Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>C(Cl)Cl.CN(C=O)C.C(N(CC)C(C)C)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:30]3[CH2:31][CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC1CCCNC1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.3 %

Procedure:
To polymer N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene (0.038 g) in an Alltech™ tube was added a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.007 g) in DCM (0.9 ml) followed by 3-methylpiperidine (0.0025 g) in DMF (0.1 ml) and N,N-diisopropylethylamine (0.006 ml). The mixture was shaken at room temperature for 4 days. The tube was drained, the filtrate collected and the resin washed with DCM. The combined DCM solutions were concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.0023 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH3:12].C([Li])(C)(C)C.[CH3:18][Si:19]([CH3:22])([CH3:21])Cl.O>C1COCC1.CCCCC>[CH3:1][CH:2]1[C:10]2[C:5](=[C:6]([Si:19]([CH3:22])([CH3:21])[CH3:18])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH3:12]
Reactant: CC1=C(C)C(C)c2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1=C(C)C(C)c2cccc([Si](C)(C)C)c21
Reaction time: 8 h

Procedure:
1,2,3-Trimethylindene in an amount of 4.09 g (26 mmol) was dissolved in 100 mL of dried THF, and to the resultant solution was added dropwise, under ice-cooling 19 mL of a 1.7M solution of tert-butyllithium in pentane. After 2 hours of reaction at room temperature, the reaction product was incorporated under ice-cooling with 3.25 g (30 mmol, 3.8 mL) of trimethylchlorosilane (TMSCl) that had been subjected to simple distillation, was brought back to room temperature and was allowed to stand overnight. The yellow solution thus obtained was incorporated with 20 mL of water for quenching and THF was removed under reduced pressure. Then, the solution was extracted and separated with 300 mL of hexane, the organic phase thus obtained was dried with magnesium sulfate anhydride as the drying agent, the used drying agent was filtered away, and the volatile components were distilled away under reduced pressure. As the result, there was produced 1,2,3-trimethylindenyltrimethylsilane in the form of yellow oil in a yield of 4.27 g (18.5 mmol) and in a yield rate of 72%.
Reaction SMILES: [SH2:1].[CH3:2][C:3]1([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[O:5][CH2:4]1.C(NC(C)C)(C)C>O1CCCC1.CCOCC>[SH:1][CH2:4][C:3]([CH3:2])([OH:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: S
Reactant: CCCCCC1(C)CO1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCCCCC(C)(O)CS
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Hydrogen sulfide gas was bubbled into a solution of 5 (3.84 g, 30 mmol) in tetrahydrofuran (30 mL) containing diisopropylamine (21 mL, 150 mmol) for one hour and the reaction mixture was stirred at room temperature for 68 hours. It was diluted with ether and washed with 10% aqueous hydrogen chloride, saturated sodium bicarbonate solution, and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo; 1.2 g of 1-mercapto-2-methylheptan-2-ol 6 was obtained after HPLC purification. IR (neat): 3600-3200 cm-1 (br); PMR (CDCl3): δ 2.67 (s, 1H), 2.57 (s, 1H), 2.17 (s, 1H), 1.70-1.20 (m, 9H), 1.22 (s, 3H), and 0.90 (t, 3H).
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([S:21]([C:24]4[S:28][C:27]5[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:26]=5[CH:25]=4)(=[O:23])=[O:22])[CH2:17][C:16]3=[O:34])=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)=[N+]=[N-]>C(O)(=O)C.CO.[Pd]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([S:21]([C:24]4[S:28][C:27]5[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:26]=5[CH:25]=4)(=[O:22])=[O:23])[CH2:17][C:16]3=[O:34])=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=Nc1ccnc2cc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccnc2cc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A suspension of 1-(4-azidoquinolin-7-ylmethyl)-4-(6-chlorobenzo[b]thiophen-2-sulfonyl)-piperazin-2-one (0.50 g, 1.04 mmol) in 100 mL of acetic acid/methanol (˜1:10) is treated with 10% Pd/C (0.15 g) and stirred under hydrogen for 1.5 hours. The resulting solution is filtered through Celite and the filtrate is evaporated in vacuo. The organic layer is concentrated and the residue is purified by reverse phase HPLC (gradient elution of 30% of 0.1% aqueous TFA/acetonitrile to 100% acetonitrile) and lyopholized to give the title compound (0.39 g, 0.86 mmol). MS (ISP) m/z 487, 489, (M+H), Cl pattern.
Reaction SMILES: [H-].[Na+:2].[O:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH:9](OCC)=[O:10]>CCCCCC.CCOCC>[O:8]=[C:4]1[C:5](=[CH:9][O-:10])[CH2:6][CH2:7][O:3]1.[Na+:2]
Reactant: CCOC=O
Reactant: O=C1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1OCCC1=C[O-]
Reaction time: 1 h
Yield: 102.9 %

