Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(NC(C)C)(C)C.Br[CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25].O>C(#N)C>[CH2:13]([O:12][C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:23][C:24]([N:26]3[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]3[C:32]#[N:33])=[O:25])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)=[O:11])[CH3:14]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Solvent: O
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (92.0 mg) was dissolved in acetonitrile (2 mL) and diisopropylamine (100 μL) was added to the solution. While the mixture was chilled in an ice bath, (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (100 mg) in acetonitrile (1 mL) was added dropwise. The mixture was stirred for 1.5 hours while chilled in the ice bath. Subsequently, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant:ethyl acetate:methanol=5:1) to give (2S,4S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (132 mg).
Reaction SMILES: [S:1]1[C:5]2[NH:6][CH2:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:6]2[C:5]3[S:1][CH:2]=[CH:3][C:4]=3[CH2:10][N:9]3[CH:11]=[CH:12][CH:13]=[C:8]3[CH2:7]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1cc2n(c1)Cc1ccsc1NC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccsc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mmol of 9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[N:3]=[C-:2]1.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=1)[C:15]#[N:16].CN(C)C=[O:22]>[Cl-].[Na+].O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N:3]2[CH2:4][CH2:5][O:1][C:2]2=[O:22])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: CN(C)C=O
Reactant: O=C1CO[C-]=N1
Reactant: N#Cc1cc(Cl)ccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(Cl)ccc1N1CCOC1=O
Reaction time: 0.08 h

Procedure:
(Step 1) To a solution (of 2-oxazolidone (1.23 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (0.62 g) under ice-cooling, and the mixture was stirred for 5 min. 5-Chloro-2-fluorobenzonitrile (2.0 g) was added, and the mixture was stirred at room temperature for 2 hr. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give 5-chloro-2-(2-oxo-1,3-oxazolidin-3-yl)benzonitrile (1.8 g) as a white solid.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:20])[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15].[P:21](Cl)(Cl)(=[O:33])[O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(Cl)[Cl:37]>>[Cl:37][C:24]1[CH:25]=[CH:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]=1[O:22][P:21](=[N:12][C@@H:13]([CH3:20])[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])=[O:33]
Reactant: ClCCl
Reactant: CCCOC(=O)[C@H](C)N
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCCOC(=O)[C@H](C)N=[P+]([O-])Oc1c(Cl)ccc2ccccc12
Yield: 82 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (S)-propyl 2-aminopropanoate (2.00 g, 11.93 mmol), naphth-1-yl phosphorodichloridate (3.11 g, 11.93 mmol) and TEA (3.32 mL, 23.86 mmol) in 30 mL of dry DCM, were combined to give (2S)-propyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate in 82% yield (3.50 g), as a clear, yellow, thick oil.
Reaction SMILES: [CH:1]([S:4]Cl)([CH3:3])[CH3:2].[C:6]1([NH:12][P:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH:1]([S:4][N:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:14])([CH3:3])[CH3:2]
Reactant: O=P(Nc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)SCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)SN(c1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 11.1 parts of isopropyl sulphenyl chloride in 100 parts of carbon tetrachloride is added to a suspension of 30.9 parts of N,P,P-triphenylphosphinic amide and 10.0 parts of triethylamine in 150 parts of carbon tetrachloride at room temperature. The mixture is stirred for a further 1 hour. The triethylamine hydrochloride is filtered off and the filtrates evaporated under reduced pressure to give a white solid. This is recrystallised from methylated spirits to yield 16.5 parts of N-isopropylthio-N,P,P-triphenylphosphinic amide as a colourless solid m.p. 148°-150°C. Found, C, 67.2; H. 6.2; N, 4.0; P, 8.1 percent, C21H22NOPS requires C, 68.7; H, 6.0; N, 3.8; P, 8.45 percent. