Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH:19]([NH:21][CH3:22])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C=O.[CH:25](O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH:19]([N:21]([CH3:25])[CH3:22])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CO
Reactant: CNC(C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: C=O
Solvent: CO
Product: CC(C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1)N(C)C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a solution of 47 (200 mg, 0.60 mmol) in MeOH (5 mL) was added HCHO (35 mg, 37%, 1.20 mml), HCO2H (0.3 mL) and NaB(CN)H3 (75 mg, 1.20 mmol). The reaction mixture was stirred for 20 min before being concentrated. The residue was dissolved in MeOH (2 mL) and subjected to reverse phase column chromatography (CH3CN/H2O/0.1% formic acid=5% to 100%) to give 48 (188 mg, 91%). 1H NMR (400 MHz, CDCl3)δ 7.34 (d, J=8.4 Hz, 1 H), 7.25 (m, 2 H), 7.20 (m, 2 H) 7.12 (m, 2 H), 7.0 (dd, J=2.0, 8.4 Hz, 1 H), 6.83 (d, J=7.6Hz, 1 H), 6.40 (s, 1 H), 4.10 (t, J=8.4 Hz, 1 H), 2.65 (d, t, J=6.4, 13.2 Hz, 1 H), 2.65 (dd, J=6.8, 16.4 Hz, 1 H), 2.54 (dd, J=9.2, 16.4 Hz, 1 H), 2.21 (s, 6 H), 1.01 (d, J=6.8 Hz, 1 H); 13C NMR (100 m Hz, CDCl3)δ 144.87, 142.04, 136.44, 134.67, 132.42, 130.61, 130.45, 128.16, 127.78, 127.53, 177.43, 126.61, 124.19, 124.12, 67.03, 43.72, 43.83, 43.50, 32.36, 16.45; ESI MS m/z 346.1
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1>>[F:18][C:19]1[CH:31]=[C:30]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:29]=[CH:28][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC1(C)OB(c2ccc(CN3CCC(O)C3)c(F)c2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CN2CCC(O)C2)c(F)c1
Yield: 52.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (180 mg, 0.58 mmol) was reacted with 1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]pyrrolidin-3-ol (280 mg, 0.87 mmol) to afford the desired product (130 mg, 48%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 7.79-7.72 (m, 1H), 7.66 (d, J=5.4 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.42 (d, J=9.1 Hz, 1H), 7.33-7.21 (m, 2H), 6.09 (td, J=5.3, 2.4 Hz, 1H), 4.75-4.53 (m, 3H), 3.91-3.66 (m, 4H), 3.66-3.34 (m, 3H), 2.55-2.44 (m, 1H), 2.28-2.15 (m, 1H), 2.14-2.04 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1N
Temperature: 100 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
[step 2] Under a nitrogen atmosphere, 4-bromo-6-methyl-2-nitroaniline (2.80 g, 12.1 mmol) obtained in step 1 was dissolved in DMF (60 mL), phenylboronic acid (4.40 g, 36.3 mmol), cesium carbonate (7.90 g, 24.2 mmol) and tetrakis(triphenylphosphine)palladium (1.40 g, 2.42 mmol) were added, and the mixture was stirred at 100° C. for 4 hr. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1) to give 4-amino-3-methyl-5-nitrobiphenyl (2.25 g, 81%).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[C:24]([CH3:37])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@@H:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[C:24]([CH3:37])=[C:25]2[C:29](=[CH:30][CH:31]=1)[C@@H:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2)(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C[C@H]1CCc2c1ccc(O)c2C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C[C@H]1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 309.2 %

Procedure:
To a solution of pyridine (440 μL, 5.45 mmol) in dichloromethane (5.0 mL) cooled to 0° C. trifluoromethanesulfonic anhydride (840 μL, 4.99 mmol) was added. The resultant mixture was stirred for 5 min, and methyl (R or S)-(5-hydroxy-4-methyl-indan-1-yl)acetate (1.00 g, 1.34 mmol, from Step H) was added as a solid. The reaction mixture was warmed to ambient temperature, stirred for 1 hr and diluted with dichloromethane. The organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 gave 1.46 g of the title compound as a pale yellow liquid: 1H NMR (500 MHz, CDCl3) δ 1.69-1.91 (m, 1H), 2.33 (s, 3H), 2.38-2.56 (m, 2H), 2.69-2.79 (m, 1H), 2.79-3.01 (m, 2H), 3.49-3.65 (m, 1H), 3.76 (s, 3H), 7.09 (s, 2H).
Reaction SMILES: O[C@@H]1CC[N:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12](OC(F)(F)F)=[CH:11][CH:10]=2)=[O:8])[C@H]1C(NOCC1C=CC=CC=1)=O.COC(=O)C(NC(=O)C1C=CC(C#CC#CC2C=CC(N)=CC=2)=CC=1)CNC(OC(C)(C)C)=O.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:7]([NH2:4])(=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NOCc1ccccc1)[C@H]1[C@H](O)CCN1C(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COC(=O)C(CNC(=O)OC(C)(C)C)NC(=O)c1ccc(C#CC#Cc2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Reaction time: 0.08 h

