Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([O-])(=O)C.[Na+].[Br:33]Br>O>[CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([Br:33])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCc2ccccc2)c(Br)c(=O)n1Cc1ccccc1

Procedure:
The product from example 35, 1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one (4.2 mmol, 1.3 g), acetic acid (50 mL), and sodium acetate (5.0 mmol, 0.41 g) were stirred at room temperature. Bromine (4.2 mmol, 0.67 g) was added drop wise with stirring. After M hour, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentrating, the mixture was purified by flash column chromatography eluting with ethyl acetate:hexanes (12). The appropriate fractions were concentrated to yield a light oil. (1.0 g, 62%): 1H NMR (DMSO-d6/300 MHz) 7.4-7.0 (m, 10H), 6.5 (s, 1H), 5.29 (s, 2H), 5.27 (s, 2H), 2.2 (s, 3H). ES HRMS m/z 384.057 (M+H, C20H18NO2Br requires 384.060).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][CH2:17]O>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Yield: 89 %

Procedure:
A solution of (2,4-difluoro-5-nitro-phenyl)acetic acid (16 g, 74 mmol) in EtOH (200 mL) and 98% H2SO4 (14 mL) was refluxed at 80° C. for 2.5 h under a N2 atmosphere. The reaction mixture was poured into ice-water, and the resultant solution was extracted with ether. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography to give ethyl 2-(2,4-difluoro-5-nitrophenyl)acetate (16 g, 89% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.22 (t, J=8.1 Hz, 1H), 7.55 (t, J=11.1 Hz, 1 H), 4.06 (m, 2 H), 3.77 (s, 2 H), 1.13 (t, J=6.9 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:51])[C:41]5[C:46]([O:47][CH2:48][CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH:40]([OH:51])[C:41]5[C:46]([O:47][CH2:48][CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:61])=[CH:38][CH:39]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ncccc4OCCC)cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4c(OCCC)ccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 75.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-propoxypyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (480 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.2 g) at 0° C. and the mixture was stirred for 30 hours at room temperature. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-3-propoxypyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 112) (370 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH2:12][C:13]1[CH:14]=[C:15]([C@H:19]([OH:23])[CH2:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:12][C:13]3[CH:14]=[C:15]([C@H:19]([OH:23])[CH2:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: N#CC[C@@H](O)c1cccc(N)c1
Product: N#CC[C@@H](O)c1cccc(NCc2ccc3cc[nH]c3c2)c1

Procedure:
Reaction between 1H-indole-6-carbaldehyde and (R)-3-(3-aminophenyl)-3-hydroxypropanenitrile gives (R)-3-(3-(((1H-indol-6-yl)methyl)amino)phenyl)-3-hydroxypropanenitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[CH:25]([O:24][CH2:23][CH2:22][CH2:21][NH:20][C:18](=[O:19])[CH:17]=[CH:16][C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COCCOCOc1ccc(C=CC(=O)NCCCOC(c2ccccc2)c2ccccc2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C=CC(=O)NCCCOC(c2ccccc2)c2ccccc2)ccc1O
Yield: 73.3 %

Procedure:
To a solution of 378 mg (0.75 mmol) of the amide compound in methanol (10 ml) was added 19 mg (0.1 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was heated and refluxed for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, which .was extracted with ethyl acetate, and the organic layer was concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform - methanol (50 : 1), to give 230 mg (0.55 mmol) of 3-[3-[3-methoxy-4-hydroxyphenyl)-2-propenoyl]aminopropyl benzhydryl ether. Spectrophotometric data of the product support the structure shown below. ##STR86##
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])=[N:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cnc(C(=O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cnc(C(=O)OCc2ccccc2)cn1
Reaction time: 22 h