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=O.[H-].[Na+].CS(OC[C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH2:36][CH2:37][O:38][CH2:39][CH:40]=3)=[C:31]([F:41])[CH:30]=2)[CH2:24]1)(=O)=O>CN(C)C=O.CCCCCC>[O:10]1[CH:11]=[CH:12][C:8]([NH:7][CH2:5][C@@H:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH2:36][CH2:37][O:38][CH2:39][CH:40]=4)=[C:31]([F:41])[CH:30]=3)[CH2:24]2)=[N:9]1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(C2=CCOCC2)c(F)c1
Temperature: 55 °C
Yield: 50 %

Procedure:
To a stirred solution of 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (631 mg, 2.43 mmol) in dry N,N-dimethylformamide (10 ml), under a nitrogen atmosphere was added a suspension of sodium hydride (107 mg of a 60% dispersion in oil, 2.67mmol) in hexane followed by 5(R)-methanesulfonyloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (see WO 97/09328; 226 mg, 0.61 mmol) in dry DMF (3 ml). Over a period of 24 hours further batches of sodium hydride totalling (428 mg of a 60% dispersion in oil, 10.7 mmol), were added and the reaction mixture heated to 50-60° C. for 24 h, after which time TLC indicated the formation, of the desired product (Rf 0.34, 50% ethyl acetate/hexane). The majority of the N,N-dimethylformamide was evaporated under hi-vacuum and the product isolated by MPLC (50%THF/Hexane) and then triturated with ether to yield the title compound as a white amorphous solid (63.4 mg, 29%). NMR: 2.42 (m, 2H), 3.45 (m, 2H), 3.81 (m, 3H), 4.15 (t, 1H), 4.21 (d, 2H), 4.90 (m, 1H), 6.01 (d, 1H), 6.09 (m, 1H), 6.53 (t, 1H), 7.31 (dd, 1H), 7.40 (t, 1H), 7.48 (dd, 1H), 8.39 (d, 1H); m/z: ES+ (M+H)=360.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(Cl)(=O)C(Cl)=O.[CH2:28]([NH:30][CH3:31])[CH3:29]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[N:30]([CH3:31])[CH2:28][CH3:29])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: CCNC
Reactant: O=C(O)c1ccc(Sc2ccc([N+](=O)[O-])c(Cl)c2F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1ccc(Sc2ccc([N+](=O)[O-])c(Cl)c2F)cc1
Reaction time: 8 h
Yield: 34.9 %

Procedure:
2-Chloro-3-fluoro-4-(4-carboxyphenylsulphanyl)nitrobenzene (Method 24; 5.5 g, 16.8 mmol) was suspended with stirring in DCM (100 ml) and oxalyl chloride (3.22 ml) was added. A couple of drops of DMF were added to initiate the reaction and it was left to stir overnight. The mixture was evaporated to dryness and then redissolved in DCM (20 ml). N-ethyl-N-methylamine (0.46 ml, 5.28 mmol) was dissolved in DCM (1 ml) and to this with stirring was added some of the above acid chloride solution (2.4 mmol). The solution was left to stir overnight and then washed with water, brine and dried by pouring onto a Chem Elut column eluting with EtOAc. The resulting solution was evaporated down to dryness and then purified by chromatography on a Mega Bond Elut column eluting with a graduated solvent of hexane/EtOAc to yield the title compound (680 mg). NMR: 1.1 (s, 3H), 2.9 (d, 3H), 3.2 (s, 1H), 3.4 (s, 1H), 7.2 (m, 1H), 7.5 (d, 2H), 7.6 (d, 2H), 8.0 (m, 1H); m/z 369.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Si:16]([O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: OCc1ncn2ccsc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ncn2ccsc12
Reaction time: 2 h

Procedure:
