Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([O:8][C:9]([C@@H:11]1[CH2:15][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:10])(C)C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O1CCCC1.O>[CH2:27]([O:26][C:24]([C@@H:12]1[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19])[CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:25])[CH3:28]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.4 %

Procedure:
To a solution of (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-cyclopentane-1,2-dicarboxylic acid 1-ethyl ester 2-(tert-Butyl-dimethyl-silanyl) Ester (epimeric mixture, 12.09 g) in ethanol (340 mL) and tetrahydrofuran (114 mL) was slowly added a solution of potassium carbonate (16.68 g) in water (114 mL). After 45 min at room temperature, the solvents were removed in vacuo. Brine was added to the residue and the mixture was cooled to 0° C. then the pH was adjusted to 4-5 using a 10% aqueous solution of potassium hydrogenosulfate. The resulting mixture was extracted with diethylether. The combined organic layers were washed with brine then dried over sodium sulfate and concentrated in vacuo to afford the title compound (8.03 g, 90%) as light yellow oil, used in the next step without further purification. MS (EI): 315.2 (M−H)−.
Reaction SMILES: OCC([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)[OH:8])O)=O.[OH:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18].[Na+]>>[OH:8][CH:7]([CH3:5])[CH2:9][C:11]([O-:12])=[O:13].[OH:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])CCCO
Agent: [Na+]
Product: CC(O)CC(=O)[O-]
Yield: 20 %

Procedure:
The procedure of Example 2 was repeated except that the fructose was replaced with sodium 4-hydroxybutyrate (manufactured by Aldrich Corporation) to produce 1.2 g of 3-hydroxybutyrate-4-hydroxybutyrate copolymer (comprising 20% by mole of 4-hydroxybutyrate unit) having a number average molecular weight of 467,000. The thus produced copolymer product was added to a 100 ml solution comprising 1 volume of aqueous solution of sodium hypochroride (manufactured by Wako Pharmaceutical K.K.) and 1 volume of distilled water, and the suspension was heated to 50° C. for 2 hours. The resulting product had a number average molecular weight of 182,000.
Reaction SMILES: C(O[C:4](=[O:15])[C@H:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]=[S:28]>>[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]1[N:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[C@@H:5]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:4](=[O:15])[S:28]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CCOC(=O)[C@H](CC(C)C)NCC(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(=O)[C@H](CC(C)C)N1CC(C)C

Procedure:
N-Isobutylleucine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C11a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidin-5-one.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([Cl:30])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:24]1[C:23]2[CH:22]=[C:21]([C:19]3[O:18][N:17]=[C:16]([CH2:15][O:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:20]=3)[O:29][C:28]=2[CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(Cl)nccc4o3)n2)CC1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Clc1nccc2oc(-c3nc(COC4CCNCC4)no3)cc12
Reaction time: 1 h

Procedure:
A stirred solution of 4-[5-(4-chlorofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 57, 150 mg, 346 μmol) in CH2Cl2 (4 mL) was treated with H2O (6 μL) and TFA (1.5 mL). After 1 h, the reaction was concentrated in vacuo, then the excess TFA was removed through azeotropic distillation with PhMe under reduced pressure. The remainder was partitioned between EtOAc and 2M NaOH. The aqueous phase was extracted further with EtOAc, then the combined EtOAc extracts were washed with brine and dried (MgSO4). Filtration and solvent evaporation furnished 4-chloro-2-[3-(piperidin-4-yloxymethyl)-[1,2,4]oxadiazol-5-yl]furo[3,2-c]pyridine: m/z (ES+)=335.1 [M+H]+. A mixture of this amine (105 mg, 315 μmol), 2-bromopyrimidine (55 mg, 346 μmol) and DBU (95 μL, 630 μmol) in dioxane (2 mL) was stirred at ambient temperature for 16 h. The reaction was concentrated and the residue purified by column chromatography (EtOAc-IH, 3:7) to yield the title compound: RT=3.40 min; m/z (ES+)=413.1 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]([NH:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)=[O:32])[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:39][CH:40]=1)=[O:32])[CH3:27]
Reactant: CN(C)CC(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethylcarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C([O:8][CH:9]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]=2[N:11]2[C:28]([CH3:31])=[N:29][N:30]=[C:10]12)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[OH:8][CH:9]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:12]=2[N:11]2[C:28]([CH3:31])=[N:29][N:30]=[C:10]12
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2O

