Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([CH:22]=[C:23]([C:26]#[N:27])[C:24]#[N:25])=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1.[C-:28]#[N:29].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[CH:20]=[CH:19][C:18]([C:22]([C:28]#[N:29])=[C:23]([C:24]#[N:25])[C:26]#[N:27])=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c3ccccc3c3cc(C=C(C#N)C#N)ccc32)cc1
Reactant: [C-]#N
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2c3ccccc3c3cc(C(C#N)=C(C#N)C#N)ccc32)cc1
Reaction time: 0.17 h
Yield: 27.9 %

Procedure:
1.00 g (2.87 mmol) of N-(4-methoxyphenyl)-3-(2,2-dicyanoethenyl)carbazole and 12.5 ml of N,N-dimethylformamide as solvent were placed in a 500 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 0.15 g (2.87 mmol) of sodium cyanide and 0.5 ml of water, which was stirred for 10 minutes. Further, 1.74 g (3.93 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 100 ml of chloroform was added. To the resultant aqueous solution was added 100 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a red solid, which was recrystallized in the presence of benzene to obtain 0.30 g of a red crystal.
Reaction SMILES: CC1(C)O[C:6](=O)[CH:5]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:19])[CH:17]=3)[NH:12][CH:11]=2)C(=O)O1.[NH2:22][C:23]1[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH:35]([CH3:37])[CH3:36])[CH:29]=1)=[O:26].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>N1C=CC=CC=1>[Br:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:9][CH2:5][C:6]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH:35]([CH3:36])[CH3:37])[CH:29]=2)[C:25](=[O:26])[C:24]2[C:23](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:22]=1
Reactant: CC1(C)OC(=O)C(Cc2c[nH]c3ccc(Br)cc23)C(=O)O1
Reactant: CC(C)Oc1cccc(NC(=O)c2ccccc2N)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CC(C)Oc1cccc(-n2c(CCc3c[nH]c4ccc(Br)cc34)nc3ccccc3c2=O)c1

Procedure:
A solution of 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)methyl-5-bromoindole (4.12 g, 12 mmol), 2-amino-N-(3-isopropoxyphenyl)benzamide (3.48 g, 13 mmol), and PPTS (1.64 g, 6.5 mmol) in 50 ml of pyridine was refluxed for 3.5 days. The reaction mixture was then evaporated in vacuo to dryness, and the residue was taken up in methylene chloride. The product was chromatographed (30% ethyl acetate/hexanes, SiO2) and the title product (2.13 g, 36%) crystallized by allowing the fractions containing product to evaporate: mp 179°-181° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].C1(C)C=CC=CC=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)([O-:19])=[O:18]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:8][N:9]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: NNc1ccccc1I
Reactant: C#Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cc2n[nH]c3ccccc23)cc1
Yield: 19.3 %

Procedure:
Into a dry reaction vessel, 10.3 g (44 mmol) (2-iodophenyl)hydrazine, 100 mL toluene, 50 mL triethylamine, 8.41 g (57.2 mmol) p-nitro phenylacetylene, 500 mg (Ph3P)2PdCl2, 250 mg cuprous iodide were respectively added, and reacted at 110° C. under protection of nitrogen for 4.5 h. It was cooled, rotate evaporated to dryness to remove the solvent, chromatographed on a column to obtain a red liquid 2.15 g (8.50 mmol), at a yield of 19.3%.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]([CH3:15])=[C:10]2[C:5]=1[CH2:6][CH2:7][C@@:8]([CH3:32])([CH2:16][CH2:17][CH2:18][C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[O:9]2)[CH:2]=[CH2:3].C(#N)C.[O:36]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O>O>[CH2:1]([C:4]1[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[C:10](=[O:9])[C:5]=1[CH2:6][CH2:7][C@@:8]([OH:36])([CH3:32])[CH2:16][CH2:17][CH2:18][C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(C)c2c1CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A 50 mL RBF flask was charged with (R,R,R)-5-allyl-2,8-dimethyl-2-(4,8,12-trimethyl-tridecyl)-chroman-6-ol (Ex-1E-3) (280 mg, 0.63 mmol) and ACN (14 mL), then cooled to 0° C. A solution of CAN (710 mg, 1.30 mml) in water (2 mL) was added dropwise over 1 min to the reaction resulting in a bright orange solution. After 15 min, the reaction was deemed complete (TLC—5:1 hept:EtOAc). The reaction was extracted with MTBE (3×15 mL). The combined MTBE layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to yield (R,R,R)-2-allyl-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5-methyl-[1,4]benzoquinone (Ex-1E-4) as an orange oil (270 mg, 96%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.59 (d, J=1.4 Hz, 1H), 5.82 (ddt, 1H), 5.10-5.06 (m, 2H), 3.27 (d, J=6.2 Hz, 2H), 2.60-2.56 (m, 2H), 2.06 (s, 6H), 1.59-1.04 (m, 21H), 0.89-0.85 (m, 15H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: c1ccc(Cn2cccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2cccn2Cc2ccccc2)c1
Reaction time: 8 h

