Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:41][C:42](=O)[NH:43][C:44]1[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:48]=1>O1CCOCC1>[C:49]([C:47]1[CH:48]=[C:44]([NH:43][C:42]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][N:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:41])[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@@H]5CCCCN5C)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
To a solution of Intermediate 62c (140 mg, 0.37 mmol) in 1,4-dioxane (4.00 mL) was added DIPEA (129 μL, 0.74 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 150 mg, 0.37 mmol). The reaction was heated to 60° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% MeOH in DCM. Further purification by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (73 mg, 31%). LCMS (Method 5): Rt 3.75 min, m/z 633.2 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.45 (1H, m), 1.60-1.83 (3H, m), 1.83-1.93 (2H, m), 1.93-2.07 (5H, m), 2.11 (1H, m), 2.20-2.33 (2H, m), 2.38 (3H, s), 3.05 (1H, dt, J 11.8, 2.8), 3.79 (1H, dd, J 10.9, 2.8), 4.91 (1H, dd, J 9.0, 5.7), 5.32 (1H, t, J 4.0), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.64 (1H, d, J 10.0), 8.43 (1H, d, J 1.7).
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: Cc1cccc(C)c1CNc1ccc2nc(-n3cc(C(=O)O)cn3)nc(N3CCOCC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI/CI): predicted mass C25H26N6O3, 458.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13](Br)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([NH:19][NH2:20])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: N#Cc1c(OCc2ccccc2)ccnc1Br
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(OCc2ccccc2)ccnc1NN
Temperature: 150 °C
Yield: 95.3 %

Procedure:
To a solution of intermediate compound D2 (1.2 g, 4.15 mmol) in THF (12 ml), was added hydrazine monohydrate (0.416 g, 8.301 mmol). The reaction mixture was subjected to microwave heating at 150° C. for 1 min. After cooling, additional hydrazine monohydrate (1 eq) was added to the resulting mixture, which was then subjected to microwave heating at 150° C. for 0.5 min. After cooling, the reaction mixture was concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield intermediate compound D3 (0.95 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:13].[Cl:14]OC(C)(C)C.O.[OH-].[NH4+]>C(OCC)C.ClOC(C)(C)C>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[CH2:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[F:13]
Reactant: CC(C)(C)OCl
Reactant: CC1(C)Cc2ccc(F)c(N)c2O1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1(C)Cc2c(Cl)cc(F)c(N)c2O1
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of 39.27 g (0.217 mole) of 7-amino-2,3-dihydro-2,2-dimethyl-6-fluorobenzofuran in 750 mL of diethyl ether was cooled to -5° C to 0° C., and 23.54 g (0.217 mole) of t-butyl hypochlorite was added in a dropwise manner during a fifteen minute period. The temperature rose to 10° C., but was lowered to 0°-5° C. at which the reaction mixture stirred for 20 minutes. Gas chromatographic analysis showed that the reaction was incomplete, and an additional 4.54 g (0.042 mole) of t-butyl hypochlorite was added. The mixture was stirred at 0°-5° C. for an hour after which gas chromatographic analysis showed that the reaction was still incomplete. Therefore, an additional 1.82 g (0.017 mole) of t-butyl hypochlorite was added to the reaction mixture, and stirring was continued for one more hour. At the conclusion of this period the reaction was determined to have been completed, and it was poured into 400 mL of water. To this mixture was added 100 mL of 10% ammonium hydroxide. The aqueous and organic phases were separated. The aqueous phase was washed with diethyl ether, and this wash was combined with the organic phase. The combined material was dried over anhydrous sodium sulfate, filtered, and the solvent 20 evaporated from the filtrate under reduced pressure, leaving a dark red oil as the residue. This oil was passed through a column of silica gel, eluting with petroleum ether:diethyl ether (9:1). Product-containing fractions were combined, and the solvent was evaporated under reduced pressure, yielding 40.24 g of 7-amino-4-chloro-2,3-dihydro-2,2-dimethyl-6-fluorobenzofuran as a red oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39]Br.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][CH2:39][C:38]1[C:37]([Cl:36])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:45])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
To a solution of 288 mg (0.74 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of dichloromethane, 0.21 ml (1.48 mmol) of triethylamine and 214 mg (0.89 mmol) of 2,6-dichlorobenzyl bromide were added, and the resulting mixture was stirred at room temperature for one day. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=60:1) to obtain 195 mg of 2-(2,6-dichlorobenzylamino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
With cooling on ice, an anhydrous N,N-dimethylformamide (DMF) solution (70 ml) of 1H-indole-2-carboxylic acid ethyl ester (45 g, 0.238 mol) was added dropwise to a solution of 50% sodium hydride (13.7 g, 0.286 mol) in anhydrous N,N-dimethylformamide (DMF) (90 ml). After one and half hour of stirring with cooling on ice, the reaction mixture was warmed to room temperature, and then stirred for one hour. After cooling on ice, an anhydrous N,N-dimethylformamide (DMF) solution of benzenesulfonyl chloride (50.4 g) was added dropwise, and the resulting mixture was stirred for one hour. An aqueous solution of 0.5 N hydrochloric acid was added dropwise to the reaction mixture, and then water was added thereto. The mixture was stirred for 30 minutes. The resulting solid was collected by filtration, and washed with water and then with n-hexane. The solid was dissolved in ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give crude 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester. The obtained crude product was recrystallized (ethyl acetate/hexane) to give 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester (68.9 g, 79%).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][C:7]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[OH:24])=[O:11])[CH2:6]1)(=[O:3])[CH3:2].C=O.S(O)([C:36]1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][C:7]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])([C:10]([N:12]2[CH2:13][C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:17]=[CH:16][C:15]=3[O:24][CH2:36]2)=[O:11])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCC(C(=O)NCc2cc(C(F)(F)F)ccc2O)(C(C)OC(C)=O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OC1CCC(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)(C(C)OC(C)=O)C1

