Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[CH:11](N)([CH3:13])[CH3:12]>O>[CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[CH3:12][CH:11]([OH:3])[CH3:13].[CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3]
Reactant: CC(C)N
Agent: O=C(O)CNCP(=O)(O)O
Solvent: O
Product: CC(C)O

Procedure:
A series of concentrated herbicide formulations were prepared as described above in Example 1 by combining glyphosate acid (technical grade, as a wet cake) with varying amounts of isopropyl amine ranging from a molar ratio glyphosate acid to isopropyl amine of 1:1 to 1:15. The resulting aqueous solutions were combined with a tallowamine ethoxylate (10 EO) and diluted with a sufficient amount of water to yield a concentrated glyphosate IPA salt formulation with 480 gae/l glyphosate and 110 g/l tallowamine ethoxylate. Table 3 provides a listing of the series of 62% glyphosate isopropylammonium salt components that were used to prepare the formulations, which ultimately contained 480 gae/l glyphosate isopropylammonium salt and 110 g/l tallowamine ethoxylate surfactant.
Reaction SMILES: CS(Cl)(=O)=O.C([N:8]([CH2:11][CH3:12])CC)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C@H:22]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH:31]=1)[O:23][CH2:24][C:25]1(CO)[CH2:27][CH2:26]1.C([O-])(O)=O.[Na+].S([O-])(=O)(=O)C.[C-]#N.[Na+]>C(Cl)Cl.CS(C)=O.O>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][C@H:22]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH:31]=1)[O:23][CH2:24][C:25]1([CH2:12][C:11]#[N:8])[CH2:27][CH2:26]1
Reactant: CCN(CC)CC
Reactant: OCC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (2.90 mL, 37.5 mmol) and triethylamine (6.50 mL, 46.6 mmol) were added to a solution of the alcohol of Step 5 (15.30 g, 31.3 mmol) in 200 mL of CH2Cl2 at -40° C. and the solution was stirred at -40° C. for 30 min and at 0° C. for 1 hr. Aq. saturated NaHCO3 was then added and the mesylate was extracted in CH2C12, dried over Na2SO4, concentrated, and stripped twice with toluene. To a solution of this mesylate in 240 mL of anhydrous dimethylsulfoxide was added NaCN (7.69, 157 mmol) and the mixture was stirred at room temperature overnight. Water (1 L) was then added, followed by 250 mL of saturated NaHCO3 and the product was extracted in ether, washed with brine, dried over Na2SO4, and purified by flash chromatography on silica with EtOAc:toluene 5:95; yield: 13.43 g (86%).
Reaction SMILES: [I-].[K+].Cl[CH2:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:29][O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH:34]1[CH3:39])=[O:32]>C(C(C)=O)C>[CH3:29][O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH:34]1[CH3:39])=[O:32]
Reactant: ClCCCN1c2ccccc2CCc2ccccc21
Reactant: COC(=O)C1CCCNC1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: COC(=O)C1CCCN(CCCN2c3ccccc3CCc3ccccc32)C1C
Reaction time: 2 h

