Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18](Cl)[C:17]([CH3:22])=[CH:16]2>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:17]([CH3:22])=[CH:16]2
Reactant: Cc1cc2cccc(Br)c2nc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cccc(Br)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
Phenol (954 mg, 10.14 mmol) was added to a suspension of NaH (60% w/w in mineral oil; 406 mg, 10.14 mmol) in DMF (10 mL) at 0° C. and the resulting solution was stirred at 25° C. for 15 min. 8-Bromo-2-chloro-3-methylquinoline (510 mg, 1.988 mmol) was then added, and the resulting solution was heated at 60° C. for 2.5 d. The mixture was cooled to 25° C. and partitioned between EtOAc (100 mL) and saturated aq. NH4Cl (80 mL). The organic layer was separated, sequentially washed with water (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% EtOAc/hexanes) furnished 8-bromo-3-methyl-2-phenoxyquinoline (505.5 mg, 1.609 mmol, 81% yield) as a colorless oil, which was used without further purification in the subsequent step: m/z (ESI, +ve) 314.0 (M+H)+.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.[CH3:16][O:17][CH2:18]Cl>C1C=CC=CC=1>[CH3:16][O:17][CH2:18][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCOc1ccccc1O

Procedure:
110 parts by weight of pyrocatechol is dissolved in 400 parts by weight of benzene. At room temperature there are simultaneously dripped into this solution 101 parts by weight of triethylamine and 81 parts by weight of chloromethyl methyl ether in such a manner that the reaction medium has a weakly alkaline reaction. Subsequently the mixture is heated for an hour under reflux and then allowed to cool. The hydrochloride is removed by suction filtration and the product is washed, dried over Na2SO4, concentrated and distilled in vacuo.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([O:9][CH2:10][C:11]1[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])=[N:13][O:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[CH2:2]2.CN(C)C(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:43]1[S:44][C:45]2[CH:51]=[C:50]([C:52]([O:54][CH3:55])=[O:53])[CH:49]=[C:48]([F:56])[C:46]=2[N:47]=1>C(OCC)(=O)C>[CH:16]1([C:15]2[O:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:28])([F:27])[F:29])[C:11]=2[CH2:10][O:9][CH:3]2[CH2:2][CH:1]3[N:8]([C:43]4[S:44][C:45]5[CH:51]=[C:50]([C:52]([O:54][CH3:55])=[O:53])[CH:49]=[C:48]([F:56])[C:46]=5[N:47]=4)[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH2:17][CH2:18]1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Reactant: COC(=O)c1cc(F)c2nc(Br)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(F)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 25-mL round-bottom flask equipped with a stir bar was added sequentially 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (I-1H) (0.525 g, 1.29 mmol), 3.6 mL of N,N-dimethylacetamide, cesium carbonate (1.08 g, 3.31 mmol), and methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (1.12 g, 3.87 mmoles). After stirring the resulting slurry at room temperature for 10 minutes, the mixture was then warmed to 60° C. and stirred for 1 h. The reaction slurry was allowed to cool to RT, and was diluted with 200 mL of ethyl acetate and washed with water (3×30 mL). The organic extracts were concentrated under vacuum and directly purified using normal phase silica gel chromatography (40 g silica column) with a 15 min gradient of 10% to 60% ethyl acetate/hexanes. Desired fractions were concentrated in vacuo, and the resulting residue crystallized upon standing to give the desired product as a white crystalline solid.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:47])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:46][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41][CH3:42])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:47]=[O:16])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C)c3c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1
Temperature: 76 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
AIBN (22.2 mg, 0.135 mmol) was added to a stirring solution of NBS (88 mg, 0.49 mmol) and methyl 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)benzoate (163 mg, 0.451 mmol) in CCl4 (40 mL) and was heated to 76° C. The mixture was allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (63 mg, 0.54 mmol) and subjected to MW irradiation (150° C.) for 10 min. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2× followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product methyl 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)benzoate (34 mg, 0.091 mmol, 20% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.31 (1H, s), 8.79 (1H, d, J=2.44 Hz), 8.74 (1H, d, J=2.44 Hz), 8.28 (1H, s), 8.16-8.25 (2H, m), 8.00-8.13 (2H, m), 7.72 (1H, t, J=7.78 Hz), 7.49-7.57 (2H, m), 3.92 (3H, s). LC-MS retention time: 1.72 min; m/z (MH+): 376. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:24][C:23]1=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([S:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:6])[NH:24][C:23]1=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1Sc1ccccc1