Procedure:
3-[1-(Acetyloxy)ethyl]-3-({[2-hydroxy-5-(trifluoromethyl)benzyl]amino}carbonyl)cyclopentyl acetate was combined with paraformaldehyde (ca. 6 g) and TsOH H2O (ca. 100 mg) in 130 mL of toluene. The flask was equipped with a Dean Stark trap and condenser and the reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was filtered to remove remaining paraformaldehyde and the filtrate was concentrated. Purification of the resulting residue was accomplished by MPLC (silica, 65% ethyl acetate/hexanes) to afford 3-[1-(acetyloxy)ethyl]-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentyl acetate as a mixture of 8 diasteomers.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([N:33]([CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([N:33]([CH2:38][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:31][CH2:32]3)=[O:24])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CCCCN(CC(=O)OC(C)(C)C)[C@H]1CC[C@H](N)CC1
Product: CCCCN(CC(=O)OC(C)(C)C)[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (785 mg, 2.32 mmol) and t-butyl trans-(4-aminocyclohexyl-N-n-butylamino)acetate (680 mg, 2.32 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1-1/4) to give 1.06 g of t-butyl trans-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl)carbonylamino)cyclohexyl-N-n-butylamino]acetate as a colorless solid (75%).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28]
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CN(C)CCN
Product: COc1cc(NCCN(C)C)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 85 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using N,N-dimethylethylenediamine instead of thiomorpholine to the title compound (202 mg, 85%) which was obtained as an off-white solid. MS: m/e=438.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:28]3[NH:34][N:33]=[N:32][N:29]=3)([CH3:31])[CH3:30])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nc(CCCCCC(C)(C)C#N)oc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CCCCCC(C)(C)c3nnn[nH]3)oc2-c2ccc(OC)cc2)cc1
Yield: 50.8 %

Procedure:
5 g of 7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl)-2,2-dimethylheptanenitrile in 12 cm3 of dimethylformamide are treated with twice 2.7 g of sodium azide and twice 4.95 g of triethylamine hydrochloride according to the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 3.5 cm in diameter containing 120 g of silica gel (50 to 200μ). The column is eluted, collecting 50 cm3 fractions, with 0.5 liter of diisopropyl ether and then with 1.3 liters of a diisopropyl ether/ethyl acetate (70:30 by volume) mixture. The fractions emerging at between 0.85 liter and 1.3 liters are concentrated under reduced pressure (0.2 kPa). The solid is taken up with 30 cm3 of diethyl ether and drained, washed with 10 cm3 of diethyl ether and dried. 2.8 g (50%) of 5-{7-[ 4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-methyl-2heptyl}-1H-tetrazole are obtained in the form of white crystals, melting point 82° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:37][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:31][C:32]=2[CH3:48])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[S:6](Cl)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[NH2:5][CH:3]([CH3:4])[CH2:2][NH:1][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CC(N)CN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(N)CNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,2-Diaminopropane (1.00 g, 13.5 mmol, 1.15 mL, 1.1 eq.) was placed in CH2Cl2 (30 mL) and cooled to 0° C. Mesyl chloride (1.40 g, 12.3 mmol, 0.95 mL, 1.0 eq.) was added over a period of five minutes followed by triethylamine (3.72 g, 36.9 mmol, 5.17 mL, 3.0 eq.). The reaction was stirred for 30 minutes and then concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-15% MeOH/CH2Cl2 as the eluting solvent to obtain N-(2-amino-propyl)-methanesulfonamide as a clear, colorless oil (504 mg, 27%). 1H-NMR (CDCl3, 400 MHz) δ 3.17-3.03 (m, 2H), 2.98 (s, 3H), 2.88-2.80 (m, 1H), 1.12 (d, 3H, J=6.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[CH3:15][NH:16][CH2:17][CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[C:11]([I:13])[CH:10]=[C:6]([C:7]([N:16]([CH3:15])[CH2:17][CH2:18][CH3:19])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: CCCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
Mix 5-iodo-isophthalic acid monomethyl ester (3.6 g), N-methyl propyl amine (1.2 mL, 11.8 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.3 g, 11.8 mmol), and 1-hydroxybenzotriazole hydrate (1.6 g, 11.8 mmol) in dichloromethane (40 mL) and stir at room temperature for 4 h. Dilute with dichloromethane (20 mL), wash with water, 5% aqueous ammonium chloride solution, 5% aqueous sodium bicarbonate solution. Dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (3.2 g, 74%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:37]([NH:41][C:42]([C@@H:44]1[C:48]([CH3:50])([CH3:49])[S:47][CH2:46][N:45]1[C:51](=[O:69])[C@@H:52]([OH:68])[C@@H:53]([NH:61][C:62](=[O:67])[C@@H:63]([NH2:66])[CH2:64][CH3:65])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C.C(OCC)(=O)C>[C:37]([NH:41][C:42]([C@@H:44]1[C:48]([CH3:50])([CH3:49])[S:47][CH2:46][N:45]1[C:51](=[O:69])[C@@H:52]([OH:68])[C@@H:53]([NH:61][C:62](=[O:67])[C@@H:63]([NH:66][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([N:2]([CH3:1])[CH3:14])[CH:4]=1)[CH2:64][CH3:65])[CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:43])([CH3:38])([CH3:39])[CH3:40]
Reactant: CN(C)c1cccc(OCC(=O)O)c1
Reactant: CC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)COc1cccc(N(C)C)c1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 73 %

