Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:5][P@@:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[NH2:20][O:21][K].Cl>>[OH:21][NH:20][C:3](=[O:2])[C@H:4]([NH:5][P@@:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H](CC(C)C)N[P@](C)(=O)c1ccccc1
Reactant: NO[K]
Agent: Cl
Product: CC(C)C[C@@H](N[P@](C)(=O)c1ccccc1)C(=O)NO
Reaction time: 7 h

Procedure:
N-((R)-Methylphenylphosphinyl)-D-leucine methyl ester (60 mg, 0.21 mmol) is treated with a solution of NH2OK (0.57 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 7 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The residue is purified by silica gel flash chromatography (95:5 ethyl acetate:ethanol) to give N-hydroxy-2(R)-[[(R)-methylphenylphosphinyl]amino]-4-methylpentanamide as a colorless solid: MS-IS m/z 285 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][P:13]([OH:16])(=[O:15])[OH:14])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2.C(=O)([O-])[O-].[Na+].[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][P:13]([OH:16])(=[O:14])[OH:15])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Reaction time: 1 h

Procedure:
100 mg of 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl) methanephosphonic acid is adjusted in 20 ml of water to a pH of 9.5 with a saturated sodium carbonate solution and combined with 0.2 ml of acetic anhydride. After one hour of stirring, the mixture is concentrated, dissolved in a minimum amount of water, introduced into an ion exchanger (IR 120, strongly acidic), and eluted with water: The corresponding fractions are combined, concentrated, and dried, thus obtaining 110 mg of 1-(6-acetylamino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid, mp: 120° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:23]=4[CH:41]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:42]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:23]=4[CH:41]=3)=[O:42])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21
Reactant: OO
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][CH:5]([OH:13])[C:4]=2[CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18]Br.O>CN(C=O)C>[Br:16][CH2:17][CH2:18][N:7]1[CH2:6][CH:5]([OH:13])[C:4]2[CH:3]=[C:2]([Cl:1])[S:10][C:9]=2[S:8]1(=[O:11])=[O:12]
Reactant: O=S1(=O)NCC(O)c2cc(Cl)sc21
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)c2sc(Cl)cc2C(O)CN1CCBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
To a solution of 6-chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (2.0 g, 8.37 mmol) in DMF (50 mL) was added sodium hydride (0.37 g, 9.2 mmol), after stirring for 30 min 1,2-dibromoethane (2.36 g, 16.7 mmol) was added and this mixture was stirred at room temperature for 72 hr. The reaction mixture was poured into water and the aqueous mixture was extracted with ether. The combined extracts were dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 30% ethyl acetate/hexane) to give 1.52 g (53%) of the desired product as a viscous syrup which was used in the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2.Br[CH2:19][C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=3)[C:10]([CH3:11])=[C:2]2[CH3:1])=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(CBr)cc1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(OCC(=O)OC)cc1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of the allyl 2,3-dimethyl-1H-indole-5-carboxylate (500 mg, 2.2 mmol) in anhydrous DMF (20 mL) was added the methyl 2-(4-(bromomethyl)phenoxy)acetate (565 mg, 2.2 mmol) followed by NaH (131 mg, 3.3 mmol). The resulting solution was allowed to stir overnight under argon atmosphere. The remaining NaH was hydrolyzed by the careful addition of a 0.5 N HCl solution. The mixture was diluted with ethyl acetate, washed with a 0.5 N HCl solution and brine, dried on MgSO4, and concentrated. The crude residue was purified by chromatography on silica gel (Hexane/Ethyl acetate 5/5) to afford yellow oil (536 mg, 61%). ESI-MS (m/z): 408 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2-benzyloxyphenol (2.00 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.44 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified to give the title compound (4.16 g).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[NH:32]1[C:33]2[C:29](=[C:28]([CH2:27][NH:26][C:25]([C:19]3[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])[C:3]([OH:38])=[O:2])=[O:16])=[C:21]([CH:22]([CH3:24])[CH3:23])[CH:20]=3)=[O:37])[CH:36]=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (S)-2-({5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-isopropyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (109.6 mg, 0.020 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (84 mg, 2.0 mmol) in water (6 mL). The mixture was then stirred at room temperature 2 d. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 85.8 mg (79%). MS m/e 540.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C1C[O:24]CC1>O.C(O)(=O)C.OO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([OH:24])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1c2cc(B(O)O)ccc2ccc2ncc(Cl)cc12
Reactant: C1CCOC1
Agent: OO
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1c2cc(O)ccc2ccc2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)boronic acid (1.00 g, 3.5 mmol) was dissolved in a 0° C. solution of 25 mL of THF, 25 mL of water, 0.5 mL of acetic acid and 0.5 mL of 30% (w/w) hydrogen peroxide. The solution was stirred and allowed to warm to ambient temperature. After 6 h, the reaction mixture was partially concentrated and dissolved in 500 mL ethyl acetate. The organic layer was washed with water (2×100 mL), dried with magnesium sulfate, filtered, and concentrated to afford solids. The solids were dissolved in 20 mL dichloromethane and 60 mL hexanes and stirred as solids crystallized from the solution. After 2 hours, the crystalline solids were filtered and dried to afford the title compound. 1H NMR (600 MHz, DMSO-D6) δ 10.50 (s, 1H); 8.93 (s, 1H); 8.45 (s, 1H); 7.68 (d, 1H); 7.58 (d, 1H); 7.39 (d, 1H); 7.23 (d, 1H); 7.12 (d, 1H). LRMS (APCI) calculated for C14H9ClNO2 [M+H]+, 258.0; found 258.1.
Reaction SMILES: [CH:1]([C@@H:3]1[C@:11]2([CH3:12])[C@@:6]([OH:19])([CH2:7][C@@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:5][CH2:4]1)=O.C(=O)(O)O.[NH2:24][NH:25][C:26]([NH2:28])=[NH:27]>Cl.O1CCOCC1>[NH:25](/[N:24]=[CH:1]/[C@@H:3]1[C@:11]2([CH3:12])[C@@:6]([OH:19])([CH2:7][C@@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:5][CH2:4]1)[C:26]([NH2:28])=[NH:27]
Reactant: N=C(N)NN
Reactant: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2C=O
Agent: Cl
Agent: O=C(O)O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2/C=N/NC(=N)N
Yield: 69.2 %