Procedure:
Resin 1 (142 mg, 0.109 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 3-ethynylpyridine 2 (38 mg, 0.368 mmol) and Et3N (200 μL, 1.4 mmol) in DMF (2 mL) was added and the resin agitated for 5 min. A mixture of PdCl2(PPh3)2 (22 mg, 0.031 mmol) and CuI (25 mg, 0.131 mmol) was added and the resin was agitated for 72 h. The resin was drained, washed with DMF (3×2 mL), DCM (3×2 mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution was collected and the resin was rinsed with additional 10% TFA/DCM (1.0 mL). The cleavage fractions were combined, treated with neat TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue. Purification by RP-HPLC (C18 column, CH3CN gradient 5-65%, 0.1% TFA, UV analysis 300 nm, 24 min) and lyophilization of the collected fractions afforded 4.4 mg (11% yield) of N-((2R)-hydroxy-(1S)-hydroxycarbamoyl-propyl)-4∝-pyridin-3-yl-buta-1,3-diynyl)-benzamide. LRMS (ES+) m/z 364.0 (C20H17N3O4+H requires 364.13); RP-HPLC (300 nm, 24 min run) 11.2 min.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6]OCC[C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[O:16]1[CH2:21][CH2:20]C(CC=O)[CH2:18][CH2:17]1.[S].C(CC(OCC)=O)#N>>[NH2:1][C:2]1[S:10][C:5]([CH:6]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=CCC1CCOCC1
Reactant: CCOC(=O)c1c(N)sc2c1CCOC2
Agent: [S]
Solvent: CCOC(=O)CC#N
Product: CCOC(=O)c1cc(C2CCOCC2)sc1N

Procedure:
Prepared by proceeding in a similar manner to Intermediate 7, starting from (tetrahydropyran-4-yl)acetaldehyde, sulphur and ethyl cyanoacetate
Reaction SMILES: B(Br)(Br)Br.[CH:5]([C:8]1[C:17]([O:18]C)=[C:16]([O:20]C)[CH:15]=[C:14]2[C:9]=1[C:10](=[O:44])[C:11]([CH3:43])=[C:12]([C:23]1[C:24](=[O:42])[C:25]3[C:30]([C:31](=[O:34])[C:32]=1[CH3:33])=[C:29]([CH:35]([CH3:37])[CH3:36])[C:28]([O:38]C)=[C:27]([O:40]C)[CH:26]=3)[C:13]2=[O:22])([CH3:7])[CH3:6].Cl>C(Cl)Cl>[OH:18][C:17]1[C:8]([CH:5]([CH3:7])[CH3:6])=[C:9]2[C:14](=[CH:15][C:16]=1[OH:20])[C:13](=[O:22])[C:12]([C:23]1[C:24](=[O:42])[C:25]3[C:30]([C:31](=[O:34])[C:32]=1[CH3:33])=[C:29]([CH:35]([CH3:36])[CH3:37])[C:28]([OH:38])=[C:27]([OH:40])[CH:26]=3)=[C:11]([CH3:43])[C:10]2=[O:44]
Reactant: COc1cc2c(c(C(C)C)c1OC)C(=O)C(C)=C(C1=C(C)C(=O)c3c(cc(OC)c(OC)c3C(C)C)C1=O)C2=O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C2=C(C)C(=O)c3c(cc(O)c(O)c3C(C)C)C2=O)C(=O)c2cc(O)c(O)c(C(C)C)c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
0.54 mL of BBr3 (1.43 g, 5.71 mmol) was added dropwise into a solution of compound 10 (260 mg, 0.48 mmol) in 10 mL of anhydrous CH2Cl2 at −78° C. Stirring was continued at −78° C. for 1 h, 0° C. for 1 h, and ambient temperature for 1 h. 50 grams of ice containing 5 mL of 6M HCl was added to the mixture and stirred for 1 h at room temperature. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layer was washed with water, brine and dried over MgSO4. The solvent was concentrated in vacuo and the residue was purified using C-18 column chromatography (H2O/Acetonitrile) followed by recrystallization from ethyl acetate/hexane to give 163 mg of compound 6a (70%) as brown-yellow solid. 1H NMR (600 MHz, CD3OD) δ 7.31 (s, 2H), 4.32 (m, 2H), 1.88 (s, 6H), 1.42 (s, 6H), 1.40 (s, 6H). 13C NMR (600 MHz, (CD3)2SO)) δ 187.10, 182.51, 150.92, 149.54, 147.60, 137.78, 137.10, 126.24, 125.00, 111.03, 27.07, 20.50, 20.35, 15.00. HPLC purity 99.5%, tR=11.60 min (Method A). HRMS calcd for C28H26O8 491.1700 (M+H). found 491.1696.
Reaction SMILES: [NH:1]=[C:2]1[N:6]=[C:5]([N:7]([CH3:9])[CH3:8])[S:4][S:3]1.[C:10]([N:14]=[C:15]=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[C:10]([NH:14][C:15]([N:1]=[C:2]1[N:6]=[C:5]([N:7]([CH3:9])[CH3:8])[S:4][S:3]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N=C=O
Reactant: CN(C)c1nc(=N)ss1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1nc(=NC(=O)NC(C)(C)C)ss1

