Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]2[C@H:11]([NH:12][C:13](=[O:29])/[C:14](=[N:21]\[O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])/[C:15]3[N:16]=[C:17]([NH2:20])[S:18][CH:19]=3)[C:10](=[O:30])[N:9]2[S:31]([OH:34])(=[O:33])=[O:32])[C:3]1=[O:35].Cl.[N:37]1([C:42](=N)[NH2:43])C=CC=N1>>[NH2:20][C:17]1[S:18][CH:19]=[C:15](/[C:14](=[N:21]/[O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])/[C:13]([NH:12][C@@H:11]2[C:10](=[O:30])[N:9]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:8]2[CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:42]([NH2:43])=[NH:37])[C:3]2=[O:35])=[O:29])[N:16]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CC[C@H](N)C1=O)c1csc(N)n1)C(=O)O
Reactant: N=C(N)n1cccn1
Agent: Cl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CC[C@H](NC(=N)N)C1=O)c1csc(N)n1)C(=O)O

Procedure:
Prepared in analogous manner to example 20 using 2-(((Z)-(2-(((2R,3S)-2-(((S)-3-amino-2-oxopyrrolidin-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid and 1H-pyrazole-1-carboximidamide HCl. LCMS: m/z=576.2 (M+1); 1H NMR (400 MHz, D2O): δ 6.95 (s, 1H), 5.31 (d, J=6.0 Hz, 1H), 4.72-4.57 (m, 1H), 4.27 (t, J=9.6 & 9.2 Hz, 1H), 3.85 (dd, J=9.6 Hz, 1H), 3.59 (t, J=9.2, 8.8 Hz, 1H), 3.49 (q, 1H), 3.34 (dd, 1H), 2.46 (m, 1H), 1.88 (m, 1H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH2:17]O)=[C:5]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23].S(Cl)([Cl:26])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH2:17][Cl:26])=[C:5]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1c(CO)n(CC2CC2)c(=O)c2ccc(Br)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC2CC2)c(=O)c2ccc(Br)cc12
Yield: 95.6 %

Procedure:
To a solution of 6-bromo-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone (5.70 g, 15 mmol) in toluene (50 mL) was added thionyl chloride (2.2 mL, 30 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-bromo-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone (5.72 g, 95.7%) as crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[C:22]([CH2:23][CH:24](O)[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([OH:33])[C:8]2[N:9]=[C:10]([CH3:20])[N:11](COCC[Si](C)(C)C)[C:7]=2[CH:6]=1)=[O:4].P(=O)(O)(O)O.[OH-].[Na+]>O>[CH3:1][N:2]([CH3:34])[C:3]([C:5]1[C:22]2[CH2:23][CH2:24][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:33][C:21]=2[C:8]2[N:9]=[C:10]([CH3:20])[NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: Cc1nc2c(O)c(CC(O)Cc3ccccc3)c(C(=O)N(C)C)cc2n1COCC[Si](C)(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2c3c(c(C(=O)N(C)C)cc2[nH]1)CCC(c1ccccc1)O3
Temperature: 80 °C
Yield: 72.4 %

Procedure:
A suspension of 0.69 g (1.4 mmol) 7-hydroxy-6-(2-hydroxy-3-phenyl-propyl)-2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazole-5-carboxylic acid dimethylamide and 7 ml phosphoric acid (85%) was heated at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was poured into water and neutralized with 6N sodium hydroxide solution. The precipitate was filtered off and purified by column chromatography on silica gel (dichloromethane/methanol=10:1) to afford 0.34 g (72%) of the title compound as a yellow foam.
Reaction SMILES: [CH3:1][CH:2]1[S:6](=[O:8])(=[O:7])[NH:5][CH2:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:11]=1>>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[S:6]3(=[O:8])=[O:7])=[CH:11][C:12]=2[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:23][CH2:22]1
Reactant: CC1CCNS1(=O)=O
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCC(C)S4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 21.2 %

Procedure:
Using 5-methylisothiazolidine 1,1-dioxide (360 mg) described in Preparation Example 5 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (803 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 4, the title compound (191 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)([Cl:21])(OC1C=CC=CC=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:21])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 180 °C