Procedure:
A solution of 0.57 g of (1S,3aS,5S,7aR)-1-formyl-5-phenyl-7a-methylperhydroinden-3a-ol and 1.50 g of aminoguanidine hydrogencarbonate in 30 ml of 0.01N hydrochloric acid and 80 ml of dioxane was kept at room temperature for 3 days and then evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as the eluant. The fractions containing the title compound were collected and evaporated to dryness. The residue was triturated with ethanol/ethyl acetate to give 0.48 g of the title compound (I-aa) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]([CH2:31][C@H:32]1[O:34][CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH2:33][C@H:32]([OH:34])[CH2:31][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1cc2c(cc1OC)CC(NCc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Reaction time: 3 h
Yield: 68.5 %

Procedure:
Under nitrogen, to a solution of N-benzyl-(2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (440 mg) and (2S)-1-phenoxy-2,3-epoxypropane (190 mg) in dichloromethane (10 ml) was added ytterbium(III) trifluoromethanesulfonate (157 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S)-1-[N-benzyl-N-(2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (400 mg).
Reaction SMILES: C([O:8][C:9](=[O:49])[CH2:10][C@@H:11]([N:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[CH:33]1)[C:12]([NH:14][C@H:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:16][O:17]C(OCC1C=CC=CC=1)=O)=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:29][C:28]([CH3:31])([CH3:30])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)=[CH:33]1)[CH2:10][C:9]([OH:49])=[O:8])[CH2:16][OH:17]
Reactant: CC(C)(C)[C@H](COC(=O)OCc1ccccc1)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reaction time: 3 h

