Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:77])[C@H:2]1[O:7][C@@H:6]2[O:8][C@H:9]3[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]4[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]5[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]6[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]7[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]8[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]1[C@H:4]([OH:76])[C@H:5]2[OH:75])[O:56][C@@H:55]8[CH2:63][OH:64])[O:47][C@@H:46]7[CH2:65][OH:66])[O:38][C@@H:37]6[CH2:67][OH:68])[O:29][C@@H:28]5[CH2:69][OH:70])[O:20][C@@H:19]4[CH2:71][OH:72])[O:11][C@@H:10]3[CH2:73][OH:74].[Na+].[Cl-]>CS(C)=O>[CH3:3][CH:2]([OH:7])[CH2:1][O:70][CH2:69][C@H:28]1[O:29][C@@H:30]2[O:35][C@H:36]3[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]4[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]5[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]6[C@H:4]([OH:76])[C@@H:5]([OH:75])[C@@H:6]([O:8][C@H:9]7[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]8[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]1[C@H:32]([OH:33])[C@H:31]2[OH:34])[O:20][C@@H:19]8[CH2:71][O:72][CH2:60][CH:54]([OH:53])[CH3:55])[O:11][C@@H:10]7[CH2:73][O:74][CH2:32][CH:27]([OH:26])[CH3:28])[O:7][C@@H:2]6[CH2:1][O:77][CH2:14][CH:9]([OH:8])[CH3:10])[O:56][C@@H:55]5[CH2:63][O:64][CH2:37][CH:36]([OH:35])[CH3:41])[O:47][C@@H:46]4[CH2:65][O:66][CH2:46][CH:45]([OH:44])[CH3:50])[O:38][C@@H:37]3[CH2:67][O:68][CH2:19][CH:18]([OH:17])[CH3:23]
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(O)COC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCC(C)O)O[C@@H]7COCC(C)O)O[C@@H]6COCC(C)O)O[C@@H]5COCC(C)O)O[C@@H]4COCC(C)O)O[C@@H]3COCC(C)O

Procedure:
40 mg (0.13 mmol) of compound described in example 2 and 1.46 g of hydroxypropyl-beta-cyclodextrin (DS 0.58-Mw 1386 g.·L−1) were dissolved in 15 mL of dichloromethane and 10 mL of methanol. The limpid mixture was evaporated under reduced pressure at room temperature giving 1.80 g of a pale yellow powder containing 2 wt % of product described in example 2 (mol/mol ratio for the complex “dihydro-compound/beta-cyclodextrine”: ⅛). The included molecule is now soluble (10 g·L−1) in a mixture of 9 wt % NaCl aqueous solution (80 Vol. %), dimethylsulfoxide (10 Vol. %) and Chremofor EL (10 Vol. %).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([CH2:12][CH2:13][NH2:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][CH2:2][C:3]([NH:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
Chloroacetylchloride (13.55 g, 120 mmol) was dropped into a solution of 2-phenylethylamine (12.12 g, 100 mmol), sodium bicarbonate (10.6 g, 126 mmol) in dichloromethane (100 ml) under ice cooling and the mixture was stirred for 2 hours. After addition of ice-water, the organic layer was separated and washed with 1N hydrochloric acid and brine. The solvents were removed under reduced pressure and the residue was recrystallized from mixture of water (20 ml) and methanol (30 ml) to afford 2-chloro-N-phenethyl-acetamide (18.33 g, 93%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[CH2:12][CH2:13][CH2:14][N:15]=1>CO.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: Fc1ccc(F)c(C2=NCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Fc1ccc(F)c(C2CCCN2)c1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
NaBH4 (12 g, 314.9 mmol) was added to a solution of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (28.5 g, 157.4 mmol) in a mixture of MeOH:H2O (4:1, 250 mL) and stirring was continued at 25-35° C. for 2 h. The reaction mixture was quenched with 1N aqueous HCl solution and basified with 2N aqueous NaOH solution, extracted with DCM, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 23 g of the title compound.
