Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].BrC1C=C2C(=CC=1)NC(=O)C(C1C=CC=CC=1Cl)=C2O.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][N:37]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:40][C:39]1[CH:38]=[N:37][C:36]([C:35]([F:45])([F:34])[F:44])=[CH:43][CH:42]=1)=[C:5]2[OH:13]
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Oc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-4-hydroxyquinolin-2(1H)-one (3.2 g, 18.3 mmol, Intermediate 8: step a), 6-(trifluoromethyl)nicotinaldehyde (4.0 g, 16.7 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.2 g, 16.7 mmol), in pyridine (34 mL) were heated to 105° C. for 3 hours. The solution was allowed to cool to ambient temperature, resulting in the formation of a solid. Minimal isopropanol was added to the mixture and the slurry was stirred for 1 hour, sonicated, and filtered. The filtered solids were rinsed with isopropanol and dried under continuous air flow to provide the title compound as an off-white solid. Additional product was recrystallized from the filtrate, filtered, and rinsed with isopropanol.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:22]=[O:23].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:8]([C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:22][OH:23])#[N:9]
Reactant: C=O
Reactant: N#CC(c1ccccc1)c1ccccn1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: N#CC(CO)(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice cold stirred solution of phenyl-2-pyridyl acetonitrile* (50 g., 0.26 mole) in 350 ml. of pyridine containing a suspension of paraformaldehyde (31 g., 1.0 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give a thick oil 58 g, which is identified by nmr.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:7][C:6]=12.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C)C=O>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)c1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
A mixture of 3-iodo-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (6.49 g, 14.2 mmol), trimethylsilylacetylene (3.54 mL, 25.6 mmol) and triethylamine (3.94 mL, 28.4 mmol) in N,N-dimethylformamide (15 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (100 mg, 1 mol %), PPh3 (37 mg, 1 mol %) and CuI (8 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4.5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (2×50 mL) and brine (70 mL), dried (MgSO4) and evaporated to give 7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (6.2 g, 102%) as a light brown solid, which was dissolved in THF (30 mL) and MeOH (70 mL), while stirring at 0° C. potassium carbonate (200 mg, 1.45 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (200 mL) and extracted with TBME (3×200 mL). The combined organic layers were washed with brine (300 mL), dried (MgSO4) and evaporated. The crude product was further purified by silica gel column chromatography (heptane/EtOAc 9:1) followed by trituration with heptane to give 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (3.23 g, 63%) as an orange solid. MS (EI) 355.0 [(M)+]; mp 154° C.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[NH2:14][C:15]1[N:20]=[C:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:18]=[C:17]([NH:31][C@H:32]([CH3:35])[CH2:33][OH:34])[CH:16]=1>CN(C=O)C>[Si:6]([O:34][CH2:33][C@H:32]([NH:31][C:17]1[CH:16]=[C:15]([NH2:14])[N:20]=[C:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:18]=1)[CH3:35])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C[C@H](CO)Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Reaction time: 20 h

Procedure:
Imidazole (1.2 g) was added to a solution of tert-butyldimethylsilyl chloride (2.83 g) and the subtitle product of step iii) (1.8 g) in DMF (10 ml). The reaction was stirred for 20 h before partitioning between EtOAc (100 ml) and H2O (200 ml). The aqueous was extracted further with EtOAc (2×100 ml), the organics combined, washed with H2O (100 ml), brine (100 ml), dried (MgSO4) and concentrated in vacuo to a crude solid. This material was purified by column chromatography (50% Et2O/iso-hexane) to afford the subtitle compound as a yellow oil. Yield: 1.80 g.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[OH-].[Na+].CS(C)=O.Cl[CH2:18][CH2:19][CH2:20][Si:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:18][CH2:19][CH2:20][Si:21]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1O
Reactant: CO[Si](CCCCl)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: C=CCc1ccccc1OCCC[Si](OC)(OC)OC
Temperature: 115 °C
Yield: 90 %

Procedure:
Using the general procedure described in Example 1 a reactor was charged with 73.7 g (0.55 mole) of o-allylphenol, 43.28 g of a 50% by weight aqueous solution of sodium hydroxide (0.54 mole NaOH), 112 cc dimethylsulfoxide and 120 cc toluene. The resultant mixture was heated to the boiling point for six hours under a nitrogen atmosphere to remove all of the water present by azeotropic distillation. The reaction mixture was then allowdd to cool to about 75° C., at which time 109 g (0.56 mole) of 3-chloropropyl trimethoxysilane was added dropwise while the reaction mixture was stirred. Following completion of the addition the reaction mixture was heated at 115° C. for about 16 hours, following which the mixture was allowed to cool and was filtered to remove any solid material. The solvents were then removed under a pressure of about 15 mm of mercury at a temperature of about 60° C. The pressure was then reduced to 2 mm of mercury and the material boiling at 146° C. was collected. The weight of this fraction was equivalent to a yield of 90% based on starting materials. Analysis by vapor phase chromatography indicated that the purity of the product was greater than 98%. The infrared and nuclear magnetic resonance spectra of the product were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1[O:21][C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Reaction time: 6 h

