Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:15][CH:14]=1>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][N:3]2[CH:7]=[CH:6][CH:5]=[N:4]2)=[CH:22][CH:23]=1
Reactant: Fc1cc(F)cc(Oc2ccc(OCCCBr)cc2)c1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(F)cc(Oc2ccc(OCCCn3cccn3)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.3 %

Procedure:
To a mixture of anhydrous N,N-dimethylformamide (30 ml) and sodium hydride (60% oil suspension; 0.70 g), pyrazole (1.19 g) was added, and the resultant mixture was stirred for 30 minutes. A solution of 3-[4-(3,5-difluorophenoxy)phenoxy]propyl bromide (5.00 g) in anhydrous N,N-dimethylformamide (20 ml) was dropwise added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate (200 ml), washed with a saturated aqueous ammonium chloride solution two times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily substance thus obtained was subjected to column chromatography to give 4.20 g of 1-{3-[4-(3,5-difluorophenoxy)phenoxy]propyl}pyrazole as a colorless oil. nD23.5 1.5746.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:37]([NH:39][CH2:40][CH3:41])[CH3:38]>O1CCCC1>[CH2:37]([N:39]([CH2:40][CH3:41])[C:22](=[O:24])[CH2:21][CH2:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:19]=1)[CH3:38]
Reactant: CCNCC
Reactant: O=C(O)CCc1nc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCc1nc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12

Procedure:
The procedure is as in Example 7, starting with 2-(4-nitrophenyl)-4-quinazolinepropanoic acid (1.35 g), carbonyldiimidazole (0.82 g) and diethylamine (0.9 cc) in anhydrous tetrahydrofuran (20 cc). After chromatography on silica gel with ethyl acetate as eluant, and recrystallization in ethyl acetate, N,N-diethyl-2-(4-nitrophenyl)-4-quinazolinepropanamide (0.35 g), m.p. 168° C., is obtained.
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8]C=CC=2)[C:6](=O)[C:5]1=O)CC.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCC(C)C>>[CH2:5]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([CH3:15])=[CH:24][CH:23]=2)[C:19](=[O:26])[C:20]1=[O:25])[CH2:6][CH:7]([CH3:12])[CH3:8]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CC(C)CCBr
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCC(C)C

Procedure:
Made in an analogous fashion to 1-propylindoline-2,3-dione using commercially available 5-methyl isatin (purchased from Fisher Scientific) and 1-bromo-3-methylbutane (purchased from Fisher Scientific). 1H NMR δ 7.41 (m, 2H), 6.78 (d, 1H), 3.71 (t, 2H), 2.33 (s, 3H), 1.57 (m, 3H), 0.99 (d, 6H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C@:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: Cc1cnc(Br)cn1
Reactant: CC1(C)OB(c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cnc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
A solution of the compound (300 mg, 0.54 mmol) synthesized in Example 52-2), 2-bromo-5-methylpyrazine (234 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.11 mmol), and potassium carbonate (149 mg, 1.08 mmol) in water (2 mL) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (70 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=60:40 to 100:0) to obtain the title compound (139 mg, 49%) as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:11](=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54](Cl)=O)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>CC(=O)OCC>[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[O:1][N:2]=[C:3]([C:5]4[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:11](=[O:21])[C:12]5[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=5)=[CH:30][CH:31]=4)[N:4]=3)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(C(=N)NO)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2ccc(-c3nc(-c4ccc(CN(CC(=O)OC(C)(C)C)C(=O)c5ccc([N+](=O)[O-])cc5)cc4)no3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Prepared using General Procedure 20. To a stirred solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-nitrobenzamido)acetate (7.25 g, 16.6 mmol) INT-57 in dioxanes (25 mL) was added DIEA (3.19 mL, 18.24 mmol) then 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (3.83 g, 16.6 mmol). The reaction mixture was stirred at room temperature for 30 mins then at 120° C. for 3 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (400 mL) and washed with brine (500 mL). The organics were pre-absorbed onto silica gel and purified by chromatography (MeCN/DCM) to provide 7.35 g (73%) of tert-butyl 2-(N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-58 as a white powder. LCMS-ESI (m/z) calculated for C35H32N4O6: 604; found 549 [M-t-Bu+H]+, tR=3.24 min (Method 10).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.C1C2C3=CC4C(C(C=O)=C3[O:23][C:22]=2C=CC=1)=CC=CC=4>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1[C:9]2[C:8]3[C:10]([CH:22]=[O:23])=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: c1ccc2cc3c(cc2c1)oc1ccccc13
Reactant: O=Cc1c2ccccc2cc2c1oc1ccccc12
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=Cc1c2ccccc2cc2oc3ccccc3c12
Yield: 58 %

