Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[S:5][CH:6]=1.[O:11]=[S:12]1(=[O:39])[CH2:17][CH2:16][CH:15]([C:18]2[C:26]3[C:21](=[C:22](C(N)=O)[CH:23]=[C:24](B4OC(C)(C)C(C)(C)O4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O>[CH:8]1([CH2:7][C:4]2[S:5][CH:6]=[C:2]([C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[C:18]4[CH:15]3[CH2:16][CH2:17][S:12](=[O:11])(=[O:39])[CH2:13][CH2:14]3)[CH:3]=2)[CH2:10][CH2:9]1
Reactant: Brc1csc(CC2CC2)c1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=S1(=O)CCC(c2c[nH]c3ccc(-c4csc(CC5CC5)c4)cc23)CC1
Temperature: 100 °C
Yield: 24.6 %

Procedure:
4-Bromo-2-(cyclopropylmethyl)thiophene (50 mg, 0.23 mmol), 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (80 mg, 0.19 mmol) and K2CO3 (105 mg, 0.76 mmol) was taken up in 1,4-dioxane (3 mL) and water (1.5 mL) in a microwave vial. The mixture was degassed by bubbling argon through it for 5 min. PdCl2(dppf).DCM adduct (25 mg, 0.031 mmol) was added, and the reaction was heated in a microwave for 5 min at 100° C. The reaction mixture was concentrated, diluted in DMSO, and purified on a Gilson HPLC(NH4OH buffer). The desired fractions were concentrated, giving 18 mg (22%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:24][CH2:25][OH:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:28].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([CH2:24][C:25]([OH:28])=[O:26])[CH2:10]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
(S)-2-(2-Hydroxy-ethyl)-piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (cf. WO 96/31501; S. Fustero et al., Org. Lett. 9 (2007), 5283; 2.862 g, 7.85 mmol) was dissolved in 78.5 ml of DCM and pyridinium dichromate (14.772 g, 39.27 mmol) was added. The mixture was stirred at room temperature overnight, then diluted into brine (330 ml) and extracted three times with EA (70 ml). The combined organic phases were washed with water (300 ml), filtered over diatomaceous earth, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The product was dissolved in EA and extracted three times with a 1 N solution of sodium hydroxide. The combined aqueous phases were acidified to pH 1 with 6 N hydrochloric acid, extracted with EA and the combined extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness. 2.226 g of the title compound were obtained as a thick colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][O:23]C)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].CCCCCCC>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCCCCCC
Product: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Reaction time: 1 h
Yield: 729.8 %

Procedure:
To a solution of 4-(3-bromo-4-fluorophenyl)-3-(4-(2-methoxyethylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (can be prepared according to Example 1, steps A-G; 1232 g, 3.08 mol) in dichloromethane (12 L) stirring in a 22 L flask at 0° C. was added boron tribromide (354 mL, 3.67 mL) dropwise at a rate so that the temperature did not exceed 10° C. After stirring on ice for 1 h, a solution of saturated aqueous sodium bicarbonate (2 L) was carefully added at a rate so that the temperature did not exceed 20° C. (addition time 10 min). The resulting mixture was transferred to a 50 L separatory funnel, diluted with water (10 L), and the pH of the aqueous layer adjusted from 1 to 8 using solid sodium bicarbonate. The layers were separated, and the organic layer was washed with water (10 L), and the solvents removed in vacuo to afford a tan solid (24 mol processed in multiple runs, 9.54 kg, quant. yield). The material was slurried in 4 volumes of 7:1 heptane:ethyl acetate (4×22 L flasks), filtered, and dried to furnish the title compound as a tan solid (8679 g, 94%). The product was a mixture of the hydroxy- and the corresponding bromo-species.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=1.[Cl-:30].[NH4+]>BrC(Br)C.CCOCC.O1CCCC1>[ClH:30].[F:10][C:11]1[CH:29]=[CH:28][C:14]2[C:15]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][C:24]([OH:27])([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:9])[CH2:25][CH2:26]3)=[N:16][O:17][C:13]=2[CH:12]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Reactant: Cc1ccccc1Br
Reactant: [Cl-]
Agent: CC(Br)Br
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1C1(O)CCN(CCCc2noc3cc(F)ccc23)CC1
Product: Cl
Reaction time: 1 h