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1S(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
1.5 g of 3-chloroperoxybenzoic acid was added, whilst ice-cooling, to a solution of 2 g of (3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-phenylthio-2-azetidinone [prepared as described in step (i) above] in 30 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 6 hours. At the end of this time, the reaction mixture was mixed with 30 ml of methylene chloride, and the organic layer was separated and washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and again with water, in that order. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash chromatography, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, to give 1.9 g of the title compound consisting of two diastereomers, differing in the configuration of the sulfoxide group, as colorless crystals, melting at 65°-70° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[CH:11]=[C:12]([OH:25])[CH:13]=[C:14]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)[CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][O:29][CH2:30][C@H:31](O)[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C.O>[CH3:28][O:29][CH2:30][C@H:31]([CH3:32])[O:25][C:12]1[CH:13]=[C:14]([B:16]2[O:17][C:18]([CH3:23])([CH3:24])[C:19]([CH3:21])([CH3:22])[O:20]2)[CH:15]=[C:10]([O:9][C:8]2[CH:26]=[CH:27][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:11]=1
Reactant: COC[C@@H](C)O
Reactant: CC1(C)OB(c2cc(O)cc(Oc3ccc(S(C)(=O)=O)cc3)c2)OC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
3-[4-(Methylsulfonyl)phenoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (13.20 g, 33.8 mmol) synthesized in Example (1d) was dissolved in tetrahydrofuran (300 mL), and (R)-(−)-1-methoxy-2-propanol (3.70 mL, 37.8 mmol) and triphenylphosphine (9.78 g, 37.3 mmol) were added, and subsequently cooled to 0° C. Diethyl azodicarboxylate (40% toluene solution, 16.2 mL, 37.2 mmol) was added dropwise over 10 minutes under nitrogen atmosphere and stirring was carried out at 0° C. for 30 minutes, followed by raising the temperature naturally and stirring at room temperature overnight. Water (300 mL) and ethyl acetate (300 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-40%) to afford the desired compound (11.94 g, yield 76%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[O:20][C:21]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=3)=[C:22]([C:24]([O:26]CC)=[O:25])[N:23]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].O.[OH-].[Li+].Cl.C(OCC)(=O)C>CO.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[O:20][C:21]([CH2:29][C:30]3[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:31]=3)=[C:22]([C:24]([OH:26])=[O:25])[N:23]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N[C@H]2C[C@@H](CC)N(C(=O)OCC)c3ccc(OC)nc32)oc1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2nc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)o2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(4-ethoxycarbonyloxazol-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) and lithium hydroxide monohydrate (78 mg) are dissolved in a mixture of methanol (3 ml) and water (500 μl), and the mixture is stirred at room temperature for 2 hours. The reaction solution is acidified by adding 2N aqueous HCl solution, then added ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-(4-carboxyoxazol-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (190 mg). MS (m/z): 617 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:20])[NH:9][CH2:10][CH2:11][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[H-].[Na+]>CN(C)C=O.O.[Cl-].[Na+]>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1=[O:20])[CH3:16]
Reactant: CCOC(CCCNC(=O)OCCCCCCl)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CCCN1CCCCCOC1=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.9 %

Procedure:
To a solution of (4,4-diethoxybutyl)carbamic acid 5-chloro-pentyl ester (11.4 g, 44 mmole) dissolved in N,N-dimethylformamide (100 mL) was added de-oiled sodium hydride (1.01 g, 42.3 mmole). The reaction mixture was stirred for 15 hours at room temperature, and then at 70° C. for 3 hours. The mixture was diluted with water, saturated aqueous sodium chloride was added, and extracted with ethyl ether. The organic phase was washed with water, dried (magnesium sulfate), and concentrated. Purification by silica gel chromatography, gave 3-(4,4-diethoxybutyl)-[1,3]oxazocan-2-one (2.03 g) as a viscous oil.
