Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[C:2]([O:8][CH:9]([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:12](Cl)(=[O:14])[CH3:13].S(=O)(=O)(O)O>C(O)C.ClC(Cl)(Cl)Cl>[C:4]([CH:3]([C:12]([CH3:13])=[O:14])[C:2]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])(=[O:5])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)CC(=O)OC(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(C(C)=O)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
5 ml of tetrachloromethane are added to 23.3 g (1 mol) of magnesium turnings in 50 ml of dry ethanol under nitrogen and in the absence of moisture. After the beginning of gas evolution, a solution of 147.1 g (1 mol) of isopropyl acetoacetate in 100 ml of dry ethanol was slowly added dropwise, the reaction mixture being kept at the reflux temperature. Stirring was carried out for a further 4 hours at this temperature, after which the mixture was cooled. 78.5 g (1 mol) of acetyl chloride was slowly added dropwise at 10° C. Stirring was continued for a further 4 hours at room temperature and hydrolysis was then effected with a mixture of 450 ml of ice water and 25 ml of concentrated sulfuric acid. The organic phase was separated off, dried, and evaporated down under reduced pressure. 192.3 g of >96% pure isopropyl 2-acetylacetoacetate were obtained.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10]2)([O-:5])=[O:4].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][N:10]1[C:11]2[C:7](=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:9]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 48 h
Yield: 78 %

Procedure:
Sodium hydroxide (3M, 20 ml) was added to a vigorously stirred solution of ethyl 4-nitroindole-2-carboxylate (4 g), 3,4-dichlorobenzyl chloride (4.73 ml) and tetra-n-butylammonium hydrogensulphate (0.2 g) in dichloromethane (60 ml). The reaction was stirred for 48 hours then partitioned between 2M HCl and dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using iso-hexane: 20% ethyl acetate as eluent to give the product as a yellow crystalline solid (5.26 g, 78%); NMR δ (CD3SOCD3) 1.3 (t, 3H), 4.3 (q, 2H), 5.95 (s, 2H), 6.9 (m, 1H), 7.6 (m, 4H), 8.2 (t, 2H); M/z (+) 393.3 (M+).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1)[CH3:2].[CH2:12](O)[CH2:13][CH3:14].[OH-].[K+]>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]([CH2:12][CH2:13][CH3:14])[C:8]#[N:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCCO
Reactant: CCc1ccc(CC#N)cc1
Agent: [K+]
Agent: [OH-]
Product: CCCC(C#N)c1ccc(CC)cc1
Yield: 51 %

Procedure:
Following the same procedure given in b), 4-ethylbenzylcyanide (5.08 g, 35 mmol), 1-propanol (21 ml, 280 mmol) were reacted with potassium hydroxide (99.1 mg, 1.75 mmol) and [RuCl2(p-cym)]2 (55.1 mg, 0.09 mmol) at 100° C. for 1 h. Removal of the solvent and distillation under reduced pressure gave the desired nitrile with a yield of 51%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][CH:5]=[C:6]([O:16]CC2C=CC=CC=2)[C:7]=1[O:8]CC1C=CC=CC=1>C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:7](=[O:8])[C:6]([OH:16])=[CH:5][NH:4][C:3]=1[C:24]([OH:26])=[O:25]
Reactant: O=C(O)c1ncc(OCc2ccccc2)c(OCc2ccccc2)c1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(O)c1[nH]cc(O)c(=O)c1Br

Procedure:
3.24 g of the title compound of Example 8 were stirred in a mixture of 20 ml thioanisole and 30 ml TFA at room temperature for 16 hours. The solvents were distilled off in vacuo and the residue stirred with 50 ml ice water at pH 5.5 (NaHCO3 were added). Solid title compound, beige crystals, were isolated by filtration after washing with water and drying over P2O5 ; yield: 2.2 g title compound. Title compound was also obtained by hydrogenation of the title compound of Example 8 in DMF, Pd/C (10%) as catalyst.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]1[CH2:14][NH:15][CH2:16][CH2:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]1[CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:16][CH2:17][CH:18]=1
Reactant: COc1ccc2[nH]cc(CC3=CCCNC3)c2c1
Reactant: Fc1ccc(CCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC3=CCCN(CCCCc4ccc(F)cc4)C3)c2c1
Temperature: 25 °C