Procedure:
To a suspension of 0.9 g of magnesium shavings and a few drops of dibromoethane in 30 ml of ether was added a solution of 6.2 g of 2-bromotoluene in 30 ml of ether. After the addition was complete, the mixture was stirred under reflux for one hr, cooled, and a solution of 5 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 ml of tetrahydrofuran was added. After one hr, the mixture was diluted with ether, poured into 400 ml of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was converted to 6.4 g (82%) of product by treatment with ethereal hydrogen chloride. Recrystallization from ethyl acetate/methanol gave the analytical sample, mp 191°-192° C. (dec).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH2:13]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:8][C:7]3[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=3[F:9])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pentafluorophenol (11.5 mmol) is added at 0° to a mixture of 10.5 mmol 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylic acid and 10.5 mmol of dicyclohexylcarbodiimide in ethyl acetate. The mixture is stirred at 25° C. for a period of 18 hours whereupon a precipitate is formed. The reaction mixture is filtered, the filtrate washed with water and brine and dried, the solvent removed in vacuo to obtain pentafluorophenyl 4'-n-octyloxy[1,1'-biphenyl]-4-ylcarboxylate, C27H25F5O3, M.W. 492.5.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:38]/[C:39](/[CH3:46])=[CH:40]\[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:39]([CH3:46])[NH:38][C:12]([CH3:14])=[C:11]2[C:10]([O:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:23][CH2:24]2)=[O:15])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1ccc(Cl)cc1
Yield: 32.8 %

Procedure:
A mixture of p-chlorobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and ethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl ethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a yellow powder, m.p. 75°-79° C. (sintering). Yield 32.8%. IR(Nujol)cm-1 : 3300, 1695, 1670. NMR(CDCl3) δ: 1.17(3H,t,J=7.5,--CH2CH3), 2.28(6H,s, ##STR38## 4.95(1H,s,C(4) --H), 5.77(1H,broad s, NH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.O.C=O.[CH:34](O)=O>C1COCC1>[CH3:34][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Agent: C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C)CC2)cn1
Temperature: 80 °C

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide (200 mg, 4.8 mmol) was dissolved in 5 mL of THF and 0.5 mL of water and 0.04 mL of 38% formaldehyde and 0.06 mL of formic acid was added. The reaction was heated for 12 h at 80° C. The solution was extracted with methylene chloride and sodium bicarbonate. The resultant organics were concentrated and purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 33.3, 36.0, 43.1, 46.1, 53.0, 54.7, 55.3, 102.6, 102.9, 103.1, 105.9, 112.3, 112.6, 131.5, 137.7, 138.7, 162.0, 164.5, 169.2; MS 432.2 m/z (M+1).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: OB(O)c1cccs1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1csc(-c2nccs2)c1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
2-Bromothiazole (15.0 g) and 2-thiopheneboronic acid (14.0 g) were dissolved in dimethoxyethane (150 ml). To the mixture was added bis(triphenyl)phosphine palladium(II)dichloride (3.2 g) and 2M sodium carbonate (137 ml), and the mixture was refluxed under argon atmosphere for 2 hours. The mixture was cooled to room temperature, and the reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was collected, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=96:4) to give 2-(2-thienyl)thiazole (9.87 g) as oil. APCI-Mass m/z 168 (M+H)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:2]1([O:1][N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: OC1C=CCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1C=CCCC1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
A mixture of 3-hydroxycyclohexene (4.0 g), N-hydroxyphthalimide (6.7 g) and triphenyl phosphine (9.2 g) in tetrahydrofuran (200 ml) was stirred at room temperature. After the addition of diethyl azoformate (7.9 g), the resulting mixture was stirred for 20 hours at room temperature. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel (80 g), using chloroform as an eluent. The fractions containing the objected compounds were combined and evaporated to give N-(2-cyclohexen-1-yl)oxyphthalimide (6.5 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>CS(C)=O.O>[N:12]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)nc1
Yield: 76.3 %

