Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[C:2]=1[OH:8].[C:10](=O)(O)[O-].[K+].CI>CC(C)=O>[CH3:10][O:8][C:2]1[C:3]([OH:7])=[CH:4][CH:5]=[CH:6][C:1]=1[OH:9]
Reactant: Oc1cccc(O)c1O
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(O)cccc1O
Temperature: 25 °C
Yield: 27 %

Procedure:
To a stirring solution of benzene-1,2,3-triol (2 g, 15.87 mmol) in acetone was added potassium bicarbonate (1.90 g, 19.04 mmol) and methyl iodide (3.38 g, 23.80 mmol) and the resultant reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to RT and filtered through celite bed. The filtrate was concentrated under reduced pressure, triturated with diethyl ether and the obtained solid was separated and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (silica gel, 0-15% ethyl acetate in pet ether) afforded 2-Methoxybenzene-1,3-diol as a solid (600 mg, 27.2%). 4-Bromo-2-methoxybenzene-1,3-diol: To a stirring solution of 2-methoxybenzene-1,3-diol (3.0 g, 21.42 mmol) in tetrahydrofuran (30 mL) at −78° C. was added N-bromosuccinimide (4.57 g, 25.71 mmol) and the reaction mixture was stirred at −78° C. for 2 h. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained residue has mixture of products (mono and dibromo) which was used as such for further reactions (4.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH2:10][OH:11])[CH2:8][O:9][C:4]=2[CH:3]=1.CN(C=O)C.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:11][CH2:10][CH:7]1[O:6][C:5]2[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=2[O:9][CH2:8]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: OCC1COc2cc(Br)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)OCC(COCc1ccccc1)O2
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
A mixture of (6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (3.94 g, 16.1 mmol) and DMF (35 mL) at rt is treated with a 60% dispersion of NaH in mineral oil (0.706 g, 17.7 mmol). After 15 min, the mixture is treated with benzyl bromide (2.10 mL, 17.7 mmol). After 2 h, the mixture is poured into H2O and extracted with EtOAc (2×125 mL). The combined organics are washed with H2O (3×100 mL), brine, dried (MgSO4), filtered, and concentrated. The resulting oil is adsorbed onto SiO2 and chromatographed (Biotage 40M+SIM, 5% EtOAc/Hexane). The product fractions are pooled and concentrated to give an oil which solidified (upon standing) to give 3.91 g (73%) of 2-[(benzyloxy)methyl]-6-bromo-2,3-dihydro-1,4-benzodioxine: 1H NMR (400 MHz, CDCl3) δ 7.30-7.45, 7.06, 6.99, 6.81, 4.60-4.70, 4.30-4.40, 4.05-4.15, 3.65-3.85; MS (EI) m/z 244 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH3:13][NH:14][CH3:15].O>O1CCCC1>[CH3:13][N:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH3:15]
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CN(C)C)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 6-bromomethylnicotinate (350 mg) in tetrahydrofuran (5 ml) was added a 50% aqueous dimethylamine solution (3 ml), and the mixture was vigorously stirred at room temperature for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=100:1) to obtain methyl 6-(dimethylamino)methylnicotinate (276 mg) as brownish powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8](=[CH:14]N(C)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.Cl.[C:24]([NH2:27])(=[NH:26])[CH3:25].C(N(CC)CC)C>C(O)C>[CH3:25][C:24]1[N:27]=[C:6]([C:5]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:26]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc(C)nc1-c1ccc(OC)c(OC)c1
Yield: 45.9 %

Procedure:
A solution of ethyl 2-(3,4-dimethoxybenzoyl)-2-(dimethylaminomethylene)acetate (31 g), acetoamidine hydrochloride (13.3 g) and triethylamine (16.2 g) in ethanol (200 ml) was refluxed for 10 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The separatedorganic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl ether to give ethyl 2-methyl-4-(3,4-dimethoxyphenyl)-5-pyrimidinecarboxylate (14 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>ClCCl.CCOCC>[I:45][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]2
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(CO)ccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCc2cc(CI)ccc21
Reaction time: 0.33 h

Procedure:
To a solution of (R)-tert-butyl 6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (415.5 mg, 1.5 mmol) in dichloromethane/ether (1:1, 30 mL) at room temperature were added triphenylphosphine (590 mg, 2.25 mmol) and imidazole (153 mg, 2.25 mmol). To this stirred solution was then added iodine (571 mg, 2.25 mmol). After stirring for 20 min, the reaction was quenched with 10% Na2S2O3 (15 mL) until it became a clear two-phase solution. The aqueous phase was extracted with ether. The combined organic phase was dried over Na2SO4, filtered, and evaporated to dryness. Flash chromatography (SiO2, hexane/CH2Cl2=3:1 to pure CH2Cl2) afforded the title compound as a white solid. B. Preparation of (R)-tert-butyl 6-(2-(1,3-dithian-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate.
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([Cl:18])[CH:3]=1.COC1C(OCOCC[Si](C)(C)C)=CC(C)=C([B:27]([OH:29])[OH:28])C=1>>[Cl:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:27]([OH:29])[OH:28])[CH:3]=1
Reactant: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(C)cc1OCOCC[Si](C)(C)C
Product: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1B(O)O
Yield: 54 %