Procedure:
A mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (1.4 g; 0.0058 mol), potassium carbonate (4 g; 0.0029 mol), a catalytic amount of potassium iodide (0.030 g) and compound of Description 9 [1-(4-chloro-butyl)-4-fluoro-benzene] (5.4 g; 0.029 mol) in dimethylformamide (40 ml) was heated at 80° C. for 6 hours. The reaction mixture was cool down to room temperature. quenched with water and then extracted with ethyl acetate. The organic extract was dried (MgSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol/ammonia (95/5/0,5), the desired compound was obtained as an oil. A solution of this oil in methanol was saturated with gaseous hydrogen chloride. A solid was precipitated. The title compound hydrochloride was collected by filtration, washed with hexane and dried under vacuum (0.66 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3cccnc3)cc1)n2C)c1ccccn1
Yield: 40 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and nicotinic acid chloride. Yield: 40% of theory, C32H30N8O4 (590.7); Rf value: 0.47 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=591; (M+H+Na)++=307; (M+Na)+=613.
Reaction SMILES: [N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:8])[CH2:2]2.[ClH:9]>[Pt]=O.CCO>[ClH:9].[N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:8])[CH2:2]2
Reactant: O=C1CN2CCC1C2
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: OC1CN2CCC1C2

Procedure:
A mixture of 1-azabicyclo[2.2.1]heptan-3-one (Journal of Medicinal Chemistry, 1990, 33, pp. 2690-2697), hydrochloride (350 mg), platinum oxide (35 mg), and EtOH (5 mL) was stirred at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 1-azabicyclo[2.2.1]heptan-3-ol hydrochloride as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:31][NH:32][O:33][CH3:34]>C(#N)C.CN(C=O)C.C(N(CC)CC)C>[CH3:31][N:32]([O:33][CH3:34])[C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Br)o1
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a suspension of 5-bromo-2-furancarboxylic acid (5.00 g) and N-hydroxysuccinimide (3.31 g) in acetonitrile (50 ml) was added 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (5.52 g) at room temperature, and the mixture was stirred for 2 hours. To the reaction mixture was added a suspension of N,O-dimethylhydroxyl-amine hydrochloride (2.81 g) and triethylamine (10 ml) in acetonitrile (20 ml), and the mixture was stirred for 1 hour. To the reaction mixture were added 1,8-diazabicyclo-[5.4.0]-7-undecene (4.3 ml) and DMF (50 ml), and the mixture was stirred for 3 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:4→1:3→1:2) to give N-methyl-N-methoxy-5-bromofuran-2-carboxamide (2.77 g) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:26](I)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[OH-].[K+].C(O)CCC>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc(O)c(F)c3)s2)cc1
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: CCCCCCOc1ccc(-c2nnc(-c3ccc(CCCCCC)cc3)s2)cc1F
Temperature: 25 °C
Yield: 35.1 %