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].[Br-].[Li+].C(N(CC)CC)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>C(#N)C>[N+:1](=[C:3]([C:17]([O:18][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Into 5 ml of dry acetonitrile were suspended 263 mg (1 millimole) of p-nitrobenzyl 2-diazoacetoacetate and 122 mg (1.4 millimoles) of lithium bromide. To the mixture were added 220 μl (1.6 millimoles) of triethylamine and then 190 μl (1.5 millimoles) of trimethylsilyl chloride while agitating under an argon atmosphere at a room temperature. The resultant was heated up to 40° C. and agitated at the same temperature overnight, followed by concentration under a reduced pressure. To the residue was added 20 ml of dry hexane, and the resultant was agitated for 30 min. at a room temperature. Insoluble materials were removed by filtration and the filtrate was concentrated to dryness under a reduced pressure to give 330 mg (yield 87%) of the desired compound in a yellow solid. The physical properties of the product were in agreement with those of the product obtained in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:16]1([Mg]Cl)[CH:21]=[CH:20]C=[CH:18][CH:17]=1>O1CCCC1>[CH3:1][N:2]([CH3:15])[C:3]1([C:13]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
50.0 g of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile were dissolved in 400 ml of analytical grade tetrahydrofuran; 216 ml of a commercially available two molar solution of phenylmagnesium chloride in tetrahydrofuran were added dropwise under a nitrogen atmosphere, while cooling with an ice bath, and stirring was carried out overnight at room temperature. For working up, 200 ml of ice-cold ammonium chloride solution (20 wt. %) were added with stirring, while cooling with an ice bath, and after 30 minutes the phases were separated. The aqueous phase was extracted twice using 250 ml of ether each time, and the extracts were combined with the organic phase, washed with 200 ml of water followed by 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 60.0 g of dimethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine were obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-])=O)=[N:7][CH:8]=1>C(O)(=O)C.Cl.[Zn]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=1
Reactant: CSc1ccc([N+](=O)[O-])nc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CSc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
This nitropyridine (300 mg, 1.8 mmol) was dissolved in a mixed solvent of acetic acid (7 ml) and conc. hydrochloric acid (0.5 ml), and zinc (692 g, 10.6 mmol) was added thereto in small portions while being cooled with ice for 5 minutes. After the mixture was stirred for 30 minutes at the room temperature, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=1:1→chloroform:methanol=20:1) to obtain 158 mg (yield 64%) of 2-amino-5-methylthiopyridine as a pale-yellow powdery crystal.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][NH:4][C:3]1=[O:14].Cl.[OH-].[Na+]>C(#N)C.[Cu].[Cu]Cl>[CH3:1][C:2]1[C:3](=[O:14])[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CC1CC(c2ccccc2)=NNC1=O
Agent: Cl[Cu]
Agent: [Cu]
Agent: Cl
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)n[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
(Csende, F et al. Synthesis, 1995, 1240-1242) 7.0 g (35 mmol) of 13 was dissolved in 30 ml of acetonitrile in a 250 ml single-necked round bottom flask. 11.3 g (84 mmol, 2.4 equiv) of anhydrous copper (H) chloride Was added to the solution and the reaction mixture was heated to reflux for 2 hours. To control the HCl gas that formed during the course of the reaction, a NaOH solution was used to absorb the HCl that escapes from dry tube. The reaction mixture was cooled to ambient temperature, and placed into an ice-water bath. 150 mL of ice-water was added to quench the reaction. The mixture was stirred vigorously for 10 minutes to give a gray precipitate and blue liquid containing copper (I) chloride. The precipitate was then collected by filtration (pH of the filtrate is 0-1) and washed first with 1N HCl (100 mL), then with Milli-Q water (5×100 mL). To remove remaining copper by-products, the filter cake was stirred in 1N HCl (150 mL) for 0.5 h and then filtered. The filter cake was washed with water until the filtrate is at pH 7 (approximately 7 washes). The solid was dried over a medium flit sintered glass funnel in vacuo to give 14 as a light gray powder in 93.8% yield, 1H NMR (DMSO-d6): δ 7.95 (s, 1H), 7.85 (d, J=7.5 Hz; 2H), 7.47 (m, 2H), 7.43 (m, 1H), 2.13 (s, 3H). HPLC (tr/purity): 21.48 min, >97%; ESI m/z (MeOH) 187.36 (MH+).