Procedure:
In a flask were placed 3.0 ml (22.9 mmol) 3-methylbenzoyl chloride and 50 ml methylene chloride. Then 22.9 ml (1.0M in CH2Cl2, 22.9 mmol) stannic chloride was added dropwise. The contents of the flask were mixed for 5 minutes, then 3.6 g (22.9 mmol) N-benzylpyrrole in 10 ml methylene chloride was added dropwise. The reaction mixture was stirred overnight, then quenched with water, washed with brine, dried and condensed to yield an oil. The oil was purified by flash chromatography with ethyl acetate/hexanes/silica gel, yielding two fractions. These were analyzed spectroscopically; one was found to be the desired 2-benzoyl compound, the other the corresponding 3-benzoyl compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O1CCCC1.[CH2:26]([Mg]Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O>[CH2:26]([C:8]1([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccc(CN=C2CCC3(CC2)OCCO3)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNC2(Cc3ccccc3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a heated flask a 0.6 M solution of (1,4-dioxaspiro[4,5]dec-8-ylidene)-(4-methoxybenzyl)amine in tetrahydrofuran (17 ml, 10 mmol) was added slowly dropwise under argon and with ice cooling to a 2 M solution of benzyl magnesium chloride in tetrahydrofuran (10 ml, 20 mmol). The mixture was stirred for 20 h at room temperature and then added dropwise to 20% ammonium chloride solution (20 ml) with iced water cooling. The organic phase was separated off and the aqueous phase was extracted with diethyl ether (3×20 ml). The combined organic phases were washed with 2 N sodium hydroxide solution (20 ml) and water (20 ml), dried with sodium sulfate and concentrated to small volume under vacuum. The crude product (3.7 g) was purified by flash chromatography (370 g, 22×7.5 cm) with ethyl acetate/cyclohexane (1:2) with 1% triethylamine. Yield: 1.27 g (34%), yellowish oil.
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3].[Br:9]C(C1C=CC=CN=1)CC>>[Br:9][CH:1]([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nccs1
Reactant: CCC(Br)c1ccccn1
Product: CCC(Br)c1nccs1

