Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)=[N:4]1.[CH3:27][C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCOCC1>[O:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([NH:26][C:28](=[O:29])[CH3:27])[CH2:22][CH2:21]3)[CH2:16][CH2:17]2)=[N:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1

Procedure:
A mixture in dioxane (5 ml) of trans-4-[2-(4-isoxazolo[4,5-c]pyridin-3-yl-piperazin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (100 mg, 0.25 mmol), AcOH (22 mg, 0.37 mmol), iPr2NEt (161 mg, 1.2 mmol) and TBTU (96 mg, 0.30 mmol) was stirred 16 h at r.t. After evaporation to dryness sat. aq. NaHCO3 was added and the product was extracted with 2 portions of CH2Cl2. The organic layers were directly loaded on a column. Flash chromatography (20 g SiO2, CH2Cl2/MeOH 100:0→90:10) yielded 62 mg (67%) of the title compound as white solid. m/z=372.2 ([M+H]+).
Reaction SMILES: [N:1]1([C:7](=O)[CH2:8][C@@H:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.Cl>O1CCCC1>[N:1]1([CH2:7][CH2:8][C@@H:9]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:26])=[O:27])=[CH:21][C:20]=2[S:29]([C:32]([F:33])([F:34])[F:35])(=[O:30])=[O:31])[CH2:10][S:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c(S(=O)(=O)C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Borane tetrahydrofuran complex (4.21 mmol) was added dropwise over 2 h to the amide intermediate c (1.24 mmol) in tetrahydrofuran (10 ml) at room temperature under a nitrogen atmosphere. The solution was then stirred at 55° C. for 24 h. The solution was cooled to 0° C. and treated with methanol (2 ml). To this mixture was added concentrated hydrochloric acid (0.5 ml) and the solution heated at 65° C. for 10 h. The solution was then concentrated in vacuo and poured into a 2 N sodium hydroxide solution (10 ml). The aqueous layer was then extracted with ethyl acetate (2×10 ml), the organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was applied to silica chromatography gradient eluting with 100% dichloromethane to 10% methanol/dichloromethane to yield intermediate 4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide, 4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonamide as a white solid (76%). 1H NMR (300 MHz, DMSO) δ 7.97 (1H, d, J 2.2 Hz), 7.83 (1H, dd, J 9.2 and 2.3 Hz), 7.35-7.26 (6H, m, ArH), 7.20 (1H, tt, J 7.0 and 1.8 Hz), 7.04 (1H, d, J 9.6 Hz), 6.89 (1H, bd, J 9.1 Hz), 4.12-4.02 (1H, m), 3.49 (4H, bs), 3.37-3.22 (2H, m), 2.33-2.14 (6H, m), 1.94-1.88 (1H, m), 1.76-1.70 (1H, m).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: OC1CN2CCC1CC2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Quinuclidinol (Aldrich, 0.51 g, 4 mmol) coupled with 4′-nitro-1,1′-biphenyl-4-ol (TCl, 0.43 g, 2 mmol) with DIAD (di-isopropyl azadicarboxylate, Aldrich, 0.81 g, 4 mmol) and Ph3P (Aldrich, 1.04 g, 4 mmol) in THF (anhydrous, Aldrich, 40 mL) at ambient temperature for two days. The reaction mixture was concentrated. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as solid (400 mg, yield, 62%). 1H NMR (300 MHz, CD3OD) δ 1.45–1.57 (m, 1H), 1.63–1.91 (m, 2H), 1.97–2.12 (m, 1H), 2.17–2.24 (m, 1H), 2.66–3.00 (m, 5H), 3.30–3.41 (m, 1H), 4.56–4.64 (m, 1H), 7.05 (dt, J=8.8, 2.6 Hz, 2H), 7.68 (dt, J=9.2, 2.6 Hz, 2H), 7.82 (dt, J=8.8, 2.7 Hz, 2H), 8.28 (dt, J=8.8, 2.8 Hz, 2H) ppm. MS (DCl/NH3) m/z 325 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:37])[C:5]2=[C:6]([CH2:8][C@H:9]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3Br)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])[N:7]=1.B1([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[N:53]=2)OCCN(C2C=CC=CC=2)CCO1.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]=[C:4]([CH3:37])[C:5]2=[C:6]([CH2:8][C@H:9]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[N:53]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])[N:7]=1
Reactant: COC(=O)[C@H](CCO/N=C1\N[C@@H](c2ccc(F)cc2Br)Cc2nc(N)nc(C)c21)O[Si](C)(C)C(C)(C)C
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](CCO/N=C1\N[C@@H](c2ccc(F)cc2-c2cccc(OC)n2)Cc2nc(N)nc(C)c21)O[Si](C)(C)C(C)(C)C
Temperature: 85 °C