Procedure:
44.6 g of 4-(benzyloxy)-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 400 ml of ethanol containing 2.0 g of Raney nickel is hydrogenated at an initial hydrogen pressure of 40 p.s.i. After 0.1 mole of hydrogen has been absorbed, the reaction is stopped, filtered and the solvent evaporated. The residue is triturated in ether and the title compound filtered off and dried.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH:46]6[CH2:48][CH2:47]6)[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH:46]6[CH2:48][CH2:47]6)[CH:43]=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CC4CC4)cc2)CCN3CC(C)C)cc1
Solvent: CSC
Solvent: ClCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CC4CC4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylmethylimidazol-5-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (1.1 g) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (440 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylmethylimidazol-5-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (614 mg) (Compound 386) as yellow amorphous.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=3[F:30])[CH:12]=2)=[N:9][CH:10]=1)[CH3:2]>CCO.[Pd]>[CH2:32]([O:31][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[F:30])[CH:12]=2)=[N:9][CH:10]=1)[CH3:33]
Reactant: CCOC(OCC)c1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(OCC)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1
Reaction time: 8 h
Yield: 51.4 %

Procedure:
The intermediate 51 (0.29 g, 0.62 mmol) was solubilized in EtOH (100 mL) and palladium on charcoal 10% (0.075 g) was added. The reaction mixture was stirred overnight under hydrogen atmosphere, filtered through a celite pad and the filtrate was concentrated under reduce pressure. The residue was purified by column chromatography with 60-80% EtOAc in hexanes to afford intermediate 52 (0.14 g, 52% yield) as a colorless solid. MS (m/z): 440.1 (M+H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][CH:41]([C:43]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[O:44])[CH2:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Cc1ccccc1-3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCOCC1)Cc1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
TBTU (69 mg, 0.22 mmol) was added to a stirred solution of racemic 14b (60 mg, 0.0.144 mmol), morpholine (19 μL, 0.22 mmol), and N,N-diisopropylethylamine (300 μL, 1.7 mmol) in DMF (3 mL). The mixture was shaken at 22° C. for 18 hr. The resulting solution was injected on a Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave methyl 13-cyclohexyl-6,7-dihydro-6-(morpholinylcarbonyl)-5H-indolo [2,1-a][2]benzazepine-10-carboxylate as a colorless solid (60 mg, 86%). ESI-MS m/z 487 (MH+).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:18]C(Cl)(Cl)C(Cl)(Cl)Cl.O>O1CCCC1>[C:1]([N:5]1[C:9]([Cl:18])=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1cc(C(=O)O)cn1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(C(=O)O)c1Cl
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
tert-butyl-1H-pyrazole-4-carboxylic acid (5 g, 29.73 mmol) was dissolved in tetrahydrofuran (50 ml) at room temp. In a separate flask was added n-butyllithium (2.5M solution in hexane, 29.73 ml, 74.33 mmol) and was cooled to −15° C. The 1-tert-butyl-1H-pyrazole-4-carboxylic acid solution was added dropwise to the n-Butyllithium solution, maintaining internal temperature below −10° C. The total addition time lasted 30 min. The resulting brownish suspension was stirred and maintained between −10° C. and −15° C. for 40 min. The reaction was then cooled to −15° C. to −20° C. A solution of hexachloroethane (14.08 g, 59.46 mmol) in tetrahydrofuran (50 ml) was added dropwise, maintaining internal temperature below −10° C. The total addition time lasted 20 min. After the addition, the resulting dark brownish solution was stirred at −10° C. to −15° C. for 30 min and was warmed up to room temp. over 1 h. The reaction mixture was then cooled to 15° C. and water (50 ml) was added slowly, maintaining internal temperature below 20° C. 120 ml of organic solvents were distilled under reduced pressure at 25° C. water bath leading to a suspension. Heptane (50 ml) was added leading to a clear brownish biphasic solution. After stirring at room temp. for 15 min, the aqueous layer (pH=11.8) was separated. The organic layer was extracted once with NaOH (1N, 20 ml). The combined aqueous phase was washed with heptane (25 ml) and was cooled in an ice-bath. Hydrochloric acid (6N) was added to adjust pH=2, maintaining internal temperature below 20° C. The suspension was stirred in the ice-bath at 0-5° C. for 1 h and the solid was filtered and washed with water (40 ml). After drying in vacuo at 60° C. for 18 h, 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5.28 g) was obtained as a light yellow solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:5]1([S:11]([C:19]2[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(S(=O)(=O)c2ccccc2)cc1
Yield: 101 %