Procedure:
Three-neck, round-bottomed flask equipped with mechanical stirrer, addition funnel, and reflux condenser was placed in a hood behind a shield. The condenser was fitted with a drying tube which was connected to a mineral oil bubble chamber so hydrogen evolution could be monitored. After NaH (4.4 g of 60% oil dispersion, 0.11 mol) was washed with n-C6H14 (2×50 mL), filtered with brief suction drying, and transferred to the flask, sufficient Et2O was added to cover the resulting solid. A catalytic amount of C2H5OH (ca. 2 drops) was added directly to the Et2O—NaH suspension and dropwise addition without stirring of a solution of dihydrofuran-2(3H)-one (8.61 g, 0.1 mol) and ethyl formate (7.41 g, 0.1 mol) in Et2O (10 mL) was started. As soon as the Et2O began to reflux, additional Et2O (50-60 mL) was rapidly added through the reflux condenser and stirring was started. Lactone-formate addition was complete in 1 hr, and stirring was continued for an additional 22 h. Filtration, washing with Et2O, and vacuum drying gave desired product (14.0 g) as a fine powdery solid.
Reaction SMILES: [CH:1]12[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:5][CH2:4][CH2:3][NH:2]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20](O)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([N:2]2[CH2:3][CH2:4][NH:5][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:1]23)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: C1CCC2NCCNC2C1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCCC21

Procedure:
The title compound of Example 15 base (0.49 g, 3.5 mmol) was coupled with 3,4-dichlorophenylacetic acid (1.07 g, 5.2 mmol) as described in Example 5 to give the amide as a crystalline solid: mp 119-120° C. (2-propanol); 1H-NMR (CDCl3) σ 7.39 (d, J=8.3 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 4.48 (m, 1H), 3.66 (br s, 2H), 3.64 (m, 1H), 3.29 and 2.87 (m, 1H), 2.64-2.85 (complex m, 2H), 2.41 and 2.09 (m, 1H), 1.93-2.06 (complex m, 2H), 1.40-1.87 (complex m, 5H), 1.12-1.36 (complex m, 2H); Anal (calcd for C16H20Cl2N2O): C 58.72, H 6.16, N 8.56. Found: C 58.80, H 6.17, N 8.52.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].BrCC[F:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH2:29][F:35])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: FCCBr
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting 1-bromo-2-fluoroethane and making non-critical variations provided the title compound as a light yellow amorphous solid. IR (diffuse reflectance) 2972, 2934, 1564, 1551, 1498, 1468, 1392, 1377, 1206, 1182, 1123, 1102, 1046, 826, 750 cm−1; OAMS supporting ions at: ESI+ 473.9; MS (EI) m/z 473 (M+); [α]25D=−87 (c 0.77, methylene chloride); Anal. Calcd for C25H26Cl2FN3O: C, 63.30; H, 5.52; N, 8.86. Found: C, 63.10; H, 5.60; N, 8.79.
Reaction SMILES: N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CCCNC(=N)N[S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].[NH:48]([C:63]([O:65][CH2:66][CH:67]1[C:79]2[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=2)[C:73]2[C:68]1=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])[C@H:49]([C:60]([OH:62])=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1>C(O)(C(F)(F)F)=O>[NH:48]([C:63]([O:65][CH2:66][CH:67]1[C:68]2[C:73](=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:74]2[C:79]1=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:64])[C@H:49]([C:60]([OH:62])=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][C:52]=1[S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:10])=[O:11]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C)c(S(=O)(=O)c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Temperature: 30 °C

Procedure:
Fmoc-Arg(Pmc)-OH (0.5 g, 0.75 mmol) and Fmoc-Trp-OH (0.43 g, 0.1 mmol) was dissolved in 10 ml 100% TFA and heated at 30° C. for 1.5 hours. After evaporation of TFA, Fmoc-Arg-OH was removed by column chromatography on silica gel with heptane/ethyl acetate 2:1 as mobile phase. Fmoc-Trp(2Pmc)-OH was isolated by preparative HPLC (C18, 70-100% B in 15 min., tR 14.8 min, (A: H2O+0.1% TFA; B: CH3CN +0.1% TFA)). Isolated yield 130 mg (0.19 mmol, 25%).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:12]2[C:13]([CH3:16])=[N:14][S:15][C:11]=2[CH:10]=1.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[Cl:22][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:12]2[C:13]([CH3:16])=[N:14][S:15][C:11]=2[CH:10]=1
Reactant: Cc1nsc2cc(N)c([N+](=O)[O-])cc12
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1nsc2cc(Cl)c([N+](=O)[O-])cc12
Temperature: 65 °C