Procedure:
5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared in 54% yield from [2-(4-bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane according to the procedure for 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid. 1H NMR (300 MHz, CDCl3) δ 8.11 (s, 1 H), 7.09 (s, 1 H), 5.37 (s, 2 H), 3.84 (t, 2 H, J=8.4 Hz), 2.76 (s, 3 H), 0.98 (t, 2 H, J=8.4 Hz), 0.01 (s, 9 H). Anal. (C13H22BClO4Si—H2O) C, H. Calculated: C, 52.28; H, 6.75. Found: C, 51.98; H, 6.84.
Reaction SMILES: C([N:4]([CH2:8][CH3:9])[CH:5]([CH3:7])[CH3:6])(C)C.[C:10]1(C)[CH:15]=CC=C[CH:11]=1.O>CO>[NH:4]1[C:5]2[C:6](=[CH:11][CH:10]=[CH:15][CH:7]=2)[CH:9]=[CH:8]1
Reactant: Cc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: c1ccc2[nH]ccc2c1

Procedure:
In Scheme VIII, Step 4, 4-Benzyloxypropiophenone is brominated in acetic acid with bromine. When the reaction is complete the mixture can be quenched with water and the resulting precipitate is washed with dilute acetic acid, water and heptane. The resulting solid is dried to give IV, 4-benzyloxyaniline hydrochloride. In Step 5, a mixture of IV, N,N-diisopropylethylamine and toluene is heated under reflux with removal of water. When the reaction is complete the mixture may be cooled and diluted with methanol. The solids produced can be collected, washed with methanol and dried to give compound indole V. A mixture of compounds V and III can be mixed in Step 6 with sodium tert-butoxide in N,N-dimethylformrnamide and stirred until the reaction is complete. Then the mixture may be quenched with brine and extracted with toluene. The extracts are concentrated and the residue diluted with methanol. The resulting solids may be collected, dissolved in ethyl acetate, clarified, and diluted with methanol. The solids may be collected from this dilution and dried to give compound VI.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:33])=[CH:30][CH:29]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, light yellow solid (73 mg, 63%), MS (ISP) m/z=467.3 [(M+H)+], mp 224° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-chloro-benzoic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]([OH:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:9][C:8]([F:11])([F:10])[C:7]([C:5]1[S:6][C:2]([C:18]2[CH:19]=[CH:20][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: OC(c1ccc(Br)s1)C(F)(F)F
Reactant: CSc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CSc1ccc(-c2ccc(C(=O)C(F)(F)F)s2)cc1

Procedure:
1-(5-Bromo-4-thienyl)-1,2,2-trifluoroethanol (C1) in DUE added to Polymer-Bound Triphenylphosphine Pd(0) (0.5% eq) followed by 4-(methylthio)phenylboronic acid (1.3 eq)) in EtOH and K2CO3 (1.5 eq) in water and the mixture was stirred at 75° C. for 24 h. The suspension was filtered and the filtrate was purified by reverse phase HPLC as described for Example 3. MS (ES) C13H9F3OS2 requires: 302, found: 303 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:9])[CH3:8])[CH2:2]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:9])[CH3:8])[CH2:2]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
(R)-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene by method C. This resulted in the product with the molecular weight of 249.27 (C12H15N3O3); MS (ESI): 250 (M+H+).
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1>O1CCOCC1>[CH:7]1([CH2:6][NH:5][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=4)=[N:23][O:24][C:25]=3[CH2:26][OH:27])=[N:15][CH:14]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: NCC1CC1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.8 mL, 1.60 mmol) was added to a solution of aminomethylcyclopropane (78 mg, 1.06 mmol) in dioxane (5 mL). The mixture was stirred for 1 h at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=2:3 to 3:2) to afford the title compound (30 mg, 27%) as a colourless oil. MS: m/e=416.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1([C:17]2[O:21][N:20]=[CH:19][C:18]=2[CH2:22][CH2:23][C:24](O)=[O:25])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:18]2[CH:19]=[N:20][O:21][C:17]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A mixture of 4-aminobenzamide (0.55 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.87 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.88 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-carbamoylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.95 g, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 250–251° C.
Reaction SMILES: C(=O)(OC)O[CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.C1([C@@H]([N:25]([C@H:49]([C:51]2[CH:56]=[CH:55]C=CC=2)C)P2OC3C=CC4C=CC=CC=4C=3C3C4C(C=CC=3O2)=CC=CC=4)C)C=CC=CC=1.C1(NC)CC1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCO>[CH:51]1([CH2:49][NH:25][C@H:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH:4]=[CH2:3])[CH2:56][CH2:55]1
Reactant: COC(=O)OC/C=C/c1ccc(OC)cc1
Reactant: C[C@@H](c1ccccc1)N([C@@H](C)c1ccccc1)p1oc2ccc3ccccc3c2c2c(ccc3ccccc32)o1
Agent: CNC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: C=C[C@H](NCC1CC1)c1ccc(OC)cc1
Reaction time: 2.5 h
Yield: 839.2 %