Procedure:
A suspension of 5-bromo-2-hydroxy-3-nitro-pyridine (19.2 g; ex. Maybridge) in phenyl dichlorophosphate (40 ml) was heated at 180° C. for 30 minutes to give a red oil. The reaction mixture was then purified as described in Example 1 Method 1(a) to give the title compound as a pale yellow solid (20.4 g).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:21][CH2:20][CH:19](Br)[C:18]2=[O:23])[C:13]([I:24])=[C:12]([C:25]([NH:27][CH2:28][CH:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:30][O:31][C:32](=[O:34])[CH3:33])=[O:26])[C:11]=1[I:39])=[O:9])(=[O:3])[CH3:2]>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[C:1]([O:4][CH:5]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:21][CH2:20][CH:19]([O:4][C:1](=[O:3])[CH3:2])[C:18]2=[O:23])[C:13]([I:24])=[C:12]([C:25]([NH:27][CH2:28][CH:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:30][O:31][C:32](=[O:34])[CH3:33])=[O:26])[C:11]=1[I:39])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCC(Br)C2=O)c1I)OC(C)=O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCC(OC(C)=O)C2=O)c1I)OC(C)=O
Temperature: 25 °C

Procedure:
N,N'-Bis-[2,3-diacetyloxypropyl]-5-[3-bromo-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 5a, (6.43 g, 6.30 mmol) was dissolved in glacial acetic acid (63 ml) and then treated with silver acetate (4.21 g, 25.21 mmol) at reflux under nitrogen for 26 hours. The reaction mixture was cooled to room temperature and the solids filtered off. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and brine. The organic layer was dried and removal of the solvent afforded the crude product as a colored foam. Purification by silica gel flash chromatography furnished N,N'-bis-[2,3-diacetyloxypropyl]-5-[3-acetyloxy-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off white foam (4.45 g, 71% yield).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:34][O:35]C(C)=O)[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:33])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([O:29]C(C)=O)[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].C1(C)C=CC=CC=1.[OH-].[K+]>C(O)C>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:34][OH:35])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:33])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 66.6 %

Procedure:
In a glass duplicated reactor, equipped with a shaft stirrer, reflux condenser, inlet tube and blow valve, 2.00 kg of betulin diacetate of example 5 was dissolved under stirring in the mixture of 10 l of toluene and 8 l of ethanol containing 700 g of potassium hydroxide. The reaction mixture was refluxed for 2 hours, then under heating filtered through a PP cloth and the filtrate was inoculated with pure betulin crystals. After cooling down, the crystallized betulin was filtered off on a processing filter, washed with 3 l of ethanol, 3 l of 50% ethanol and 30 l of boiling water and finally 5 l of boiling distilled water. The crystalline betulin was dried in a hot-air oven at the temperature of 70-75° C. for the period of 48 h. 1.12 kg (66%) of betulin in the form of fine crystalline power was obtained, having the m.p. 256-258° C., [α]D+16 (10% v/v CH3OH in CHCl3; 0.35 g/100 ml), which has the HPLC purity of 98.9-99.1%. 1H NMR spectrum of the obtained betulin measured in CDCl3 with the addition of 10% v/v CD3OD is as follows: 0.76 s, 0.83 s, 0.97 s, 0.98 s, 1.02 s, 1.68 s, 6×3H (6×CH3); 2.39 ddd, 1H (J′=10.98, J″=10.8, J′″5.8, H-19β); 3.19 dd, 1H (J′=11.1, J″=5.2, H-3α); 3.33 dd, 1H (J′=11.0, J″=1.2, H-28a); 3.80 dd, 1H, (J′=10.8, J″=1.8, H-28b); 4.58 m, 1H (ΣJ=6.5, H-29E); 4.68 m, 1H (ΣJ=2.9, H-29Z). 13C NMR spectrum of the obtained betulin measured in CDCl3 with the addition of 10% v/v CD3OD is as follows: 14.74, 15.34, 15.96, 16.09, 18.28, 19.07, 20.81, 25.19, 27.02, 27.37, 27.97, 29.15, 29.73, 33.95, 34.21, 37.14, 37.29, 38.69, 38.84, 40.90, 42.70, 47.77, 47.77, 48.74, 50.38, 55.27, 60.53, 78.97, 109.68, 150.46. By concentrating the mother liquor to the final volume of 8 l was after inoculation and cooling down obtained a second fraction of the crystalline betulin, which was also filtered on a processing filter and washed in the same way as the first fraction. After drying in the hot-air oven at the temperature of 70-75° C. for the period of 48 h further 0.46 kg (27%) of the second fraction of betulin was obtained, having the m.p. 256-257° C., [α]D+16 (10% v/v CH3OH in CHCl3; 0.35 g/100 ml), which, according to HPLC analysis, has the purity of 98.7-99.0%. The overall yield of the hydrolysis is thus 1.58 kg of betulin (93%).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][F:8])[C:3]([F:6])([F:5])[F:4].S(=O)(=O)(O)[OH:10]>O>[CH3:1][C:2]([OH:10])([CH2:7][F:8])[C:3]([F:6])([F:5])[F:4]
Reactant: O=S(=O)(O)O
Reactant: CC(CF)C(F)(F)F
Solvent: O
Product: CC(O)(CF)C(F)(F)F