Procedure:
A mixture of tert-butyl nitrite (3.30 mL, 0.0278 mol) and copper(II) chloride (2.98 g, 0.0222 mol) in acetonitrile is heated to 65° C., treated portionwise with 6-amino-3-methyl-5-nitro-1,2-benzisothiazole (3.88 g, 0.0185 mol), stirred at 65° C., cooled to room temperature, and poured into 20% hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with 20% hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and methylene chloride/hexanes solutions (1:1 and 3:1) gives the title product as a pale, yellow solid (2.54 g, mp 156-158° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:19]([C:20]3[N:21]=[CH:22][N:23]([C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH:24]=3)=[C:18]([CH3:34])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1>>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[C:19]([C:20]3[N:21]=[CH:22][N:23]([C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([NH:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:29])[CH:24]=3)=[C:18]([CH3:34])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)NC3CCOCC3)c2)cn1
Yield: 49 %

Procedure:
As described for Example 71c, tetrahydro-pyran-4-ylamine was converted, using 3-{4-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (100 mg, 0.28 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (56 mg, 49%) which was obtained as an off-white solid. MS: m/e=447.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)[C:8]=2[F:13])[C:3]=1[OH:29].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CCOCC>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:19]=3)[C:8]=2[F:13])[C:3]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1ccc(-c2ccc3c(O)c(F)c(F)cc3c2F)cc1
Reactant: CCCCCCCCBr
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc3c(OCCCCCCCC)c(F)c(F)cc3c2F)cc1

Procedure:
From 2,3,5-trifluoro-6-(4-octyloxyphenyl)naphthalen-1-ol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccn2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of 5-bromoisatin (10.0 g, 44.4 mmol) in anhydrous N,N-dimethylformamide (100 mL) at 0° C. was added slowly sodium hydride (60% w/w dispersion in mineral oil, 3.90 g, 97.7 mmol). The solution was stirred for 30 min and 2-(bromomethyl)pyridine hydrobromide (11.2 g, 44.4 mmol) was added. The solution was stirred at ambient temperature for 16 h and poured into ice water (1.3 L) with vigourous stirring, causing a precipitate to be deposited. The solid was collected by filtration to afford 5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione (4.93 g, 35%) as a orange solid: 1H NMR (300 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 7.72-7.56 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.18 (m, 1H), 6.93-6.88 (m, 1H), 5.03-4.99 (m, 2H).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]1([CH3:36])[C@H:14]([NH:15][C:16]2[C:17]3[N:18]([CH:25]=[C:26]([C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH:27]=3)[N:19]=[CH:20][C:21]=2[C:22]([NH2:24])=[O:23])[CH2:13][CH2:12][NH:11][CH2:10]1.[NH2:37][C:38](=[O:42])[C:39](O)=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:37][C:38](=[O:42])[C:39]([N:11]1[CH2:12][CH2:13][C@@H:14]([NH:15][C:16]2[C:17]3[N:18]([CH:25]=[C:26]([C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH:27]=3)[N:19]=[CH:20][C:21]=2[C:22]([NH2:24])=[O:23])[C:9]([CH3:36])([CH3:8])[CH2:10]1)=[O:40]
Reactant: COc1ccc(-c2cc3c(N[C@@H]4CCNCC4(C)C)c(C(N)=O)cnn3c2)cn1
Reactant: NC(=O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(N[C@@H]4CCN(C(=O)C(N)=O)CC4(C)C)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To solution of (R)-4-(3,3-dimethylpiperidin-4-ylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt (20 mg, 0.039 mmol), 2-amino-2-oxoacetic acid (4.20 mg, 0.047 mmol) and HATU (22.43 mg, 0.059 mmol) in DMF (0.3 mL) was added triethylamine (0.022 mL, 0.157 mmol) and the resulting mixture was stirred at rt overnight. The mixture was quenched with 0.3 mL of MeOH, diluted with MeOH, filtered and was purified via preparative reverse phase HPLC. The fraction containing the major product was concentrated under vacuum to afford the title compound as a tan solid (10 mg, 0.015 mmol, 38%). HPLC (Method B) retention time=2.88 min. LCMS (m+1)=466.3. 1H NMR (400 MHz, METHANOL-d4) δ 8.59 (t, J=2.2 Hz, 1H), 8.24 (dt, J=8.7, 2.8 Hz, 1H), 8.21 (s, 1H), 8.03 (t, J=2.0 Hz, 1H), 7.31 (dd, J=5.7, 1.8 Hz, 1H), 7.05 (dd, J=8.5, 2.3 Hz, 1H), 4.46-4.30 (m, 2H), 4.07-4.00 (m, 4H), 3.78 (dd, J=13.8, 1.7 Hz, 1H), 3.68-3.51 (m, 1H), 3.21-3.08 (m, 1H), 2.23 (dt, J=13.6, 4.0 Hz, 1H), 2.04-1.75 (m, 1H), 1.22-1.06 (m, 6H).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(O)CCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
(±)-Heptan-1,6-diol (1.06 g, 8 mmol) and pyridine (1.36 ml, 1.33 g, 16.8 mmol) were dissolved in dichloromethane (20 ml) and the mixture was cooled in ice. Methanesulfonyl chloride (0.65 ml, 0.96 g, 8.4 mmol) was added dropwise and the mixture was stirred at room temperature for 18 hours. Dichloromethane (50 ml) was added and the mixture was washed with aqueous HCl (1M, 50 ml) and brine (30 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/20% hexane, to give the alcohol as an oil (1.01 g, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][NH:31][S:32]([CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:34])=[O:33])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17](CC[Si](C)(C)C)[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][NH:31][S:32]([CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:33])=[O:34])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:27])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCNS(=O)(=O)CC3CCCCC3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(CCNS(=O)(=O)CC3CCCCC3)cc2OCc2ccccc2)S(=O)(=O)N1

