Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([OH:17])[C:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:15]=2[CH:16]=1.O[C@H:19]([C@H:21]1[CH2:25][N:24]([C@H](C2C=CC(OC)=CC=2)C)[C:23](=[O:36])[CH2:22]1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[C:9]([O:17][C@@H:19]([C@H:21]2[CH2:25][NH:24][C:23](=[O:36])[CH2:22]2)[CH3:20])[CH:8]=1
Reactant: Oc1cc(-c2ccccn2)cc2ncccc12
Reactant: COc1ccc([C@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccccn2)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
20 mg of 7-(Pyridin-2-yl)quinolin-5-ol, 30 mg of ((R)-4-((S)-1-hydroxyethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one and 50 mg of triphenylphosphin was dissolved in 2 mL of DCM. 45 mg of DBAD was added and the mixture stirred for 14 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and dissolved in 0.5 mL of TFA and heated 30 min at 90° C. in the microwave. The mixture was purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 21 mg of Example 6 as solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([C:16]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[CH:17]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:25]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]4[S:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[CH:17]=4)=[O:15])=[CH:5][C:4]=3[N:1]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cc2ccccc2s1
Reactant: O=Cc1ccccc1
Product: O=C(Nc1ccc2[nH]c(-c3ccccc3)nc2c1)c1cc2ccccc2s1

Procedure:
Compound 201 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)benzo[b]thiophene-2-carboxamide and benzaldehyde. 1H NMR (500 MHz, CD3OD) δ 8.18 (d, J=2 Hz, 1H), 8.14 (s, 1H), 8.06 (d, J=8 Hz, 2H), 7.91 (m, 2H), 7.85 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.53 (m, 3H), 7.44 (m, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:30]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C@H:31]1[C:40](O)=[O:41].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@H:2]([NH:1][C:40]([C@@H:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39][N:30]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:41])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](N)Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1

Procedure:
tert-Butyl (3S)-3-{N-[(1S)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2S)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Step 2) (380 mg, 0.87 mmol), according to the procedure for Preparation XIX using Boc-L-Tic-OH (250 mg, 0.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (540 mg, 1.8 mmol), HOAT (140 mg, 1.0 mmol), and DMF (25 mL). Crude material was obtained in a quantitative yield and used without further purification. MS (ESI, pos. ion) m/z: 696 (M+H), (ESI, neg. ion) m/z: 694 (M−H). Calc'd for C35H42ClN5O6S: 695.25.
Reaction SMILES: Cl.[S:2]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])(=[O:4])[NH2:3].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].CCN(CC)CC>>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:11]2[CH2:12][CH2:13][C:8]3([C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:6]([S:2](=[O:4])(=[O:5])[NH2:3])[CH2:7]3)[CH2:9][CH2:10]2)=[O:31])=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(N)(=O)=O)c2ccccc23)cc1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a suspension of 1-sulfamoylspiro[indoline-3,4′-piperidine]hydrochloride 3-1 (100 mg, 0.33 mmol) and phenyl 4-acetylphenylcarbamate 3-2 (92 mg, 0.36 mmol) in CHCL3 (3 mL) was added Et3N (0.23 mL, 1.65 mmol) at room temperature. The reaction mixture was heated to reflux for 1 h. The resulting suspension was cooled to room temperature. The resulting suspension was filtered and the filter cake was washed with CHCl3 to give 300 (47 mg, 33%) as a white solid.
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[Cl:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1>CO>[Cl:10][C:11]1[CH:22]=[CH:21][C:14]([O:15][CH:16]([CH3:20])[CH:17]([NH2:7])[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(=O)C(C)Oc1ccc(Cl)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)C(C)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.3 %