Procedure:
A suspension of 4.75 parts of the hydrobromide salt of 3-imino-5-dimethylamino-3H-1,2,4-dithiazole, two parts of t-butyl isocyanate, two parts of triethylamine, and 50 parts of tetrahydrofuran was stirred and refluxed for two days. The reaction mixture was cooled and the insoluble triethylammonium bromide was removed by filtration and discarded. The filtrate was then evaporated under reduced pressure leaving a white solid, which was recrystallized from isopropanol to afford 3.4 parts of 1-t-butyl-3-(5-dimethylamino-3H-1,2,4-dithiazol-3-ylidene)urea, m.p. 174°-177°C. dec.
Reaction SMILES: [OH:1]C(CCCCC)CCN1C(=O)CS(=O)C1CCCCCCC(O)=O.[OH:26][CH:27]([CH2:46][O:47][CH2:48][CH2:49][CH3:50])[CH2:28][CH2:29][N:30]1[C:34](=[O:35])[CH2:33][S:32](=[O:36])[CH:31]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44]>>[OH:26][CH:27]([CH2:46][O:47][CH2:48][CH2:49][CH3:50])[CH2:28][CH2:29][N:30]1[C:34](=[O:35])[CH2:33][S:32](=[O:1])(=[O:36])[CH:31]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44]
Reactant: CCCOCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Reactant: CCCCCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Product: CCCOCC(O)CCN1C(=O)CS(=O)(=O)C1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the same procedure as described in Example 3 except that the 7-[3-(3-hydroxyoctyl)-1,4-dioxo-2-thiazolidinyl]heptanoic acid is replaced by 7-[3-(3-hydroxy-4-propoxybutyl)-1,4-dioxo-2-thiazolidinyl]heptanoic acid. Chromatographic purification of the resulting product on silica gel gives the title compound as a viscous, pale yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[N:31]2[C:27]([S:28][C:29]([CH2:32][O:33][CH3:34])=[N:30]2)=[N:26][C:25]=1[C:35]([F:38])([F:37])[F:36])=[N+]=[N-]>C1COCC1.O>[CH3:34][O:33][CH2:32][C:29]1[S:28][C:27]2=[N:26][C:25]([C:35]([F:38])([F:36])[F:37])=[C:24]([CH2:23][NH2:20])[N:31]2[N:30]=1
Reactant: COCc1nn2c(CN=[N+]=[N-])c(C(F)(F)F)nc2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCc1nn2c(CN)c(C(F)(F)F)nc2s1
Temperature: 25 °C
Reaction time: 60 h
Yield: 88 %