Reaction SMILES: [OH:1][C@H:2]([CH3:34])[C@H:3]([NH:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17]C#CC2C=CC(CN3CCOCC3)=CC=2)=[CH:12][CH:11]=1)[C:4](=[O:7])[NH:5][OH:6].C([CH:54]([NH2:67])[CH2:55][NH:56][C:57](=[O:66])[C:58]1[CH:63]=[CH:62][C:61]([C:64]#[CH:65])=[CH:60][CH:59]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.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>[OH:1][C@H:2]([CH3:34])[C@H:3]([NH:8][C:9](=[O:33])[C:10]1[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:65]#[C:64][C:61]2[CH:60]=[CH:59][C:58]([C:57](=[O:66])[NH:56][CH2:55][CH2:54][NH2:67])=[CH:63][CH:62]=2)=[CH:14][CH:15]=1)[C:4](=[O:7])[NH:5][OH:6]
Reactant: C[C@@H](O)[C@H](NC(=O)c1ccc(C#CC#Cc2ccc(CN3CCOCC3)cc2)cc1)C(=O)NO
Reactant: C#Cc1ccc(C(=O)NCC(N)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](NC(=O)c1ccc(C#CC#Cc2ccc(C(=O)NCCN)cc2)cc1)C(=O)NO
Reaction time: 0.08 h
Yield: 3.8 %

Procedure:
Resin 4 (150 mg, 0.116 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 4-ethynylbenzamide 3 (151 mg, 0.350 mmol) and Et3N (150 μL, 1.10 mmol) in DMF (2.0 mL) was added and the resin agitated for 5 min. A mixture of PdCl2(PPh3)2 (21 mg, 0.030 mmol) and CuI (28 mg, 0.147 mmol) was added and the resin was agitated for 60 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, 26 min) and lyophilization of the collected fractions afforded 2.0 mg (4% yield) of (1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-{4-[4-(2-amino-ethylcarbamoyl)-phenyl]-buta-1,3-diynyl}-benzamide. LRMS (ES+) m/z 449.1 (C24H24N4O5+H requires 449.18); RP-HPLC (300 nm, 26 min run) 17.0 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O.[C:25](=[O:28])([O-])[OH:26].[Na+]>C(#N)C.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:15]([O:26][C:25]([N:21]1[CH2:22][CH2:23][CH:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1)=[O:28])([CH3:18])([CH3:16])[CH3:14]
Reactant: O=C([O-])O
Reactant: COc1cc(N2CCC(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Agent: [Zr+4]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a suspension of 1-(3-methoxy-4-nitro-phenyl)-[4,4′]bipiperidinyl (1.75 g, 5.48 mmol), di-tert-butyl-dicarboxylate (1.20 g, 5.48 mmol) in acetonitrile (55 mL), zirconium tetrachloride (128 mg, 0.55 mmol) is added and the mixture is stirred at ambient temperature for 30 min. After water and aqueous sodium hydrogen carbonate are added, the mixture is filtrated and dried to give 1′-(3-Methoxy-4-nitro-phenyl)-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester (5.11 g, 92% yield) as yellow solids.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>O1CCOCC1.ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:31]([NH:30][C:26]3[CH:25]=[C:24]([CH3:33])[CH:29]=[CH:28][CH:27]=3)=[O:32])[CH2:20][CH2:19]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3ccc(F)cc3)csc2n1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)N2CCN(c3nc(N)nc4scc(-c5ccc(F)cc5)c34)CC2)c1
Reaction time: 8 h

Procedure:
To a solution of Example 1 (115 mg, 0.35 mmol) in 1,4-dioxane (15 mL) was added m-tolyl isocyanate (0.38 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and the organic layer was extracted several times with water. The combined organic layers were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 0.5% to 1% methanol in dichloromethane), yielding the title compound as a white powder. MS (m/z) 463 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[N:34]=[N:35][NH:36][N:27]=4)[CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(NS(=O)(=O)c3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Yield: 44.9 %

