Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.CC(O[Na])=O.[CH3:16][NH:17][C:18]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[Cl:31])[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1>CO.O.O>[CH2:3]([O:2][N:1]=[C:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C:18]1([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:31])[NH:17][CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC1(c2ccccc2Cl)CCCCC1=O
Reactant: NOCc1ccccc1
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC1(c2ccccc2Cl)CCCCC1=NOCc1ccccc1
Temperature: 25 °C

Procedure:
To as solution of NH2OCH2Ph. HCl and CH3COONa. H2O in MeOH:H2O (7:3) stirred at room temperature for 15 minutes, was added ketamine and the resulting solution was stirred at reflux for 16 hrs before cooling to room temperature. The reaction mixture was filtered and the filtrate was partitioned between CH2Cl2 and sat. NaHCO3 solution. The filtrate was extracted with CH2Cl2 (2×30 mL) and the combined organic layer was washed with brine solution. The organic layer was dried over anhydrous. Na2SO4 and concentrated under reduced pressure. The crude reaction mixture received was purified over silica gel column chromatography by eluting with initially CH2Cl2 and later with (1:9) MeOH:CH2Cl2 to receive benzoxime 4 as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.7 (d, J=8.06 Hz, 1H), 7.1-7.4 (m, 8H), 5.0-5.2 (q, J=8.2 Hz, 2H), 2.9-3.1 (m, 2H), 2.2-2.3 (m, 3H), 1.9-2.0 (m, 2H), 1.3-1.8 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 158.3, 138.7, 135.1, 132.1, 131.1, 129.9, 128.7, 128.4, 127.8, 127.6, 66.4, 38.8, 29.1, 26.0, 24.5, 22.1.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@H:25]3[CH2:30][O:29][CH2:28][CH2:27][N:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:31][N:26]1[CH2:27][CH2:28][O:29][CH2:30][C@@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: CN1CCOC[C@@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCOC[C@@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
To a suspension of NaH (60% in mineral oil, 51.0 mg, 1.27 mmol) in DMF (1.50 mL) was added Intermediate A (51.0 mg, 0.32 mmol) and the reaction stirred for 20 min. Intermediate 83c (75.0 mg, 0.32 mmol) was added in DMF (1.50 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (31 mg, 26%). LCMS (Method 4): Rt 0.32, m/z 380.0 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[OH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[OH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:31]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(C)(O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(OC(=O)CC(C)(C)O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.1 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (200 mg; 0.487 mmol), 3-hydroxy-3-methylbutanoic acid (74.4 g, 0.63 mmol), triethylamine (0.11 mL, 0.79 mmol) and 4-dimethylaminopyridine (64.0 mg, 0.524 mmol) in tetrahydrofuran (10.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144.9 mg, 0.76 mmol) at room temperature. The mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-60% ethyl acetate/n-hexane gradient mixture to give the title compound (103.3 mg, 0.20 mmol, 41%) as a colorless amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][NH:12]2.Cl.CN(C)CCCN=C=NCC.[N:29]1([C:35]2[N:36]=[C:37]([CH2:42][C:43]([O-])=[O:44])[NH:38][C:39](=[O:41])[CH:40]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][N:12]2[C:43](=[O:44])[CH2:42][C:37]1[NH:38][C:39](=[O:41])[CH:40]=[C:35]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:36]=1
Reactant: Fc1ccccc1-c1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccccc3F)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
115 mg of 4-(2-fluorophenyl)-2,3-dihydro-1H-indole (diluted in 3 ml of pyridine) and 125 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 211 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 3 ml of pyridine. The reaction mixture is stirred at ambient temperature for 3 days. The reaction medium is diluted in ethyl acetate (100 ml) and then successively washed with an aqueous 1N hydrochloric acid solution, an aqueous 1N sodium hydroxide solution and a saturated aqueous sodium chloride solution. The organic phase is then dried over magnesium sulfate, filtered through sintered glass, and concentrated under reduced pressure. 187 mg of 2-{2-[4-(2-fluorophenyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][C@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:30](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:30][N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:11][CH:10]=3)[N:14]=[C:15]([NH:23][CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:16]=2[CH2:22]1
