Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@@H:34]2[CH2:36][O:35]2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@@H:34]([OH:35])[CH2:36][N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[C:20]5[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=4[S:19][CH2:18]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=5)[CH2:13][CH2:14]2)=[CH:30][CH:29]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@H](O)COc4ccc(C(C)(C)C)cc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 227 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Z. Mp.=153-156° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.22 (d, J=2.4 Hz, 1H), 7.11 (dd, J=2.4, 8.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 4.85 (d, J=4.8 Hz, 1H), 3.96-3.92 (m, 2H), 3.92 (s, 3H), 3.86-3.81 (m, 1H), 3.07 (s, 2H), 2.81 (dd, J=10.8, 22 Hz, 2H), 2.54 (m, 1H), 2.45-2.39 (m, 3H), 1.98 (d, J=14.0 Hz, 2H), 1.84-1.76 (m, 2H), 1.25 (s, 9H); LCMS: 538 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22]C)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COc1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: Br
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(O)c3O2)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (10.00 g, 0.030 mol) was added hydrogen bromide (20 mL, 30 wt. % in acetic acid) and the resulting solution was heated to 40° C. The reaction mixture was allowed to stir at 40° C. for 4 h. The reaction mixture was cooled to room temperature and was diluted with water (250 mL) and extracted with diethyl ether (3×200 mL). The combined organic extracts were washed with saturated sodium bicarbonate (3×300 mL), water (200 mL), and saturated aqueous sodium chloride (200 mL), were dried (magensium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:3) provided 7.34 g (77%) of (±)-(7-hydroxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as white solid. Rf=0.31 (silica, ethyl acetate:hexanes 1:3); mp 122-125° C.; Anal. calcd. for C16H16O5S: C, 59.99; H, 5.03. Found: C, 59.8; H, 4.73.
Reaction SMILES: [CH2:1]([C:7]1[C:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:27][C:26]2[C:9](=[CH:10][C:11]3[C:12](=[O:48])[C:13]4[C:22]([C:23](=[O:35])[C:24]=3[CH:25]=2)=[CH:21][C:20]2[C:15](=[CH:16][C:17]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:19]=2)[CH:14]=4)[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([BH-](CC)CC)C.[Li+].Cl>O1CCCC1>[CH2:36]([C:18]1[C:17]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:16][C:15]2[C:20](=[CH:21][C:22]3[CH:23]([OH:35])[C:24]4[C:11]([CH:12]([OH:48])[C:13]=3[CH:14]=2)=[CH:10][C:9]2[C:26](=[CH:27][C:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=2)[CH:25]=4)[CH:19]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCc1cc2cc3c(cc2cc1CCCCCC)C(=O)c1cc2cc(CCCCCC)c(CCCCCC)cc2cc1C3=O
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCc1cc2cc3c(cc2cc1CCCCCC)C(O)c1cc2cc(CCCCCC)c(CCCCCC)cc2cc1C3O

Procedure:
A solution of 649 mg of 2,3,9,10-tetra(n-hexyl)-6,13-pentacenequinone dissolved in 30 mL of tetrahydrofuran (THF) was added to 5 mL of a 1 mol/1000 mL THF solution of lithium triethylborohydride, and the mixture was heated for 12 hours under reflux in a nitrogen atmosphere. The resulting solution was neutralized with diluted aqueous hydrochloric acid, and the organic phase was separated, concentrated and dried under a vacuum to produce 2,3,9,10-tetra(n-hexyl)-6,13-dihydro-6,13-dihydroxypentac ene almost stoichiometrically (see the following reaction formula).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:15][CH:16]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH:17]([CH3:19])[CH3:18])(=[O:14])[CH3:13]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:15][CH:16]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH:17]([CH3:19])[CH3:18])(=[O:14])[CH3:13]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl acetate (306 mg, 1.12 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 40 (89 mg, 28% yield) as an oily solid after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.83-0.95 (br. m, 8H), 1.18-1.37 (m, 3H), 1.65-1.73 (br. m, 2H), 1.84-1.97 (br. m, 3H), 2.02 (s, 3H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.78-2.84 (m, 2H), 6.41 (d, J=5.2 Hz, 1H), 7.39 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH2:27])[CH:16]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:28])[C@@H:15]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:22][C:23]([F:25])([F:26])[F:24]
Reactant: COC(=O)[C@@H](N)C(CC(F)(F)F)CC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
4-Chlorophenyl sulphonyl chloride (211 mg, 1.00 mmol) was added to a solution of (2S)-2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester (267 mg, 1.00 mmol) and pyridine (0.45 mL, 3.00 mmol) in CH2Cl2 (5 mL) and the reaction was subsequently stirred for 18 h at 25° C. The solvent was removed in vacuo and the residue was dissolved in EtOAc (20 mL). This solution was washed with 1M HCl (2×10 mL) and brine (10 mL), dried over Na2SO4 and evaporated to afford a crude oil which was purified by flash chromatography eluting with 20:80 EtOAc:hexanes to provide the title compound (380 mg) as an oil in 86% yield. Mass Spectrum (−ESI): 446.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2cccc(Cl)c2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(Cl)c1

