Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=O)C.C(O)=O.[NH2:8][CH2:9][C:10]1[S:14][C:13]2=[CH:15][N:16]=[CH:17][N:12]2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[CH:1]([NH:8][CH2:9][C:10]1[S:14][C:13]2=[CH:15][N:16]=[CH:17][N:12]2[CH:11]=1)=[O:4]
Reactant: CC(=O)O
Reactant: NCc1cn2cncc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Solvent: ClCCl
Product: O=CNCc1cn2cncc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixed solution of 0.14 ml of acetic acid and 0.28 ml of formic acid which had been beforehand reacted with each other at 50° C. for 15 minutes was added to 3 ml of dry dichloromethane containing 154.6 mg of 2-aminomethylimidazo[5,1-b]thiazole at room temperature, and the mixture was then stirred at room temperature for 1 hour. Then, 2 ml of water was added to the reaction solution, and the solution was alkalified with anhydrous potassium carbonate under stirring. The solution was extracted with dichloromethane (15 ml×3). The combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was then evaporated under reduced pressure. The resulting crude product was purified by a silica gel column chromatograph to obtain 118.4 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.FC(F)(F)C(O)=O>[C:1]([NH:5][C:6](=[O:7])[C:8]1[CH:28]=[CH:27][CH:26]=[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH3:25])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNCCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Yield: 51.3 %

Procedure:
(R)-tert-Butyl 4-(3-(tert-butylcarbamoyl)benzyl)-3-methylpiperazine-1-carboxylate (8.03 g, 20.61 mmol) was stirred in a mixture of dichloromethane:trifluoroacetic acid (1:1) for 2 hours. The reaction mixture was concentrated under vacuum and purified by strong cation exchange column chromatography to afford the title compound (3.06 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C@:19]1([CH3:25])[CH2:23][O:22]C(=O)[NH:20]1)[N:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)C.[OH-].[Li+]>O>[NH2:20][C@@:19]([C:14]1[N:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=2)[N:15]=1)([CH3:25])[CH2:23][OH:22]
Reactant: CCCCCCCOc1ccc2nc([C@]3(C)COC(=O)N3)ncc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCOc1ccc2nc([C@@](C)(N)CO)ncc2c1
Temperature: 80 °C
Yield: 57 %

Procedure:
(R)-4-(6-Heptyloxy-quinazolin-2-yl)-4-methyl-oxazolidin-2-one (40.0 mg, 0.000116 mol) was dissolved in ethanol (2 mL, 0.03 mol), followed by 4 M lithium hydroxide in water (1 mL). The reaction mixture was then heated at 80° C. for 2 hours. All solvent was removed. The solid was extracted with DCM, and was purified via chromatography (SiO2, 4 g, 0-100% (10% of MeOH with 2N ammonia in DCM and DCM) to give the desired product (21 mg, 57%). 1H NMR (CHLOROFORM-d) δ: 9.25 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.49 (dd, J=9.7, 2.4 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.60 (br. s., 3H), 4.26 (d, J=11.8 Hz, 1H), 4.17 (d, J=11.8 Hz, 1H), 4.06 (t, J=6.7 Hz, 2H), 1.81-2.00 (m, 4H), 1.77 (s, 3H), 1.43-1.61 (m, 2H), 1.20-1.43 (m, 4H), 0.84-1.01 (m, 3H). MS (ES, M+1): 318.30.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]([O:13][CH3:14])=[O:12].N1C=CN=C1>CN(C=O)C>[Si:5]([O:9][C@@H:10]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:11]([O:13][CH3:14])=[O:12])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC[C@@H](C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Temperature: 40 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
tert-Butylchlorodimethylsilane (7.09 g, 47.01 mmol) was added to (S)-methyl 2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y6) (7.53 g, 39.18 mmol) and 1H-imidazole (5.33 g, 78.35 mmol) in DMF (50 mL) at room temperature under nitrogen. The resulting solution was stirred at 40° C. for 5 hours. The reaction mixture was evaporated to dryness and re-dissolved in ethyl acetate (125 mL), and washed sequentially with water (50 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% ethyl acetate in isohexane to afford the product (2.58 g, 21.5%). 1H NMR (400 MHz, DMSO) δ −0.01 (d, 6H), 0.81 (s, 9H), 0.97 (d, 3H), 3.13-3.29 (m, 5H), 3.49-3.64 (m, 6H), 4.26-4.31 (m, 1H); m/z (ESI+) M-C4H9=249; GC tR=10.92 min.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:9]=[C:10]([OH:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].S(O[CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(C1C=CC(C)=CC=1)(=O)=O>CC(N(C)C)=O>[CH3:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[O:17][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:32][CH2:31]1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 77.9 %