Procedure:
To a solution of (S)-methyl 4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate (91 g, 244 mg, 0.41 mmol) in DMA was added 6-methoxypyridine-2-boronic acid N-phenyldiethanolamine ester (488 mg, 1.64 mmol), Pd(dppf)2Cl2 (66 mg, 0.08 mmol), and 2 N Na2CO3 (2 mL, 4.1 mmol). The resultant mixture was degassed with N2 for 5 min then heated in a sealed tube at 85° C. for 14 h. The reaction was allowed to cool to r.t. and filtered through a pad of Celite topped with anhydrous Na2SO4, rinsing with EtOAc and CH3OH. The filtrate was concentrated to provide a black residue which was purified by preparative HPLC eluting with TFA/ACN/H2O. The fractions were dried down in vacuo to yield (S)-methyl 4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate. This material was directly taken up in dioxane (700 μL) and treated with 1:9 TFA:H2O (1 mL) for 3 h. The solvents were removed in vacuo to yield (S)-methyl 4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanoate (91h, 15 mg, 0.03 mmol). [M+H] calc'd for C25H27FN6O5, 511. found, 511.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O-]S(C(F)(F)[F:16])(=O)=O.F[N+]1C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:16])[C:3]=1[CH3:10]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Cc1cc(O)cc(C)c1Br
Agent: F[n+]1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc(O)c(F)c(C)c1Br
Yield: 36.2 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (2.00 g, 9.95 mmol) in 1,2-dichloroethane (20 mL) was added N-fluoropyridinium triflate (6.15 g, 24.9 mmol), and the mixture was heated under reflux for 7 hr. The reaction mixture was treated with 1 M aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.790 g, yield 36%) as a colorless oil.
Reaction SMILES: COC1C=CC(C[N:8]([C:38]2[S:42][N:41]=[CH:40][N:39]=2)[S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[N:17][CH:16]=[CH:15]3)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[CH:34]=[CH:33][C:32]([C:23]2[CH:24]=[C:25]([C:28]([F:30])([F:29])[F:31])[CH:26]=[CH:27][C:22]=2[C:18]2[C:19]3[C:14](=[CH:13][C:12]([S:9]([NH:8][C:38]4[S:42][N:41]=[CH:40][N:39]=4)(=[O:11])=[O:10])=[CH:21][CH:20]=3)[CH:15]=[CH:16][N:17]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccncc4)nccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-c3ccncc3)nccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.6 %

Procedure:
To a solution of N-(4-methoxybenzyl)-1-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (100 mg, 0.158 mmol) in DCM (1578 μl) was added TFA (60.8 μl, 0.789 mmol). The reaction mixture was stirred at room temperature. After 2 hours, LC/MS showed mainly product. Purification was done using a Phenomenex Gemini 5 μm, C18, 110 Å, 150×30 mm column with 0.1% TFA in ACN and water as mobile phase to afford 1-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (6.2 mg, 0.012 mmol, 7.65%). MS (ESI): 514.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 7.19-7.22 (m, 2H), 7.80 (s, 2H), 7.85 (d, J=8.01 Hz, 1H), 8.01-8.06 (m, 2H), 8.11 (d, J=5.77 Hz, 1H), 8.37 (br. s., 2H), 8.47 (s, 1H), 8.54 (s, 1H), 8.61 (d, J=5.66 Hz, 1H).
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O-:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].[K+].C(OCC(CO)O)(=O)CCCCCCCCCCCCCCCCCCCCC>>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]
Reactant: O=C([O-])[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: [K+]
Product: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21