Procedure:
0.30 g (0.84 mM) of 2-(3-fluoro-4-hydroxyphenyl)-5-(4-hexylphenyl)-1,3,4-thiadiazole, 0.23 g (1.09 mM) of hexyl iodide, 0.08 g of 85%-potassium hydroxide and 6 ml of butanol were mixed, followed by refluxing for 5 hours under stirring. After the reaction, 10 ml of methanol was added to the reaction mixture, followed by cooling to room temperature and further cooling in a freezer to precipitate a crystal. The crystal was recovered by filtration and washed with methanol. The resultant crystal was dissolved in toluene and washed with water, followed by drying with anhydrous magnesium sulfate. The magnesium sulfate was recovered by filtration and the filtrate was condensed into a solid. The solid was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (ethanol/hexane) to obtain 0.13 g of 2-(3-fluoro-4-hexyloxyphenyl)-5-(4-hexylphenyl)-1,3,4-thiadiazole (Yield: 35.1%). ##STR23##
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1CCN(c2ccc(S(=O)(=O)NCc3ccccc3)cc2)CC1
Product: O=c1[nH]c2cccc(OCC(O)CNC3CCN(c4ccc(S(=O)(=O)NCc5ccccc5)cc4)CC3)c2[nH]1

Procedure:
The title compound was prepared from 4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 70, N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a grey solid. 1H NMR (DMSO) δ 1.37 (m, 2H), 1.90 (m, 2H), 2.73 (m, 2H), 2.84(m, 2H), 2.99(m, 4H), 3.87(m, 3H), 4.03(m, 1H), 5.07(bs, 1H), 6.67 (m, 1H), 6.85(t, 1H, J=8.1 Hz), 7.07(d, 2H, J=9.0 Hz), 7.32 (m, 6H), 7.59 (d, 2H, J=8.7 Hz), 10.59 (bs, 1H), 10.72 (bs, 1H); MS (ES) m/z: 552.1 (MH+); HRMS for C28H33N5S5S: 552.2267 (MH+)
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][CH:11]1[O:15][C:14](=[O:16])[NH:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[O:3]([CH2:10][CH:11]1[O:15][C:14](=[O:16])[N:13]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCC(COc2ccccc2)O1
Reactant: CCOC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CC(COc2ccccc2)OC1=O
Yield: 72.6 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 113 mg of sodium hydride (as a 55% by weight dispersion in mineral oil), 10 ml of anhydrous dimethylformamide, 420 mg of 5-phenoxymethyloxazolidin-2-one (prepared as described in Preparation 112) and 471 mg of ethyl 3-bromopropionate were used, to give 463 mg of the title compound having an Rf value of 0.34 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: CC1C=C(C)C=CC=1C1(C2C=CC=CC=2)C=C2C(=CC3C4OCC=CC=4C4C5C=CC=CC=5SC=4C=32)C=C1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1([C:70]2[CH:75]=[CH:74][C:73](OC)=[CH:72][CH:71]=2)[CH:69]=[C:68]2[C:49](=[CH:50][C:51]3[C:60]4[O:59][CH2:58][CH:57]=[CH:56][C:55]=4[C:54]4[C:61]5[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=5[S:63][C:53]=4[C:52]=32)[CH:48]=[CH:47]1>>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:69]=[C:68]2[C:49](=[CH:50][C:51]3[C:60]4[O:59][CH2:58][CH:57]=[CH:56][C:55]=4[C:54]4[C:61]5[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=5[S:63][C:53]=4[C:52]=32)[CH:48]=[CH:47]1
Reactant: COc1ccc(C2(c3ccccc3F)C=CC3=Cc4c5c(c6c(sc7ccccc76)c4C3=C2)C=CCO5)cc1
Agent: Cc1ccc(C2(c3ccccc3)C=CC3=Cc4c5c(c6c(sc7ccccc76)c4C3=C2)C=CCO5)c(C)c1
Product: Fc1ccccc1C1(c2ccccc2)C=CC2=Cc3c4c(c5c(sc6ccccc65)c3C2=C1)C=CCO4