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NC[C@H]5CCCO5)n3)CNCC4)cc2)o1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@H]3CCCO3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
(R)-N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (135 mg, 0.34 mmol, example 80a) was dissolved in methanol (3 mL). Acetic acid (0.020 mL, 0.34 mmol) was added followed by formaldehyde (0.026 mL, 0.34 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (21.62 mg, 0.34 mmol) MP—CNBH3 was added. The reaction was stirred overnight, the MP—CNBH3 was filtered off and the solvent was evaporated under reduced pressure. The crude was dissolved in methanol, filtered and purified by HPLC yielding (R)-6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (46.0 mg, 30.3%). MS (ES+) m/z 407.2 (M+H)+
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:26]([CH3:40])=[CH:25][C:24]=1[SH:41])([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[C:26]([CH3:40])=[CH:25][C:24]=1[S:41][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(S)c(C(C)(C)C)cc1OCCO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer and an addition funnel were added tosyl bromide (6.07 g, 26.0 mmol), CCl4 (70 mL) and NEt3 (3.59 mL, 26.0 mmol), and this solution was cooled to 0° C. The 2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-benzenethiol material prepared in Example OOO (4.6 g, 13.0 mmol) was dissolved in CCl4 (70 mL) and added dropwise to the tosyl bromide solution. The addition was complete in 3.5 hours, at which time the ice bath was removed and the reaction stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and washed with saturated NH4Cl and dried (MgSO4). The solvent was then evaporated and the residue was submitted to flash chromatography (1:1 CH2Cl2 :hexane) to yield the title compound. 1H NMR (CDCl3) δ 0.04 (s, 6 H), 0.85 (s, 9 H), 1.20 (s, 9 H), 2.01 (s, 3 H), 2.37 (s, 3 H), 3.93 (t, 2 H), 3.99 (t, 2 H), 6.82 (s, 1 H), 7.0 (s, 1 H), 7.19 (d, 2 H), 7.44 (d, 2 H).
Reaction SMILES: [Na].C(O[CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:25])[CH:11]2[NH:15][C:16](=[O:24])[CH2:17][C:18]2[O:19][CH2:20][CH2:21][S:22][CH:23]=2)[C:8]=1[C:26]([OH:28])=[O:27])(=O)C.C(=O)(O)[O-].[Na+].[CH3:34][C:35]1[S:36][C:37](=[S:40])[NH:38][N:39]=1>O>[C:26]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][S:40][C:37]1[S:36][C:35]([CH3:34])=[N:39][N:38]=1)[CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[O:19][CH2:20][CH2:21][S:22][CH:23]=1)[C:10]2=[O:25])([OH:28])=[O:27]
Reactant: Cc1n[nH]c(=S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=CSCCO3)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC4=CSCCO4)C3SC2)s1
Temperature: 60 °C
Reaction time: 6 h
Yield: 45.6 %

Procedure:
The sodium salt of 3-acetoxymethyl-2-carboxy-7-[(5,6-dihydro-1,4-oxathiin-2-yl )acetamido]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (14 g.) is dissolved in distilled water (350 cc.). Sodium bicarbonate (2.69 g.) followed by 2-methyl-5-thioxo-1,3,4-thiadiazoline (4.65 g.) are added to the solution and the reaction mixture is heated with stirring at 60° C. for 6 hours. After cooling, the reaction mixture is washed with ethyl acetate (2 × 150 cc.) and then acidified to pH 2 by addition of 4N hydrochloric acid in the presence of ethyl acetate (350 cc.). After decanting the organic phase, the aqueous phase is extracted twice with ethyl acetate (total 150 cc.). The organic extracts are combined, washed six times with water (total 600 cc.), dried over sodium sulphate, treated with decolourizing charcoal, filtered and then concentrated under reduced pressure (20 mm.Hg) to a final volume of 80 cc. After 30 minutes at 2° C., the solid compound which has formed is filtered off and then washed twice with ethyl acetate (10 cc.) and finally with diisopropyl ether (100 cc.). After drying under reduced pressure (0.5 mm.Hg), 2-carboxy-7-[(5,6-dihydro-1,4-oxathiin-2-yl )acetamido]-3-[(5-methyl-1,3,4-thiadiazol-2-yl )thiomethyl]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (7.5 g.) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]([CH2:16]C)[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:18]([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]([CH3:16])([CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(Br)CC
Reactant: O=C([O-])[O-]
Reactant: Sc1ccccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Sc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromothiophenol (0.99 g, 5.0 mmol), ethyl 2-bromobutyrate (1.17 g, 6.0 mmol) and K2CO3 (0.966 g, 7.0 mmol) in DMF (2 mL) is stirred at room temperature for 2 hours. Ethyl acetate is added and the organic phase washed with brine, dried (MgSO4), concentrated and purified by chromatography to yield ethyl 2-(2-bromophenylthio)-2-methylpropanoate.