Procedure:
To a solution of 16 g of AlCl3 dissolved in 21.6 g of anisol was added dropwise 17.6 g of benzenesulfonyl chloride. The reaction mixture was heated to reflux for 8 hours and poured into 1N HCl solution containing ice. The resultant solution was extracted with ethyl acetate (100 ml×3), washed with 100 ml of saturated NaHCO3 aqueous solution, dried over Na2SO4 and concentrated to obtain residue, which was recrystallized from hexane-ethyl acetate to obtain 25 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([OH:18])=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH:34]1[CH2:38][CH2:37][C@@:36]2([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40](=[O:47])[O:39]2)[CH2:35]1>>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([N:34]4[CH2:38][CH2:37][C@@:36]5([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=6[C:40](=[O:47])[O:39]5)[CH2:35]4)=[O:18])[CH2:14][CH2:15]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1(c2ccc(-c3ccccc3)nc2)CC1
Reactant: O=C1O[C@]2(CCNC2)c2ccccc21
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccccc5)nc4)CC3)C2)c2ccccc21

Procedure:
1-(6-Phenylpyridin-3-yl)cyclopropanecarboxylic acid was then coupled with (1S)-(+)-10-camphorsulfonic acid salt of (1R)-3H-spiro-[2-benzofuran-1,3′-pyrrolidin]-3-one using procedures analogous to those of Example 83 to afford (1R)-1′-{[1-(6-Phenylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one. MS (ESI): (M+H)+=411.1
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11](=[O:20])[O:12]CC1C=CC=CC=1.CC#N.O.CCN(CC)CC>C(#N)C>[C:1]([NH:8][C@@H:9]([C:21]([OH:23])=[O:22])[CH2:10][C:11]([OH:12])=[O:20])(=[O:3])[CH3:2]
Reactant: N[C@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(=O)N[C@H](CC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic anhydride (85 μl, 0.90 mmol.) in acetonitrile (1 ml), there is added a solution of commercially available H-D-Asp(OBn)-OH (Senn Chemicals, CH-Dielsdorf) (200 mg, 0.90 mmol.) in a CH3CN.H2O/Et3N (3.5/1.0/0.4 ml) mixture. The reaction mixture is stirred for 18 hours at room temperature. The organic solvent is evaporated and the remaining aqueous phase is cooled down to 0° C., acidified with a 10% aqueous solution of citric acid till pH=3 and extracted with EtOAc (2×). The organic layers are pooled and dried over MgSO4, filtered and evaporated. The -benzyl ester of N-acetyl-D-aspartic acid obtained as a white crystalline solid (192 mg, 81%) is used in the next step with no further purification. (Rf=0.45 in 20/1 CH2Cl2/MeOH containing 2% of acetic acid, phosphomolybdinium compound and U.V. color development agent).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]([OH:10])=O)[O:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N(Cl)C(=O)C1.[CH3:38][O:39][C:40]([C:42]1[S:43][C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:45][C:46]=1[NH:47][CH:48]([CH3:50])[CH3:49])=[O:41]>ClCCCl>[CH3:38][O:39][C:40]([C:42]1[S:43][C:44]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[CH:45][C:46]=1[N:47]([CH:48]([CH3:50])[CH3:49])[C:8]([CH:5]1[O:4][CH2:3][CH:2]([CH3:1])[CH2:7][O:6]1)=[O:10])=[O:41]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reactant: CC1COC(C(=O)O)OC1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1OCC(C)CO1)C(C)C
Yield: 35.7 %

