Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.C(OC(C)(C)C)(=O)C=C>C1(C)C=CC=CC=1>[OH:4][CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC=Cc1ccccc1
Agent: C=CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: OC=Cc1ccccc1
Temperature: 60 °C

Procedure:
A 22 L reactor was charged with 2.919 kg acetoxystyrene, 1.538 kg t-butyl acrylate, 231 g BPO and 6 L toluene. The reactor was purged with nitrogen, and the reaction solution was heated at 60° C. under a N2 atmosphere for 23 h. The solution was then cooled to room temperature, diluted with an additional 12 L of toluene, and 248 L of heptane:isopropyl alcohol (30:1) was added. The precipitate was collected by vacuum filtration, and washed with 24 L heptane. The solid was recrystalized by first dissolving it in 15 L acetone and then adding 300 L isopropyl alcohol:water (51:24 v/v). The product was collected by vacuum filtration, rinsed with 30 L 1:1 isoproyl alcohol:water, and then dried at 50-55° C. under vacuum to a constant weight.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([C:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH:12]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1

Procedure:
To a mixture of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.52 g, 4.93 mmol), 2-bromo-5-nitropyridine (1.00 g, 4.93 mmol) and PdCl2(PPh3)2 (173 mg, 0.246 mmol) under nitrogen was added dioxane (30 mL) followed by 3 M aqueous Na2CO3 (4.93 mL, 14.8 mmol). The resulting mixture was degassed with a stream of nitrogen for 10 minutes then heated at reflux for 16 hours. On cooling, EtOAc (150 mL) was added and the resulting mixture was washed with water (3×50 mL) and brine (50 mL). The organics were dried (Na2SO4), filtered and concentrated under reduced pressure to give a brown solid that was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound I5 as a yellow solid (1.43 g, 95%); 1H NMR (400 MHz, CDCl3) δ 9.37 (dd, J=2.6, 0.5 Hz, 1H), 8.43 (dd, J=8.8, 2.7 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.95-6.83 (m, 1H), 4.20 (d, J=3.0 Hz, 2H), 3.67 (t, J=5.6 Hz, 2H), 2.70-2.63 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 6.140 min; m/z 304 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:30]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)([C:14](=[O:15])[NH:37][CH2:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)NCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (6.32 mmol; 2.5 g) in DMF (50 mL) was added cyclohexylmethylamine (7.59 mmol; 0.99 mL), N,N-diisopropyl-N-ethylamine (15.8 mmol; 2.80 mL) and HBTU (7.59 mmol; 2.88 g), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, and the resulting solution was washed with a 1N hydrochloric acid solution (2×25 mL), and brine (25 mL), and dried over magnesium sulfate. After filtration and evaporation, the residue was purified via flash column chromatography (eluent gradient: 0 to 50% EtOAc in heptane) to yield 4-biphenyl-4-ylmethyl-4-(cyclohexylmethyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester after evaporation. The material thus obtained was dissolved in THF (8 mL) and a 4N HCl solution in 1,4-dioxane (15 mL) was added. The resulting mixture was stirred overnight at room temperature and evaporated. The residue was triturated with diethyl ether and dried to yield 4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt. MS (ESI) m/z 391.09 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-:28].[K+].[K+]>C(#N)C.C(OC(=O)C)C>[CH2:12]([O:28][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: O=C(CO)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCOc1ccccc1C(C)=O
Yield: 81.6 %