Procedure:
60.0 g (0.2 mole) of benzyloxycarbonyl-D-phenylalanine [H. Yajima and K. Kubo: J. Am. Chem. Soc. 87, 2039-2044 (1965)] and 39.4 g (0.2 mole) of 2,4,5-trichlorophenol are dissolved in 200 ml of tetrahydrofuran, the solution is cooled to 5° to 10° C., then at stirring 41.2 g (0.2 mole) of dicyclohexylcarbodiimide are added in about 30 minutes. The reaction mixture is stirred for 6 hours without refrigeration. The precipitated dicyclohexylurea is filtered, washed three times with 50 ml of tetrahydrofuran and the combined tetrahydrofurane solutions are evaporated at reduced pressure. The residue is crystallized from 300 ml of hot etanol, filtered, washed twice with 50 ml of ethanol having a temperature of 5° to 10° C., then the crystals are dried in a vacuum desiccator. Yield: 72 g (75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:19]1([N:25]=[C:26]=[S:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[S:27])[CH2:6][CH2:7]2)=[CH:17][CH:16]=1
Reactant: S=C=Nc1ccccc1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: S=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccccc1
Yield: 29.7 %

Procedure:
1-(3-Aminopropyl)-4-(4-chlorobenzyl)piperazine (5.36 g; 20 mmole) was reacted with phenyl isothiocyanate 2.82 g; 21 mmole) in methylene chloride (35 ml) in the manner described in Example 17. The crude product was isolated and chromatographed on silica gel in analogous manner. The product crystallized from ethanol to yield the title compound (2.39 g; 30% yield) as an off-white crystalline solid, m.p. 155°-156° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][C@H:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([NH:33][CH3:34])([CH3:32])[CH3:31].[BH4-].[Na+].[OH-].[Na+]>C(Cl)Cl.CCCCCC.CO.CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:33]([CH:30]([CH3:32])[CH3:31])[CH3:34])[CH2:19][C@H:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CNC(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Example 1, Alternative Step 9e: Cyclohexanone 5 (22.5 g, 0.06M, 1 eq), DMSO (30 mL) and Ti(O-iPr)4 (33.7 mL, 0.11M, 2.04 eq) were placed in a round bottom flask. N-isopropyl-N-methylamine (11.6 mL, 0.11M, 2.0 eq) was then added in one portion. The mixture was left to stir for 30 mins at room temperature before being cooled to <3° C. in ice/water. MeOH (30 mL) was then added followed by the portionwise addition of NaBH4 (4.33 g, 0.11M, 2.04 eq)—temperature kept <8° C. 30 mins after the addition was completed the reaction mass was diluted with methylene chloride (300 mL) and then NaOH (1N, 40 mL). The resulting slurry was filtered through Celite, and the cake washed with methylene chloride (100 mL). The resulting liquor was concentrated under reduced pressure and the residue dissolved in EtOAc (500 mL). This solution was extracted with 1N HCl (2×400 mL), the combined aqueous layers were then basified with Na2CO3. Extraction with EtOAc (4×250 mL) provided a clear and colorless organic phase which was dried over Na2SO4 and concentrated to give a white powder (24.6 g, 96%, 7:1 d.r.). This material was then slurried overnight in hexane (670 mL). The solid was isolated by filtration and dried under reduced pressure to give ethyl (1R,2S,5R)-2-((3S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylate 6 as a while solid (20.9 g, 81%, 24:1 d.r.). 1H-NMR: (300 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.55 (d, J 4.5, 1H), 5.10 (s, 2H), 4.42 (q, J 4.5, 1H), 4.23-4.12 (m, 1H), 4.08 (dq, J 10.5, 7.0, 1H), 4.02 (dq, J 10.5, 7.0, 1H), 3.84 (t, J 9.0, 1H), 3.46-3.36 (m, 1H), 3.04 (septet, J 6.5, 1H), 2.86-2.80 (m, 1H), 2.63-2.48 (m, 2H), 2.17 (s, 3H, Me), 2.10-1.63 (m, 7H), 1.22 (t, J 7.0, 3H), 1.00 (d, J 6.5, 3H), 0.97 (d, J 6.5, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.01M NH4OAc (MeOH:water 20:80) to 0.01M NH4OAc (MeOH:water:MeCN 20:5:75) 10 to 100% 15 min gradient. 8.23 (Compound 6), 8.88 (5-epi-Compound 6). HRMS: 460.2798 [Calc: C25H38N3O5 460.2811].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:22]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=5)[N:13]=[CH:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To 10 mL of a chloroform solution containing 327 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 230 mg of 2,3-dihydro-1,4-dioxino[2,3-c]pyridine-7-carbaldehyde, 65 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 364 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform], to give 311 mg of 1-(2-(4-((2,3-dihydro-1,4-dioxino[2,3-c]pyridin-7-yl)methylamino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][C:12]3([CH2:16][C:15](O)([C:17]4[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=4)[CH2:14]3)[CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]2[CH2:11][C:12]3([CH2:16][C:15]([C:17]4[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=4)=[CH:14]3)[CH2:13]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CC3(C2)CC(O)(c2cc(F)c(F)c(F)c2)C3)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](C2CC3(C=C(c4cc(F)c(F)c(F)c4)C3)C2)CC1