Procedure:
N-(2-{3-Benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-ethyl)-C-cyclohexyl-methanesulfonamide (0.106 g, 0.17 mmol) is dissolved in THF (3 mL) and TBAF (0.089 mg, 0.099 mL of 1N in THF, 0.34 mmol) is added. The mixture is refluxed for 30 min and then diluted with 1N HCl and extracted with EtOAc. The combined organic layers are washed with 1N HCl, dried over MgSO4 and evaporated to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH2:43]([O:50][C:51]1[CH:60]=[CH:59][C:54](/[C:55](=[N:57]/O)/[NH2:56])=[CH:53][CH:52]=1)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>CN(C=O)C>[C:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][NH:57][C:55](=[NH:56])[C:54]3[CH:53]=[CH:52][C:51]([O:50][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:60][CH:59]=3)=[O:19])=[CH:21][CH:22]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CCCCCCCOc1ccc(/C(N)=N/O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=N)NOC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reaction time: 2 h

Procedure:
Prepared using General Procedure 5: To a solution of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid, INT-1 (10.0 mg, 0.026 mmol) in anhydrous DMF (1 mL) was added HOBt (5.27 mg, 0.39 mmol) and EDC (7.48 mg, 0.39 mmol). After stirring for 2 h, (Z)-4-(heptyloxy)-N′-hydroxybenzimidamide (9.76 mg, 0.39 mmol) was added. The reaction mixture was stirred at RT for 2 h, partitioned between saturated aqueous NaHCO3 (5 ml) and EA (5 mL), and concentrated under reduced pressure to afford the intermediate (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(((4-(heptyloxy)benzimidamido)oxy)carbonyl)phenyl)propanoate. The intermediate was dissolved in DMF (1 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to RT and partitioned between EA (5 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was extracted with water (2×5 mL) and brine (5 mL). The organic layer was dried over MgSO4 and concentrated. The brown oil was purified by preparative HPLC to afford 4.5 mg (29%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.3; no m/z observed, tR=12.75 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.85 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.9 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.9 Hz, 2H), 4.87-4.56 (m, 1H), 4.06 (t, J=6.5 Hz, 2H), 3.67 (s, 3H), 3.32-3.13 (m, 4H), 1.74 (dd, J=14.2, 6.5 Hz, 2H), 1.51-1.37 (m, 2H), 1.33 (s, 4H), 1.26 (d, J=20.2 Hz, 9H), 0.88 (t, J=6.9 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 175.00, 171.91, 167.89, 166.27, 161.21, 154.37, 143.68, 130.78, 130.30, 128.76, 127.80, 127.18, 125.07, 121.69, 118.21, 115.07, 67.72, 53.61, 52.05, 36.15, 34.60, 31.20, 30.87, 28.54, 28.39, 25.40, 22.02, 13.93.
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:12][OH:13]>C(O)C.O>[C:1]1(=[N:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCCc2ccccc21
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5 mL (37.5 mmole) 1-tetralone in 25 mL ethanol was added 2.7 mL (40 mmole) of 50% hydroxylamine in water. The reaction mixture was heated under reflux for 2 hrs, then stirred at room temperature for 16 hrs. The solution was concentrated under reduced pressure. The residue was recrystallized from toluene/hexane to give 1-tetralone oxime (3,4-dihydro-2H-naphthalen-1-one oxime), 3.86 g, m.p. 101-102°.