Procedure:
A mixture of N-(1-benzyloxycarbonyloxy-3,3-dimethylbut-2(R)-yl)-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (140 mg, 0.212 mmol) and Pd(OH)2 (60 mg of 20% Pd by content) in MeOH (1 mL) and EtOAc (9 mL) was stirred under H2 atmosphere for 3 hours. The catalyst was filtered onto Celite and rinsed with 10% MeOH/CHCl3 (75 mL). The filtrate was concentrated in vacuo to provide a yellow solid, which was precipitated from hot CHCl3 solution with hexane to firnish 68 mg (95%) of N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid, mp 192-4° C. 1H NMR (CD3OD): δ 8.56 (d, 1H, J=5.9 Hz), 7.78-7.60 (m, 7H), 7.37 (t, 1H, J=1.9 Hz), 6.96 (t, 1H, J=2.5 Hz), 6.54 (t, 1H, J=1.6 Hz), 5.22 (dd, 1H, J=2.5 Hz), 3.83-3.70 (m, 2H), 3.45-3.40 (m, 1H), 3.22 (d, 1H, J=7.5 Hz), 3.02 (dd, 1H, J=7.2, 16.8 Hz), 0.90 (s, 9H). IR (KBr): 3405, 2960, 1718, 1656, 1602, 1560, 1408, 1364, 1203, 922, 818, 783 cm−1. HRFABMS: Calculated for C25H29N3O4Cs (M+Cs+): 568.1212. Found: 568.1189. Anal. Calculated for C25H29N3O4•0.10 CHCl3: C, 67.38; H, 6.55; N, 9.39. Found: C, 67.69, H, 6.90; N, 9.65.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)([OH:3])=[O:2].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>CO.C1C=CC=CC=1>[CH3:15][O:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)=[O:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccnc(NC(C)=O)c1

Procedure:
4-Carboxy-2-acetylaminopyridine (3.4 g, 19 mmol) was dissolved in methanol/benzene (100 mL, 1:1). TMS-diazomethane was added (1M, Aldrich) with cooling until the yellow color just persisted, then the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography (50/50 hexane/ethyl acetate) and 3.0 g of product was recovered.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH3:34])[C:27]=4[F:35])=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:11][CH:12]=2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([C:7]1[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH3:34])[C:27]=3[F:35])=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:11][CH:12]=1)[CH2:4][OH:3]
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3cnc([C@H]4COC(C)(C)O4)cn3)C2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3cnc([C@H](O)CO)cn3)C2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.5 %

Procedure:
A solution of (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (prepared in Example 150, 0.300 g, 0.57 mmol) in tetrahydrofuran (20 mL) was treated with 1N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 20 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% to 100% (9:1 dichloromethane:methanol)/hexanes) to afford (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide (0.188 g, 68%) as a fluffy white solid: HR-ES-MS m/z calculated for C24H29FN4O6, [M+H]+ 489.2144 observed 489.2143; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.36 (t, J=6.9 Hz, 3H), 1.42-1.57 (m, 1H), 1.57-1.73 (m, 1H), 1.74-1.90 (m, 1H), 3.47-3.61 (m, 1H), 3.68 (dt, J=10.8, 5.3 Hz, 1H), 4.15 (q, J=6.9 Hz, 2H), 4.26 (d, J=18.4 Hz, 1H), 4.53-4.68 (m, 2H), 4.73 (t, J=5.7 Hz, 1H), 4.92 (s, 1H), 5.03 (dd, J=10.6, 4.2 Hz, 1H), 5.55 (d, J=4.8 Hz, 1H), 6.98-7.08 (m, 1H), 7.08-7.25 (m, 2H), 8.45 (s, 1H), 9.17 (s, 1H), 11.15 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:33]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:39]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)(=[O:41])=[O:40])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(NS(=O)(=O)N1CCOCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 65 %