Procedure:
A mixture of 12 mmol of 4F, 100 ml of toluene and 0.5 g of p-toluenesulfonic acid is heated on a water separator for 10 hours. After conventional work-up the product is obtained, which is processed further without purification.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[N:21]=[C:20]2[CH3:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([O:5]C)=[O:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C(Cl)Cl>[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[N:21]=[C:20]2[CH3:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([OH:5])=[O:4]
Reactant: CCCc1cc(Cn2c(C)nc3cccnc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc(Cn2c(C)nc3cccnc32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 54.6 %

Procedure:
A 5N sodium hydroxide solution (0.4 mL) was added to a stirred mixture of the product of Step D (53.5 mg, 0.104 mmol) in methanol (4 mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 2 h. The solution volume was reduced to ~10% in vacuo then 5% citric acid solution was added. The mixture was extracted with ethyl acetate (3 times). The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was chromatographed (8, 10% methanol/methylene chloride) to give the titled compound (28.5 mg) as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([OH:5])=O.C(O)(=O)C(O)=O.[C:24]1([C:30]2[O:34][C:33]([CH2:35][NH2:36])=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([NH:36][CH2:35][C:33]1[O:34][C:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:31][N:32]=1)=[O:5]
Reactant: NCc1nnc(-c2ccccc2)o1
Reactant: O=C(O)C(O)CCCCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1nnc(-c2ccccc2)o1)C(O)CCCCCCc1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-8-phenyloctanoic acid (458 mg, 1.94 mmol), 5-phenyl-1,3,4-oxadiazol-2-yl methanamine oxalate (514 mg, 1.94 mmol), HOBt (314 mg, 2.3 mmol) and diisopropylethyl amine (501 mg, 3.9 mmol) in DMF (15 mL) was added 1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride (446 mg, 2.3 mmol). The suspension was stirred for 48 h then filtered. The filtrate was diluted with EtOAc and washed sequentially with water, saturated NaHCO3, and brine. The organic phase was dried (Na2SO4) and filtered and the residue triturated with EtOAc to yield 2-hydroxy-8-phenyl-N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)octanamide (MH+=394).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[N:23]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:44]=[CH:45][CH:46]=[N:47]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:17])[NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:32]=[CH:31][C:27]([C:28](=[O:29])[NH:47][CH:46]3[CH2:44][CH2:45]3)=[CH:26][N:25]=2)[N:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-{2-[((S)-1-Benzyloxycarbonyl-pyrrolidine-2-carbonyl)-amino]-thiazol-4-yl}-nicotinic acid (0.18 g, crude), HATU (0.07 g, 0.18 mmol)), and DIEA (0.1 mL, 0.77 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. then cyclopropylamine (0.030 ml, 0.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. Purification by reverse phase HPLC furnished the desired product. 1HNMR (DMSO-d6) δ(ppm) 12.58-12.57 (d, 1H), 9.03 (s, 1H), 8.72-8.71 (d, 1H), 8.34-8.31 (m, 1H), 8.07-8.00 (m,2H), 7.44-7.38 (m, 2H), 7.22-7.12 (m, 2H), 5.17-4.95 (m, 2H), 4.61-4.55 (m, 1H), 3.59-3.52, (m, 2H), 2.95-2.90 (m,1H), 2.34-2.32 (m, 1H), 2.04-1.92 (m, 3H), 0.80-0.78 (m,4H); MS: 492.1 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25](=O)[CH3:26])[O:22][N:21]=2)=[CH:16][CH:15]=1>C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:24]=[C:23]([CH:25]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[CH3:26])[O:22][N:21]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)c1cc(-c2ccc(F)cc2)no1
Reactant: Ic1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1ccncc1)c1cc(-c2ccc(F)cc2)no1
Reaction time: 0.17 h
Yield: 30.8 %

Procedure:
To a stirred solution of 4-iodopyridine (0.3 g, 1.463 mmol) in THF (10 mL) was added n-BuLi (0.6 mL, 0.96 mmol) at −78° C. and stirred for 10 min. A solution of 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanone (0.1 g, 0.484 mmol) in THF (5 mL) was added to the reaction and the mixture stirred at −78° C. for 2 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated, washed with saturated ammonium chloride (3×150 mL) followed by brine solution (2×20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200μ silica gel; 50% ethyl acetate in hexane) to obtain 3-(4-fluorophenyl)-5-(1-(pyridin-4-yl)ethyl)isoxazole as off-white solid (0.04 g, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, 2H), 7.91 (dd, 2H), 7.46 (d, 2H), 7.32 (t, 2H), 6.81 (s, 1H), 7.04 (s, 1H), 1.86 (s, 3H); LC-MS m/z calculated for [M+H]+ 285.10. found 285.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:8]1[O:16][C@@H:15]([CH3:17])[C@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 23 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-n-butyl-3-L-rhamnopyranosylurea are dissolved in 10 ml of formic acid, and 1.5 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 0.8 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-L-rhamnopyranosylurea is thereby obtained as yellow caramel.