Procedure:
82 g of ammonium acetate and 6.7 g of sodium cyanoborohydride were added to a solution containing 21 g of 3-(4-chlorophenoxy)-2-butanone dissolved in 500 ml of methanol, and the reaction mixture was stirred for 20 hours at room temperature. After the reaction mixture was concentrated under reduced pressure, 180 ml of concentrated hydrochloric acid, 100 ml of water, and 300 ml of diethyl ether were added to the residue. The obtained water layer was alkalified using a 5% aqueous solution of sodium hydroxide, and then the organic substances were extracted with 500 ml of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. A fraction possessing a low boiling point was removed from the obtained oily products to afford 18 g (yield 86%) of the desired product.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1.[CH2:22]([SH:24])[CH3:23].O>CN1C(=O)CCC1>[CH2:22]([S:24][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:12]=2[N:13]=1)[CH3:23]
Reactant: CCS
Reactant: FC(F)(F)c1ccc2oc(-c3sccc3Br)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCSc1ccsc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.11 g of sodium hydride (60%) was added to a solution of 0.65 g of 2-(3-bromothiophen-2-yl)-5-(trifluoromethyl)benzoxazole and 0.2 ml of ethanethiol in NMP 6 ml at 0° C., and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous salt solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.8 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethyl)benzoxazole (Compound of Present Invention (36)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[N:11]([CH3:21])[C:10]=1[CH2:22]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>C(#N)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[N:11]([CH3:21])[C:10]=1[CH2:22][Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(CC(F)(F)F)cc(=O)c(OCc2ccccc2)c1CO
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: Cn1c(CC(F)(F)F)cc(=O)c(OCc2ccccc2)c1CCl
Reaction time: 0.17 h

Procedure:
To a suspension of 3-benzyloxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (0.34 g, 1.04 mmol) in acetonitrile (15 mL), was added thionyl chloride (0.38 mL, 5.19 mmol) at room temperature. A clear solution resulted and the reaction was completed within 10 min. The reaction mixture was evaporated to dryness to give the crude 3-benzyloxy-2-chloromethyl-1-methyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as an oil, which was taken up in ethanol (15 mL) to give a clear solution. Sodium borohydride (430 mg, 11.4 mmol) was added to the solution portionwise. The reaction mixture was stirred for another 10 min, and the progress of the reaction was monitored by TLC (methanol/dichloromethane, 1/10 v/v as eluant). There was still some unreacted chloride derivative present at this time. Additional sodium borohydride (360 mg, 9.5 mmol) was added in several portions. The reaction mixture was stirred for another 10 min. The reaction mixture was purified by column chromatography on silica gel (methanol/dichloromethane, 1/20 v/v as eluant) to give 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as an oil (0.20 g, 61% for the two combined steps, HPLC Method 1 (Example 24), RT=15.1 min, HPLC purity (peak percent area): 92% at λ=280 nm). This material, 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (0.20 g, 0.64 mmol) was taken up in methanol (25 mL) to give a clear solution. To the solution was added Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 90 mg). The hydrogenation reaction was conducted under a hydrogen pressure of 50 psi. The reaction was completed in 30 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was evaporated to give the first crop of 3-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as a solid product (free base, 74 mg, 52% yield), HPLC Method 1 (Example 24), RT=9.9 min, HPLC purity (peak percent area): 96.4% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 6.25 (s, 1H), 3.94 (q, J=11 Hz, 2H), 3.57 (s, 3H), 2.32 (s, 3H). MS-ESI (m/z) 222.2 ([M+1]+, 100%), 202.3, 153.2.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH:20]=2)=[C:11]([C:32]2[CH2:36][C:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[O:34][N:33]=2)[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:49]([O:48][C:46](=[O:47])[CH2:45][C:35]1([CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[O:34][N:33]=[C:32]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=2[CH:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:31])[CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:20]2)[CH2:36]1)([CH3:50])([CH3:51])[CH3:52]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CCC(=O)N1CC=C(c2ccc(OCc3ccccc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC(=O)N1CCC(c2ccc(O)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Yield: 76.6 %