Procedure:
2-(2,4-dimethylphenyl)-2-phenyl-2,14-dihydro-[1]benzothieno[3,2-f]indeno[1,2-h]chromene, 2-(2-fluorophenyl)-2-(4-methoxyphenyl)-2,14-dihydro-[1]benzothieno[3,2-f]indeno[1,2-h]chromene,
Reaction SMILES: N#N.[C:3]([C:6]1[N:7]=[C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:32])[O:23][C:24]=3[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:14]=[N:13]2)[S:9][CH:10]=1)(=[O:5])[CH3:4].[CH3:33][Al](C)C.[Cl-].[NH4+].Cl>C(Cl)Cl.CCCCCCC>[OH:5][C:3]([C:6]1[N:7]=[C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[C:22]([CH3:32])[O:23][C:24]=3[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:14]=[N:13]2)[S:9][CH:10]=1)([CH3:33])[CH3:4]
Reactant: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Reactant: C[Al](C)C
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)(C)O)cs3)n2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of N-(2-((4-acetylthiazol-2-yl)methyl)-2H-1,2,3-triazol-4-yl)-2-methyl-5-(m-tolyl)oxazole-4-carboxamide (example 75 from WO 2009/077990; 50 mg, 0.12 mmol) in CH2Cl2 (1.1 mL) was treated at 0° C. with AlMe3 (0.3 mL of a 1.0M solution in heptane, 0.3 mmol) and the resulting mixture was stirred for 2 h at 0° C. The reaction mixture was carefully poured into a sat. aq. solution of ammonium chloride (5 mL) and diluted with CH2Cl2 (10 mL). 1N HCl (5 mL) was then added. The layers were separated and the org. phase was dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a colorless oil: TLC: rf (1:1 hept-EA)=0.20. LC-MS-conditions 02: tR=0.88 min, [M+H]+=438.94.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)([CH2:11]2)[C:9]1=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH3:24]>CCOCC.C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:13][CH:12]1[CH2:11][C:10]1([C:9](=[O:22])[CH3:24])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Cl)c(Cl)c2)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CC1CNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a flame-dried, 10 mL round-bottomed flask was added a solution of 1-(3,4-dichlorophenyl)-2-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in 2 mL of ether and 1.0 mL of THF under Ar (g). The solution was cooled in a dry ice/acetone bath with stirring. A solution of MeLi was added drop-wise and the resulting orange colored mixture was stirred at −78° C. for 3 hours. The solution was warmed to ambient temperature and quenched with 15 mL of 1N HCl. The organic layer was extracted with EtOAc (2×20 mL) and the combined layers washed with brine (20 mL). The organic layer was dried over sodium sulfate for 2 hours and filtered, concentrated under reduced pressure, and dried for 1 hour to afford 1.1 g of a brown oil. The oil was purified on a filter pad of silica eluting with 100/1 (v/v) CHCl3/MeOH. The desired fractions were collected, concentrated under reduced pressure, and dried to afford a yellow oil. Yield: 0.659 g 52%; 1H NMR (300 MHz, CDCl3) 7.46 (d, 1H, J=2.1 Hz, ArH), 7.39 (d, 1H, J=5.4 Hz, ArH), 7.20 (dd, 1H, J=5.4, 2.1 Hz, ArH), 4.73 (m, 1H, NH), 3.41 (m, 1H, CH2N), 3.15 (m, 1H, CH2N), 2.04 (s, 3H, CH3), 1.80 (m, 1H, CHCH2N), 1.45-1.58 (m, 9H, tert-Bu), 1.20 (dd, 2H, J=4.5 Hz, ArCCH2).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][O:17][C:18]1[N:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[CH2:24]([Sn:28]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])Cl)[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>C(OCC)C>[CH3:16][O:17][C:18]1[N:19]=[N:20][CH:21]=[CH:22][C:23]=1[Sn:28]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COc1cccnn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccnnc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 7.1 mL, 17.75 mmol) was slowly added (0.2 mL/min) to a solution of 2,2,6,6-tetramethylpiperidine (3 mL, 17.75 mmol) in dry diethyl ether (16 mL) at −30° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 30 minutes before being cooled down to −78° C. and a solution of 3-methoxypyridazine (Preparation 8a, 0.85 g, 7.72 mmol) in dry diethyl ether (4 mL) was slowly added (0.03 mL/min). The reaction mixture was stirred at this temperature for 10 additional minutes before the addition of tributylchlorostannane (2.5 mL, 9.22 mmol). After stirring at −78° C. for 45 minutes, a mixture of diethyl ether and aqueous saturated solution of ammonium chloride (15 mL/5 mL) was added and the temperature was allowed to warm up to ambient temperature. Additional diethyl ether (300 mL) was then added to the mixture and the organic layer was separated, washed with saturated aqueous solution of ammonium chloride, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (100% hexanes to 1:1 hexanes/diethyl ether) to give the title compound (0.31 g, 10%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@:11]3([CH2:16][C@@H:15]([C:17]([OH:19])=O)[N:14]([C:20](=[O:36])[C@@H:21]([NH:26][C:27](=[O:35])[CH2:28][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13]3)[O:10][C:9]2=[O:37])[CH:5]=[CH:6][CH:7]=1.[NH2:38][C@@H:39]([CH2:48][CH2:49][CH3:50])[CH:40]([OH:47])[C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@:11]3([CH2:16][C@@H:15]([C:17]([NH:38][C@@H:39]([CH2:48][CH2:49][CH3:50])[CH:40]([OH:47])[C:41]([NH:43][CH:44]4[CH2:45][CH2:46]4)=[O:42])=[O:19])[N:14]([C:20](=[O:36])[C@@H:21]([NH:26][C:27](=[O:35])[CH2:28][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:13]3)[O:10][C:9]2=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1cccc(Cl)c1)C(=O)O2
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 32.6 %