To a solution of 2.42 mg of 7-hydroxymethylimidazo[5,1-b]thiazole in 15 ml of DMF were added under ice-cooling 1.4 g of imidazole and 2.73 g of t-butyldimethylsilylchloride, and the mixture was stirred at the same temperature for 2 hours. DMF was removed under reduced pressure, and the residue was extracted two times with ethyl acetate. The organic layer was washed two times with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and removed under reduced pressure to give 7-(t-butyldimethylsilyloxy)methylimidazo[5,1-b]thiazole in a yield of 4.02 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:19]1[CH2:24][C@@H:23]([C:25]2[O:29][N:28]=[C:27]([CH3:30])[N:26]=2)[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.[ClH:48]>>[ClH:48].[ClH:48].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([C@H:19]1[CH2:24][C@@H:23]([C:25]2[O:29][N:28]=[C:27]([CH3:30])[N:26]=2)[CH2:22][NH:21][CH2:20]1)[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nc(C)no3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](c3nc(C)no3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3R, 55)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg), N-hydroxy acetamidine (56 mg), 1H-benzotriazol-1-ol (95 mg) and N,N-diisopropylethylamine (259 μl)) were dissolved in DMF (10 ml), WSC.HCl (144 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in toluene (15 ml), and the mixture was refluxed under heating for 15 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give tert-butyl(3S, 5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (324 mg). The obtained tert-butyl(3S, 5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was dissolved in methanol (3 ml), 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (74 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH3:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.O1CCCC1.[Cu]I.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>[CH3:12][O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: COC1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 88.7 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)-benzene (Intermediate 59, 300.0 mg, 1.32 mmol) in triethylamine (4 mL) and anhydrous tetrahydrofuran (4 mL) was treated with copper(I)iodide (93.0 mg, 0.13 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.39 g, 14.2 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (93.0 mg, 0.13 mmol). The resulting reaction mixture was heated to 70° C. for 60 h. The title compound (286.0 mg, 90%) was isolated by chromatography (0-3% EtOAc-hexanes).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:9])=[O:8])[N:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]([NH2:9])=[O:8])=[N:5]1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1nc(C(N)=O)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(C(N)=O)nn1Cc1cccc(Br)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a solution of 5-methyl-1H-1,2,4-triazole-3-carboxamide (2.5 g, 19.8 mmol) and 1-bromo-3-(bromomethyl)benzene (5.45 g, 21.8 mmol) in THF (99 mL), K2CO3 (5.5 g, 39.6 mmol) was added. The mixture was stirred at 50° C. for 18 h, and then the reaction was filtered under vacuum. The solvent was removed under reduced pressure and the crude product was purified on a Biotage pre-packed silica gel column with a gradient of 0% to 20% MeOH:DCM to afford 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxamide (1.5 g, 26%) as a viscous oil. MS (ES+) C11H11BrN4O requires: 294, 296. found: 295, 297 [MH]+(1:1).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][CH3:17])[CH2:12]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH2:24](N(CC)CC)C>C(Cl)Cl>[CH:22]([O:21][C:19](=[O:20])[N:16]([C@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([Br:1])=[CH:3][N:4]=3)[N:7]=2)[CH2:12]1)[CH3:17])([CH3:23])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CN[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N(C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
[(S)-1-(3-Bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-amine (951 mg, 3.2 mmol) was taken up in DCM, and ethyl chloroformate (459 uL, 4.8 mmol) and triethylamine (895 uL, 6.4 mmol) were added. The reaction was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was then washed with water then 1N HCl. The DCM layer was dried over magnesium sulfate, filtered and reduced in vacuo to give crude product (1.1 g) that was used as is in part C. LRMS (ESI) m/z 382/384 [(M+H)]+, calc'd for C15H20BrN5O2: 382.26.