Procedure:
To a solution of (4RS,5SR)-5-(3-chlorophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (3.70 g, 9.16 mmol) in ethanol (30 ml) was added 8N aqueous sodium hydroxide solution (5.7 ml, 46 mmol), and the mixture was heated under reflux for 3 hrs. The reaction solution was concentrated and diluted with water (100 ml). The mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (3.0 g, 87%).
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:55][N:56]([CH3:61])[CH2:57][C:58](O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:8]([O:27][CH2:28][CH2:29][CH2:30][N:31]([C:58](=[O:59])[CH2:57][N:56]([CH3:61])[CH3:55])[CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN(C)CC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCNCCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCN(CCCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(Z)-azanediylbis(propane-3,1-diyl) dioleate TFA salt (750 mg, 1.13 mmol) was diluted with DCM (5 mL) and added to a pre-activated mixture of N,N-dimethylglycine (128 mg, 1.24 mmol), HATU (517 mg, 1.36 mmol) and DIEA (413 uL, 2.37 mmol) in DCM (5 mL). Flask was flushed with argon and allowed to stir at room temperature overnight. The reaction mixture was concentrated, and subjected to silica gel chromatography with a DCM/MeOH gradient to yield (Z)-((2-(dimethylamino)acetyl)azanediyl)bis(propane-3,1-diyl) dioleate.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[NH2:18][OH:19]>CO>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=[N:18][OH:19])[CH2:5][CH2:4]1
Reactant: CON1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON1CCC(=NO)CC1

Procedure:
To a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (258 g, 2.0 mol) and triethylamine (305.2 ml, 221.9 g, 4.4 mol) in methanol (3000 ml) was added hydroxylamine hydrochloride (277.6 g, 4.0 mol), and the reaction mixture heated at reflux for 1.5 hours. The solvent was evaporated, the residue diluted with diethyl ether and the suspension filtered. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated. Yield: 286.25 g of 1-methoxy-piperidin-4-one oxime as a colorless, viscous oil. This material was used without further purification in the next step.
Reaction SMILES: COC1C=CC=C2C=1OC1C(OC)=C(OC)C(OC)=C(OC)C=1C2=O.C[O:27][C:28]1[C:29]([O:51]C)=[C:30]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[C:37]1[C:36]([O:43]C)=[C:35]([O:45]C)[C:34]([O:47]C)=[C:33]([O:49]C)[C:32]=1[O:31]2>>[OH:27][C:28]1[C:29]([OH:51])=[C:30]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[C:37]1[C:36]([OH:43])=[C:35]([OH:45])[C:34]([OH:47])=[C:33]([OH:49])[C:32]=1[O:31]2
Reactant: COc1ccc2c(=O)c3c(OC)c(OC)c(OC)c(OC)c3oc2c1OC
Agent: COc1c(OC)c(OC)c2c(=O)c3cccc(OC)c3oc2c1OC
Product: O=c1c2ccc(O)c(O)c2oc2c(O)c(O)c(O)c(O)c12
Yield: 90.8 %

Procedure:
2-hydroxy-3,4,5-trimethoxybenzoic acid (1.14 g, 0.005 mol) and 1,2,3,4-tetramethoxybenzene (0.99 g, 0.005 mol) and 25 ml of a 9% solution of P2O5 in methanesulfonic acid were shaken in a 50 ml cylindrical glass tube with a Teflon-lined screw-cap at room temperature for 54 hours. The dark orange mixture was then poured onto crushed ice (150 ml). After melting, the product was extracted with methylene chloride (3×40 ml). After removal of the solvent, the residue was chromatographed on silica gel (30 g) with CH2Cl2. Of the three fractions obtained (the eluent was monitored by thin-layer chromatography), the middle one was uniform and left pure 2-hydroxy-3,4,5,2′,3′,4′, 5′-heptamethoxybenzophenone (0.51 g, 25%) as a yellow oil upon evaporation of the solvent. This was dissolved in 100 ml 75% alcohol whereafter 5 ml of 10N NaOH were added and the mixture was heated to boiling in a beaker for three hours; the volume was kept at 100 ml by occasional addition of water. The mixture was then transferred to a 250 ml round bottom flask and refluxed for another 17 hours. After cooling, suction filtration yielded 0.36 g of 2,3,4,5,6,7-hexamethoxyxanthone as a white product (small needles, matted, 77%). In a deprotection procedure, similar to the one described above for pentamethoxyxanthone, 0.42 g of the hexamethoxyxanthone produced 0.296 g of hexahydroxyxanthone (91%) as a pale yellow powder. It was found advantageous to circumvent the need for centrifugation by stirring the methylene chloride-water mixture (from the quenching of the BBr3-solution) in a wide-mouthed container for several hours, leading to the evaporation of the methylene chloride; the mixture is then easily filterable.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][NH:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:30][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)NCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1
Yield: 73.5 %