Reaction SMILES: [Si]([O:8][C@H:9]([C:43]1[CH:44]=[CH:45][C:46]([OH:54])=[C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:48]=1)[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C@@H:27]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:28][CH2:29][N:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:21]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F>O1CCCC1>[NH3:11].[CH:34]([N:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:28][C@@H:27]([C:22]1[CH:21]=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:43]2[CH:44]=[CH:45][C:46]([OH:54])=[C:47]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:48]=2)[OH:8])[CH:25]=[CH:24][C:23]=1[OH:26])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([CH3:36])[CH3:35]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCCCCNC[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Product: N
Reaction time: 12 h

Procedure:
N-(5-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-[(8-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}octyl)amino]ethyl}-2-hydroxyphenyl)methanesulfonamide (Preparation 55, 74 mg, 0.095 mmol) was dissolved in tetrahydrofuran (3 ml) and triethylaminetrihydrofluoride (90 ul, 0.54 mmol) was added in one portion at room temperature. The reaction was stirred for 12 hours and the solvent removed under reduced pressure, the residue was dissolved in methanol (10 ml) and 880 ammonia (1 ml) and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (97/3/0.3 to 85/15/1.5 by volume) to furnish the title compound as a yellow solid, 34 mg.
Reaction SMILES: [N:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)=[N+]=[N-].[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]2[O:22][CH-:21][N:20]([NH2:23])[C:19]2=O)[CH2:13][CH2:12]1.Cl.C([OH:28])C>C(O)C.O>[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]2[O:22][C:21](=[O:28])[N:20]([N:23]=[CH:9][C:7](=[O:8])[CH:6]=[CH:5][C:4]#[N:1])[CH2:19]2)[CH2:13][CH2:12]1
Reactant: CCO
Reactant: NN1[CH-]OC(CN2CCOCC2)C1=O
Reactant: [N-]=[N+]=Nc1ccc(C=O)o1
Agent: Cl
Solvent: O
Product: N#CC=CC(=O)C=NN1CC(CN2CCOCC2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of 5-azido-2-furaldehyde (33 mg, 0.24 mmole) in 2 ml of ethanol was added dropwise to a solution of 5-morpholinomethyl-3-amino-2-oxazolidone (Sigma, 43 mg, 0.21 mmole) in 2.5 ml of ethanol:water (5:1) mixture, followed by 0.5 ml of 1N HCl. The reaction mix was stirred at room temperature overnight and evaporated to dryness. The residue was partitioned between 20 ml of ethyl acetate and 10 ml of 2% sodium bicarbonate. The ethyl acetate layer was kept and the aqueous layer extracted with 2×15 ml of ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and evaporated to dryness. (51 mg, 0.17 mmole, 83% yield). Silica gel TLC analysis showed a homogeneous single spot with Rf of 0.44 when developed in ethyl acetate. 1H NMR analysis of 4 revealed that it is a mixture of two isomers with the acrylonitrile moiety in cis (Z) and trans (E)-configurations (coupling constant J=11.6 and 16.5 Hz, respectively).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.N1C=CN=[CH:13]1.Cl[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[H-].[Na+].IC>CN(C)C=O.C(OCC)(=O)C>[Si:18]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH3:13])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: c1c[nH]cn1
Reactant: O=c1[nH]c2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a solution of 6-hydroxy-1,3-benzoxazol-2(3H)-one (4.9 g, 32 mmol) in anhydrous N,N-dimethylformamide (40 mL) was added imidazole (2.6 g, 39 mmol) and chloro-tert-butyldimethylsilane (5.4 g, 35 mmol). The reaction mixture was stirred at ambient temperature for 16 h and diluted with ethyl acetate (100 mL). The resultant suspension was filtered and the filtrate was concentrated in vacuo. The residue was taken up in anhydrous N,N-dimethylformamide (50 mL) and cooled to 0° C. To this solution was added sodium hydride (1.6 g, 60% dispersion in mineral oil, 39 mmol) and the reaction mixture was stirred at 0° C. for 15 min. Iodomethane (6.1 mL, 97 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was taken up in water (100 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic solution was washed with water (2×100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/ethyl acetate (5/1) to afford 6-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one (6.55 g, 72%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ6.79-6.72 (m, 2H), 6.69-6.64 (m, 1H), 3.36 (s, 3H), 0.98 (s, 9H), 0.17 (s, 6H).