Procedure:
148.8 mg of potassium clavulanate was blended with 141.2 mg of glyceryl behenate in a Hobart blender (batchsize: 7 kgs), and the blend thus obtained was granulated as described above, to obtain Clavulanate compression mix Formula B2.
Reaction SMILES: [F:1][C:2]1[C:3]([O:32]C)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=1[CH:15]=[N:16][N:17]([CH3:24])[C:18]3=[O:23])[C:7]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:6][C:5]2([CH3:31])[CH3:30].B(Br)(Br)Br>>[F:1][C:2]1[C:3]([OH:32])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=1[CH:15]=[N:16][N:17]([CH3:24])[C:18]3=[O:23])[C:7]([OH:29])([C:25]([F:28])([F:26])[F:27])[CH2:6][C:5]2([CH3:30])[CH3:31]
Reactant: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Agent: BrB(Br)Br
Product: Cn1ncc2c(NC3c4ccc(F)c(O)c4C(C)(C)CC3(O)C(F)(F)F)cccc2c1=O
Yield: 64 %

Procedure:
29 mg of the compound of Example 69 is reacted analogously to Example 1 with 0.13 ml of BBr3 (1N in dichloromethane) to form 18 mg of the title compound.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:19]=[CH:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[CH:12][C:11]([CH3:20])=[N:10]3)[N:7]=1)(=O)C.[BrH:21]>>[Br:21][CH2:5][C:6]1[CH:19]=[CH:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[CH:12][C:11]([CH3:20])=[N:10]3)[N:7]=1
Reactant: CC(=O)OCc1ccc2ccc3ccc(C)nc3c2n1
Reactant: Br
Product: Cc1ccc2ccc3ccc(CBr)nc3c2n1
Yield: 42 %

Procedure:
The acetate (21) was dissolved in 60 mL of 31% HBr in HoAc and refluxed for 4 hours. After cooling, all the solvent was removed in vacuo. The resulting black residue was suspended in a mixture of CH2Cl2 and dilute aqueous NaHCO3. Four 200 mL CH2Cl2 extracts removed the desired bromide from the insoluble material floating at the solvent interface. After drying over Na2SO4 and removal of the solvent, the dark residual solid was relatively pure phenanthroline (22) containing a trace amount of 2,9-dimethyl-1,10-phenanthroline. The dark impurities were removed by chromatography on silica gel using CH2Cl2 as the eluent which gave 3.5 g (42%) of 22. 1H NMR (CDCl3) 2.9 (s, 3H); 4.94 (s, 2H); 7.43 (ABq, 1H, J=9 Hz), 7.6 (s, 2H); 7.8 (ABq, 1H, J=9 Hz); 7.97 (ABq, J=9 Hz); 8.1 (ABq, 1H, J=9 Hz).
Reaction SMILES: N=C1N(CC[S:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)C2C=CC(OC(F)(F)F)=CC=2S1.C(N1CCC(SC(=O)C)CC1)C1C=CC=CC=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[OH-].[Na+]>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:10]([SH:9])[CH2:11][CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)SC1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: SC1CCN(Cc2ccccc2)CC1
Reaction time: 16 h