Procedure:
As another example, 2-methyl-1,1,1,3-tetrafluoro-2-propanol may be prepared by reacting commercially available methacrylic acid with hydrogen fluoride to form 2-methyl-3-fluoropropanoic acid which may then be fluorinated to form 2-methyl-1,1,1,3-tetrafluoropropane. The 2-methyl-1,1,1,3-tetrafluoropropane may then be dehydrogenated and reacted with sulfuric acid and then water to form 2-methyl-1,1,1,3-tetrafluoro-2-propanol.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH3:22][C:23]([O:26][C:27]([N:29]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:30]([C:38]1[C:43]([F:44])=[C:42](Cl)[N:41]=[C:40]([Cl:46])[N:39]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:28])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:25][C:23]([O:26][C:27]([N:29]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[N:30]([C:38]1[C:43]([F:44])=[C:42]([N:6]2[CH2:7][C:4]([CH3:3])([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:5]2)[N:41]=[C:40]([Cl:46])[N:39]=1)[C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[O:28])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CC1(N2CCCC2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CC(C)(N3CCCC3)C2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a stirred solution of 1-(3-methyl-3-azetidinyl)pyrrolidine dihydrochloride (0.128 g, 86% pure, 0.52 mmol) in DMF (8 mL) at 0° C. was added DIPEA (0.34 mL, 1.94 mmol) followed immediately by tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.24, 0.49 mmol). The reaction was warmed up to rt and stirred overnight. The mixture was purified by RP-HPLC to provide tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.225 g, 77%). LCMS: (M+H)+: 601.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])[CH2:23][CH2:22]2)=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:73]1([C:76]2[O:77][CH:78]=[C:79]([C:81](O)=[O:82])[N:80]=2)[CH2:75][CH2:74]1>O.C(OCC)(=O)C>[Cl:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:81]([C:79]2[N:80]=[C:76]([CH:73]3[CH2:75][CH2:74]3)[O:77][CH:78]=2)=[O:82])=[C:3]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH3:34])[CH2:25][CH2:26]2)[CH:4]=1
Reactant: O=C(O)c1coc(C2CC2)n1
Reactant: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2coc(C3CC3)n2)CC1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and a fitted with a nitrogen inlet, the 5-amino-2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 16g (130 mg, 0.27 mmol) was taken up in clean, dry N,N-dimethylformamide (3.00 ml, 38.74 mmol) and the mixture was allowed to stir under nitrogen at room temperature until all solids were in solution. To this mixture was added the HATU (121.60 mg, 0.32 mmol) followed by the N,N-diisopropylethylamine (0.14 ml, 0.80 mmol) and the mixture was allowed to stir until all solids were taken into solution. The 2-cyclopropyl-oxazole-4-carboxylic acid 1h (56.80 mg, 0.37 mmol) was added to the reaction mixture and the reaction stirred at room temperature overnight. The reaction was diluted with 10 ml of water and 10 ml of ethyl acetate. The layers were separated and the product was extracted from the aqueous using ethyl acetate (3×15 ml). The organic phases were combined, washed with brine (1×25 ml) and with saturated aqueous lithium chloride solution (2×25 ml). The solution was then dried over Na2SO4; the solution was then decanted and the solvent was removed under reduced pressure. The product was purified from the resultant