Procedure:
A mixture of tert-butyl 4-(4-(4-(benzyloxy)-2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate (52.1 mg), 10% Pd/C (containing about 55% water, 20 mg), and THF (1 mL) was stirred at room temperature for 6 hours in a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (35.0 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](=[O:15])O[C:11]2=[O:14])=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:3])[CH3:2].[NH2:19][CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27]>>[O:27]=[C:21]1[CH:20]([N:19]2[C:9](=[O:15])[C:8]3[C:12](=[CH:13][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][C:7]=3[N+:16]([O-:18])=[O:17])[C:11]2=[O:14])[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1
Reactant: CC(C)Oc1cc2c(c([N+](=O)[O-])c1)C(=O)OC2=O
Reactant: NC1CCC(=O)NC1=O
Product: CC(C)Oc1cc2c(c([N+](=O)[O-])c1)C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 6-isopropoxy-4-nitroisobenzofuran-1,3-dione with 3-aminopiperidine-2,6-dione to form 2-(2,6-dioxopiperidin-3-yl)-6-isopropoxy-4-nitroisoindoline-1,3-dione;
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][C:12]([NH2:14])=[S:13].C([O-])([O-])=O.[Na+].[Na+]>CC#N.C1COCC1>[NH2:14][C:12]1[S:13][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:11]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1sc(N)nc1C
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a stirred solution of ethyl 2-chloroacetoacetate (6.0 mL, 43.35 mmol) in MeCN (24 mL) and THF (6 mL) was added thiourea (3.0 g, 39.41 mmol) and Na2CO3 (0.417 g, 39.41 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 30 minutes, cooled to r.t., partitioned between EtOAc and water, and the organic fraction was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (2.76 g, 38%) as a cream solid. δH (CDCl3) 5.47 (2H, br. s), 4.27 (2H, q, J 7.2 Hz), 2.53 (3H, s), 1.33 (3H, t, J 7.2 Hz). MS (ES+) 187.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:17]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:39])=[CH:41][CH:42]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 6.4 g. (50 m moles) 4-chlorophenol and 7.6 g. (75 m moles) triethylamine in 500 ml. methylene chloride is added 10.4 g. (25 m moles) 4-(hexadecylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated and the residue is crystallized from diisopropyl ether.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[C:3]([CH3:8])([N+:5]([O-:7])=[O:6])[CH3:4].C(OCC)(=O)C>CO.[C].[Pd]>[CH3:8][C:3]([N+:5]([O-:7])=[O:6])([CH3:4])[CH2:2][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: CC(C)(C(Cl)c1ccc2ccccc2c1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(Cc1ccc2ccccc2c1)[N+](=O)[O-]
Reaction time: 2 h
Yield: 79.9 %

Procedure:
2-(1-Chloro-2-methyl-2-nitropropyl)naphthalene (200 mg) obtained in Step 4 was dissolved in methanol (5 ml) and ethyl acetate (5 ml) and to the solution was added 10% palladium carbon (20 mg). A hydrogenation reaction was performed at pressure of 3 atm for 2 hr. After filtration of the reaction mixture using Celite, the title compound (139 mg) was obtained by purification using silica gel column chromatography (n-hexane:ethyl acetate=95:5).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[N:63]=[C:64]([O:66][CH:67]([CH3:69])[CH3:68])[NH2:65]>CN(C=O)C>[CH:67]([O:66][C:64]1[N:65]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:28][N:63]=1)([CH3:69])[CH3:68]
Reactant: CC(C)OC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg (1.20 mmol) of the carboxylic acid from Example 9A in 15.0 ml of DMF were added, at RT, 545 mg (1.43 mmol) of HATU and 0.46 ml (2.63 mmol) of N,N′-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 565 mg (3.56 mmol; 75% purity) of isopropyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and at 120° C. for 2 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 344 mg (58% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([NH2:26])[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:26][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CON=C1C[C@@H](C(=O)Nc2ccccc2N)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 48 h
Yield: 99.2 %

Procedure:
A solution was prepared containing the central building block, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 7) (2.1 g, 8.1 mmol), an ortho-substituted aromatic amine or amine salt, e.g. 1,2-benzenediamine (0.88 g, 8.1 mmol) and DMAP (1.59 g, 13.0 mmol). in dry dichloromethane (30 ml). This solution was cooled to 0° C. and treated with EDC (1.56 g, 8.2 mmol) before warming to room temperature and stirring for 2 days. The solvent was removed in vacuo and the product purified by silica gel chromatography, eluting with a gradient of 30–80% ethyl acetate in hexane to give the desired anilide product, e.g. tert-butyl (2S,4EZ)-2-[(2-aminoanilino)carbonyl]-4-(methoxyimino)-1-pyrrolidinecarboxylate 2.8 g, 97% as a colourless foam.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[C:9]([C:17]1[CH:43]=[CH:42][C:20]([O:21][CH2:22][CH:23]([OH:41])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:28]([OH:40])[CH:27]=2)=[CH:19][C:18]=1[OH:44])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:45]([CH2:47][C:48](O)=[O:49])#[N:46]>ClCCCl>[C:45]([CH2:47][C:48]([O:41][CH:23]([CH2:22][O:21][C:20]1[CH:42]=[CH:43][C:17]([C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:18]([OH:44])[CH:19]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:28]([OH:40])[CH:27]=1)=[O:49])#[N:46]
Reactant: N#CCC(=O)O
Reactant: O=C(c1ccccc1)c1ccc(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Product: N#CCC(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Yield: 87 %

Procedure:
3 g of trifluoromethanesulfonic acid were added to a solution of 48.5 g (0.1 mole) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-2-propanol and 51 g (0.6 mole) of cyanoacetic acid in 750 ml of 1,2-dichloroethane, and the solution was heated for 9 hours at a temperature of 80° to 85° C. After cooling to room temperature, the reaction mixture was washed with three times 400 ml of water. The 1,2-dichloroethane was distilled off from the reaction mixture under a pressure of 50 mbar and a temperature of 35° to 45° C. The residue remaining was recrystallized from acetonitrile. After drying, 48 g (87 percent of theory) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl cyanoacetate were obtained in the form of slightly yellow, fine crystals having a melting point of 167° to 168° C. and a purity of 99 percent (HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[Cl:1])=[S:38])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(N=C=S)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-chloro-1-benzenecarbonyl isothiocyanate was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 61%).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Cl[CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18]>>[N+:1]([C:4]1[N:5]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=C1OCCN1CCCCl
Reactant: O=[N+]([O-])c1ncc[nH]1
Product: O=C1OCCN1CCCn1ccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A mixture of 6 % of 2-nitroimidazole (53 mmol) and 7.32 % of KzCO3 was heated at 60° C. for 0.5 hours. Then 8.6 % (53 mmol) of 3-(3-chloropropyl)-2-oxazolidinone (Ann. Pharm. Franc., 13, 565 (1955)) was added and stirring continued for 18 hours at 60° C. The mixture was then cooled and concentrated. The residue was partitioned between CHCl3 and water, the organic layer was dried and concentrated to give 10.4 g of a solid which was recrystallized from ethanol to provide 5.4 g (42%) of the desired product, 3-3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone; mp 89°-91° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH:15]3[C:13]([CH2:17][O:18][C:19]4[C:20]([C:25]([O:27]CC)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=4)([CH2:14]3)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(OCC)=O)=NC=1>>[F:31][C:2]([F:1])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH:15]3[C:13]([CH2:17][O:18][C:19]4[C:20]([C:25]([OH:27])=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=4)([CH2:14]3)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ncccc1OCC12CC1CN(C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1)C2
Agent: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: O=C(O)c1ncccc1OCC12CC1CN(C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1)C2

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 31 using ethyl 3-((3-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)picolinate (EXAMPLE 88 Step 3) in stead of ethyl 5-methoxy-3-(((R)-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.