Procedure:
Triphenylphosphine (1.31 g, 4.98 mmol, 1 eq) is added at room temperature to a suspension of 5-(azidomethyl)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a18 (1.45 g, 4.98 mmol, 1 eq) in THF/H2O (18 ml/2 ml). The reaction mixture is stirred at room temperature for 60 h. The solvent is evaporated under reduced pressure, water is added to the residue, the solution is acidified to pH 2 with aqueous 5N HCl, then extracted with Et2O (1×50 ml). The aqueous layer is basified (pH 8) by addition of a Na2CO3 aqueous solution, and extracted with dichloromethane (2×50 ml), the cumulated organics layers are dried over MgSO4, filtered and evaporated under reduced pressure to afford 1-[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine a19.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:14]([CH3:16])([CH3:15])[CH2:13][NH:12][C:11]1=[O:17])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:14]([CH3:15])([CH3:16])[CH2:13][NH:12][C:11]1=[O:17]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)NCC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNC(=O)N1CCN
Reaction time: 16 h
Yield: 93 %

Procedure:
[2-(5,5-Dimethyl-2-oxo-imidazolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (450 mg, 1.75 mmol) was dissolved in DCM (5 mL) and TFA (1 mL) was added. The mixture was allowed to stand for 16 h, concentrated, and purifed by SCX ion exchange chromatography to give the product as a yellow oil (256 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC=CC=4)=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1.B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[C:5]2[CH:6]=[N:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[C:9]=2[CH:10]=1
Reactant: Oc1cc(Cl)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(-n2ncc3c(O)cc(Cl)cc32)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of 6-chloro-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazol-4-ol (D11) (60 mg, 0.163 mmol) in dry DCM (2 mL) cooled to −78° C. was added BBr3 (1M in DCM, 0.326 mL, 0.326 mmol) dropwise. The resulting mixture was stirred at this temperature for 1 hour, then it was warmed to room temperature, treated with water and the pH adjusted to 7 by addition of saturated NaHCO3. The solution was extracted with EtOAc (2×) and the combined organics were dried over MgSO4. The crude material (49 mg) was then purified by flash chromatography with a gradient of 5-100% EtOAc in hexane to give a the title compound (E8) as a colourless solid (35 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:20]=[C:19](F)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH2:1]([NH:8][C:19]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([F:9])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1F
Temperature: 0 °C

Procedure:
Benzylamine (7.6 mL, 69 mmol) in 30 mL THF was added to ethyl 2,4-difluoro-5-nitro-benzoate (16.0 g, 69 mmol) in 270 mL THF with TEA (19.7 mL, 140 mmol) under stirring at 0° C. The mixture was stirred for 3.5 h at ambient temperature. The mixture was concentrated i.vac., the residue stirred with water, filtered off, washed with water and dried.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH2:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].Cl.[NH:25]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:26]([C:31](ON1C(=O)CCC1=O)=[O:32])[CH2:27][CH2:28][S:29][CH3:30].C(N(CC)CC)C.O>CN(C=O)C.C(O)C>[NH:25]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:26]([C:31]([NH:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH2:23])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:32])[CH2:27][CH2:28][S:29][CH3:30]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)N[C@@H](C(N)=O)c1ccccc1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 84.9 %