brown semi-solid using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. A secondary purification was required and the compound was purified using reverse-phase prep HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a 5 min period. The product, 2-cyclopropyl-oxazole-4-carboxylic acid {4-chloro-2-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-phenyl}-amide 16h (11.20 mg, 0.02 mmol), was isolated as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]=3[CH3:23])[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:28].[C:30]([N:37]([CH2:39][C:40](O)=[O:41])C)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[OH:29][CH:3]([CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[S:19][CH:20]=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]=3[CH3:23])[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:28])[CH2:2][NH:1][C:40](=[O:41])[CH2:39][NH:37][CH3:30]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC(O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNCC(=O)NCC(O)COc1c(C)cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A solution of rac-1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (100 mg, 0.241 mmol) in DCM (1 mL) is added to a stirred solution of Boc-sarcosine (60 mg, 0.317 mmol), DIPEA (38 mg, 0.292 mmol) and TBTU (85 mg, 0.265 mmol) in DCM (5 mL). The mixture is stirred at rt for 1 h, diluted with DCM (50 mL) and washed with sat. aq. Na2CO3 (2×20 mL). The organic extract is dried (Na2SO4), filtered and evaporated. The residue dissolved in 4M HCl in dioxane (10 mL) and stirred for 1 h. The mixture is diluted with DCM (75 mL) and washed with 1 N aq. NaOH (50 mL). The aq. phase is extracted with DCM (3×30 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated. The residue is purified on prep. TLC plates with DCM containing 10% of 7 N NH3 in MeOH to give rac-N-(2-hydroxy-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propyl)-2-methylamino-acetamide (89 mg) as a white powder; LC-MS: tR=0.89 min, [M+1]=487.26; 1H NMR (D6-DMSO): δ 7.85 (t, J=6 Hz, 1H), 7.70 (s, 2H), 7.65 (s, 1H), 5.27 (d br, J=5 Hz, 1H), 3.93-3.85 (m, 1H), 3.76-3.65 (m, 2H), 3.43-3.35 (m, 1H), 3.24-3.14 (m, 1H), 3.02 (s, 2H), 2.54 (s, 3H), 2.45 (d, J=6.4 Hz, 2H), 2.30 (s, 6H), 2.20 (s, 3H), 1.83 (hept, J=7.0 Hz, 1H), 0.88 (d, J=7.0 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]([CH3:30])[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][C:16]=1[F:29].O.NN>C1COCC1>[C:2]([NH:3][C@@H:12]([CH3:30])[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:17][C:16]=1[F:29])(=[O:1])[CH3:10]
Reactant: C[C@@H](COc1ncc(NC(=O)OC(C)(C)C)cc1F)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](C)COc1ncc(NC(=O)OC(C)(C)C)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
A mixture of tert-butyl (6-(((2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl)oxy)-5-fluoropyridin-3-yl)carbamate (1.62 g), hydrazine monohydrate (0.976 g) and THF (15 mL) was stirred overnight at 60° C. The precipitate was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was mixed with acetic anhydride (0.736 mL), triethylamine (1.09 mL) and ethyl acetate (15 mL), and the obtained mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.05 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[I-].[K+].[OH-].[Na+]>CC(O)(CC)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCBr)cc1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: COc1ccc(CCCCn2ccnc2)cc1