Procedure:
A solution of Ethyl 2-(2-(4-nitrophenyl)-2-oxoethylamino)-2-oxoacetate (Intermediate 1, step C, 5 g) and Lawesson's reagent (7.22 g) in 1,4-Dioxane (100 ml) was refluxed for 2 hours. The reaction mixture was cooled, water was added and the mixture was neutralized with saturated solution of Na2CO3. This was followed by addition of EtOAc and then the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to get dark brown residue. The residue was chromatographed on silica gel in 0.5:9.5 EtOAc:CHCl3 to get dark yellow colored solid which was crystallized in CHCl3/pet ether to yield 3.65 g (73%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 8.33 (d, 2H), 8.3 (s, 1H), 7.83 (d, 2H), 4.54 (q, 2H), 1.49 (t, 3H); MS (ES+) m/z 279 (M+1).
Reaction SMILES: Cl[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:17][C:18]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=1)=[S:19]>C(O)(C)C>[C:27]([NH:26][C:22]1[CH:21]=[C:20]([C:18]2[S:19][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:17]=2)[CH:25]=[CH:24][N:23]=1)(=[O:29])[CH3:28]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1Cl
Reactant: CC(=O)Nc1cc(C(N)=S)ccn1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1-c1ccccc1Cl
Temperature: 94 °C
Reaction time: 23 h
Yield: 21.4 %

Procedure:
To a stirred solution of crude ethyl 2-chloro-3-(2-chlorophenyl)-3-oxopropanoate (1.390 g, 5.320 mmol) in absolute isopropyl alcohol (50.00 mL) was added N-[4-(aminocarbonothioyl)pyridin-2-yl]acetamide (1.140 g, 5.860 mmol) and the resulting solution was fitted with a condenser and stirred for 23 h at 94° C. The mixture was cooled to ambient temperature and half the solvent was removed in vacuo. Diethyl ether (30.0 mL) was added to allow the formation of the thioamide by-product. The by-product was separated by filtration and the solvent was removed in vacuo. The residue was purified by column chromatography (SiO2, elution with 0-100% EtOAc in hexanes) to provide 0.457 g of product as a yellow oil (21% 2 steps). LC/MS (AA) ES+ 402. NMR (400 MHz, d1 CDCl3) δ: 8.77 (br s, 1H), 8.37-8.35 (m, 1H), 7.71-7.70 (m, 1H), 7.50-7.46 (m, 2H), 7.41-7.46 (m, 3H), 4.24 (q, J=7.2 Hz, 2H), 2.24 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:26])[N:7]([CH:14]1[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:26])[N:7]([CH:14]1[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13]
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC1CC(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O

Procedure:
A solution of 3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1 g, 3.1 mmol) and Pd/C (10%, 0.1 g) in methanol (100 mL) is shaken under hydrogen (50-60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with methanol to give 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which can be further purified by column chromatography.
Reaction SMILES: N[C@@H]1CCCC2C=C(CO)C=CC1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[CH:30]([N:34]=[N+:35]=[N-:36])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=1)=[O:23].[OH-].[Na+]>C1COCC1.O>[CH3:20][O:21][C:22]([C:24]1[CH:33]=[CH:32][C:31]2[C@H:30]([N:34]=[N+:35]=[N-:36])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=1)=[O:23]
Reactant: COC(=O)c1ccc2c(c1)CCCC2N=[N+]=[N-]
Agent: N[C@@H]1CCCc2cc(CO)ccc21
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCC[C@H]2N=[N+]=[N-]
Temperature: 25 °C