Procedure:
3-dimethylaminophenoxyacetic acid (51 mg), HOBt (35mg), and EDC.HCl (53 mg) were added to a solution of H-Abu-Apns-Dmt-NHtBu (120 mg) obtained in the step 1 in DMF and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography to obtain the title compound (120 mg).
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2([C:16]([OH:18])=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C:20]([NH:23][C:24](=[O:33])[CH:25]([OH:32])[C@@H:26]([NH2:31])[CH2:27][CH2:28][CH2:29][CH3:30])([CH3:22])[CH3:21].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(OCC)(=O)C>[OH:32][CH:25]([C@@H:26]([NH:31][C:16]([C:10]1([NH:9][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:18])[CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([NH:23][C:20]([CH3:19])([CH3:21])[CH3:22])=[O:33]
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Reactant: CCCC[C@H](N)C(O)C(=O)NC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)C(O)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
0.26 g (1.26 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid (1.26 mmol), 0.27 g (1.26 mmol) of (2RS,3S)-N-(2-methyl-2-propyl)-3-amino-2-hydroxyheptanamide and 0.24 g (1.5 mmol) of 1-hydroxybenzotriazole were dissolved in 15 ml of anhydrous methylen chloride and then, under air current of nitrogen, 0.29 g (1.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added thereto at 0° C. Thereafter, the reaction solution was warmed to the room temperature and stirred overnight. The reaction solution was concentrated under reduced condition. The residue thus obtained was dissolved in 100 ml of ethyl acetate and washed successively with water, aqueous solution of 10% potassium hydrogensulfate, aqueous solution of saturated sodium hydrogencarbonte and saturated brine. After drying over anhydrous magnesium sulfate, the reaction mixture was concentrated under reduced pressure. The residue was separated out with the silicagel column chromatography, whereby 0.35 g of N-[(2RS,3S)-2-hydroxy-1-[N-(2-methyl-2-propyl)amino]-1-oxo-3-heptyl]-1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxamide was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:29])[C:7]([C:10](=S)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C[O:31][C:32](=[O:46])[C:33](=[N+]=[N-])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]2[O:41][CH2:42][O:43][C:37]=2[CH:36]=1>CCOCC>[CH2:1]([C:5]1[N:6]([CH3:29])[C:7](/[C:10](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([OH:23])=[O:22])=[C:33](\[CH2:34][C:35]2[CH:40]=[CH:39][C:38]3[O:41][CH2:42][O:43][C:37]=3[CH:36]=2)/[C:32]([OH:46])=[O:31])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)=[N+]=[N-]
Reactant: CCCCc1ncc(C(=S)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C
Solvent: CCOCC
Product: CCCCc1ncc(/C(=C(\Cc2ccc3c(c2)OCO3)C(=O)O)c2ccc(OC)cc2OCC(=O)O)n1C

Procedure:
The freshly prepared 2-n-butyl-1-methyl-5-(2-t-butoxycarbonylmethoxy-4-methoxythiobenzoyl)-1H-imidazole (206 mg, 0.49 mmol) was dissolved in ether (2 ml) and methyl-2-diazo-3-(3,4-methylenedioxyphenyl)propionate as prepared in Example 1(g) (117 mg, 0.50 mmol) was added under argon. After standing at ambient temperature for 1 week, several drops of hexanes were added to the Et2O solution and the resulting white ppt (162 mg) was collected by filtration to afford the (2RS,3RS) isomer of the title compound. Further addition of hexanes and cooling afforded the (2RS,3SR) isomer as a pale pink solid (60 mg). The filtrate containing the title mixture of thiiranes was chromatographed on silica gel to afford complete separation. (167 mg, (2RS,3RS) isomer; 116 mg (2RS,3SR) isomer; 92%).