Reaction SMILES: [C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:43])[CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:42][CH:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:34]([C:31]1[CH:32]=[CH:33][C:28]([C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[CH:29][CH:30]=1)=[O:43]
Reactant: CCCCCCC(C)C(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Yield: 42.2 %

Procedure:
Into a flask were charged 80.7 mg (0.29 mmol) of 4-nonanoyloxy benzoic acid, 84.2 mg (0.27 mmol) of 4-hydroxy-4'-(2-methyloctanoyl) biphenyl, 63.5 mg (0.31 mmol) of dicyclohexylcarbodiimide, 6.0 mg (0.05 mmol) of 4-dimethylamino pyridine and 5 ml of dried dichloromethane, which was heated under reflux for 6 hours. After the cooling, the resulting solid was filtered off, and washed with dichloromethane. The organic phase was washed with 0.1 normal hydrochloric acid and then water, dried on anhydrous magnesium sulfate, and the solvent was distilled off. This product was purified by a column chromatography and recrystallized with ethanol to obtain 65.3 mg (yield 42%) of white 4-nonanoyloxy benzoic acid-4-(2-methyloctanoyl) biphenyl.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30](O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(Cl)(Cl)=O)C=CC=CC=1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by dropwise addition of phenylphosphonic dichloride (1.63 ml.) over 5 minutes. After stirring for 3 hours at 20° C., the reaction mixture was cooled to 0° C. and morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction temperature maintained at 0°-5° C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: [CH2:1]1[N:6]2[CH2:7][CH2:8][N:3]([CH2:4][CH2:5]2)[CH2:2]1.[Cl-:9].[Li+]>O1CCCC1>[CH2:1]1[N:6]2[CH2:7][CH2:8][N:3]([CH2:4][CH2:5]2)[CH2:2]1.[ClH:9]
Reactant: [Cl-]
Agent: C1CN2CCN1CC2
Agent: [Li+]
Solvent: C1CCOC1
Product: Cl
Reaction time: 2 h

Procedure:
In 100 ml of anhydrous tetrahydrofurane under argon at 0° C., 20.27 g (10 mmoles) of 4-styrenesulfonyl chloride CH2═CHC6H4SO2Cl (commercially available from Monomer-Polymer & Dajac Laboratories) were reacted with 14.91 g (10 mmoles) of trifluoromethane-sulfonamide CF3SO2NH2 and 22.44 g (20 mmoles) of (DABCO). After 2 hours at 0° C. and 48 hours at room temperature, the solution was filtered to remove the DABCO hydrochloride formed, and it was thereafter treated with 424 mg (10 mmoles) of anhydrous lithium chloride, which is stored and weighed in a glove box. Immediately, a precipitate of DABCO hydrochloride was formed and the reaction mixture was then again filtered after stirring for 6 hours. After evaporation and drying under vacuum, during 24 hours at room temperature, 31.16 g of the lithium salt of trifluoromethane-sulfonyl(4-styrenesulfonyl)imide were recovered which have a purity characterized by a proton and fluorine RMN higher than 97%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]([C:15]3[CH:16]=[C:17]([C:22]([NH2:24])=[NH:23])[S:18][C:19]=3[S:20][CH3:21])[S:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(OC1C=C(C2N=C(C3C=C(C(OC)=O)SC=3SC)SC=2)C=CC=1OC)(=O)C.[Cl-:53].[NH4+].C[Al](C)C>C1(C)C=CC=CC=1.CN(C=O)C.CO.C(Cl)Cl>[ClH:53].[OH:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]([C:15]3[CH:16]=[C:17]([C:22]([NH2:24])=[NH:23])[S:18][C:19]=3[S:20][CH3:21])[S:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: [Cl-]
Agent: COC(=O)c1cc(-c2nc(-c3ccc(OC)c(OC(C)=O)c3)cs2)c(SC)s1
Agent: COc1ccc(-c2csc(-c3cc(C(=N)N)sc3SC)n2)cc1O
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cl

Procedure:
4-[4-(3-Hydroxy-4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine hydrochiloride: A portion of the mixture (320 mg, ca. 0.788 mmol as based on the 1H-NMR spectrum) containing the 2-methoxy-5-{2-[5-(methoxvcarbonyl)-2-methylthio(3-thienyl)](1,3-thiazol-4-yl)}phenyl acetate (as prepared in the previous step) was treated according to the procedure in Example 10, step (b), using 415 mg (7.76 mmol) of ammonium chloride in 3.5 mL of toluene and 3.88 mL (7.66 mmol) of 2 M trimethylaluminum in toluene. After chromatography of the resulting residue on a 10 g silica SPE column (Waters Sep-Pak) with 10-40% MeOH-CH2Cl2, a light yellow solid was obtained which was dissolved in 45 mL of DMF and filtered to remove silica gel. Concentration under high vacuum and recrystallization from MeOH—Et2O afforded the title compound as a light tan solid (132 mg, 44%). 1H-NMR (300 MHz, DMSO-d6) δ 9.49 (broad s, 2H), 9.16 (broad s, 2H), 8.67 (s, 1H), 7.98 (s, 1H), 7.5 (obscured m, 3H), 7.00 (obscured d, 1H, J=8.3 Hz), 3.82 (s, 3H), and 2.79 (s, 3H). Mass spectrum (ESI) calcd. for C16H15N3O2S3: 378.0 (M+H). Found: 378.1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[OH-].[Pd+2].[OH-]>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1ccc2cc(O)ccc21
Temperature: 35 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