Procedure:
Preparation (5(R)-Amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol: To an oven-dried, 3-neck, 2 L round-bottomed flask equipped with argon inlet/outlet, addition funnel, thermometer, and overhead stirring was added 700 mL of THF and LAH (470 mL of a 1M soln in THF, 470 mmol, Aldrich). The reaction was cooled in a ice-salt bath, and 5-azido-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (27 g, 120 mmol) in 100 mL of THF was added over ca. 30 min. The mixture was warmed to RT overnight, then cooled in an ice-salt bath the next morning. Water (18 mL) in THF (20 mL) was added to the reaction mixture over 4 h. Vigorous gas evolution occurred. 5M NaOH (18 mL) was added over 30 min followed by 54 mL of water. After stirring for an additional 1 h, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was reconstituted in MeOH and CH3CN, and concentrated in vacuo again to provide the title compound as light-brown solid. MS (+ ion ESI) m/z=161 (M-NH3).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:39])[CH3:40])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:23][C@H:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC#Cc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-{[(2-tert-butyl-4-(hex-1-yn-1-yl)pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (218 mg) and palladium-carbon (20 mg) were suspended in methanol and the mixture was stirred under a hydrogen atmosphere (1 atom) at room temperature for 16 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (219 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([O:17]C)=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:13][C:12]=2[F:25])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([OH:17])=[CH:15][C:14]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:13][C:12]=2[F:25])=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCOCC2)cc(F)c1C(=O)NCc1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)cc(N2CCOCC2)cc1F
Temperature: 25 °C
Yield: 37.8 %

Procedure:
To a solution of N-[(4-chlorophenyl)-methyl]-2-fluoro-6-methoxy-4-morpholin-4-yl-benzamide (1.3 g, 3.44 mmol) in dichloromethane (40 ml) is added neat boron tribromide (0.82 ml, 8.6 mmol) at −78° C. The temperature is raised to room temperature over a period of 2 h. The reaction mixture is poured onto cold water, extracted with dichloromethane (3×50 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (silica gel, 5% ethyl acetate/dichloromethane) to yield N-[(4-chlorophenyl)-methyl]-2-fluoro-6-hydroxy-4-morpholin-4-yl-benzamide (0.5 g, 1.3 mmol, 39%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:26])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH:23]([CH3:25])[CH3:24])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].CCO[C:32]([CH3:34])=[O:33]>CN1C(=O)CCC1>[F:26][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:10]4[CH2:9][CH2:8][N:6]([CH3:5])[C:32](=[O:33])[CH2:34]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH:23]([CH3:25])[CH3:24]
Reactant: CC(c1c(F)cc2c(cnn2C(C)C)c1F)c1cnc2ccc(Cl)nn12
Reactant: CCOC(C)=O
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2c(cnn2C(C)C)c1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 4 h

Procedure:
(rac)-6-chloro-3-(1-(4,6-difluoro-1-isopropyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (Intermediate U, 56.4 mg, 0.15 mmol), KF (43.6 mg, 0.75 mmol) and 1-methylperazine-2-one hydrochloride (51.4 mg, 0.45 mmol) were suspended in NMP (0.4 mL). The RM was stirred at 180° C. for 4 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 4.06 min (conditions 5), MH+=454.3, 1H-NMR in DMSO-d6: 8.09 (s, 1H); 7.81 (d, 1H); 7.53 (s, 1H); 7.43 (d, 1H); 7.05 (d, 1H), 4.86 (m, 2H); 4.03 (d, 1H); 3.81 (d, 1H); 3.64 (m, 2H); 3.24 (m, 2H); 2.80 (s, 3H); 1.79 (d, 3H), 1.41 (m, 6H)).
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].O=[C:11]1O[C@H:16]([C@H:18]([CH2:20]O)[OH:19])[C:14](O)=[C:12]1O>CS(C)=O>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[CH:11]1[C:12]([C@H:4]2[CH2:5][O:6][C:7]3[CH:8]=[C:18]([OH:19])[CH:16]=[CH:14][C:12]=3[CH2:11]2)=[CH:14][CH:16]=[C:18]([OH:19])[CH:20]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCOCCOCCO
Solvent: CS(C)=O
Product: Oc1ccc([C@H]2COc3cc(O)ccc3C2)cc1
Temperature: 37 °C

Procedure:
Approximately 20 to 40 mg of the test material was weighed into pre-tared sterile glass vials and the precise weight was recorded. Vehicle volume was then calculated to give a 50% w/v solution, and the vehicle was added. Two different vehicles were used, as indicated in Examples. DMSO vehicle was prepared from 100% DMSO (EMD Biosciences Cat. #MX1458-6, Lot #42364321). Transcutol vehicle was prepared from 100% transcutol (Gattefosse a.s.a., Cedex, France). Samples were then vortexed vigorously until the dry powder was visually brought into solution. In some cases, samples need to be briefly warmed to 37° C. Stock solution aliquots can be frozen in small aliquots and maintained at approximately −20° C., or used immediately after preparation. Racemic mixtures of equol were prepared for testing at concentrations of 0 (control), 0.3, 1.0, and 5.0%. A positive control was prepared using ascorbic acid at a concentration of 50 μg/ml in DMEM/F-12. After stock solutions were diluted for use they were then discarded.