Procedure:
A mixture of (2E)-3-(4-methoxyphenyl)prop-2-en-1-yl methyl carbonate (440 mg), N,N-bis[(1S)-1-phenylethyl]dinaphtho[1,2-f:2′,1′-d][1,3,2]dioxaphosphepin-4-amine (108 mg), [Ir(COD)Cl]2 (27 mg), cyclopropyl methyl amine (374 μL) and EtOH (5 mL) was stirred under refluxing EtOH for 6H under N2. The progress of the reaction was monitered by HPLC. At the end of the reaction, addition of co-solvent (20 ml EtOH and 20 ml THF) and MP-TsOH resin (6 g) and the mixture was allowed to stirred at RT with swilling every 15 mins for 2-3 hours. Filtered the resin and washed the resin with plenty of EtOH, THF, DCM. The resin was taken up in 3.5N NH3 in MeOH (20 mL) and let it stir for overnight. Filtered the resin and washed the resin excessively with EtOH, THF and DCM. Combined the filtrate and evaporated all the solvent. The crude product was purified by flash chromatography (10% EtOAc/Hexane) to afford the title compound as a viscous oil (365 mg, 84%). 1H NMR (300 MHz, CDCl3) δ 0.27 (m, 2H), 0.47 (m, 2H), 1.10 (m, 1H), 2.40 (m, 2H), 3.75 (s, 3H), 4.51 (m, 1H), 5.25-5.39 (m, 3H), 6.89-7.06 (m, 4H) (revealed branched/linear ratio (9:1)). MS APCI, m/z=218 (M+1). LC/MS 1.1 min., Method A. 80% ee was determined by NMR in the presence of TFAE-d11.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28](O)=[O:29])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:11])[F:13])=[O:29])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 5-(3-Chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=444.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[NH2:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([NH:9][C@H:10]([C:18]([NH:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:44])[CH3:45])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:5][CH2:6]1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of N-morpholinocarbonyl-L-phenylalanine (114 mg) and 2(S)-(L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (150 mg) in dry N,N-dimethylformamide (20 ml) which was cooled to 0° C., were added a solution of diphenyl phosphorylazide (125 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (46 mg). The mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (2% methanol in chloroform as eluent) to give 2(S)-(N-morpholinocarbonyl-L-phenylalanyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (174 mg) as an amorphous powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26](O)=[CH:25][C:23]=2[N:24]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:26]2[CH:27]=[CH:28][C:22]3[S:21][C:20]([CH3:19])=[N:24][C:23]=3[CH:25]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3sc(C)nc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 2-methyl-5-benzothiazolol and cleavage from the resin (Standard Procedure G) to give an oily solid. 1H-NMR (200.15 MHz, CDCl3): 7.65 (d, 1 H, J=8.9), 7.36–7.35 (m, 1 H), 7.16 (d, 2 H, J=8.9), 7.03 (dd, 1 H, J=8.9, 2.4), 6.86 (dd, 2 H, J=6.5, 1.9), 4.22 (t, 2 H, J=35.9), 4.18 (t, 2 H, J=6.2), 4.01 (dd, 2 H, J=6.4, 5.4), 3.43 (s, 3 H), 3.14–2.94 (m, 2 H), 2.87 (s, 3 H), 2.27 (qn, 2 H, J=6.2) ppm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[F:27][C:26]([F:29])([F:28])[CH2:25][CH2:24][CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: FC(F)(F)CCCBr
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCC(F)(F)F)CC1)O2

Procedure:
Compound 141 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-bromo-1,1,1-trifluorobutane and conditions outlined in procedure V. LCMS: 412 [M+H]; Rt=0.96 min.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:8]([CH3:22])[CH2:7]1)(=O)=O.[CH3:30][N:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>CN(C)C=O>[CH3:30][N:31]1[CH2:35][C:34](=[O:36])[N:33]([CH2:5][C@@H:6]2[CH2:20][C@H:19]3[C@@H:9]([CH2:10][C:11]4[C:21]5[C:14](=[CH:15][CH:16]=[CH:17][C:18]3=5)[NH:13][CH:12]=4)[N:8]([CH3:22])[CH2:7]2)[C:32]1=[O:37]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: CN1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CN1CC(=O)N(C[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)C1=O
Yield: 69.9 %

Procedure:
A mixture of 0.5 g of 6-methylergolin-8β-ylmethyl tosylate, 1.0 g of 1-methylimidazolidin-2,4-dione, 1.0 g of potassium carbonate, 10 ml of methyl ethyl ketone and 10 ml of dimethylformamide was refluxed for 4 hours with stirring, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residue (which was dissolved in dichloromethane and adsorbed on silica gel) was purified by silica gel column chromatography (eluted with ethyl acetate and then with ethyl acetate:isopropyl alcohol=1:1 by volume). The product was recrystallized from dichloromethane-hexane to obtain 0.3 g of the titled product as colorless needles having a melting point higher than 210° (with decomposition).