5-(Benzyloxy)-1-methyl-1H-indole (Example 46, 254 mg, 1.07 mmol) was dissolved in EtOH (15 mL) and 20% palladium (II) hydroxide on carbon (30.0 mg) was added. Ammonium formate (540 mg, 8.6 mmol) was added, and the mixture was stirred for 30 min at rt and subsequently for 2 h at 35° C. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was taken up in water, and the aqueous solution was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide 141 mg (90%) of the title compound as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 3.78 (s, 3H), 6.33 (br, 1H), 6.79 (d, 1H), 7.03 (br, 2H), 7.19 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=Cc1ccccc1
Product: Oc1ccc(CCNCc2ccccc2)cc1

Procedure:
According to scheme 6, tyramine (1) is reacted with benzaldehyde under reductive amination conditions to yield 4-(2-benzylamino-ethyl)-phenol (28). The amine 28 is protected as the t-butyl carbamate (29). The carbamate 29 is reacted with 4-fluoronitrobenzene under basic reaction conditions (as shown or known modifications thereof) to afford the coupled product 30. The coupled product 30 is then reduced at the nitro group utilizing catalytic hydrogenation (palladium on carbon) to afford {2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (31). The resulting amine 31 may be acylated with one of various acid chlorides to form the desired reverse amide compound 32. The Boc protecting group is removed with TFA in dichloromethane to afford compound 33, a compound of the invention.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CS(O[C@@H:21]([CH3:25])[CH2:22][CH2:23][CH3:24])(=O)=O.[Cl-].[NH4+]>COCCOC.C(O)C.C(Cl)Cl>[CH3:25][C@@H:21]([CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])[CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC[C@H](C)OS(C)(=O)=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCO
Product: CCC[C@@H](C)C(C(=O)OCC)C(=O)OCC
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
At room temperature, a three-neck flask with internal thermometer, dropping funnel and stirrer was initially charged under protective nitrogen gas with 41.8 g of sodium ethoxide (95% pure, 0.583 mol) in 250 ml of dry 1,2-dimethoxyethane and 30 ml of dry ethanol. Subsequently, 97.5 g of diethyl malonate (0.609 mol) were added dropwise at from 20 to 40° C., in the course of which a clear solution formed. The clear mixture was stirred at 40° C. for 30 min, and 85.7 g of (S)-1-methylbutyl methanesulfonate (0.516 mol) were added undiluted. The mixture was heated to 80° C. and stirred for 6 h. After cooling to 25° C., the suspension was admixed with 800 ml of methylene chloride and 500 ml of 5% by weight ammonium chloride solution. After phase separation, the organic phase was washed with 200 ml of water and then dried over sodium sulfate. After distillative removal of solvent, diethyl [(R)-1-methylbutyl]malonate was obtained in a yield of 113 g (95% of theory) and a chemical purity of 96% (GC).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](OC)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].C([Al+]CC(C)C)C(C)C.CO.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:11][CH2:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A stirred solution of methyl indole-6-carboxylate (50 g) (see Example 1, part b) in dry toluene (1 liter), in a three-necked three-liter flask fitted with a mechanical stirrer, thermometer and dropping funnel, was cooled to -70° under an atmosphere of nitrogen, and treated dropwise with a solution of diisobutylaluminum hydride (381 ml of 1.5M solution in toluene) over 50 min. After 2.5 hr a further portion of diisobutylaluminum hydride (25 ml) was added dropwise, and the mixture stirred for a further 30 min. Methanol (100 ml) and saturated aqueous sodium sulfate (100 ml) were added sequentially, at -78°. The cooling bath was removed, the reaction allowed to warm to room temperature, and 6M hydrochloric acid (25 ml) was added dropwise. The mixture was filtered through a pad of diatomaceous earth, the filter cake washed with toluene and water, the organic phase separated and washed with water, dried (MgSO4) and evaporated to give 6-hydroxymethylindole (34.2 g, 82%) as an oil which slowly solidified; partial NMR (250 MHz, CDCl3): 1.73(s, 1H, CH2OH), 4.78(s, 2H, CH2OH), 6.55(m, 1H, H3 -indole), 8.20(br s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](F)([F:12])[C:7](F)([F:14])[CH:6]=[CH:5]2.[NH4+].[OH-]>[Zn].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([F:14])[CH:6]=[CH:5]2
Reactant: FC1(F)C=Cc2cc(Br)ccc2C1(F)F
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: Fc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C
Yield: 46.6 %

Procedure:
Zinc (2.439 g, 36.6 mmol) was added to a stirred mixture of 5.01 g (17.8 mmol) of 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene, 11 ml of THF, and 22 ml of NH4OH that was cooled in an ice bath. The mixture was allowed to warm slowly to room temperature. After 4½ hours reaction time, the zinc was removed by filtration. The phases were separated, and the aqueous layer was extracted three times with hexanes. The combined organic phase was washed twice with brine and dried over MgSO4. The MgSO4 was filtered off, and the solvent removed under vacuum. Crude 6-bromo-1,2-difluoronaphthalene (4 g) containing 15% impurities (estimated) remained. The estimated yield of the crude 6-bromo-1,2-difluoronaphthalene was 91%. Brown needles (2.0 g, 8.3 mmol, 46% yield) were recovered after recrystallization from hexanes.