Procedure:
In acetonitrile (50 mL), 2-hydroxyacetophenone (3.9 g) and 1-bromopentadecane (8.4 g) were dissolved. Potassium carbonate (7.9 g) was added thereto and refluxed with heating for 48 hours. After cooling the reaction solution, it was diluted with ethylacetate and filtered with Celite (brand name). The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10). To the obtained solid, methanol was added, filtrated and dried under reduced pressure to obtain the title compound (8.1 g) having the following physical property values.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][CH3:7])C.[CH3:9][C:10]([CH3:12])=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>CCOCC.CCO>[CH3:9][C:10]1[CH:12]=[C:4]([CH2:5][CH2:6][CH3:7])[NH:18][C:16](=[O:17])[C:15]=1[C:13]#[N:14]
Reactant: CC(C)=O
Reactant: N#CCC(N)=O
Reactant: CCCC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CCCc1cc(C)c(C#N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of NaNH2 (32.5 g, 862 mmol) in anhydrous ether (500 mL) at 30° C. was added dropwise a mixture of butyric acid ethyl ester (50 g, 431 mmol) and acetone (37.5 g 646.5 mol). After addition, the reaction mixture was stirred for 4 h. The reaction mixture was poured onto ice water with stirring. Additional ether was added, and the layers were separated. The aqueous layer was acidified to pH 5.0 with 2 N HCl and then to pH 7.5 with Na2CO3. The aq. layer was then extracted with ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product (20 g, 156 mmol) and 2-cyanoacetamide (13.12 g, 156 mmol) were suspended in EtOH (160 mL) at 75° C., followed by addition of piperidine (13.2 g, 156 mmol). The contents were stirred and heated at reflux for 1 h. The mixture was cooled to room temperature, and filtered. The collected solid was suspended in water and stirred for 1 h. The mixture was filtered and dried to give 4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinecarbonitrile (11 g, 40%). LCMS E-S (M+H)=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.3-12.4 (br s, 1H), 6.25 (s, 1H), 3.64 (s, 3H), 2.50 (t, 2H), 1.63 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([Cl:10])[N:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:10][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]2[NH:13][N:12]=[N:11][N:9]=2)=[CH:6][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc(Cl)nc1N
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1nc(Cl)ncc1-c1nnn[nH]1
Temperature: 100 °C
Yield: 43.1 %

Procedure:
Into a sealed tube were added 4-amino-2-chloro-pyrimidine-5-carbonitrile (837 mg, 5.4 mmol), sodium azide (7.1 mmol, 1.3 eq.), triethylamine hydrochloride (7.1 mmol, 1.3 eq.) and 14 mL of toluene. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate, transferred to a separatory funnel and extracted three times with water. The aqueous extractions were combined and acidified to a pH of 4 with concentrated HCl. The precipitate was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 460 mg of the product, which was used without further purification. MS (EI) for C5HClN7: 198 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1>C(O)CCC>[N:12]1([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: c1ccc2[nH]cnc2c1
Solvent: CCCCO
Product: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reaction time: 17 h
Yield: 26.2 %

Procedure:
8 g of 2,6-dichloropurine, 150 ml of butanol and 5.5 g of benzimidazole are mixed and brought to a temperature of 80° C. for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum are carried out, and 3 g of expected product are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:4][CH2:3]1.CN1CCNCC1.C(#N)C=C.[C:23](Cl)(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:4][CH2:3]1
Reactant: CN1CCN(CCCN)CC1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CN1CCNCC1
Solvent: C=CC#N
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)NCCCN1CCN(C)CC1

Procedure:
4.7 g. (0.03 mol) of N-methyl-N'-(3-aminopropyl)-piperazine (prepared from N-methyl piperazine and acrylonitrile and subsequent reduction to the primary amine) in 200 mL chloroform was cooled down in an ice bath. To this was added 7.3 g. (0.03 mol) of myristoyl chloride dropwise for two hours. The reaction mixture was brought to room temperature and then allowed to react for another four hours. The reaction mixture was treated with 10 g. of sodium bicarbonate in 100 mL water and the separated chloroform layer was washed with water (2×200 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Crystallization from acetonitrile afforded 8 g. (72.3%) of the subject product.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[CH:5]=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.[CH2:21]([Mg]Cl)[CH2:22][CH2:23][CH3:24].Cl>C1COCC1.C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cccc(Br)n1
Reactant: CCCC[Mg]Cl
Agent: Cl
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCC(=O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromo-N-methoxy-N-methylpyridine-2-carboxamide (5.29 g, 21.58 mmol) in dry THF (120 mL) at −78° C. (dry ice/acetone bath) under nitrogen was added nBuMgCl (15.2 mL of a 20% wt solution in THF/toluene, 25.84 mmol) drop-wise over 15 minutes. The resulting yellow mixture was stirred at this temperature for 1 hour and was then allowed to warm to 0° C. (ice/water bath) slowly over 1.5 hours and then to rt over 18 hours. The yellow cloudy mixture was then added portion-wise to a stirred solution of aqueous HCl (2M, 200 mL) and the resulting mixture partitioned with EtOAc (200 mL) and the layers separated. The aqueous was re-extracted with EtOAc (200 mL) and the combined organic layer washed with brine (300 mL), dried (MgSO4) filtered and reduced to give a yellow/orange oil. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 20:1 to 1:2) afforded the title compound (2.51 g).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:14]2[O:13][C:12]([CH3:16])([CH3:15])[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[S:17](=[O:21])(=O)(O)[OH:18].[ClH:22].S(=O)=O>O.ClCCCC.C(O)(=O)C>[CH3:15][C:12]1([CH3:16])[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:17]([Cl:22])(=[O:21])=[O:18])[C:14]=2[O:13]1
Reactant: O=S(=O)(O)O
Reactant: Cl
Reactant: CC1(C)Cc2cccc(N)c2O1
Agent: O=N[O-]
Agent: O=S=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCl
Product: CC1(C)Cc2cccc(S(=O)(=O)Cl)c2O1
Temperature: 10 °C
Reaction time: 0.4 h