Procedure:
A solution of methyl 6-chloronicotinate (25.4 g) and piperazine (38.3 g) in dimethylsulfoxide (125 ml) was heated at 100° C. for 2 hours then cooled and diluted with water, followed by extraction with ethyl acetate (4×). The combined organic layers were washed with water then dried over magnesium sulfate, filtered and evaporated to give a crude product that was triturated with isopropyl ether-hexane to yield methyl 6-(1-piperazinyl)nicotinate (25 g) as a light yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH3:10].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:10])[CH3:19]
Reactant: COc1ccccc1C(C)=O
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1OC
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2′-methoxyacetophenone (50 mmol), ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmol), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether.
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:28]>C(OCC)C>[Cl-:28].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Reactant: Cl
Solvent: CCOCC
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A suspension of 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (0.4 g, 1.08 mmol), prepared from example 3, and 1.0 M HCl solution in diethyl ether (0.047 g, 1.30 mmol) in diethyl ether (4 mL) was stirred at room temperature overnight. The reaction mixture was filtered and dried in vacuum to afford a 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium chloride as a crystalline white solid (0.43 g, 97.9% yield).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([CH2:8][CH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([NH:16][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](CCC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 24 h
Yield: 83 %

Procedure:
Compound 4 (139 mg, 0.6 mmol) was dissolved in dry CH2Cl2 (6 mL) and treated with L-Phe-OMe.HCl (142 mg, 0.66 mmol), EDCI.HCl (138 mg, 0.72 mmol), DIEA (128 μL, 0.72 mmol). The reaction mixture was stirred for 24 h, diluted with EtOAc, acidified with 10% citric acid and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaHCO3 and brine, dried (MgSO4) and concentrated. The crude residue was purified via column chromatography eluting with EtOAc/hexane to afford pure product 5 (188 mg, 80%) as a white solid. An analytical sample was purified by recrystallization (hexanes/EtOAc): m.p. 119.5-121° C. TLC Rf=0.60 (EtOAc/hexanes, v/v, 1:1). 1H NMR (500 MHz, CDCl3) δ 7.32-7.23 (m, 3H), 7.17-7.15 (m, 2H), 6.36 (bd, J=6.6 Hz, 1H), 4.96-4.89 (m, 1H), 4.54 (bs, 1H), 3.72 (s, 3H), 3.18, 3.07 (AB of ABX, JAB=13.9 Hz, JAX=6.0 Hz, JBX=7.2 Hz, 2H), 3.00-2.84 (m, 2H), 2.08-1.98 (m, 1H), 1.73-1.49 (m, 3H), 1.44 (s, 9H), 1.47-1.36 (m, 1H), 0.85 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.23, 172.47, 156.43, 136.40, 129.38, 128.79, 127.28, 79.42, 53.16, 52.46, 46.46, 38.72, 38.18, 33.16, 28.61, 26.21, 12.04; HRMS m/z (ESI): calc. for C21H32N2O5Na [M+Na]+415.2204, found 415.2199. Optical rotation: [α]rtD+14.9 (c 1.06, CHCl3). In addition, N-Boc γ-lactam (7.6 mg, 6%) was isolated via column chromatography eluting with EtOAc/hexane.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[C:25]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=[CH:29][C:28]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:27][CH:26]=1
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.1 %