Procedure:
5.0 g (14 mmoles) of H-Asp(OtBu)-D-Phg-NH2.HCl, prepared as described in Example 1, Step 4, and 4.85 g (14 mmoles) of BOC-Met-OSu are dissolved in 60 ml of DMF, and 1.96 ml (14 mmoles) of triethylamine are added to the solution. Next day the resulting suspension is evaporated in vacuo, and the residue is isolated with water. The obtained crude product, weighing 7.83 g, is decolourized in 40 ml of hot ethanol, and 40 ml of water are added to the hot solution to precipitate the product. 6.57 g (84%) of BOC-Met-Asp(OtBu)-D-Phg-NH2 are obtained; the chromatographically uniform product melts at 194°-196° C. A sample of the product melts at 197°-198° C. after recrystallization from ethanol. Rf4 =0.75; [α]D =-67.2° (c=1.0, in dimethyl formamide).
Reaction SMILES: C[C:2]1(C)[O:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4](=[O:18])[O:3]1.C[O-].[Na+].Cl>C1(C)C=CC=CC=1>[OH:6][CH:5]([CH2:7][C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[C:4]([O:3][CH3:2])=[O:18]
Reactant: CC(C)(C)OC(=O)CC(=O)CC1OC(C)(C)OC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(O)CC(=O)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of tert.-butyl 4-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-3-oxobutanoate (16.30 g, 60.08 mmol) in toluene (120.0 ml) which had been cooled to 0° C., sodium methoxide (1M in methanol) (60.3 ml) was dropwise added in an argon atmosphere. After stirring the solution at 0° C. for 30 minutes, 1N hydrochloric acid (160.5 ml) was dropwise added and the mixture was stirred for 10 minutes at 0° C. Most of the organic solvent was evaporated off under reduced pressure, and the residual mixture was extracted with ethyl acetate and washed with a saturated saline and a phosphate buffer solution (pH 7.0). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:acetone=2:1) to give pure 1-methyl 6-tert.-butyl 2-hydroxy-4-oxoadipate (13.26 g, 53.85 mmol). Yield, 89.6 %.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12].B.CSC.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: COC(=O)CCCCCCCC(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)CCCCCCCCO
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of nonanedioic acid monomethyl ester (4.80 g, 20 mmol) in THF (20 mL) at −20° C. was added a solution of borane-dimethylsulfide in THF (2.0 M, 10 mL) over 10 min. The resulting mixture was stirred for an additional 10 min, and then allowed to stir at room temperature overnight. Aqueous K2CO3 solution was added, and the product was extracted with ethyl ether (3×). The crude product was purified by flash column chromatography (hexane/EtOAc:2/1) to yield 9-hydroxy-nonanoic acid methyl ester 4-B (2.0 g, 55%).
Reaction SMILES: O.P([O-])(O)(O)=O.[Na+].OO.Cl([O-])=O.[Na+].[Cl:14][C:15]1[C:24]([CH:25]=[O:26])=[C:23]([Cl:27])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].Cl.S([O-])(O)=[O:30].[Na+]>O.C(#N)C>[Cl:14][C:15]1[C:24]([C:25]([OH:30])=[O:26])=[C:23]([Cl:27])[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc(Cl)c(C=O)c1Cl
Reactant: O=S([O-])O
Agent: Cl
Agent: O=P([O-])(O)O
Agent: OO
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Temperature: 5 °C
Reaction time: 12 h

Procedure:
5.9 g (0.043 mol) of sodium dihydrogen phosphate monohydrate in 70 ml of water, 20.5 g (0.181 mol) of 30% strength hydrogen peroxide solution and 27.3 g (0.241 mol) of 80% strength sodium chlorite solution were added in succession to a solution of 40.0 g (0.172 mol) of methyl 2,4-dichloro-3-formylbenzoate and 500 ml of acetonitrile. The reaction solution was stirred for 1 hour at 5° C. and for 12 hours at room temperature. It was subsequently brought to pH 1 with 10% strength hydrochloric acid, and 500 ml of 40% strength sodium hydrogen sulfite solution were added. After the mixture had been stirred for 1 hour at room temperature, the aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with 1.0 l of 10% strength sodium hydrogen sulfite solution and subsequently dried. After the solvent had been distilled off, 40.0 g of methyl 2,4-dichloro-3-hydroxycarbonylbenzoate were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][C:22](=O)[CH2:21][C:20]2=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.O1CCCC1.CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:22]2[CH2:21][C:20]3[C:19]4[C:28](=[CH:29][CH:30]=[C:17]([O:16][CH3:15])[CH:18]=4)[N:27]=[CH:26][C:25]=3[O:24][CH2:23]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ncc3c(c2c1)CC(=O)CO3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NC(=O)OC(C)(C)C)CC1)CO3
Temperature: 25 °C
Reaction time: 15 h
Yield: 6.4 %

Procedure:
A solution of piperidin-4-yl-carbamic acid tert-butyl ester (76 mg, 0.38 mmol, 1.0 eq) in 1,2-dichloroethane (1 mL) is added at room temperature to a stirred solution of 6-methoxy-4H-1-oxa-9-aza-phenanthrene-3-one (87 mg, 0.38 mmol, 1.0 eq) in tetrahydrofuran (6 mL), followed by acetic acid (5 μL, 0.08 mmol, 0.2 eq) and the resulting mixture is heated under reflux for 3 hours. The reaction mixture is then cooled down to room temperature before the addition of a solution of sodium cyanoborohydride (48 mg, 0.76 mmol, 2.0 eq) in methanol (1 mL). After 15 hours stirring at room temperature, solvents are evaporated and to give a residue that is purified by preparative HPLC to afford [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a light yellow solid (10 mg, 6% yield).