Procedure:
Benzo[b]naphtho[2,3-d]furan (H. G. Pars Pharmaceutical Laboratories, Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960). The crude aldehyde appeared to be mainly one isomer accompanied by a small amount of a second aldehyde by TLC. Purification by chromatography (SiO2, PhCH3) followed by recrystallization (CH2Cl2 /hexane) gave the main component in 58% yield identified using NMR techniques to be benzo[b]naphtho[2,3-d]furan-6-carbaldehyde, (2A) mp 169°-171.5°, (C,H). The minor component, obtained in 3.4% yield was shown by NMR to be benzo[b]naphtho2,3-d]-furan-11-carbaldehyde, mp 128°-132°, (C,H), (PhCH3 /hexane).
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22](=[O:24])[CH3:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH3:25][C:26]1[CH:27]=[CH:28][C:29](B2OC(C)(C)C(C)(C)O2)=[C:30]([NH2:32])[CH:31]=1.C(=O)([O-])O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:32][C:30]1[CH:31]=[C:26]([CH3:25])[CH:27]=[CH:28][C:29]=1[C:2]1[N:3]([CH2:21][C:22](=[O:24])[CH3:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(N)c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(C)=O)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(C)cc3N)n(CC(C)=O)c2c1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carboxylate (700 mg, 1.78 mmol) and 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (456 mg, 1.96 mmol) in 1,2-dimethoxyethane (6 ml) and water (2 ml) were added sodium hydrogen carbonate (177 mg, 2.14 mmol) and tetrakis(triphenylphosphine)palladium (103 mg, 0.09 mmol), and the mixture was heated under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give methyl 2-(2-amino-4-methylphenyl)-3-cyclohexyl-1-(2-oxopropyl)-1H-indole-6-carboxylate (727 mg, yield 97%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:14]([CH2:13][Br:12])=[O:9])=[CH:16][CH:17]=1
Reactant: Clc1ccc(SCBr)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=S(CBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
90% m-Chloroperbenzoic acid (17 mmol) in chloroform (35 ml) solution was added dropwise with stirring over 1 h at 0° C. to a solution of 1-bromomethylsulfenyl-4-chlorobenzene (15 mmol) in chloroform (35 ml). The mixture was stirred at room temperature overnight, shaken with 1M K2CO3 aq., the dried (MgSO4) chloroform solution evaporated and the solid residue recrystallized from CHCl3 : pet. ether; yield 3.20 g (84%), m.p. 100° C. 1H NMR (CDCl3): δ 4.28 (CH2), 7.53 (Ph). IR (KBr): 1040-1030 cm-1 (SO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][S:38]([CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:48][CH2:47]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: CS(=O)(=O)CCN1CCNCC1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(2-methanesulfonyl-ethyl)-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C35H43N4O5SCl2 [(M+H)+] 701.2326, observed 701.2325.
Reaction SMILES: [F:1][C:2]([F:21])([S:19][CH3:20])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.ClC1C=CC=C(C(OO)=[O:30])C=1.O>C(Cl)Cl>[F:21][C:2]([F:1])([S:19]([CH3:20])=[O:30])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: O
Product: CS(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a 10 ml solution of 150 mg (0.47 mmol) of 3,3-difluoro-2-(2',4'-difluorophenyl)-3-methylthio-1-(1H-1,2,4-triazol-1-yl)propan-2-ol [Compound (1a-1)] in methylene chloride, 114 mg (0.56 mmol) of m-chloroperbenzoic acid were added at room temperature, followed by stirring for 30 minutes. To the reaction mixture, water was added, followed by extraction with chloroform. The extract was then washed successively with a 10% aqueous solution of sodium thiosulfate and a 10% aqueous solution of sodium carbonate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The oil so obtained was purified by chromatography on a silica gel column using chloroform : methanol (10:1), whereby 64 mg of the title Compound (1b-1) [diastereomers (1b-1A):(1b-1B)=2.5:1] were obtained in the form of colorless crystals (yield: 40%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(C1[O:22]C1)Cl.C(O)(C)C.[OH-].[Na+]>O>[OH:1][C:2]1([OH:22])[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH2:3]1
Reactant: ClCC1CO1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=Cc1ccccc1)C1=CCC(O)(O)C=C1
Temperature: 55 °C