Procedure:
5-aminopyrazine-2-carboxylic acid (493 mg, 3.54 mmol; Ark Pharm, Inc., Libertyville, Ill.) was stirred in dry N,N-dimethylformamide (3.0 mL) at room temperature under nitrogen. Solid potassium carbonate (742 mg, 5.37 mmol) was added, followed by benzyl bromide (0.43 mL, 3.6 mmol). The mixture was stirred for 22 hours and then diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica chromatography using a 40 g pre-packed column, eluting with ethyl acetate. The product fractions were combined, evaporated, and dried under high vacuum to afford (I-22a) (161.2 mg, 0.70 mmol, 20%): m/z 229.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][CH:35]([F:36])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: FC(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
23 mg (0.91 mmol) 95% Sodium hydride were given to a solution of 200 mg (0.91 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 260 mg (0.91 mmol) 4-chloromethyl-2-[2-(4-difluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. for 12 h. After addition of 20 ml water the resulting precipitate was collected, washed with water (2×10 ml), methanol/water 1:1 (2×10 ml), a small amount of diethyl ether and dried in vacuo at 40° C. to yield 256 mg (60%) of the product as beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[CH3:38][O:39][C:40](=[O:45])[C@H:41]([CH2:43][OH:44])[NH2:42]>>[CH3:38][O:39][C:40](=[O:45])[CH:41]([NH:42][C:23](=[O:24])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:43][OH:44]
Reactant: COC(=O)[C@@H](N)CO
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: COC(=O)C(CO)NC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with L-serine methyl ester hydrochloride.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1B(O)O>>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(F)cc2F)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 2,4-difluorophenylboronic acid under the conditions described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CO.C(Cl)(Cl)Cl>CN(C)C=O.O>[Si:21]([O:12][CH:10]1[CH2:9][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:13]([O-:15])=[O:14])=[CH:3][C:2]=2[F:1])[CH2:11]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)c(F)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc([N+](=O)[O-])cc2F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A solution of 3-fluoro-4-(3-hydroxy-1-azetidinyl)nitrobenzene (5.51 g, 26.0 mmol) in N,N-dimethylformamide (104 mL) under nitrogen was cooled to 0° C. with an ice bath and treated with imidazole (1.86 g, 27.3 mmol) and then tert-butyldimethylsilyl chloride (4.12 g, 27.3 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature overnight. TLC analysis (5% methanol/chloroform) at this time revealed a small amount of starting material still remained. An additional amount of tert-butyldimethylsilyl chloride (0.392 g) was added. After stirring overnight, TLC analysis indicated the reaction was complete. The reaction mixture was diluted with water (500 mL) and extracted with dichloromethane (4×70 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to a yellow solid. Chromatography over silica gel (200 g), eluting with 5% and 10% ethyl acetate/hexane, afforded, after concentration of appropriate fractions, 6.30 g (74%) of the title compound as a yellow solid with mp 98.5°-99.5° C. and MS(EI) 326 (M+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][C:13](=O)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:17]([O:21][C:22](=[O:28])[NH:23][CH:24]1[CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:17]([O:21][C:22](=[O:28])[NH:23][CH:24]1[CH2:27][N:26]([CH:13]2[CH2:14][CH2:15][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[CH:11][CH2:12]2)[CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=C1CC=C(c2ccc3c(c2)OCO3)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Reaction time: 4 h

Procedure:
A solution of 4-benzo[1,3]dioxol-5-yl-cyclohex-3-enone (as prepared in the previous step, 680 mg, 3.15 mmol) and azetidin-3-yl-carbamic acid tert-butyl ester (BetaPharma, 542 mg, 3.15 mmol) in DCM (10 mL) was treated with NaBH(OAc)3 (Aldrich, 2.0 g, 9.45 mmol) at room temperature. The reaction was stirred for 4 hours and quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using hexanes and ethyl acetate as eluent (from pure hexanes to pure ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[CH2:20]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(SCC(OC)C[NH2:48])CCCCCCCCCCCCCCC.C1(=O)NC(=O)C2=CC=CC=C12>>[CH2:1]([S:17][CH2:18][CH:19]([O:22][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[CH2:20][NH2:48])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CO)Oc1ccon1
Agent: O=C1NC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCSCC(CN)Oc1ccon1

Procedure:
3-Hexadecylthio-2-(3-isoxazolyloxy)propanol Vj1 is allowed to react and worked up by the same procedure as described in (3). The phthalimide compound: m.p. 73°-74° C. The summary of the experimental condition and the physical data of the product are listed in Tables 5 and 6.
Reaction SMILES: C(O)C.[Na].[C:5]1([CH2:11][C:12](=[NH:14])[NH2:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:15]([N:22]1[CH2:28][CH2:27][C:26](=O)[CH:25]([C:30](OCC)=[O:31])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:11]([C:12]1[NH:14][C:30](=[O:31])[C:25]2[CH2:24][CH2:23][N:22]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:28][CH2:27][C:26]=2[N:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CCC1=O
Reactant: N=C(N)Cc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(Cc2ccccc2)nc2c1CCN(Cc1ccccc1)CC2

Procedure:
Ethanol (50 ml) was cooled in an ice bath then sodium (442 mg, 19.2 mmol) added, with vigorous stirring. Once the sodium was dissolved, 2-phenylethanimidamide (1.29 g, 9.6 mmol) and ethyl 1-benzyl-5-oxoazepane-4-carboxylate (2.5 g, 8 mmol) was added. The reaction mixture was refluxed, under nitrogen, for 17 h. Water (10 ml) was added to quench the reaction then the reaction mixture concentrated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with DCM:MeOH (98:2 to 95:5), to afford a white solid, 1.35 g, 49%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=O.[Cl:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH2:7][C:15]2[S:14][C:13]([Cl:12])=[CH:17][CH:16]=2)[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: Clc1cccs1
Product: Clc1ccc(Cc2cc(Br)ccc2I)s1