Procedure:
A diazonium salt was prepared by adding 13.8 g of sodium nitrite to a suspension of 32.6 g of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran and 40 ml of concentrated sulfuric acid in 200 ml water cooled 0° to 5° C. After stirring for about 0.4 hour at 0° to 5° C., the diazonium salt suspension was poured in one portion into a mixture consisting of 170 ml of acetic acid, 40 ml of concentrated hydrochloric acid, 17 g of cupric chloride dihydrate and 30 ml of sulfur dioxide and cooled at 10° C. by an ice-water bath. The mixture was stirred about 1 hour at 15° to 25° C. Then 400 ml of 1-chlorobutane and 200 ml of water was added and the mixture was stirred and heated at 35° C. for 5 hours. After cooling to room temperature, the organic layer was separated, washed with saturated aqueous NaHCO3 and water, and dried over sodium sulfate for 0.5 hour. The solvent was evaporated under reduced pressure at less than 45° C. to give 26 g of crude 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonyl chloride as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][NH:13][S:14]([NH:17][C:18]([N:20]2[CH2:23][C@H:22]([NH:24]C(=O)OCC3C=CC=CC=3)[C:21]2=[O:35])=[O:19])(=[O:16])=[O:15])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>CCOCC>[NH2:24][C@H:22]1[CH2:23][N:20]([C:18]([NH:17][S:14]([NH:13][NH:12][C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)=[O:11])(=[O:16])=[O:15])=[O:19])[C:21]1=[O:35]
Reactant: O=C(NNS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)Nc1ccc(O)c(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: CCOCC
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)Nc2ccc(O)c(O)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 1.02 g (2.0 mmol) of (S)-[1-[[[[2-[[(3,4-dihydroxyphenyl)amino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added to a mixture of 3.31 ml of trifluoroacetic acid and 0.78 ml (6.63 mmol) of thioanisole. After stirring overnight at room temperature, the dark brown solution was dropped into 40 ml of dry ether (0° C.) and the precipitated material was collected by suction (1.15 g) and stirred with 10 ml of dry dichloromethane; yield: 0.92 g. This material was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H40Cl2N5O2 [(M+H)+] 608.2554, observed 608.2554.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:32]([OH:34])[CH3:33])/[CH:3]=[CH:4]/[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14]/[C:15](/[CH3:31])=[CH:16]/[C:17]([O:19]CCCCCCCCC(O)=O)=[O:18])[O:8][CH2:7]1.[OH-:35].[Na+]>>[CH3:1][C@@H:2]([C@@H:32]([OH:34])[CH3:33])[C:3]1[O:35][C:4]=1[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14]/[C:15](/[CH3:31])=[CH:16]/[C:17]([OH:19])=[O:18])[O:8][CH2:7]1
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reactant: [OH-]
Agent: [Na+]
Product: C/C(=C\C(=O)O)C[C@@H]1OC[C@H](CC2=C([C@@H](C)[C@H](C)O)O2)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Pseudomonic acid C (80 mgs) was dissolved in 0.1 M sodium hydroxide (20 ml) and stirred overnight at room temperature. After evaporation to low volume the solution was adjusted to pH 2 (5 M HCl), saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were dried (MgSO4) then evaporated to dryness and chromatographed on silica (2 g) eluting with gradient of 0 to 8% methanol/chloroform. Fractions containing pure product (by hplc and tlc) were combined to give monic acid C(40 mgs, 74%), νmax (KBr) 3400 (broad) 1692 (broad), 1644, 1238, 975 cm-1 ; λmax (EtOH) 218 nm (ε9679); δH (CD3OD) 0.97 (3H, d, J 8 Hz, CH3 -17), 1.08 (3H, d, J 7 Hz, CH3 -14), 2.13 (3H, s, CH3 -15), 5.4 (2H, m, H-10, H-11), 5.67 (1H, s, H-2); δC (CD3OD) 170.2 (Cl), 159.0 (C3), 135.8, 129.7 (C10, C11), 118.6 (C2), 76.2 (C5), 72.5 (C7), 71.6 (C13), 70.0 (C6), 65.8 (C16), 45.3 (C12), 44.1 (C4), 43.7 (C8), 33.7 (C9), 20.4 (C14), 19.3 (C15), 16.7 (C17). (Found: 284.1624. C16H28O6M.+ --C2H4O requires 284.1623).