Procedure:
A mixture of potassium iodide (17.5 g, 0.11 mol) and methyl ethyl ketone (180 ml) was heated at reflux temperature for 1 h. A solution of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (4.8 g, 0.019 mol, prepared similarly as described in example 1) in methyl ethyl ketone (25 ml) was added and heating at reflux temperature was continued for 2 h. Potassium carbonate (8.5 g, 0.061 mol) and 2-methyl-3-piperidinecarboxylic acid methyl ester hydrochloride (5.1 g, 0.026 mol) were added and the reaction mixture was heated just below reflux temperature for 64 h. After cooling, the reaction mixture was filtered (Hyflo) and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (275 g) using a mixture of heptane and ethyl acetate (1:1) as eluent, to give 3.4 g of 1-(3-(10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)-1-propyl)-2-methyl-3-piperidinecarboxylic acid methyl ester as an oil.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:57])[C:31]=1[CH2:32][CH2:33][C@H:34]1[O:39][CH2:38][C@H:37]([CH2:40][O:41][C:42]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:43])[N:36]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:35]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@H:8]([C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:5]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:57])[C:31]=1[CH2:32][CH2:33][C@H:34]1[O:39][CH2:38][C@@H:37]([CH2:40][O:41][C:42](=[O:43])[NH:44][CH2:45][C:46]([F:49])([F:47])[F:48])[N:36]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:35]1)=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (55 mg, 0.16 mmol) and the product from step 4 of Example 89 (76 mg, 0.16 mmol) were dissolved in pyridine (2 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 (0.02 mL, 0.19 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (2 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=808.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:13])[CH3:12].CC(C1C=CC2C(=CC=CC=2)C=1)=O.C1C2C(=CC=CC=2)C=CC=1[C@H](O)C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@@H:11]([OH:13])[CH3:12]
Reactant: CC(O)c1ccc2ccccc2c1
Agent: CC(=O)c1ccc2ccccc2c1
Agent: C[C@@H](O)c1ccc2ccccc2c1
Product: C[C@H](O)c1ccc2ccccc2c1
Reaction time: 96 h
Yield: 49.8 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized green pea protein for the substrate 1-(2-naphthyl)ethanol (201 mg) requires 4 days by going through bioconversion to 2-acetonaphthone accompanying sterically selective oxidation of (R)-1-(2-naphthyl)ethanol to obtain 100 mg of (S)-1-(2-naphthyl)ethanol at a yield of 50% at an optical purity of 99% e.e. or higher (see FIG. 1).
Reaction SMILES: O[CH:2]([CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)[CH3:3].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([SH:41])[CH:38]=[CH:39][CH:40]=1>CCOCC.ClCCl>[F:43][C:34]([F:33])([F:42])[C:35]1[CH:36]=[C:37]([S:41][CH:2]([CH:4]2[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH3:3])[CH:38]=[CH:39][CH:40]=1
Reactant: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cccc(S)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Sc1cccc(C(F)(F)F)c1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To 100 ml round bottom flask was added tert-butyl 3-(1-hydroxyethyl)azetidine-1-carboxylate (2.06 g, 10.2 mmol), triethylamine (4.2 ml, 30.7 mmol) and 40 ml dichloromethane. Methanesulfonyl chloride (0.955 ml, 12.3 mmol) was added at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hour. It was then diluted with 100 ml ether, washed with 2×50 ml saturated sodium carbonate solution. The organics were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 30 ml dimethylformamide. Potassium carbonate (3.75 g, 26.8 mmol) and 3-(trifluoromethyl)benzenethiol (1.91 g, 10.7 mmol) were added. The resulting reaction mixture was heated at 75° C. overnight. It was diluted with 120 ml ether, washed sequentially with 150 ml water, and 75 ml saturated sodium carbonate. The organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with hexane to 1:9 ethyl acetate/hexane to give 2.65 g desired product as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([NH:10][C:11](=O)[CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(I)C.CC(C)([O-])C.[K+].[OH-].[Na+]>O>[CH3:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(=O)Nc1ccc(C=O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCI
Solvent: O
Product: CCNc1ccc(C=O)c(C)c1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of purified 2-methyl-4-acetamidobenzaldehyde (9.6 g, 0.054 mole), ethyl iodide (10 ml, 0.125 mole), and 50 ml of tetrahydrofaran was warmed to about 300 with stirring under a nitrogen atmosphere. Solid potassium t-butoxide (6.25 g, 0.056 mole) was added and the mixture was stirred for 2.5 hr at 30°. The mixture was concentrated under vacuum at 50° on a rotary evaporator to a syrup. The syrup was dissolved in methanol (30 ml) before adding water (20 ml) and then sodium hydroxide (5 g, 0.125 mole) to the mixture. After heating the mixture to reflux temperature for 30 min, it was cooled to rt and water (120 ml) was added. Solid product precipitated on stirring over night. After filtering and drying, 5.1 g (58%) of 2-methyl-4-ethylaminobenzaldehyde was obtained.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:38][CH2:37]2)[CH:30]=[CH:31][C:32]=1[N+:33]([O-])=O>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)[CH2:38][CH2:37]2)[CH:30]=[CH:31][C:32]=1[NH2:33]
Reactant: COc1cc(N2CCC(CN3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(N2CCC(CN3CCN(C)CC3)CC2)ccc1N

Procedure:
2-Methoxy-4-[4-(4-methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-phenylamine was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with 1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-ylmethyl]-4-methyl-piperazine. (200 mg, 100%). LC/MS (E/I+) 319.16 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])[C:8]=2[CH:24]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])[C:8]=2[CH:24]=1
Reactant: COC(=O)c1cccc(CN2CCOc3ccc([N+](=O)[O-])cc32)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2CCOc3ccc(N)cc32)c1
Yield: 50.8 %

Procedure:
A mixture of methyl 3-(6-nitro-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (0.65 g.) and palladium-on-carbon (10% w/w, 0.025 g.) in ethyl acetate (40 ml.) was hydrogenated at an initial pressure of 2.9 bar. The catalyst was removed by filtration through diatomaceous earth, washing the filter cake with ethyl acetate, and the filtrate was evaporated to give methyl 3-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (X) (0.3 g., 51%) as a gum; partial NMR (80 MHz, CDCl3): 3.3(m,2H, N.CH2CH2.O); 3.9(s,3H, OMe); 4.15(m,2H, N.CH2.CH2.O); 4.5(s,2H, NCH2Ar ).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH3:14])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][C:8]=1[CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1CC
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC

Procedure:
A solution of crude ethyl(2-ethylphenoxy)acetate (intermediate 107) in chloroform (6 ml) was stirred with chlorosulfonic acid (1.33 ml) at ambient temperature for 4 hours. The reaction mixture was quenched by the addition of ice and the organic mixture separated by using a hydrophobic frit. The title compound was isolated by evaporation of this filtrate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([C:19](=[N:21][OH:22])[CH3:20])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([Li])[CH2:24]CC.CN(OC)C(=O)C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl.NO>O1CCCC1.N1C=CC=CC=1.ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([C:19]3[CH:20]=[C:23]([CH3:24])[O:22][N:21]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=NO)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: [Li]CCCC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CON(C)C(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)no1
Reaction time: 1 h
Yield: 14.3 %

Procedure:
7-(1-Hydroxyimino-ethyl)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (2.89 g, 9.5 mmol) was cooled to 0° C. in tetrahydrofuran (70 ml) under argon. Butyllithium (7.6 ml, 2.5M in hexane, 19 mmol) was added dropwise to give an orange solution which was stirred for 1 h. N-Methyl-N-methoxy acetamide (824 mg, 8 mmol) was added dropwise in tetrahydrofuran (30 ml) over 3 min. The mixture was stirred for 1 h and then poured into water (27 ml) and concentrated sulphuric acid (3 ml). The resulting mixture was heated to reflux for 1 h and then cooled and neutralised with solid sodium bicarbonate. The mixture was partitioned between dichloromethane (200 ml) and water (100 ml) and the layers separated. The aqueous portion was extracted with dichloromethane (2×100 ml) and the combined organic extracts were evaporated. The residue was treated with dichloromethane (50 ml) and di-tert-butyl dicarbonate (2.18 g, 10 mmol) and the mixture stirred for 20 min, washed with water (50 ml) and evaporated. The residue was treated with pyridine (10 ml) and hydroxylamine hydrochloride (0.77 g, 11 mmol) and the mixture stirred for 1 h. The solvent was evaporated and the residue dissolved in dichloromethane (50 ml) which was washed with dilute hydrochloric acid (3×50 ml, 0.5M). The solvent was evaporated and the residue was purified by silica gel chromatography (eluent dichloromethane) which gave the title compound as a colourless solid (447 mg, 61%).
Reaction SMILES: [CH3:1][C:2](=[CH2:13])[CH2:3][N:4]1[NH:10][C:9](=[O:11])[CH:8]2[CH:6]([CH2:7]2)[C:5]1=[O:12]>[Pd].C(O)C>[CH2:3]([N:4]1[NH:10][C:9](=[O:11])[CH:8]2[CH:6]([CH2:7]2)[C:5]1=[O:12])[CH:2]([CH3:13])[CH3:1]
Reactant: C=C(C)CN1NC(=O)C2CC2C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1NC(=O)C2CC2C1=O
Yield: 77.8 %