Procedure:
The title compound was prepared from 2-propylthiazole (purchased from Waterstone Technologies, Inc., Carmel, Ind.) following a procedure similar to the one described above for the synthesis of 2-(1-bromopropyl)pyridine (Example 230). Mass Spectrum (ESI) m/z=205.8 and 207.8 (M+1).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([N:46]5[CH2:47][CH2:48][O:49][CH2:50][CH2:51]5)=[CH:44][CH:45]=4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(N2CCOCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(c2ccc(N3CCOCC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.500 g, 1.28 mmol, 1 eq) and MeOH (10 ml), the product was purified by prep TLC using 4% methanol in chloroform as eluent; yield: 0.100 g (19.34%); MS m/z: 405.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.37 (s, 1H), 8.13 (d, 1H), 7.68-7.64 (m, 1H), 7.50-7.48 (m, 1H), 7.38 (m, 1H), 7.25-7.22 (m, 1H), 7.08-7.06 (m, 2H), 6.82-6.80 (m, 2H), 5.68 (d, 1H), 3.93 (s, 3H), 3.66-3.63 (m, 4H), 3.17-3.01 (m, 4H), 1.66 (s, 3H); HPLC (METHOD [A]): rt 9.33 min (96.37%)
Reaction SMILES: [Na].CS(C)=O.[OH:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[CH2:27]([O:26][C:24]([CH:23]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:8]=1)[CH3:29])=[O:25])[CH3:28]
Reactant: Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 0.54 g portion of sodium was dissolved in 15 ml of absolute ethanol, and was added to 50 ml of dimethylsulfoxide containing 5.4 g of 3-hydroxy-1-(4-trifluoromethylphenyl)-1,2,4-1H-triazole. An additional 25 ml of dimethylsulfoxide was added, and the mixture was heated on the steam bath for 15 minutes. Then 4.3 g of ethyl 2-bromopropionate was added and heating was continued for 1 hour. The mixture was then cooled and poured over ice-water, and the product was collected, dried, and purified by high-performance liquid chromatography, eluting with 1:1 hexane:ethyl acetate. The product-containing fractions were combined and evaporated under vacuum to obtain 3.5 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:6]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:10][C:11]([F:17])([F:16])[C:12](Br)([F:14])[F:13].O>CN(C=O)C>[Br:10][C:11]([F:17])([F:16])[C:12]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([F:14])[F:13]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(Br)C(F)(F)Sc1ccccc1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
In a three-necked round-bottomed flask placed under nitrogen, topped with a dry-ice condenser and a dropping funnel, thiophenol (10.2 ml, 100 mmol) was added dropwise (30 min) at 0° C. to a suspension of NaH (6 g, 150 mmol) in anhydrous DMF (100 ml). The mixture was then stirred at this temperature for 20 min then cooled to −50° C. 1,2-dibromo-1,1,2,2-tetrafluoroethane (15 ml, 125 mmol) was then added dropwise at −50° C. over 10 min. The mixture was then stirred for 2 h at this temperature, then 1 h at ambient temperature. Water (150 ml) was added to the reaction mixture, then the product was extracted with ethyl ether (3×100 ml). The organic phases were washed with water (3×100 ml) and dried over MgSO4. After evaporation of the solvent, the residue was purified by distillation under reduced pressure (99° C./40 mmHg). The product [(2-bromo-1,1,2,2-tetrafluoroethyl)sulfanyl]benzene was then obtained in the form of a colorless liquid (26.07 g, 90%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:24]O>>[CH2:1]([S:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(OCCCSCc3ccccc3)ccc2N1
Reactant: OO
Product: O=C1CCc2cc(OCCCS(=O)Cc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 123 from 6-(3-benzylmercapto-propoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: CC1(C=O)CC[C:4]2([O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][O:7]2)C1.[C:16]([O-:19])([O-])=O.[K+].[K+].BrCCCCBr.C[C:29]#[N:30]>O>[CH3:4][O:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]([N:30]([O:19][CH3:16])[CH3:29])=[O:7]
Reactant: CC#N
Reactant: CC1(C)COC2(CCC(C)(C=O)C2)OC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: BrCCCCBr
Product: COCC(C)(C)C(=O)N(C)OC
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Step 3—A mixture of 2 (0.9 g, 3.912 mmol), K2CO3 (0.595 g, 4.303 mmol) and 1,4-dibromobutane (0.49 mL, 4.108 mmol) in 14 mL of CH3CN and 1 mL of H2O was stirred at 110° C. for 30 minutes under microwave irradiation before being cooled to RT. 0.5 more equivalents of 1,4-dibromobutane were added and the resulting mixture was stirred at 110° C. for 30 minutes under microwave irradiation a second time before being cooled to RT. The reaction mixture was extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 chromatography (hexanes/EtOAc 0-8% EtOAc) to give 0.25 g of 3: 3-bromo-5-pyrrolidin-1-yl-benzoic acid methyl ester (22% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=1.BrC1C2N([C:38](=[O:41])NN=2)C(C)=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:11]2[N:12]([C:38](=[O:41])[NH:15][N:14]=2)[CH:13]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Product: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cn12
Yield: 88 %