Procedure:
Following the procedure from Example 1 step 1 using (5S,8S)-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (D5) (23 mg, 43 μmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (15 mg, 65 μmol) gave 10 mg (14 μmol) of (5S,8S)-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (E5). LC MS+/−: 702.54/700.62 at 3.63 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:6]=2)=[O:16])[CH:11]=1
Reactant: O=C(Nc1ccc(O)cc1)c1cccnc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(NC(=O)c2cccnc2)cc1)c1ccccc1

Procedure:
The title product was prepared from N-(4-Hydroxy-phenyl)-nicotinamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (1%, light yellow crystals). HPLC-MS: m/z=348.1 (M+1); Rt: 2.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16](C)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:15][CH:14]3[N:16]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CN1C2CCC1CC(Sc1ccc(Cl)cc1)C2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1C2CCC1CC(Sc1ccc(Cl)cc1)C2

Procedure:
A mixture of 3-(4-chlorophenylsulfanyl)-8-methyl-8-azabicyclo-(3.2.1)-octane (8.06 g, 30.12 mmol), 2,2,2-trichloroethyl chloroformate (4.56 mL, 33.13 mmol), and potassium carbonate (4.58 g, 33.13 mmol) in benzene (150 mL) was refluxed overnight. The solvent was removed at reduced pressure and the residue was taken up in ethyl acetate. The organic phase was washed with aqueous bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (3×4 inches) with elution proceeding as follows: hexane (350 mL), nil; 10% ethyl acetate/hexane (500 mL), discarded forerun; 10% ethyl acetate/hexane (500 mL), 20% ethyl acetate/hexane (500 mL), and 30% ethyl acetate/hexane (250 mL), 9.26 g (72%) of 3-(4-chlorophenylsulfanyl)-(2,2,2-trichloroethoxycarbonyl)-8-azabicyclo-(3.2.1)-octane as a yellow solid which had: mp 70-71.5° C.; NMR δ7.33 (long range coupled d, J=8.5 Hz, 2 H), 7.26 (long range coupled δ, J=8.5 Hz, 2 H), 4.73 (ABq, Δv1-3=58 Hz, J=12 Hz, 2 H), 4.43-4.30 (m, 2 H), 3.40 (septet, J=6 Hz, 1 H), 2.10-1.56 (m, 8 H).