Procedure:
To 40 ml of ethyl alcohol was added 2.03 g (11.28 mmol) of (±)-3-(2-methyl-2-propen-1-yl)-3,4-diazabicyclo[4.1.0]heptane-2,5-dione obtained in Reference Example 23, and 230 mg of a 5% (w/w) palladium-on-carbon catalyst was added thereto to conduct catalytic reduction under normal pressure. After completion of the reaction, the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to obtain 1.6 g (80%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27])([CH3:17])([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)=[O:13])([CH3:17])([CH3:15])[CH3:16]
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
The acid 114 (1.80 g, 9.27 mmol) was combined with (2-amino-phenyl)-carbamic acid tert-butyl ester (2.31 g, 11.1 mmol) and BOP (4.91 g, 11.1 mmol) in DMF. To this solution Et3N (5.16 ml, 37.1 mmol) was added and the mixture was stirred overnight at room temperature under nitrogen, concentrated in vacuo and purified by flash column chromatography (30% hexane/EtOAc). To further purify the product, the mixture was partitioned between EtOAc and water, organic layer was separated, dried over MgSO4 and evaporated give the title compound 115 (1.84 g, 52%). 1H-NMR (DMSO) δ: 9.72 (s, 1H), 8.66 (m, 1H); 8.22 (d, J=1.8 Hz, 1H); 7.80 (m, 3H); 7.50 (m, 2H); 7.37 (m, 1H); 7.14 (m, 2H); 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C(OCC)C.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:21])[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)=[CH:15][CH:14]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Oc1cccc2cc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(NC(=O)Oc2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 7-hydroxyindole (0.7 g.) in ethyl ether (25 ml) and triethylamine (1 ml) is added 0.8 g. 4-methoxyphenyl isocyanate (Aldrich 23860-0). The reaction is stirred for 3 days at room temperature. The solvent is removed in vacuo and the remaining oil is purified by HPLC on silica gel.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH:6]=[CH:7][C:8](=O)[CH2:9]C(OC)=O)#[N:2].[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][O:24][C:25](=[O:30])/[CH:26]=[C:27](\[NH2:29])/[CH3:28]>CCO>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][O:24][C:25]([C:26]1[CH:6]([C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([C:1]#[N:2])[CH:4]=2)[C:7]([C:25]([O:24][CH3:23])=[O:30])=[C:8]([CH3:9])[NH:29][C:27]=1[CH3:28])=[O:30]
Reactant: C/C(N)=C/C(=O)OCC1CCCO1
Reactant: COC(=O)CC(=O)C=Cc1cccc(C#N)c1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1cccc(C#N)c1
Temperature: -10 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 30 g (0.13 mol) of methyl 3-cyanobenzylideneacetoacetate and 24.24 g (0.13 mol) of (tetrahydrofuran-2-ylmethyl)-3-aminocrotonate in 130 ml of abs. ethanol was refluxed with stirring, in the absence of light, along 8 hours. The reaction mixture was then cooled to −10° C., and the product was obtained as a yellow solid (mp 127-9° C., EtOH) with a yield of 79%.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[S:49]1[CH:53]=[CH:52][N:51]=[C:50]1[C:54](=[N:56]O)[NH2:55]>CN(C=O)C>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[O:15][N:56]=[C:54]([C:50]3[S:49][CH:53]=[CH:52][N:51]=3)[N:55]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Reactant: NC(=NO)c1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1csc(-c2noc([C@@H]3CCNC3)n2)n1
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
(R)—N—Boc-pyrrolidine-3-carboxylic acid (700 mg, 3.25 mmol, 1.1 equiv), HBTU (1.23 g, 1.1 equiv) and DIEA (1.53 mL, 3 equiv) were dissolved in DMF (15 mL). The solution was stirred 5 min and then 1,3-thiazole-2-amidoxime (5a) (422 mg, 2.95 mmol, 1 equiv) was added. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with saturated aqueous NaHCO3, once with brine, then dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in 15 mL of DMF and then heated at 110° C. for 7 h. The solvent was removed under vacuum and the residue was dissolved in AcOEt. The organic layer was washed once with HCl 1N, once with saturated aqueous NaHCO3 and once with brine, then dried over MgSO4 and evaporated under reduced pressure. The obtained product was used in the next step without further purification. Boc intermediate was dissolved in dioxane (10 mL) and HCl 4N solution in dioxane (6 mL) was added. The reaction mixture was stirred overnight at room temperature and then the product was recovered by filtration and washed with petroleum ether to give 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (yield 66% over two steps). 4,4,4-trifluorobutyric acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.4 equiv) and DIEA (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 5-[(3R)-pyrrolidin-3-yl]-3-(1,3-thiazol-2-yl)-1,2,4-oxadiazole (0.62 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Beige powder; Yield 33%; 1H NMR (CDCl3) δ 8.02-8.00 (m, 1H), 7.57-7.60 (m, 1H), 3.89-4.03 (m, 2H), 3.69-3.87 (m, 2H), 3.53-3.65 (m, 1H), 2.38-2.55 (m, 6H); 13C NMR (CDCl3) cis/trans isomer mixture (60 isomer A/40 isomer B); isomer A δ 180.31, 168.50, 163.98, 153.53, 144.99, 126.94 (q, J=276 Hz), 122.87, 49.24, 45.52, 35.03, 29.05 (q, J=29 Hz), 28.86, 27.07 (q, J=3 Hz); isomer B δ 179.84, 168.31, 163.98, 153.38, 144.94, 126.92 (q, J=276 Hz), 122.81, 49.43, 45.25, 36.82, 30.28, 29.05 (q, J=29 Hz), 27.24 (q, J=3 Hz). tR LCMS 4.6 min. Purity >99%; MS [M+H]+ m/z 347.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[BH4-].[Na+].C[OH:24]>CCOCC.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([OH:24])[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC(O)CC1(C)C
Reaction time: 1 h

Procedure:
To a solution of 4a (13.7 g, 47.2 mmol) in 100 mL of methanol at 0°-5° C. was added NaBH4 (2.68 g, 70.9 mmol). The mixture was stirred for 1 hr, diluted with ether and H2O. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a quantitive yield of product which was taken forward without further purification.