Procedure:
4,4'-Dihydroxy-alpha-methylstilbene (152.73 grams, 1.35 hydroxyl equivalents) from A above, epichlorohydrin (624.58 grams, 6.75 moles), deionized water (54.31 grams, 8.0 percent by weight of the epichlorohyrin used) and isopropanol (336.31 grams, 35 percent by weight of the epichlorohydrin used) is added to a reactor and heated to 55° C. with stirring under a nitrogen atmosphere. Once the 55° C. reaction temperature is achieved, sodium hydroxide (48.6 grams, 1.22 moles) dissolves in deionized water (194.4 grams) is added dropwise to the reactor over a 45 minute period so as to maintain reaction temperature between 55° and 59° C. Ten minutes after completion of the aqueous sodium hydroxide addition, the stirring is stopped and the aqueous layer which separated from the reaction mixture is pipetted off and discarded. Stirring is resumed and after a total of twenty minutes following completion of the initial aqueous sodium hydroxide addition, a second solution of sodium hydroxide (21.6 grams, 0.54 mole) dissolved in deionized water (86.4 grams) is added to the reactor over a twenty minute period so as to maintain the 55° C. reaction temperature. Fifteen minutes after completion of the aqueous sodium hydroxide addition, the recovered reaction mixture is added to a separatory funnel and washed with 750 milliliters of deionized water. The separated organic layer is washed a second time (750 milliliters deionized water), recovered and then rotary evaporated under vacuum for 45 minutes at 110° C. then 30 minutes at 130° C. The product is recovered (218.6 grams) as a crystalline solid with an epoxide equivalent weight of 183.33.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:11]=[CH2:12])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=1)[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[CH:14]=[CH2:15]>>[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=1)[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=2[CH:11]=[CH2:12])=[CH:23][CH:22]=1)[CH:14]=[CH2:15]
Reactant: C=Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=CCOc1cccc(Oc2ccc(C=O)cc2)c1
Product: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C=C)cc2)c1

Procedure:
The product from Example 44B and the product from Example 61C were processed as in Example 6A to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1ccccc1
Reactant: Cc1cccc(N)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccccc2)n1
Yield: 35.7 %

Procedure:
To a flask were added 2.2 g of 2-amino-6-methylpyridine, 3.1 g of bromobenzene, 2.7 g of sodium tert-butoxide, and 50 ml toluene. The mixture was purged thoroughly with nitrogen and 62 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalenehthalene and 22 mg of palladium acetate were added. The reaction mixture was heated to 100 C for 16 hours, and then cooled to 22 C. After quenching with 50 ml water, the product was extracted with 20 ml ethyl acetate, and washed with 15 ml water. The product was extracted with 50 ml of 1M hydrochloric acid, and then basified with aqueous ammonium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using a gradient from 10% ethyl acetate in hexane to 15% ethyl acetate in hexane, resulting in 1.3 g of a yellow-orange oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:33])[C@@H:4]([NH:12][C:13](=[O:32])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[C:16]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:48][CH2:49][CH2:50][C:51](=O)[CH2:52][CH2:53][CH3:54].CC(O)=O>C(Cl)Cl>[CH2:5]([C@H:4]([NH:12][C:13](=[O:32])[C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[C:16]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:15]=1)[C@H:3]([OH:33])[CH2:2][NH:1][CH:51]([CH2:52][CH2:53][CH3:54])[CH2:50][CH2:49][CH3:48])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN)cc(N2CCCC2=O)c1
Reactant: CCCC(=O)CCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCOc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNC(CCC)CCC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 92 h
Yield: 11.5 %

