pyridine hydrochloride were filtered off and the filtrate was condensed under vacuo, to provide an oily substance containing N-cyclohexyl-m-toluimido chloride. The oil was then subjected to extraction with 400 ml of dried petroleum ether and 32.8 ml (0.36 mole) of aniline were added dropwise for 30 minutes under agitation and ice cooling to the extract and the mixture was let to react at room temperature for 1.5 hours. The thus deposited oily substance was decanted off from the mother liquor and dissolved in 100 ml of ethanol, adjusted pH to about 2 by addition of 1N-hydrochloric acid and added with 1.2 lit. of water. Then, the aqueous solution was washed twice with 150 ml of ethyl acetate. The aqueous phase was treated with active carbon for discoloration and then condensed under vacuo. The sedimented products were filtered off, washed, dried and recrystallized from ethanol/diethyl ether. In this way, 81.7 g of N-cyclohexyl, N'-phenyl-m-toluamidine were obtained. m.p. 174° - 176° C. Yield: 82.9%.