Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[C:12]2[C:11]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:5][CH:4]=1.[Na+].[OH-].[Na+].[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])([O-:26])=[O:25].Cl>O>[Na+:1].[Na+:1].[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:2][C:3]1[C:12]2[C:11]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:5][CH:4]=1)=[O:31])([O-:26])=[O:25]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 48.3 g portion of 4-amino-1,5-naphthalenedisulfonic acid sodium salt is suspended in 150 ml of water and 160 ml of 1N sodium hydroxide is added, then 60.0 g of m-nitrobenzoyl chloride is added all at once. The mixture is shaken for about 15 minutes or until no longer basic to test paper, then another 160 ml of 1N sodium hydroxide is added with additional shaking. The latter addition of sodium hydroxide and shaking is repeated two more times and when the mixture remains basic after 1/2 hour of shaking after the last portion is added the mixture is acidified to Congo Red with 15 ml of concentrated hydrochloric acid. Additional water is added to the mixture which is then copiously extracted with ether. The ether is removed by vacuum siphoning and the aqueous phase is filtered. The filtrate is neutralized and is concentrated at 55° C. in vacuo until crystal formation then it is cooled to room temperature. The crystallized material is collected by filtration and is washed with 250 ml of saturated saline, then with two 150 ml portions of 50% ethyl alcohol followed by two 150 ml portions of absolute ethyl alcohol and two 150 ml portions of ethyl ether. The product of the example is then oven dried at 120° C. overnight.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:30][C@@H:29]1[CH3:34])[CH3:27]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CCN1CCNC[C@@H]1C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.20 Hz, 6H) 2.33 (d, J=2.27 Hz, 3H) 3.08-3.36 (m, 4H) 3.42 (br. s., 2H) 4.11-4.93 (m, 3H) 7.64 (br. s., 1H) 7.71-7.80 (m, 1H) 7.87-8.79 (m, 4H) 9.53-10.44 (m, 1H) 12.23-14.36 (m, 1H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]1[CH3:12].Br[C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])(=O)C.[K+].C>CN(C)C(=O)C.[Pd].ClCCl>[Cl:22][C:20]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([C:6]2[N:2]([CH3:1])[C:3]([CH3:12])=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=2)[CH:21]=1
Reactant: CCOC(=O)c1ccn(C)c1C
Reactant: O=Cc1ccc(Cl)cc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(-c2cc(Cl)ccc2C=O)n(C)c1C
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
To a solution of 10.5 g of the compound obtained in Step A (62.8 mmol) in 65 mL of N,N-dimethylacetamide there are successively added 15.2 g of 2-bromo-4-chlorobenzaldehyde (69 mmol), 12.3 g of potassium acetate (125.6 mmol) and then the batch is stirred under argon for 20 minutes. There are then added 2.2 g of palladium catalyst PdC12(PPh3)2 (3.14 mmol). The reaction mixture is then heated at 130° C. overnight. The mixture is allowed to return to ambient temperature and it is then diluted with dichloromethane. Animal charcoal is added (2 g per g of product) and the batch is stirred at ambient temperature for 1 hour and then filtered. The organic phase is then washed with water, dried over MgSO4 and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel (petroleum ether/AcOEt gradient). The title product is obtained in the form of a solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][CH2:24][C@@H:23]3[CH3:27])[CH2:18]2)=[CH:13][CH:12]=1)C1C=CC=CC=1>CO>[CH3:27][C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[CH:19]1[CH2:20][CH2:21][C@H:17]([C:14]2[CH:15]=[CH:16][C:11]([NH2:10])=[CH:12][CH:13]=2)[CH2:18]1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Solvent: CO
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
{4-[(S)-3-((S)-2-Methyl-pyrrolidin-1-yl)-cyclopentyl]-phenyl}-carbamic acid benzyl ester (0.41 g, 1.08 mmol) was dissolved in MeOH (20 mL) to form a clear solution. The flask was flushed with nitrogen and Pd—C (10%) (50 mg) was added. The solution was stirred under H2 atmosphere at rt for 4 h. TLC (5% of 7N ammonia methanolic solution in DCM) indicated that the reaction was complete. The solution was filtered through a Celite pad, rinsed with MeOH. The filtrate was concentrated in vacuo to obtain 0.27 g (100% yield) of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[C:16](#[N:26])[C:17]1[CH:25]=[CH:24][C:23]2[O:22][CH2:21][O:20][C:19]=2[CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:21]1[O:22][C:23]2[CH:24]=[CH:25][C:17]([C:16](=[NH:26])[NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[CH:18][C:19]=2[O:20]1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1ccc2c(c1)OCO2
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of (4-methylsulfonyl)aniline (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of piperonylonitrile (4.85 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 90–95° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The product was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 3,4-methylenedioxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (4.8 g, 91%) was used in the next reaction without further purification: mp (DSC) 214° C. Anal. Calc'd. for C15H14N2SO4: C, 56.59; H, 4.43; N, 8.80. Found: C, 56.33; H, 4.28; N, 8.66.
Reaction SMILES: [F:1][C:2]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])(Cl)[C:3]([F:6])(Cl)[Cl:4]>[Zn].C(O)C>[Cl:4][C:3]([F:6])=[C:2]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[F:1]
Reactant: Nc1cccc(C(F)(Cl)C(F)(Cl)Cl)c1
Agent: [Zn]
Solvent: CCO
Product: Nc1cccc(C(F)=C(F)Cl)c1
Temperature: 25 °C