Procedure:
The 1-benzyl-4-mercaptopiperidine may be prepared in the following manner: 8 g of 1-benzyl-4-acetylthiopiperidine dissolved in 85 cm3 of a 6% aqueous solution of sodium hydroxide are stirred under a nitrogen stream for 16 hours. 10 cm3 of acetic acid and 57.5 g of ammonium sulphate are added to this solution. The mixture is then extracted with two times 100 cm3 of diethyl ether and the organic phase is dried over anhydrous magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (20 mm of mercury; 2.7 kPa). 5.5 g of 1-benzyl-4-mercaptopiperidine are thus directly isolated in the form of an oil which is used as it is in subsequent synthesis.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([N:33]([C:41]2[CH:45]=[C:44]([CH:46]3[CH2:49][NH:48][CH2:47]3)[NH:43][N:42]=2)C(OC(C)(C)C)=O)[C:30](=[O:50])[N:29]([CH3:51])[CH:28]=1)(=[O:3])[CH3:2].Cl.O1CCOCC1>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:41]2[CH:45]=[C:44]([CH:46]3[CH2:47][NH:48][CH2:49]3)[NH:43][N:42]=2)[C:30](=[O:50])[N:29]([CH3:51])[CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(N(C(=O)OC(C)(C)C)c3cc(C4CNC4)[nH]n3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C4CNC4)[nH]n3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 164e (300 mg, 0.42 mmol) in dioxane (2 mL) at room temperature was added HCl/dioxane (4M, 6 mL) dropwise. The reaction mixture was stirred for 1 h. After the reaction was finished, it was concentrated to afford 164f (crude product) as a black solid, which was used in the next step without purification. LCMS: (M+H)+ 617
Reaction SMILES: C[CH:2]([CH2:11][CH2:12]C=C(C)C)[CH2:3][CH2:4][CH2:5][C:6](=[O:10])[C:7]([O-:9])=[O:8].O=C(CCC)C(O[CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=O.CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.CC(CC)C(=O)C(OCCC(C)CCC=C(C)C)=O.C(C1C=CC(C(=O)C(OCCC(C)CCC=C(C)C)=O)=CC=1)(=O)C.CC(CCCCCCCCCCCC)C(=O)C(OCCC(C)CCC=C(C)C)=O.O=C(C1C=CC=CC=1)C(OCCC(C)CCC=C(C)C)=O.O=C(CCCCCCCCCCCCCC)C(OCCC(C)CCC=C(C)C)=O>>[CH:5]1([C:6](=[O:10])[C:7]([O:9][CH2:22][CH2:23][CH:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[O:8])[CH2:4][CH2:3][CH2:2][CH2:11][CH2:12]1
Reactant: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Reactant: CCCC(=O)C(=O)OCCC(C)CCC=C(C)C
Agent: CC(=O)c1ccc(C(=O)C(=O)OCCC(C)CCC=C(C)C)cc1
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)c1ccccc1
Product: CC(C)=CCCC(C)CCOC(=O)C(=O)C1CCCCC1

Procedure:
MS (EI): 294 (M+, 1); 276 (1); 266 (1); 233 (1); 193 (1); 183 (4); 165 (1); 155 (2); 139 (2); 138 (13); 137 (4); 123 (14); 112 (2); 111 (16); 110 (3); 109 (6); 96 (4); 95 (16); 94 (2); 84 (7); 83 (100); 82 (15); 81 (22); 80 (3); 70 (2); 69 (29); 68 (4); 67 (11); 56 (4); 55 (42); 54 (3); 53 (5); 43 (4); 42 (4); 41 (38); 39 (8); 29 (6); 27 (4).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH3:23])[CH:6]([CH2:11][CH3:12])[C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CN(C)C=O>[N:24]1([CH2:2][C:3]([N:5]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[CH3:23])[CH:6]([CH2:11][CH3:12])[C:7]([O:9][CH3:10])=[O:8])=[O:4])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: CCC(C(=O)OC)N(C(=O)CCl)c1c(C)ccc2ccccc12
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)N(C(=O)Cn1ccnc1)c1c(C)ccc2ccccc12
Yield: 60.8 %