Procedure:
Sulfuryl chloride (392 μl, 4.74 mmol) was added dropwise to a 0° C. suspension of triphenylphosphine-resin (1.58 g) in methylene chloride (10 ml). A solution of 4-biphenylsulfonic acid (400 mg, 1.58 mmol) and triethylamine (220 μl) in methylene chloride (5 ml) was added. The mixture was stirred at room temperature for 6 hours and stored at 5° C. for 3 days. This was filtered and the filtrate was evaporated. The residue was coevaporated with toluene twice to give the crude product as a white solid. Purification of the crude product by chromatography (silica, methylene chloride) gave 180 mg of the title product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=O)=[CH:5][CH:4]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:31])[CH3:30])[CH:24]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:30][N:29]([CH3:31])[C:25]1[CH:24]=[C:23]([N:22]([CH3:32])[CH3:21])[CH:28]=[CH:27][C:26]=1[C:7]1([C:6]2[CH:18]=[CH:19][C:3]([N:2]([CH3:20])[CH3:1])=[CH:4][CH:5]=2)[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)cc1
Temperature: 95 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)benzoic acid (26.8 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (16.4 g.) and acetic anhydride (80 g.) was heated (to 95° C.) during one hour, cooled and poured into dilute hydrochloric acid. The resulting mixture was basified. Recrystallization of the resulting solid from a mixture of toluene and hexane afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)-phenyl)phthalide (I: X=Y4 =(CH3)2N, Y2 =Z4 =Z5 =Z6 =Z7 =H) (m.p. 190°-194° C.).
Reaction SMILES: N#N.N[C@@H](CC1C=CC=CC=1)[C@H](O)CN1CCC[C@H]1C(N[C:12]([CH3:15])([CH3:14])[CH3:13])=O.C([O:34]C(N[C@H](C(O)=O)CSC)=O)C1C=CC=CC=1.OC1[C:54]2[N:53]=N[NH:51][C:50]=2[CH:49]=[CH:48][CH:47]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:12]([N:51]1[CH2:47][CH2:48][CH2:49][C@H:50]1[C:54]([NH2:53])=[O:34])([CH3:15])([CH3:14])[CH3:13]
Reactant: CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 650 mg of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N -tert.butyl- L-prolinamide and 538 mg of N-(benzyloxycarbonyl)-S-methyl-L-cysteine in 20 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 270 mg of hydroxybenzotriazole, 230 mg of N-ethylmorpholine and 412 mg of dicyclohexylcarbodiimide were added andthe mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removedby evaporation and the residue was chromatographed on silica gel using System G for the elution to give 800 mg of N2 -[3(S)-[N-(benzyloxycarbonyl)-S-methyl-L-cysteinyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide: MS: m/e 585 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:18]#[N:19])=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])#[N:2].[CH2:20]([NH2:23])[C:21]#[CH:22]>C(#N)C>[C:1]([C:3]([C:18]#[N:19])=[C:4]([NH:23][CH2:20][C:21]#[CH:22])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH3:15])#[N:2]
Reactant: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Reactant: C#CCN
Solvent: CC#N
Product: C#CCNC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Reaction time: 48 h

Procedure:
A mixture of the product of Step A (4.3 g, 14.7 mmole) and propargylamine (8.6 ml) in acetonitrile (43 ml) was stirred at reflux temperature under a positive pressure of nitrogen for 15 hours then at room temperature for an additional 48 hours. The reaction mixture was filtered to remove by-product and the filtrate was evaporated under reduced pressure. The residual gum was placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. The appropriate fractions were combined and the product recrystallized from acetonitrile to give the title compound; mp 112.5°-115°.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([NH:18][CH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=[O:17])=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-].[C].[H][H]>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([CH2:19][NH:18][C:16]([C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:17])[CH2:21]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNC(=O)[C@H]2CCCN2)C1
Reaction time: 5 h
Yield: 102.3 %

Procedure:
To a solution of 2.49 g of (2R)-1-benzyloxycarbonyl-N-({(3R)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl)pyrrolidine-2-carboxamide in 20 ml of methanol, 15 mg of 20% palladium hydroxide-carbon catalyst was added, followed by 5 hours' stirring in hydrogen atmosphere. After filtering the catalyst off, the solvent was distilled off under reduced pressure to provide 1.78 g of the title compound.