Procedure:
Heat a mixture of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-3-cyano-benzenesulfonamide (1.00 g, 2.15 mmol), sodium azide (1.40 g, 21.5 mmol), and ammonium chloride (1.15 g, 21.5 mmol) in dimethylformamide (10 mL) at 110° C. overnight. Cool the reaction to room temperature and dilute with water (120 mL). Filter the resulting mixture, wash the filtered material several times with water and dry. Dissolve the residue in hot acetone (20 mL) and purify via chromatography, eluting with 1:1 hexanes:acetone with 1% acetic acid to afford the title compound as a tan solid (490 mg, 45%): 1H NMR (DMSO-d6) δ 0.80 (t, 3H), 1.42 (sextet, 2H), 2.49 (s, 3H), 2.50 (t, 2H), 5.16 (s, 2H), 6.59 (d, 1H), 7.10 (d, 1H), 7.12 (d, 1H), 7.24 (s, 1H), 7.25 (t, 1H), 7.70 (d, 1H), 7.73 (t, 1H), 7.87 (d, 1H), 8.22 (d, 1H), 8.49 (s, 1H), 10.56 (s, 1H), 12.82 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 506 (100).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].[NH2:28][C@H:29]([C:33]([NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[C@@H:30]([CH3:32])[OH:31]>CN(C=O)C>[NH:17]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C@H:4]([C:5]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)[C@@H](C)O)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
Coupling of 7.85 g Z-Val-ONp with 5.53 p H-Thr-Leu-OtBu in 160 ml DMF in the way described in C(2) provides Z-Val-Thr-Leu-OtBu in 72% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18]O)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:32].[Li+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][Br:32])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1OCc1ccccc1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (3-benzyloxy-4-nitrophenyl)-methanol (11.0 g, 0.042 mol) in anhydrous THF is added triethylamine (8.7 g, 0.86 mol). The mixture is cooled to −20° C., followed by the addition of methanesulfonyl chloride (5.8 g, 0.051 mol) and then stirred at −20° C. for 45 min. To this mixture is added lithium bromide (37.3 g, 0.43 mol) in anhydrous THF (40 mL) over 40 min followed by stirring at RT for 2 h. The suspension is concentrated under reduced pressure and diluted with EtOAc and water. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: C([N:4](C(C)C)[C:5](=[O:21])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:8][C:7]=1[CH:19]=O)(C)C.[NH2:25]N>C(O)(=O)C>[C:13]1([CH3:18])[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[C:5]([OH:21])=[N:4][N:25]=[CH:19]2
Reactant: Cc1ccccc1-c1ccc(C(=O)N(C(C)C)C(C)C)c(C=O)c1
Reactant: NN
Solvent: CC(=O)O
Product: Cc1ccccc1-c1ccc2c(O)nncc2c1
Temperature: 110 °C

Procedure:
To a solution of N,N-diisopropyl 2-formyl-4-(2-methylphenyl)benzamide (5.45 g, 12 mmol) in acetic acid (15 mL) was added anhydrous hydrazine (0.56 mL, 18 mmol). The resulting solution was then heated at 110° C. for 16 h. The reaction mixture was cooled to RT, and the volatiles removed in vacuo. The residue was diluted with ethyl acetate (150 mL) and washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give 6-o-tolylphthalazin-1-ol as a yellow solid. MS (ESI, pos.ion) m/z: 237.2 (M+1)