Procedure:
A mixture of 3.65 g (15.0 mmol) 1-(4-bromo-butyl)-4-methoxy-benzene, 1.02 g (15.0 mmol) imidazole, 2.74 g (16.5 mmol) potassium iodide, 0.60 g (15.0 mmol) sodium hydroxide and 20 ml 2-methyl-2-butanol was heated to reflux for 7 h. Solvents were distilled off, the residue dissolved in ethyl acetate and washed with water. Drying over Na2SO4 and removal of solvents in vacuo gave 2.0 g (58%) slightly coloured oil.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:22][C:23]([NH2:25])=[O:24])[C@@H:17]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.COC1C=CC(CN[C@@H]2CC[C@@H](C(OC)=O)[C@@H]2C2C=CC(F)=CC=2)=CC=1.COC1C=CC(CN[C@H]2CC[C@@H](C(OC)=O)[C@@H]2C2C=CC(F)=CC=2)=CC=1.COC1C=CC(CN[C@H]2CC[C@H](C(OC)=O)[C@H]2C2C=CC(F)=CC=2)=CC=1.COC1C=CC(CN[C@@H]2CC[C@H](C(OC)=O)[C@H]2C2C=CC(F)=CC=2)=CC=1.COC1C=CC(N2C=NN=N2)=CC=1CN[C@H]1CC[C@@H](C(OC)=O)[C@@H]1C1C=CC(F)=CC=1.COC1C=CC(N2C=NN=N2)=CC=1CN[C@H]1CC[C@H](C(OC)=O)[C@H]1C1C=CC(F)=CC=1.FC(F)(F)C1C=C(C(N[C@H]2CC[C@@H](C(OC)=O)[C@@H]2C2C=CC(F)=CC=2)=O)C=C(C(F)(F)F)C=1.FC(F)(F)C1C=C(C(N([C@H]2CC[C@@H](C(OC)=O)[C@@H]2C2C=CC(F)=CC=2)C)=O)C=C(C(F)(F)F)C=1.FC(F)(F)C1C=C(C(N[C@H]2CC[C@@H](C(OC)=O)[C@@H]2C2C=CC(F)=CC=2)C)C=C(C(F)(F)F)C=1.FC(F)(F)C1C=C([C@H](O[C@H]2CC[C@@H](N([C@@H]3NC(=O)CC3)C)[C@@H]2C2C=CC=CC=2)C)C=C(C(F)(F)F)C=1>>[F:1][C:2]([F:32])([F:33])[C:3]1[CH:4]=[C:5]([C@@H:13]([O:15][C@@H:16]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][C:23]([NH2:25])=[O:24])[C@H:17]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](NCC(N)=O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: COC(=O)[C@@H]1CC[C@@H](NCc2ccc(OC)cc2)[C@H]1c1ccc(F)cc1
Agent: COC(=O)[C@@H]1CC[C@H](N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Agent: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Product: C[C@H](O[C@@H]1CC[C@H](NCC(N)=O)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
##STR10## 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-phenyl-3-(R)-(aminocarbonylmethylamino)cyclopentane; ##STR11## methyl 3-(R)-((4-methoxyphenyl)methylamino)-2-(R)-(4-fluorophenyl)cyclopentane-1-(R)-carboxylate; ##STR12## methyl 3-(S)-((4-methoxyphenyl)methylamino)-2-(R)-(4-fluorophenyl)cyclopentane-1-(R)-carboxylate; ##STR13## methyl 3-(S)-((4-methoxyphenyl)methylamino)-2-(S)-(4-fluorophenyl)cyclopentane-1-(S)-carboxylate; ##STR14## methyl 3-(R)-((4-methoxyphenyl)methylamino)-2-(S)-(4-fluorophenyl)cyclopentane-1-(S)-carboxylate; ##STR15## methyl 3-(S)-((2-methoxy-5-(1-tetrazolyl)phenyl)methylamino)-2-(R)-(4-fluorophenyl)cyclopentane-1-(R)-carboxylate; ##STR16## methyl 3-(S)-((2-methoxy-5-(1-tetrazolyl)phenyl)methylamino)-2-(S)-(4-fluorophenyl)cyclopentane-1-(S)-carboxylate; ##STR17## methyl 3-(S)-((3,5-bis(trifluoromethyl)phenyl)carbonylamino)-2-(R)-(4-fluorophenyl)cyclopentane-1-(R)-carboxylate; ##STR18## methyl 3-(S)-(N-((3,5-bis(trifluoromethyl)phenyl)carbonyl)-N-methylamino)-2-(R)-(4-fluorophenyl)cyclopentane-1-(R)-carboxylate; ##STR19## methyl 3-(S)-(1-(RS)-(3,5-bis(trifluoromethyl)phenyl)ethylamino)-2-(R)-(4-fluorophenyl)cyclopentane-1-(R)-carboxylate; ##STR20## 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-phenyl-3-(R)-(((S)-(2-pyrrolidon-5-yl))-methylamino)cyclopentane; ##STR21## 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-phenyl-3-(R)-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylamino)cyclopentane;
Reaction SMILES: [Si](O[C:9]1[C:13](=[O:14])[CH2:12][C:11]([OH:26])([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.O.O.[Cl-].[Na+].CCOCC>O1CCCC1>[O:19]([CH2:18][CH2:17][CH2:16][CH2:15][C:11]1([OH:26])[CH2:12][CH:13]([OH:14])[CH:9]=[CH:10]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC1=CC(O)(CCCCOc2ccccc2)CC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OC1C=CC(O)(CCCCOc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 677.3 %

Procedure:
8 g (22 mmoles) of 5-t-butyldimethylsilyloxy-3-hydroxy-3-(4-phenoxybutyl)cyclopentenone was dissolved in 25 ml of tetrahydrofuran, and 11 g (35 mmoles) of n-Bu4NF.3H2O was added. The mixture was stirred at room temperature for 4 hours. After the addition, a saturated sodium chloride solution and ether were added. The aqueous layer was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was chromatographed on a silica gel column (hexane:AcOEt=1:2) to give 37 g (68%) of 4-(4-phenoxybutyl)cyclopent-2-ene-1,4-diol.