Procedure:
The title compound (190 mg, 88% yield) as a yellow foam was prepared from 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-hydrazinylpyridine (200 mg, 0.61 mmol) in a manner analogous to that in which 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=3.83 min, [M+H]+=356.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[Zn:10]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Zn+2:10].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8]
Reactant: [Zn]
Reactant: O=C(O)c1ccccn1
Solvent: O
Product: O=C([O-])c1ccccn1
Product: [Zn+2]
Reaction time: 0.07 h

Procedure:
Thirty grams of ZnSO4.7H2O was dissolved in 200 ml. deionized water at room temperature. Thereafter, 20 g. picolinic acid (Sigma Chemical, St. Louis, MO) was added to the solution and the solution was stirred continuously. Within 3-5 minutes a precipitate began to form. After 30 minutes the stirring was discontinued and the mixture was left standing at room temperature until the precipitate had settled to the bottom. The supernatant was removed by aspiration and the precipitate was suspended in enough deionized water to yield 200 ml. This suspension was then heated in a beaker with continuous stirring until the precipitate had completely dissolved after which the beaker was placed in an ice bath and stored overnight in a cold room (4°). The following morning the supernatant was aspirated from the crystals and the crystals were freeze dried. Assay of the crystals proved that the complex contained 2 moles of picolinic acid and 1 mole of zinc [zinc dipicolinate, Zn(PA)2 ].
Reaction SMILES: [CH3:1][C:2]([CH3:52])([CH3:51])[C:3]([O:5][CH2:6][O:7][C:8]([C:10]1([C:41]([O:43]CC2C=CC=CC=2)=[O:42])[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[C:30]([F:40])[CH:29]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])=[O:4]>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:52])([CH3:51])[C:3]([O:5][CH2:6][O:7][C:8]([C:10]1([C:41]([OH:43])=[O:42])[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[C:30]([F:40])[CH:29]=4)[O:25][N:24]=3)=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:9])=[O:4]
Reactant: CC(C)(C)C(=O)OCOC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)C(=O)OCOC(=O)C1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (2,2-dimethyl-propanoyl-oxymethyl) ester (0.37 g, 0.00052 mol) in a mixture of ethanol and ethyl acetate (20 mL, 1:1) is added 5% Pd/C (0.133 g). The reaction mixture is stirred at room temperature and hydrogen gas is bubbled through it. This process is continued for 2.5 hours. The reaction mixture is filtered through a celite bed, washed with tetrahydrofuran (2×30 mL) and the filtrate is concentrated under reduced pressure to give a solid mass which is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane 15:85) to give 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid (2,2-dimethyl-propanoyloxymethyl)ester (e.g. 39).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: O=C(Cl)c1ccncc1
Product: CC(CNC(=O)c1ccncc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and isonicotinoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: Cl.[CH:2]1([C:8](=[NH:10])[NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.N[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>CN(C=O)C.O>[CH:2]1([C:8](=[NH:9])[NH:10][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N=C(N)C1CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=N)C1CCCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
To a solution of cyclohexanecarboximidamide hydrochloride (2.00 g) and tert-butyl glycinate hydrochloride (2.06 g) in DMF (16 ml) was added triethylamine (4.30 ml) at room temperature, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (0.84 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][SH:12].II.[I-].[K+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])=[CH:2]1
Reactant: COC(=O)CS
Reactant: c1ccc2[nH]ccc2c1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CSc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of indole (3.00 g, 25.6 mmol) and methyl thioglycolate (2.40 mL, 25.6 mmol) in methanol:water (80 mL:20 mL) was added iodine (6.50 g, 25.6 mmol) and potassium iodide (4.25 g, 25.6 mmol). The reaction mixture was stirred at ambient temperature for 60 hours. Methanol was removed in vacuo and the aqueous layer diluted with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated in vacuo and the resulting residue was purified on a silica gel column (0-100% ethyl acetate:hexanes over 33 min) to afford the desired product. LCMS>99% at 254 nm, RT=1.29 min, m/z=222 (M+1).