Procedure:
5-Bromo-2-iodobenzoic acid (see Jorg Frahn, A.-Dieter Schluter Synthesis 1997, 1301-1304) and 2-chlorothiophene were treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-chloro-2-thienylmethyl)-2-iodobenzene as colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]N=C2CCCCCCC2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH:21](O)([CH3:23])[CH3:22]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:21]3[CH2:23][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][C:22]=3[C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(ON=C2CCCCCCC2)cc1
Reactant: CC(C)O
Agent: Cl
Product: O=[N+]([O-])c1ccc2oc3c(c2c1)CCCCCC3

Procedure:
The core molecule was synthesized by the following procedure. Potassium t-butoxide (5.9 g, 53 mmol) was added in portions to a cooled (5° C.) solution of cycloheptanone oxime (7.5 g, 53 mmol) in DMF (100 mL). The cooled reaction mixture was stirred for 50 minutes and then 1-chloro-4-nitrobenzene (7.9 g, 50 mmol) in DMF (25 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in ether and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated to provide cyclooctanone O-(4-nitro-phenyl)-oxime (5.7 g). Cyclooctanone O-(4-nitro-phenyl)-oxime (5.3 g, 20 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (6.8 mL) was added. The reaction mixture was heated to reflux for 5 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven. The crude solid was purified by flash column chromatography (elution with 2% ethyl acetate-hexanes) to give 2-nitro-6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan (3.5 g, 14 mmol). A mixture of 2-nitro-6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan (3.4 g, 14 mmol) and Raney nickel (-4.1 g wet weight) in ethanol (170 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (elution with 20% ethyl acetate-hexanes) to give 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (2.3 g). Mp 97-98° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][NH2:17])=O)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](N)=[NH:24].C([O-])C.[Na+]>CN(C=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:4]=[C:3]([C:14]3[NH:24][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[N:17][N:16]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH:9]=1
Reactant: NNC(=O)c1nc(-c2cccnc2)cnc1N
Reactant: N=C(N)c1cccs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cccnc2)nc1-c1nnc(-c2cccs2)[nH]1
Temperature: 160 °C
Yield: 42.1 %

Procedure:
3-amino-6-(3-pyridyl)pyrazine-2-carbohydrazide (40 mg, 0.173 mmoles), thiophene-2-carboxamidine (21.92 mg, 0.173 mmoles) and sodium ethanolate (11.82 mg, 0.173 mmoles) were added to a microwave vial. DMF (1 mL) was then added and the vial sealed and heated in the microwave at 160° C. for 40 minutes. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (23.4 mg, 31% Yield). 1H NMR (400.0 MHz, DMSO-d6) d 14.96 (s, 1H), 9.55 (s, 1H), 8.99 (s, 1H), 8.84 (d, J=6.1 Hz, 1H), 8.69 (dd, J=1.2, 4.9 Hz, 1H), 7.95 (s, 2H), 7.81 (d, J=3.0 Hz, 1H), 7.73-7.68 (m, 2H) and 7.22 (dd, J=3.8, 4.8 Hz, 1H) ppm; MS (ES+) 323.10
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-])=O)[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni].CO>[ClH:1].[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: Nc1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 15 parts of 4-(diphenylmethyl)-N-(2-nitrophenyl)-1-piperazinepropanamine hydrochloride in 160 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over hyflo and the filtrate is evaporated. The solid residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off and dried, yielding N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine hydrochloride; mp. 223.1° C.
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[Br:12]Br>ClCCl>[Br:12][CH:10]([CH3:11])[C:2](=[O:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CCCCOC(=O)C(=O)CC
Reactant: BrBr
Solvent: ClCCl
Product: CCCCOC(=O)C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.9 %

Procedure:
A solution of butyl 2-oxobutanoate (described in Patent; IMPERIAL CHEMICAL INDUSTRIES PLC; Publ.: EP 375457 B1 (1994/03/16), Appl.: EP 1989-313521 (1989/12/22), 14g, 88.6 mmol) in dichloromethane (100 mL) was cooled to 0° C., and bromine (4 mL, 80 mmol) was added over 15 minutes. Following stirring at room temperature for 30 minutes, the reaction solution was washed with aqueous sodium bicarbonate solution, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 21.8 g of the title compound as a colorless liquid (100%).
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13](C)=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].Br.C(O)(=[O:20])C>>[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:20])[CH:7]=[CH:8][N:9]=1)[CH3:3]
Reactant: CC(=O)O
Reactant: CCSc1nccn1-c1ccc(C)cc1
Agent: Br
Agent: Cl
Product: CCSc1nccn1-c1ccccc1O

Procedure:
A mixture of 14 parts of 2-(ethylthio)-1-(4-methylphenyl)-1H-imidazole monohydrochloride and 113 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is dissolved in water. The solution is neutralized with sodium hydrogen carbonate. The precipitated product is filtered off and crystallized from 2-propanol, yielding 8.3 parts (72.5%) of 4-[2-(ethylthio-1H-imidazol-1-yl]phenol; mp. 165.2° C.