Procedure:
Cesium carbonate (16.29 g, 50 mmoles, 2 equivalents) was added to a stirred solution of 3-methyl-4-nitrophenol (3.82 g, 25 mmoles, 1 equivalent) and tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (10.16 g, 27.5 mmoles, 1.1 equivalent) in anhydrous DMA (25 ml). The stirred reaction mixture was then heated to 90° C. (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3×200 ml). The combined ethyl acetate solution was then washed with water (2×100 ml), saturated sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product. This material was triturated with diethylether to give a solid which was filtered off, washed with ether to give 6.82 g of tert-butyl 4-((3-methyl-4-nitrophenoxy)methyl)piperidine-1-carboxylate (yield=78%). 1H-NMR (400 MHz, DMSO-d6) δ 8.06 (d, 1H), 8.64 (d, 1H), 8.62 (s, 1H), 3.9 (s, 2H), 3.34 (m, 4H), 2.00 (m, 1H), 1.46 (m, 1.46), 1.42 (s, 9H). MS (EI): 351 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([NH2:9])[CH:8]=1.N1C=CC=CC=1.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([NH:9][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])[CH:8]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1cc(OC)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To the solution of 5-methoxy-2-methyl-phenylamine (0.118 g, 0.86 mmol) and pyridine (0.1 mL) and CH2Cl2 (3 mL) at 0° C. was added dropwise propane-1-sulfonyl choride (0.135 g, 0.95 mmol) and the reaction mixture was stirred at RT overnight. The mixture was then concentrated and purified via silica gel chromatography to give the product as an oil (0.145 g, 69%): MS(ES) m/e 244.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.O[C:24]1[C:32]2[N:31]=N[NH:29][C:28]=2[CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[NH2:29][C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][C:32]=1[NH:31][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.7 %

Procedure:
6-Chloronicotinic acid (157.5 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (216 mg, 2 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum. To the residue was added 5 ml of absolute ethanol. The solids were collected by vacuum filtration, washed with absolute ethanol and dried under vacuum to give the title compound (138 mg, 56% yield) as a brown solid. LC-MS (m/z) 248 (M+1).
Reaction SMILES: Br[C:2]1[CH:37]=[C:36]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([CH3:35])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][C:3]=1[F:38].C(P(C(C)(C)C)C1C(OC)=CC=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[F:78][CH2:79][CH2:80][CH2:81][OH:82]>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[F:38][C:3]1[CH:4]=[C:5]2[C:36](=[CH:37][C:2]=1[O:82][CH2:81][CH2:80][CH2:79][F:78])[C:15]1([N:19]=[C:18]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([CH3:35])=[N:16]1)[C:7]1([CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]1)[CH2:6]2
Reactant: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C21N=C(C)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1
Reactant: OCCCF
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: COc1ccc(C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1P(C(C)(C)C)C(C)(C)C
Product: COC1CCC2(CC1)Cc1cc(F)c(OCCCF)cc1C21N=C(C)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1
Temperature: 90 °C

Procedure:
Di-tert-butyl (6′-bromo-5′-fluoro-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-yl)imidodicarbonate (Intermediate 15, 0.261 g, 0.44 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3-methoxy-6-methylbiphenyl-2-yl)phosphine (0.012 g, 0.03 mmol), cesium carbonate (0.053 mL, 0.66 mmol), allylpalladium chloride dimer (3.1 mg, 8.78 μmol) and 3-fluoropropan-1-ol (0.069 g, 0.88 mmol) were placed in a tube. The tube was capped and inerted by vacuum-nitrogen purge cycles. Toluene (3 mL) was added and the mixture was heated at 90° C. o.n. More 3-fluoropropan-1-ol (0.069 g, 0.88 mmol) was added, and the reaction was heated for another 3 h. The mixture was allowed to cool to r.t. and was then filtered and concentrated. The product was used directly in the next step.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[O:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([C:42]([F:45])([F:44])[F:43])=[O:41])=[CH:36][CH:35]=2)[O:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:45][C:42]([F:43])([F:44])[S:40]([C:37]1[CH:38]=[CH:39][C:34](/[CH:33]=[CH:32]/[C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[O:10][CH:11]=[C:7]([CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)[N:8]=4)=[CH:13][CH:14]=3)[N:28]=2)=[CH:35][CH:36]=1)=[O:41]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(-c2nc(Cn3ccnc3)co2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(-c4nc(Cn5ccnc5)co4)cc3)co2)cc1)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.121 g (0.50 mmol) 4-(4-imidazol-1-ylmethyl-oxazol-2-yl)-phenol and 0.10 g (0.30 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 0.168 g (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethylsulfinyl-phenyl)-vinyl]-oxazole and 0.083 g (0.50 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted with two portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give, after recrystallisation from 2-propanol, 121 mg (45%) of the title compound as light brown crystals melting at 134-136° C.
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C(OCC)C.C([Li])CCC.[CH3:23][C:24]1[O:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C.O>[OH:29][CH:28]([C:27]1[O:30][C:24]([CH3:23])=[CH:25][CH:26]=1)[C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:11])=[CH:9][CH:8]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: Cc1ccc(C=O)o1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C(O)c2ccc(C=O)cc2)o1
Reaction time: 0.33 h
Yield: 12.3 %