Procedure:
To a solution of N-((1S,2R)-3-amino-1-benzyl-2-hydroxy-propyl)-3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzamide (E182) (30 mg, 0.066 mmol, 1 equiv) in (CH2Cl)2 (5 ml) were added sodium triacetoxyborohydride (20 mg, 0.094 mmol, 1.4 equiv), 4-heptanone (10 μl, 0.070 mmol, 1.1 equiv) and CH3COOH (4 μl, 0.070 mmol, 1,1 equiv). The resulting mixture was stirred at room temperature for 92 hours, diluted with CH2Cl2, washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/ethyl acetate: 3/2) gave N-[(1S,2R)-1-benzyl-2-hydroxy-3-(1-propyl-butylamino)-propyl]-3-(2-oxo-pyrrolidin-1-yl)-5-pentyloxy-benzamide (4.2 mg, 11%) as a colourless oil. [M+H]+=552.2, RT=2.98 min
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].[C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)[CH3:8].B(F)(F)F.CCOCC>C(Cl)Cl>[SH:1][CH2:2][CH:3]1[CH2:4][S:5][C:7]([CH3:8])([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:6]1
Reactant: SCC(S)CS
Reactant: COC(=O)CCCC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCCC1(C)SCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (5 g, 0.0355 mol), methyl 4-acetylbutyrate (5.1 g, 0.0355 mol) and boron trifluoride etherate (1 ml) in methylene chloride (125 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 6.5 g (69%) of product.
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].Br[CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][C:23]#[N:24])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: N#CCBr
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
[2-Hydroxy-2-(4-hydroxyphenyl)cyclopentyl][(methylethyl)sulfonyl]amine (650 mg, 2.17 mmol, prepared in example 47), bromoacetonitrile (292 mg, 1.1 eq), and potassium carbonate (360 mg, 1.2 eq) were combined with acetone (40 mL) and stirred overnight at room temperature under a nitrogen atmosphere. The solution was then filtered and the filtrate was concentrated under reduced vacuum to yield 694 mg as an oil. This two spot material was separated and purified via silica gel chromatography employing the Chromatotron® and using a 4000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 9:1 to yield the intermediate title compound (390 mg, 54%) as a white foam (top spot by TLC). Ion Spray M.S. 337.2 (M*−1) Calculated for C16H22N2O4S: Theory: C, 56.79; H, 6.55; N, 8.28. Found: C, 56.51; H, 6.46; N, 8.24.
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[O:5]/[C:6](/C)=[CH:7]/[CH2:8]O)[CH3:3].[CH3:17][C:18](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:19].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.CCOCC>[CH3:16][CH:14]([Si:4]([CH:2]([CH3:1])[CH3:3])([CH:11]([CH3:12])[CH3:13])[O:5][CH2:6]/[C:7](/[CH3:8])=[CH:17]/[CH:18]=[O:19])[CH3:15]
Reactant: C/C(=C\CO)O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(=C\C=O)CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a room temperature solution of (E)-3-[tris-(1-methylethyl)silyloxy]but-2-en-1-ol (crude from the previous step, assumed 17.6 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (9.7 g, 22.9 mmol). The resulting suspension was stirred for 60 minutes, until the reaction was judged to be complete by TLC. The reaction mixture was diluted with Et2O and a saturated aqueous solution of NaHCO3 containing Na2S2O3 was added. This mixture was stirred vigorously until both layers became clear. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5% Et2O/pentane) to afford the title compound as a colorless oil (3.69 g, 82% yield). IR (film) 2944, 2867, 1681, 1464, 1384, 1123 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.09 (d, 1H, J=8.3 Hz, CHO), 6.28 (dd, 1H, J=1.5, 8.4 Hz, CH), 4.28 (d, 2H, J=0.9 Hz, CH2OTIPS), 2.09 (d, 3H, J=0.6 Hz, CH3C), 1.1 to 1.0 (m, 21H, TIPSO); 13C NMR 75 MHz, CDCl3) δ 191.2, 161.6, 124.1, 67.0, 18.0, 14.1, 11.9; HRMS (EI+) exact mass calculated for [M]+(C14H28O2Si) requires m/z 256.1859, found m/z 256.1862.