Procedure:
A solution 5-methyl-[1,3]dioxane-2-carboxylic acid (53 mg, 0.47 mmol) in 1,2-dichloroethane at 0° C. was treated with PPh3 (124 mg, 0.47 mmol), NCS (63 mg, 0.47 mmol) and isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.36 mmol). The reaction was heated at reflux for 3 days. The mixture was evaporated to a residue that was purified by silica gel column chromatography using EtOAc:hexanes as eluent to furnished 3-[isopropyl-(5-methyl-[1,3]dioxane-2-carbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (51.8 mg, 35% yield). 1H NMR (CDCl3, 400 MHz): 7.65 (d, 2H), 7.42 (m, 3H), 7.10 (s, 1H), 4.90 (q, 1H), 4.55 (s, 1H), 4.00 (dd, 1H), 3.90 (dd, 1H), 3.85 (s, 3H), 3.10 (t, 1H), 2.95 (t, 1H), 2.10 (m, 1H), 1.25 (d, 3H), 1.05 (d, 3H), 0.58 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([CH3:32])([CH3:31])[CH2:14][CH2:15][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]#[N:18])[CH2:9][CH2:8]1.[OH:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:35]=[CH:34][CH:33]=[C:4]([CH2:5][O:6][CH:7]3[CH2:12][CH2:11][N:10]([C:13]([CH3:31])([CH3:32])[CH2:14][CH2:15][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:17]#[N:18])[CH2:9][CH2:8]3)[CH:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CCC(OCc2cccc(Br)c2)CC1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CCC(OCc2cccc(-c3cccc(O)c3)c2)CC1
Temperature: 60 °C
Yield: 72 %

Procedure:
1,1′-Bis(diphenylphosphino)ferrocenedichloro palladium(II) (8 mg, 0.09 mmol) was added to a suspension of the product of example 87 (100 mg, 0.19 mmol), 3-hydroxyphenylboronic acid (52 mg, 0.038 mmol) and sodium carbonate (40 mg, 0.038 mmol) in tetrahydrofuran (5 mL) and water (1 mL) and the mixture was heated at 60° C. for 12 hours. The suspension was allowed to cool to room temperature and then evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 99:1:0 to 98:2:0.2; to give the title compound as a gum in 72% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40]O)=[CH:30][CH:29]=1>C(Cl)Cl.[Al]>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][I:20])=[CH:30][CH:29]=1
Reactant: II
Reactant: OCc1ccccc1-c1ccc(Cl)cc1
Agent: [Al]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(-c2ccccc2CI)cc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Triphenylphosphine (8.47 g, 32.3 mmol), iodine (8.94 g, 35.2 mmol), imidazole (2.40 g, 352 mmol), and CH2Cl2 (110 mL) were combined in a round-bottom flask, and the mixture was stirred for 15 minutes. A solution of (4′-chloro-biphenyl-2-yl)-methanol in CH2Cl2 (40 mL) was then added, and the reaction was stirred at room temperature for 16 hours (flask was wrapped in aluminum foil to shield it from the light). A saturated aqueous Na2S2O2 was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The organic layers were combined, dried over MgSO4, and concentrated. The crude residue was purified by flash chromatography on silica gel (0-10% EtOAc/heptanes) to afford the title compound as an off-white solid (5.33 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.51-7.53 (m, 1H), 7.38-7.46 (m, 4H), 7.28-7.37 (m, 2H); 7.15-7.17 (m, 1H).