Procedure:
To a mixture of 4-bromobenzaldehyde dimethyl acetal (2.0 mL, 12 mmol) and diethyl ether (30 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 9.0 mL, 14 mmol) at −78° C., which was stirred for 20 minutes at the same temperature. 5-Methylfurfural (1.3 mL, 13 mmol) was added dropwise into the reaction mixture at that temperature, and stirred for 50 minutes at 0° C. Water and ethyl acetate were added to extract the reaction mixture. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:2) to obtain the title compound (320 mg, 12%).
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH2:30][CH2:31]I)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:16]2[CH2:17][CH2:18][CH:13]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=3)=[O:12])[CH2:14][CH2:15]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(OCCCI)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCCOc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 46.2 %

Procedure:
4-(4-Methylsulfonylaminobenzoyl)piperidine hydrochloride (1.97 g, 6.19 mmol) and 1-(4-nitrophenoxy)-3-iodopropane (1.90 g, 6.19 mmol) were reacted by the procedure of Example 1 to afford 1.32 g (46%) of the desired product as a white solid: mp 162°-164° C.; 1H NMR (DMSO-d6): δ10.29 (br s, 1H), 8.19 (d, J=9.30 Hz, 2H), 7.93 (d, J=8.86 Hz, 2H), 7.26 (d, J=8.84 Hz, 2H), 7.13 (d, J=9.31 Hz, 2H), 4.15 (t, J=6.34 Hz, 2H), 3.32 (m, 1H), 3.09 (s, 3H), 2.89 (m, 2H), 2.48 (m, 2H), 2.07 (m, 2H), 1.91 (m, 2H), 1.70 (m, 2H), 1.56 (m, 2H). IR (KBr): 3620, 3210, 2950, 1660, 1600 cm-1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Mg+2].[CH2:12]=[O:13].Cl>C(#N)C.C(N(CC)CC)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH:12]=[O:13]
Reactant: C=O
Reactant: Oc1ccc(I)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1cc(I)ccc1O
Temperature: 25 °C
Yield: 66 %

Procedure:
To the mixture of 20 g (91 mmol) of 4-iodophenol and 25.1 g (264 mmol) anhydrous magnesium dichloride in 455 mL of anhydrous acetonitrile was added triethylamine and paraformaldehyde. The mixture was heated to reflux for 4 h, allowed to cool to rt and treated with 500 mL of 5% HCl. The solution was extracted three times with EtOAc. The combined organic extracts were washed with brine (3×) and dried over anhydrous magnesium sulfate. The dried organic solution was evaporated to afford an oil, which was purified by silica gel chromatography with EtOAc/hexane (2:8). Concentration of the desired fractions afforded 15 g (66%) of a yellow solid, which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4](/[C:8](=[N:10]\O)/[CH3:9])[CH:5]=[CH:6][CH:7]=1>C(O)(=O)C.CO.[Zn]>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=N/O)c1cccc(Cl)c1C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(Cl)cccc1C(C)N
Temperature: 40 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To (1Z)-1-(3-chloro-2-methylphenyl)ethanone oxime (383 mg, 2.08 mmol) in acetic acid (10 ml) was added zinc dust (2.72 g, 41.6 mmol) and the resulting mixture was stirred at 40° C. for 3 hours. The reaction mixture was diluted with methanol and filtered. The filtrate was concentrated in vacuo and the obtained residue was partitioned between 1 N hydrochloric acid and ethyl acetate. The aqueous portion was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 1-(3-chloro-2-methylphenyl)ethanamine as a clear oil (290 mg, 1.7 mmol, 82% yield). 1H NMR (400 MHz, CDCl3): 8.98 (s, 1H), 7.11-7.44 (m, 3H), 2.37 (s, 3H), 1.81 (s, 3H); MS (EI) for C9H12ClN: 170 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20].O=[C:25]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19]/[N:20]=[C:29](\[CH2:28][CH2:27][CH2:26][CH2:25][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)/[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CON)c1
Reactant: CCOC(=O)CCCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(CCCCc1ccccc1)=N/OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
After a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (600 mg), ethyl 6-oxo-6-phenylhexanoate (452 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 15 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate (590 mg, yield 58%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>C1COCC1>[O:11]1[CH2:12][CH2:13][N:8]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:9][CH2:10]1
Reactant: O=C1CCC(=O)O1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)N1CCOCC1
Reaction time: 1 h
Yield: 94 %