Procedure:
12 g (0.036 mole) of methyl 2-(N-chloroacetyl-2-methylnaphth-1-ylamino)-butyrate (Example 1) were dissolved in 60 ml of dry N,N-dimethylformamide, and the solution was stirred with 7.3 g (0.108 mole) of imidazole at 70° C. for 10 hours. The mixture was concentrated under reduced pressure, and the residue was extracted by shaking with 150 ml of methylene chloride and 50 ml of water. The organic layer was separated off, washed with twice 50 ml of water, dried over sodium sulfate, and concentrated under reduced pressure. 8 g (61.6% of theory) of methyl 2-[N-(imidazol-1-ylacetyl)-2-methylnaphth-1-ylamino]-butyrate were obtained as a yellowish resin (compound No. 2).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:28]N>C(O)C>[C:6]1([C:5]2[C:4]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:3][NH:2][N:28]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
To the compound tert-butyl 4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate (4 g) dissolved in ethanol (40 ml), and hydrazine hydrate (1.17 g) was added and the reaction mixture was refluxed for 6 hrs with vigorous stirring. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:19]2[N:20]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([CH3:28])=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:23]=2)[CH:18]=1)[O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:19]2[N:20]([CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[C:21]([CH3:28])=[C:22]([S:24](=[O:26])(=[O:27])[NH2:25])[CH:23]=2)[CH:18]=1)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCOc1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(OCCCC(=O)O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of compound 15 (126 mg, 0.25 mmol) in methanol and THF (30 mL; 1:1) was added LiOH (25 mg, 1 mmol) and the mixture was stirred at rt overnight. The residue was concentrated and then poured into water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, evaporated and purified by CC to give compound 16 (98 mg, 80%). 1H-NMR (400 MHz, DMSO-d6) δ: 12.2 (br s, 1H), 6.91-6.89 (m, 4H), 6.68 (s, 1H), 6.29 (s, 1H), 4.02-3.98 (m, 2H), 3.81-3.79 (m, 2H), 2.43 (s, 3H) 2.40-2.36 (m, 5H), 1.94-1.91 (m, 2H), 1.48-1.46 (m, 3H), 1.27-1.24 (m, 12H), 0.96-0.94 (m, 3H), 0.66-0.64 (m, 2H). MS Found: 491 (M+1).
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][CH3:5].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[K+]>C1COCC1>[CH3:14][C:13]1[CH:15]=[CH:16][C:10]([S:7]([O:6][CH2:1][C:2]#[C:3][CH2:4][CH3:5])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC#CCO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC#CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 2-Pentyn-1-ol (60 g, 0.71 mol) in THF (420 mL) cooled to −5° C., tosyl chloride (142.9 g, 0.75 mol) and KOH (79.9 g, 1.42 mol) were added and the reaction mixture was stirred at room temperature for 1 h. After completion of starting material, the reaction mixture was extracted with ethyl acetate (300 mL×2), washed with water (100 mL×2), brine (50 mL×2) and dried over Na2SO4. The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-hexane) to furnish pent-2-ynyl 4-methylbenzenesulfonate (110 g, 64%) as a light red liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH:17](O)([CH3:19])[CH3:18]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH:17]([CH3:19])[CH3:18])=[O:10]
Reactant: CC(C)O
Reactant: O=C(O)Cc1ccccc1O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)Cc1ccccc1O
Temperature: 0 °C

Procedure:
Isopropyl 2-hydroxyphenylacetate was prepared using the procedure described in J. Amer. Chem. Soc., 70, 1948, 1930. To a flask were added 10 g of 2-hydroxy phenylacetic acid, 99 mL of isopropanol and 9.9 mL of concentrated sulfuric acid. The mixture was refluxed for 5.5 hrs, poured into 400 mL of ice and extracted with 3×100 mL of ether. The organic layer was washed with 100 mL of aqueous solution of sodium bicarbonate (saturated). The organic fraction was dried over sodium sulfate and the solvent removed by rotary evaporation. The residue was flash chromatographed on silica gel eluted with 10% ethyl acetate/hexane to give 9.227 g of the desired product as a white solid. 1H NMR (300 Mhz, δ, CDCl3): 7.16 (m, 1H), 7.08 (dd, 1H), 6.92 (dd, 1H), 6.80 (m, 1H), 5.04 (septet, J=6.2 Hz, 1H), 3.60 (s, 2H), 1.25 (d, 6.2 Hz, 6H).
Reaction SMILES: COC[C@@H]1[C@H](/C=C/C(/C)=C/C(O)=O)[C@@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1.[CH2:28]([O:30][CH2:31][C@H:32]1[C@H:34](/[CH:35]=[CH:36]/[C:37](/[CH3:44])=[CH:38]/[C:39]([O:41]CC)=[O:40])[C@@:33]1([CH3:57])[C:45]1[CH:50]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:48]=[C:47]([CH:54]([CH3:56])[CH3:55])[CH:46]=1)[CH3:29]>>[CH2:28]([O:30][CH2:31][C@H:32]1[C@H:34](/[CH:35]=[CH:36]/[C:37](/[CH3:44])=[CH:38]/[C:39]([OH:41])=[O:40])[C@@:33]1([CH3:57])[C:45]1[CH:46]=[C:47]([CH:54]([CH3:55])[CH3:56])[CH:48]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:50]=1)[CH3:29]
Reactant: CCOC[C@H]1[C@H](/C=C/C(C)=C/C(=O)OCC)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC[C@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 84 %

Procedure:
Following a procedure similar to that for the preparation of Compound 28 but using Compound 26b as the starting material afforded the title compound (29 mg, 84% yield) as a white solid: