Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.[CH2:2]1[CH2:6][O:5][CH2:4][CH2:3]1.[C:7]1([C@@H:13]([N:15]2CC3C[CH:16]2[CH:17]=C3)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].OO.[NH4+].[OH-]>C1COCC1>[C:7]1([C@@H:13]([N:15]2[CH2:4][C@H:3]3[CH2:17][C@@H:16]2[CH:6]([OH:5])[CH2:2]3)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: C[C@@H](c1ccccc1)N1CC2C=CC1C2
Agent: B
Agent: OO
Agent: [NH4+]
Product: C[C@@H](c1ccccc1)N1C[C@@H]2CC(O)[C@H]1C2
Temperature: 25 °C
Yield: 69.7 %

Procedure:
A solution of BH3-THF (1.0 M in THF)(24.5 ml, 24.5 mmol) was added dropwise to a 0° C. solution of 2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene in THF (90 mL). The reaction mixture was then stirred at rt. After 30 min the mixture was cooled to 0° C. and another 24.5 mL of BH3-THF solution was added dropwise. The mixture was then stirred at rt once again. After 30 min the mixture was cooled to 0° C. and a solution of NaOH (3.9 g in 5 ml water) was carefully added dropwise. The white slurry was stirred at 0° C. for 10 min and then a solution of 30% H2O2 (2.7 mL) was slowly added. The mixture was then stirred at rt. After 45 min concentrated NH4OH (31 mL) was added and the mixture was heated at 65° C. After 1.5 h heating was stopped. The mixture was cooled to rt and concentrated to ½ volume to remove some of the THF. The solution was then partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give the product (1R,4S)-2-((S)-1-phenylethyl)-2-azabicyclo[2.2.1]heptan-6-ol (3.37 gm, 15.54 mmol, 69.7% yield) as a colorless oil. Anal. Calcd. for C14H19NO m/z 217.3, found: 218.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.17 (5 H, m), 4.03 (1 H, d, J=7.1 Hz), 3.46 (1 H, q, J=6.2 Hz), 3.01 (1 H, s), 2.51 (1 H, dt, J=8.8, 3.0 Hz), 2.37 (1 H, br. s.), 2.25 (1 H, d, J=8.8 Hz), 1.86-1.78 (1 H, m), 1.54-1.38 (3 H, m), 1.37-1.21 (4 H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1C1C=CC=CN=1.[BH4-].[Na+].[BH4-]>C1COCC1.O.[Co](Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3cccc(F)c3)cc2)S1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCC(O)c3cccc(F)c3)cc2)S1
Yield: 71.7 %

Procedure:
5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (1.00 g, 2.78 mmol) was suspended in THF (15 ml) and H2O (10 ml). To this solution was added a small crystal of cobalt chloride followed by 2,2′-bipyridine (98 mg, 0.63 mmol). NaBH4 was added in portions until blue color persisted. The color gradually faded and was regenerated repeatedly by small additions of borohydride and HOAc. When HPLC analysis indicated that the reaction was complete, the reaction mixture was partitioned between EtOAc and H2O. HOAc was added until the pH of the aqueous phase was ca. 6. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.72 g (72%) of the title compound as a white solid. This material was rechromatographed on a small silica column eluting with 10-20% EtOAc/DCM. MS (ESI−) for C18H16FNO4S m/z 360.1 (M−H)−.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[C:14]1([NH:24][CH2:25][CH2:26][CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:14]1([N:24]([CH2:25][CH2:26][CH3:27])[C:11]([NH2:12])=[S:10])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCCNc1cccc2ccccc12
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: CCCN(C(N)=S)c1cccc2ccccc12
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
3.9 g of benzoyl chloride and 2.1 g of ammonium thiocyanate are introduced into anhydrous acetone in a three-necked flask under argon and maintained between 0° and 5° C., the reaction mixture is left stirring for 15 minutes and then 3.9 g of N-naphth-1-yl-N-propylamine, dissolved in acetone, are added dropwise. The reaction mixture is then heated at reflux for 1 hour and evaporated to dryness and the residue is taken up in concentrated hydrochloric acid, heated at reflux for 3 hours and allowed to return to room temperature. The organic products are extracted with diethyl ether and then successively basification is carried out with 33% sodium hydroxide, extraction is carried out with ethyl acetate, the organic phase is evaporated to dryness and the residue is purified on a column of silica gel eluted with a 75/25 (v/v) hexane/ethyl acetate mixture, to obtain 3.2 g of white crystals melting at 170°-171° C. 1H NMR (CDCl3): 0.86 (t, J=7.3, 3H, --CH2 --CH3), 1.68 (m, 2H, --CH2 --CH3), 3.72 (m, 2H, --CH2 --CH2 --CH3), 5.58 (m, 2H, --NH2), 7.37 (d, J=7.3, 1H, H2), 7.23 (m, 2H, H3 and H8), 7.75-7.80 (m, 2H, H6 and H7), 7.85-7.95 (m, 2H, H4 and H5).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[ClH:1].[F:21][C:17]1[CH:16]=[C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:25][CH3:24])[S:6]2(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=1
Reactant: CN
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1cccc(F)c1
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2cccc(F)c2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 3-(3-chloropropyl)-1-(3-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (32 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(3-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (26 mg):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:48])[C:5]([CH2:17][O:18][C:19](=[O:47])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([OH:46])[CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[C:56](Cl)(=[O:58])[CH3:57]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:17][O:18][C:19](=[O:47])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:40][CH:41]=3)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([O:46][C:56](=[O:58])[CH3:57])[CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:48])[CH3:10]
Reactant: CCOC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(O)c1)(C(=O)OCC)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(OC(C)=O)c1)(C(=O)OCC)c1ccccc1
Yield: 77.6 %

Procedure:
2-(2-{3-Hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonic acid diethyl ester (0.200 g) obtained in Example 1-a) was dissolved in toluene (4 mL), and to this solution was added triethylamine (0.040 g). After dropwise addition of a solution of acetyl chloride (0.026 g) in toluene (1 mL), the resultant mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with toluene (5 mL) and washed with saturated aqueous sodium bicarbonate (5 mL), 1N hydrochloric acid (5 mL) and water (5 mL). The toluene layer was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:3) to give the title compound (0.165 g) as a colorless crystal. The physicochemical properties of the product are shown in Table 3 below.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.[CH3:24][O:25][C:26]([C:28]1[NH:32][C:31]2[CH:33]=[CH:34][O:35][C:30]=2[CH:29]=1)=[O:27].Cl.Cl[CH2:38][C:39]1[N:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]2=[N:41][C:40]=1[C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1>>[Cl:54][C:51]1[CH:50]=[CH:49][C:48]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:39]=2[CH2:38][N:32]2[C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:29][C:30]3[O:35][CH:34]=[CH:33][C:31]2=3)=[CH:53][CH:52]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: COC(=O)c1cc2occc2[nH]1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1cc2occc2n1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride methyl 4H-furo[3,2-b]pyrrole-5-carboxylate. M/e+ 406 for C22H17ClN3O3 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.95 (d, J=7.71 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (t, J=8.8 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.22 (m, 2H), 6.82 (t, J=6.6 Hz, 1H), 5.98 (s, 1H), 4.45 (s, 2H), 3.83 (s, 3H) ppm.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3[CH:15]=[CH:16][C:17]([O:19][C@H:20]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)=[CH:18][C:13]=3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][O:34]1.[ClH:38].O1CCOCC1.C(OCC)C>ClCCl>[ClH:38].[NH:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:17]2[CH:16]=[CH:15][C:14]3[C:10]4([CH2:11][O:12][C:13]=3[CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:32][C@H:33]2[CH2:37][CH2:36][CH2:35][O:34]2)[C:2]4=[O:1])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc3c(c2)OCC32C(=O)N(C[C@H]3CCCO3)c3ccccc32)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(O[C@H]3CCNC3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of tert-butyl (3S)-3-({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)pyrrolidine-1-carboxylate (0.33 g, 0.65 mmol) in dichloromethane (5 mL) was added 4 M hydrogen chloride in dioxane (4 mL, 16 mmol). The mixture was stirred at ambient temperature for 3 h, then anhydrous diethyl ether (20 mL) was added. The white solid was precipitated out, filtered, washed with diethyl ether and dried to afford 6-[(3S)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride (0.24 g, 82%) as a colorless solid: mp 119-121° C.; 1H NMR (300 MHz, CD3OD) δ7.38-7.03 (m, 4H), 6.68-6.59 (m, 2H), 6.48-6.41 (m, 1H), 5.20-5.14 (m, 1H), 4.92-4.85 (m, 1H), 4.73 (d, J=9.3 Hz, 1H), 4.37-4.24 (m, 1H), 4.00-3.38 (m, 8H), 2.36-1.66 (m, 6H); MS (ES+) m/z 407.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:5][CH:4]=1.C1COCC1.[OH-].[Na+:39]>CO.O>[Na+:39].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)O)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC(=O)[O-])c23)cc1
Reaction time: 0.08 h

Procedure:
Dissolve 200 mg (0.464 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}hexanoic acid at RT in 0.75 ml methanol, 0.5 ml THF and a few drops of water, and add 0.464 ml 1 N sodium hydroxide solution. Stir the mixture for 5 min, then concentrate by vacuum evaporation and dry the residue at high vacuum. 221 mg of the target compound is obtained.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.Cl[C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:32]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]2[O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:54])[N:16]=1>C1COCC1.[Cu]I>[C:1]([C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:32]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]2[O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:54])[N:16]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: O=C(OC[C@H]1O[C@@H](n2ccc(Cl)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of bis-triphenylphosphine palladium (II) dichloride (0.35 g, 0.5 mmol) and copper (I) iodide (95 mg, 0.5 mmol) in THF (45 mL, distilled from Na-benzophenone ketyl) is sparged with dry argon gas for 10 min. To this suspension is added 1-hexyne (2.46 g, 30 mmol) followed by triethylamine (5 mL). The suspension is stirred at room temperature under argon for 15 min. A similarly sparged solution of the 2-chloro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)pyrimidin-4-one (13, 5.75 g, 10 mmol) in THF (15 mL) is added to the suspension of catalyst and the mixture stirred for 1 hr. The dark mixture is filtered through Celite and the filtrate evaporated in vacuo to afford a dark syrup. This syrup was triturated with cold diethylether, filtered and then dissolved in dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:22]([OH:24])=O)=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1.O.OC1C2N=N[NH:32]C=2C=CC=1.N.O1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:22]([NH2:32])=[O:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1ccc(-c2nc(-c3c(F)cccc3F)oc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(-c3c(F)cccc3F)oc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylic acid (0.026 g, 0.08 mmol) and hydroxybenzotriazole monohydrate (0.012 g, 0.08 mmol) in DMF (3 mL) was added 0.5M ammonia in dioxane (0.471 mL, 0.24 mmol) and the reaction mixture stirred at room temperature for 10 minutes. 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.015 g, 0.08 mmol) was then added and the resulting reaction mixture stirred at room temperature overnight. After a further addition of hydroxybenzotriazole monohydrate (0.008 g, 0.05 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.010 g, 0.05 mmol) and 0.5M ammonia in dioxane (0.315 mL, 0.1116 mmol) the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo, and the residue was partitioned between DCM (10 mL) and water (10 mL). The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxamide (0.018 g, 0.05 mmol, 69%) as a white solid. 1H NMR (CD3OD) δ 3.88 (3H, s), 7.03 (2H, d), 7.25 (2H, t), 7.68 (1H, m), 8.21 (2H, d). LCMS (2) Rt: 2.80; m/z (ES+) 331.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[O:27]1[C:26]2[CH:31]=[CH:32][C:23]([CH2:22][CH2:21][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][CH:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:24][C:25]=2[O:30][CH2:29][CH2:28]1
Reactant: CC(C)(N)COC(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(COC(c1ccccc1)c1ccccc1)NCCc1ccc2c(c1)OCCO2

Procedure:
A mixture of 2-amino-1-diphenylmethoxy-2-methylpropane (369 mg -- see Preparation 1), 6-(2-bromoethyl)benzodioxan (243 mg -- see Preparation 10), potassium carbonate (415 mg) and potassium iodide (166 mg) in acetonitrile (40 ml) was heated under reflux for 48 hours and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was washed with water, dried over sodium sulphate and evaporated. The residue was purified by chromatography on silica (7 g) using ethyl acetate plus 0-5% methanol as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil which was characterised as a hemihydrate (130 mg, 31%).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[N:5][C:4]=1C(O)=O)#[N:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC(O)(C)C>[C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[N:5][CH:4]=1)#[N:2]
Reactant: N#Cc1[nH]c(-c2ccc(Cl)cc2Cl)nc1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: N#Cc1cnc(-c2ccc(Cl)cc2Cl)[nH]1
Yield: 65.7 %

Procedure:
A mixture of 5-cyano-2-(2,4-dichlorophenyl)imidazole-4-carboxylic acid (40.0 g, 0.142 mol), diphenylphosphoryl azide (37.0 g, 0.142 mol) and triethylamine (14.4 g, 19.8 ml, 0.142 mol) in 2-methyl-2-propanol (dried by distillation from calcium hydride, 1400 ml) was heated at reflux for 24 hours. After cooling the mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate (2250 ml) and washed with hydrochloric acid (1 M, 250 ml) saturated aqueous sodium bicarbonate solution (2×250 ml) dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was recrystallized from ethanol to give 4-tert.butoxycarbonylamino)-5-cyano-2-(2,4-dichlorophenyl)imidazole (22.2 g) m.p. 185° C. (with decomposition) as an off-white solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH2:30][N:31]=2)[CH2:10]1)(C(C)(C)C)(C)C.Cl.C(=O)(O)[O-].[Na+]>CO>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]2[N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH2:30][N:31]=2)[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN=C1[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxy- carbonyl)-2-imidazolin-2-yl]pyrrolidine (1.4 g) in methanol was added conc. hydrochloric acid (0.4 ml). After stirring at ambient temperature for 20 hours, saturated aqueous sodium bicarbonate (3 ml) was added thereto. The mixture was evaporated, extracted with ethyl acetate, and washed with water and brine successively. The dried organic layer was evaporated, the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and methanol (20:1, V/V) to give (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]pyrrolidine (660 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.[CH2:16]([O:18][C:19]([C@H:21]1[CH2:23][O:22]1)=[O:20])[CH3:17].[O-]S(C(F)(F)F)(=O)=O.[Li+]>C(#N)C>[CH2:16]([O:18][C:19](=[O:20])[C@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:9]=[CH:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[C:4]([F:15])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)[C@H]1CO1
Reactant: Nc1ccc(N2C=CC(=O)CC2)c(F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)[C@H](O)CNc1ccc(N2C=CC(=O)CC2)c(F)c1
Yield: 45 %

Procedure:
A solution of 1-(4-amino-2-fluorophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 4, 0.412 g, 2.0 mmol) and oxirane-2(R)-carboxylic acid ethyl ester (0.394 g, 3.4 mmol) with lithium triflate (0.360 g, 3.0 mmol) in dry acetonitrile (5.0 mL) is heated at 50-60° C. for 24 h. Volatiles are removed under vacuum, and the crude material purified by silica gel flash chromatography (eluent: 5% acetone in CH2Cl2) to afford the title compound (290 mg, 45%) as a viscous yellow oil, MS (m/z): 323 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([C:31](O)=[O:32])[NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([C:31]([N:35]([CH3:34])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:39][CH:38]=1)=[O:32])[NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CNCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 33b) from (R)-N5 -(tert.-butoxy-carbonyl)-N2 -(9-fluorenylmethoxycarbonyl)-ornithine and N-methyl-4-(phenylmethoxy)benzenemethanamine in the presence of TBTU in a quantitative yield. Colourless, highly viscous oil, which was used in the following step without further purification.