Reaction SMILES: CC1C2C[C@@H:13]3[C@:19](O)(C(=O)C=2C(O)=C2C=1C=CC=C2O)[C:17](=O)[C:16](C(N)=O)=[C:15](O)[C@H:14]3[N:27]([CH3:29])[CH3:28].[CH2:32](O)[C@H:33]1[O:38][C@H:37]([O:39][C@:40]2([CH2:49]O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:36](O)[C@@H:35](O)[C@@H:34]1O.[CH2:55](S)[C@@H](O)[C@H](O)CS.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>>[CH3:28][N:27]([CH3:29])[C:14]1[CH:15]=[CH:16][C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([O:39][CH2:40][CH3:49])=[O:38])[CH:55]=2)=[CH:19][CH:13]=1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: Cc1c2c(c(O)c3c(O)cccc13)C(=O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1C2
Reactant: O[C@H](CS)[C@H](O)CS
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Product: CCOC(=O)c1cccc(-c2ccc(N(C)C)cc2)c1
Reaction time: 3 h

Procedure:
For over-expression of ATGL and CGI-58 in E. coli (XL-1) cDNA was cloned into the vector pASK-IBA5+ (IBA-BioTagnology). Cells were transformed and cultured over night at 30° C. Thereafter cells were transferred into a fresh medium and grown until OD600 reached 0.7-0.8. Expression was induced using 0.2 μg/ml anhydrotetracycline. After 3 hours incubation at 37° C. cells where harvested, resuspended in lysis buffer (0.25M Sucrose, 1 mM DTT, 1 mM EDTA) and disrupted by sonication. Lysates were centrifuged at 15,000 g for 20 min at 4° C. and the supernatant was collected.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.C(OC([NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:32]3[CH2:33][CH2:34][CH:29]([NH2:28])[CH2:30][CH2:31]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: O
Product: NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 60 °C
Yield: 66.4 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol) obtained in Step 6 of Example 1, 4-(tert-butoxycarbonylamino)piperidine (538 mg, 2.84 mmol), 1-hydroxybenzotriazole monohydrate (332 mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg, 2.67 mmol) and N-methylmorpholine (0.420 mL, 3.82 mmol) in a similar manner to Example 5, was dissolved in methanol (10.0 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (5.0 mL), followed by heating under reflux at 60° C. for 90 minutes. The reaction mixture was concentrated under reduced pressure, the residue was extracted after adding with a saturated aqueous potassium carbonate solution and ethyl acetate. The crude product was crystallized from ethyl acetate to obtain Compound 64 (435 mg, 66%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[NH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])OC(C)(C)C.NCCNC1[CH2:31][CH:30]([CH2:32][C:33]([NH:35][C@H:36]([B:49]2[O:57]C3C(C)(C4CC(C3)C4(C)C)[O:50]2)[CH2:37][C:38]2[C:39](OC)=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([OH:43])=[O:42])=[O:34])[CH2:29]1.O>C(Cl)Cl.CN(C=O)C>[NH2:10][CH2:11][CH2:12][NH:8][C:1](=[O:2])[N:3]([CH:4]1[CH2:29][CH:30]([CH2:32][C:33]([NH:35][C@H:36]2[CH2:37][C:38]3[CH:46]=[CH:45][CH:44]=[C:40]([C:41]([OH:43])=[O:42])[C:39]=3[O:57][B:49]2[OH:50])=[O:34])[CH2:31]1)[CH2:7][CH2:6][NH:5][C:17]([NH:16][CH2:15][CH2:14][NH2:13])=[O:23]
Reactant: COc1c(C[C@H](NC(=O)CC2CC(NCCN)C2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NCCNC(=O)NCCN(C(=O)NCCN)C1CC(CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1,1′-Carbonyldiimidazole (180 mg) in DCM (5 mL) was added tert-butyl 2-aminoethylcarbamate (160 mg). The resultant reaction mixture was stirred at RT for 1 hr. A portion of this solution (1 mL) was then added to 3-((2R)-2-(2-(3-(2-aminoethylamino)cyclobutyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoic acid from step 1 (20 mg) in DMF and TEA (2 eq) in a different flask. The reaction mixture was stirred overnight. Water was added and extracted with EtOAc. The combine organic phases were dried and concentrated in vacuo to afford the product which was used directly to next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[F:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:39][C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][N:49]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:7]=[C:8]([C:12]4[C:16]5[S:17][CH:18]=[CH:19][C:15]=5[O:14][N:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:48][CH2:47]2)=[CH:44][CH:45]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(N2CCN(CCCOc3cccc(-c4noc5ccsc45)c3)CC2)cc1
Yield: 100 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 1-(4-fluorophenyl) piperazine and potassium carbonate essentially as described above in example 4 except that the column is eluted with a mixture of dichloromethane:methanol (99:1). Combine the appropriate fractions and concentrate to give the title compound (0.44 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=438 m/e.