Reaction SMILES: [CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@@H:6](O)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)[F:36])(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@H:6]([F:36])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](O)C(=O)OC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](F)C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(R)-hydroxypropionate H-3 (8.7 mmol) in DCM (10 mL) was added pyridine (25 mmol), the reaction was cooled to −20° C., then triflic anhydride (12.5 mmol) was added. The solution was stirred for 1 hour, then worked up as described above. The intermediate triflate was resuspended in DCM and cooled to −50° C. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (8.7 mmol) and the solution allowed to warm to rt. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated, then purified on silica gel (ethylacetate/hexanes) to afford 4.3 mmol (50%) of methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(S)-fluoropropionate H-4.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]#[N:5].C(Cl)(Cl)(Cl)[Cl:19].ClN1C(=O)CCC1=O.O>CCOCC>[CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[Cl:19])[C:4]#[N:5]
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 484 mg (2 mmol) of 3-methyl-2-(4-trifluoromethylphenylamino)butyronitrile (III; R is hydrogen) in 5 ml. of carbon tetrachloride is added 267 mg. (2 mmol) of N-chlorosuccinimide. The mixture is heated at 65°. After about 48 hours, the mixture is poured into water and ether. The organic fraction is separated, washed with water, and brine, dried over sodium sulfate, and solvent removed to give 3-methyl-2-(2-chloro-4-trifluoromethylphenylamino)butyronitrile (III; R is chloro).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1.[BH4-].[Na+].C(Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:22][C:20]3[O:21][C:17]([CH3:16])=[CH:18][CH:19]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: Cc1ccc(C=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)o1
Temperature: -20 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (60 mg, 246 μmol) and 5-methylfuran-2-carbaldehyde (111.2 mg, 1.0 μmol) in MeOH (3 ml) was stirred at 45° C. for two days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (55.8 mg, 1.47 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. Trituration with DCM afforded an off white solid as desired product (61.3 mg, 74% yield). MS +m/z: 338 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[CH3:14][S:15](Cl)(=[O:17])=[O:16].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:11]([NH:12][S:15]([CH3:14])(=[O:17])=[O:16])=[C:2]([CH3:1])[C:3]([O:4][CH2:5][C:6]#[N:7])=[CH:8][CH:9]=1
Reactant: Cc1c(OCC#N)ccc(Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
To a solution of crude (2-methyl-3-amino-4-chlorophenoxy)acetonitrile (11.53 g) in toluene (PhMe) (60 mL) was added methanesulfonyl chloride (MsCl) (4.5 mL, 6.7 g) and the resultant solution was warmed to 35-40° C. Pyridine (py) (4.7 mL, 4.6 g) was then added slowly over 2 h. The resultant mixture was permitted to cool to ambient temperature and stirred for 24 h. The crude product mixture was then partitioned between 1N hydrochloric acid (100 mL), and a mixture of ethyl acetate (300 mL) and tetrahydrofuran (100 mL). The organic phase was washed with water, then concentrated to ca. 200 mL, leading to crystallization of the desired product. The white crystalline product was collected, rinsed with toluene, and dried to afford 10.40 g (65.1% field) of N-(6-chloro-3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (>97% pure by HPLC). This material could optionally be recrystallized from isopropanol.