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-(2-amino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (397 mg, 0.90 mmol), morpholine-4-sulphonyl chloride (334 mg, 1.8 mmol, prepared by the method of von Geldem, et al., J. Med. Chem., 1996;39:968-981), N,N-diisopropylethyl-amine (246 mg, 1.9 mmol), and DMAP (25 mg) in benzene (5 mL) was heated under reflux for 3 hours, then concentrated in vacuo and the residue dissolved in ethyl acetate, and washed with saturated NaHCO3 solution, water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The amber oil thus obtained was purified via flash chromatography (silica gel, 35% EtOAc/Hexane) to give 346 mg (65%) of the title compound as a yellow foam, mp=54-57° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:14])[S:6][C:7]=1[C:8]#[C:9][Si](C)(C)C)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:14])[S:6][C:7]=1[C:8]#[CH:9])[CH3:2]
Reactant: CCc1nc(N)sc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1sc(N)nc1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To the above prepared 4-ethyl-5-trimethylsilanylethynyl-thiazol-2-ylamine (0.595 g, 2.651 mmol), dissolved in 9 mL of MeOH, was added K2CO3 (0.550 g, 1.5 eq.) and the mixture was stirred for 2 h at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness, followed by flash chromatography (SiO2, hexane/ethyl acetate=7/3), produced 0.256 g of the title compound as light brown solid.
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)=[N+:29]=[N-:30]
Reactant: CS(=O)(=O)OC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1

Procedure:
The process is performed according to the procedure described in Example 6 (step 6.3.). Starting with 7.66 g (19.62 mmol) of 7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2-yl methanesulfonate, prepared in step 10.3., and 3.83 g (58.85 mmol) of sodium azide in 28 mL of N,N-dimethylformamide. After evaporating off the solvent, 6.60 g of product are obtained in the form of a brown oil.
Reaction SMILES: [C:1]([C@H:4]([CH2:31][CH2:32][O:33][CH3:34])[CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)([OH:3])=[O:2]>O1CCOCC1.[OH-].[Na+]>[C:1]([C@H:4]([CH2:31][CH2:32][O:33][CH3:34])[CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:15][C:16]([OH:18])=[O:17])=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C[C@H](CCCc1ccc(Cl)cc1)NC(=O)C1(C[C@@H](CCOC)C(=O)O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCC[C@H](CC1(C(=O)N[C@@H](CCCc2ccc(Cl)cc2)CC(=O)O)CCCC1)C(=O)O

Procedure:
A solution of the ester from example 52 (60 mg, 0.12 mmol) in dioxan (4 ml) and 1N sodium hydroxide (4 ml) was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The layers were separated, the aqueous acidified to pH 1 using hydrochloric acid, and this soluton then re-extracted with ethyl acetate (2×20 ml). These combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to afford the title compound, 49 mg; 1H NMR (CDCl3, 400 MHz) δ: 1.42–1.78 (m, 10H), 1.97 (m, 3H), 2.16 (m, 1H), 2.40–2.70 (m, 6H), 3.37 (m, 5H), 3.44 (m, 1H), 4.42 (m, 1H), 6.38 (d, 1H), 7.07 (d, 2H), 7.21 (d, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:54][CH:55]([CH3:57])[CH3:56])[CH2:52][OH:53]>CN(C=O)C.C(O)=O>[OH:53][CH2:52][C@@H:51]([NH:50][C:11]([C:9]1[CH:8]=[N:7][C:6]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[N:10]=1)=[O:13])[CH2:54][CH:55]([CH3:57])[CH3:56]
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Reactant: CC(C)C[C@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A mixture of 6 mg (0.024 mmol) 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid, 9.3 mg (0.029 mmol) TBTU, 9.3 mg (0.072 mmol) DIPEA and 4.2 mg (0.036 mmol) (S)-2-amino-4-methyl-pentan-1-ol (commercially available) in 1 mL DMF was shaken at room temperature for 16 h. After addition of formic acid the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The combined product fractions were evaporated to yield 2 mg (24%) of the title compound. m/z (ES+): 351.5 (M+H).