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:51][O:52][C:53](=[O:62])[CH:54]([NH2:61])[CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C=O)C.C(Cl)CCl>[CH3:51][O:52][C:53](=[O:62])[C@@H:54]([NH:61][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:28])[CH:55]1[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: COC(=O)C(N)C1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C1CCCCC1
Reaction time: 12 h

Procedure:
To a solution of 250 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 4 ml DMF were added 124 mg HOAt, 174 mg EDC, 0.37 ml DIPEA and 126 mg amino cyclohexylacetic acid methyl ester hydrochloride. After stirring for 12 h it was concentrated and the residue dissolved in dichloromethane. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil. Yield: 428 mg.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:28][CH2:29][C:30]#[N:31])=O)(C)(C)C.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+].FC(F)(F)C(O)=O>CN(C)C=O.C(Cl)Cl>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:28][CH2:29][C:30]3[NH:36][N:35]=[N:34][N:31]=3)[CH2:10]1)(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNC(CCc2nnn[nH]2)C1
Temperature: 100 °C

Procedure:
In N,N-dimethylformamide (1.5 ml) was dissolved 1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl) sulfonyl]-2-(2-cyanoethyl)piperazine (529 mg), followed by the addition of ammonium chloride (588 mg) and sodium azide (741 mg). The resulting mixture was stirred under heating at 100° C. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the resulting mixture was washed with water and saturated aqueous NaCl solution, each once. The organic layer thus extracted was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1), whereby a colorless foam was obtained. The resulting substance was dissolved in methylene chloride (5 ml), followed by the addition of trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 1 minutes. The reaction mixture was concentrated under reduced pressure. The precipitate thus obtained was washed with diethyl ether and collected by filtration, whereby the title compound (141 mg) was obtained as a colorless solid.
Reaction SMILES: C[CH:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=O.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CCOCC.[ClH:38]>ClCCl>[ClH:38].[OH:27][C@H:18]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][NH:16][CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:2][C:3]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:5])=[CH:8][CH:9]=1
Reactant: CC(Oc1ccc(OCCNCC(O)COc2ccccc2)cc1)C(=O)[O-]
Reactant: COCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COCCNC(=O)COc1ccc(OCCNC[C@H](O)COc2ccccc2)cc1

Procedure:
(-)-Methyl-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenoxyacetate (44.0 g) (the same starting material as in Example 2) and 2-methoxyethylamine (30 ml) were heated together on a steam-bath for 24 hours. The mixture was cooled and evaporated under reduced pressure to give an oily residue. This was dissolved in dichloromethane (200 ml) and treated with a solution of ether saturated with hydrogen chloride. The solvent was evaporated and the residual solid crystallised from a mixture of methanol and ethyl acetate to give (S)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]-N-(2-methoxyethyl)phenoxyacetamide hydrochloride (39.2 g), m.p. 171°-3° C.; αS =-10.7° (c=1.0; methanol); microanalysis: found C, 58.1; H, 7.0; N, 6.0; Cl, 7.9%; required for C22H31ClN2O6 : C, 58.1; H, 6.9; N, 6.2; Cl 7.8%: NMR (DMSO-d6) 3.1(m,1H,CHCH2NH); 3.24(s,3 H,OCH3); 3.24-3.45(m,7H,CHCH2NHCH2 ; NHCH2CH2OCH3): 4.0(m,2H, ArOCH2CHOH): 4.2-4.35(m,3H,CHOH; CH2CH2OAr): 5.95(d,1H,OH); 6.85-7.05(m,7H,Ar); 7.3(m,2H,Ar); 8.15(t,1H, CONHCH2): 9.16 and 9.35 (broad peaks, 2H, NH2+).