Procedure:
In 10 ml of THF was dissolved 1.814 g (81.3 mmole) of succinic anhydride, and 7.04 ml (81.3 mmole) of morpholine was added dropwise thereto from a syringe at room temperature under a nitrogen atmosphere. After stirring the reaction mixture for 1 hour, the precipitated crystals were collected by filtration and washed with a 1:2 (by volume) mixture of ethyl acetate and hexane to obtain 14.3 g (percent yield: 94%) of crude crystals of 4-morpholino-4-oxobutyric acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:33]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:30])[N:7]([CH3:33])[C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15])[CH:9]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(NC(=O)OC(C)(C)C)C2c2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CC3CC3(N(C)C(=O)OC(C)(C)C)C2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 105.6 %

Procedure:
The starting material, racemic [2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (Intermediate 8) (0.6 g, 1.4 mmol) was slurried in DMF (5 mL) and the mixture was cooled to 0° C. Sodium hydride (oil free, 0.05 g, 2.1 mmol) was added in portions and the reaction was then stirred for 0.75 hours at room temperature. Methyl iodide (0.13 mL, 2.1 mmol) was added and the reaction stirred an additional hour at room temperature. The mixture was partitioned between 1N lithium chloride solution and EtOAc. The organics were washed with brine and dried over calcium sulfate, filtered and concentrated to give methyl-[2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester as a yellow crystalline solid (0.654 g, 105%) which contained approximately 0.33 mol % of DMF by 1HNMR.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([N:14]=[C:15]2[S:19][CH2:18][C:17]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:24](Br)[CH:25]([CH3:27])[CH3:26]>>[CH2:24]([N:16]1[C:17]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:18][S:19][C:15]1=[N:14][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1ccc(N=C2NC3(CCCC3)CS2)c2c1CCCC2
Reactant: CC(C)CBr
Product: CC(C)CN1C(=Nc2ccc([N+](=O)[O-])c3c2CCCC3)SCC12CCCC2

Procedure:
1-Amino-5,6,7,8-tetrahydronaphthaline was converted to 1-acetamino-5,6,7,8-tetrahydronaphthaline according to Method A2a, Step 1. The acetanilide was converted to 1-acetamino-4-nitro-5,6,7,8-tetrahydronaphthaline according according to Method A2a, Step 2. The acetanilide was deprotected according to Method A2a, Step 3 to give 1-amino-4-nitro-5,6,7,8-tetrahydronaphthaline. The aniline was converted to 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthyl isothiocyanate according to Method C1a to give 2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(4-nitro-5,6,7,8-tetrahydro-1-naphthylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[O:23][N:22]=[C:21]([C:24]([O:26]CC)=[O:25])[CH:20]=3)[CH:16]=[CH:17][CH:18]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[O:23][N:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=3)[CH:16]=[CH:17][CH:18]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc(NC(=O)C3CCN(C(C)=O)CC3)c2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)Nc2cccc(-c3cc(C(=O)O)no3)c2)CC1

Procedure:
Ethyl 5-(3-{((1-acetylpiperidin-4-yl)carbonyl)amino}phenyl)isoxazole-3-carboxylate (68 g) was dissolved in THF (1.2 mL)and treated with 1N NaOH solution (1 mL) at ambient temperature for 2 hours, THF was removed under vacuo and 1N HCl was added. The mixture was extracted with ethyl acetate, dried with anhydrous Na2SO4, filtered, concentrated under vacuo to provide the title compound. MS (ESI(+)) m/e 258 (M+H)+, 375 (M+NH4)+, 380 (M+Na)+; 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.20 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.60 (d, 1H, J=8.1 Hz), 7.47 (t, 1H, J=8.0 Hz), 7.20 (s, 1H), 4.40 (br d, 1H, J=12.8 Hz), 3.88 (br d, 1H, J=13.4 Hz), 3.08 (br t, 1H, J=12.9 Hz), 2.60 (m, 2H), 2.01 (s, 3H), 1.84 (m, 2H), 1.60 (m, 1H, 1.44 (m, 1H).