Procedure:
74 G. of zinc dust is added to a vigorously stirred solution of 40 g. of 3-(1,2-difluoro-1,2,2-trichloroethyl)-aniline in 450 ml. of ethanol and heated at reflux for 2 hours. It is filtered hot, the solid residue washed with hot ethanol and the combined ethanol solution cooled to room temperature. About 1000 ml. of chloroform is added and the organic layer is washed with aqueous NaHCO3 solution and with water, dried over Na2SO4 and concentrated in vacuo to 23.9 g. of oily 3-(2-chloro-1,2-difluorovinyl)aniline. This gives a single peak with a retention time of 1.8 minutes at 200° C. on a gas liquid chromatography column packed with 5% SE30, and the correct values for C,H,N,Cl and F by combustion analysis.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:22][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[CH3:21])=[O:4]
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)c1ccccc1N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.6 %

Procedure:
To a mixture of isatoic anhydride (500 mg, 3.07 mmol) and 1-(4-chloro-phenyl)-ethylamine (530 mg, 3.68 mmol) in CH2Cl2 (20 mL) is added diisopropyl ethyl amine (1.2 mL, 6.89 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, concentrated and the resulting residue is purified by flash chromatography with 25% EtOAc in Hexane as the eluent to afford the desired to afford the desired 2-amino-N-[1-(4-chloro-phenyl)-ethyl]-benzamide (115 mg, 14%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:23])[CH3:22])[CH2:17]2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>C(OCC)(=O)C>[NH2:7][CH:8]([C:10]1[CH:11]=[C:12]([N:16]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:22])[CH3:23])[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(N2CCC(N(C)C)C2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(N)c1cccc(N2CCC(N(C)C)C2)c1
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of {1-[3-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.8 g) and 4 ml of 4 N HCl in ethyl acetate (10 mL) at 50° C. was stirred for 2 h. After concentration, the residue was neutralized with 10 N NaOH and extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the crude product (1.25 g) as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([S:34]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([S:34]([N:37]5[CH2:42][CH2:41][CH:40]([N:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]5)(=[O:35])=[O:36])=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CN(C)C1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(S(=O)(=O)c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1

Procedure:
Compound 362 was prepared as an off-white solid (TFA salt) from compound 4 and compound 363 using chemistry similar to that described in example 200. 1H NMR (400 MHz, CD3OD) δ ppm 9.56 (1 H, s), 9.25 (1 H, s), 8.66-8.75 (2 H, m), 8.58 (2 H, s), 8.18 (1 H, dd, J=8.8, 2.5 Hz), 5.50 (1 H, quin, J=8.8 Hz), 4.01 (2 H, d, J=12.5 Hz), 3.22 (1 H, tt, J=12.1, 3.8 Hz), 2.86 (6 H, s), 2.44-2.60 (4 H, m), 2.12-2.35 (6 H, m), 1.74-2.01 (4 H, m). LCMS-ESI (POS), M/Z, M+1: Found 521.2.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH2:6])C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[C:13]([CH3:20])[CH:12]=1>Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:4]=[CH:5][N:6]=[C:18]2[SH:19])=[C:13]([CH3:20])[CH:12]=1
Reactant: Cc1cc(Br)ccc1N=C=S
Reactant: CCOC(CN)OCC
Agent: Cl
Product: Cc1cc(Br)ccc1-n1ccnc1S
Reaction time: 0.17 h

Procedure:
105.5 Milliliters of 2,2-diethoxyethylamine was dropwise added to 138 g of 4-bromo-2-methylphenyl isothiocyanate with ice-cooling. The mixture was stirred for 10 minutes and then further stirred for 10 minutes at 100° C. The mixture was allowed to cool, and thereto was added 500 ml of 8 N hydrochloric acid. The mixture was refluxed for 2 hours. The resulting crystals were collected by filtration, washed with water thoroughly and then dried to obtain 110 g of 1-(4-bromo-2-methylphenyl)-2-mercaptoimidazole.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22](O)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH:27]=1>>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22]([NH:38][C:35]5[CH:34]=[CH:33][C:32]([C:28]6[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=6)=[CH:37][CH:36]=5)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCOCC1
Reactant: Nc1ccc(-c2cccnc2)cc1
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)c1)N1CCOCC1

Procedure:
{7-[3-(Morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (16 mg, 10%). LCMS (m/e) 513 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.88 (s, 1H), 8.79 (s, 1H), 8.61-8.52 (m, 1H), 8.49 (s, 1H), 8.41 (d, 1H, J=7.6 Hz), 7.91 (d, 1H, J=7.8 Hz), 7.80-7.60 (m, 6H), 7.40-7.31 (m, 1H), 7.08 (d, 1H, J=4.6 Hz), 7.02 (s, 1H), 6.90 (d, 1H, J=4.5 Hz), 3.75-3.66 (m, 4H), 3.09-3.00 (m, 4H).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]1)[CH2:19][CH2:18]2.[Li+].C[Si]([N-:35][Si](C)(C)C)(C)C.Cl.[OH-].[Na+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][N:26]1[CH2:27][CH2:28][CH:24]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([NH2:35])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[CH2:25]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN1CCC(N2CCc3cc(Br)ccc32)C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(N2CCc3cc(N)ccc32)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A suspension of Pd2(dba)3 (0.1 g, 0.113 mmol) and PtBu3 (1.38 mL, 0.455 mmol, 10% wt in hexane) in anhydrous THF (3 mL) was treated with a solution of compound 3 (0.64 g, 2.276 mmol) in THF (7 mL) followed by LiHMDS (4.55 mL, 4.552 mmol, 1 M solution in THF) at room temperature. The resulting dark brown mixture was heated to 100° C. and stirred for 3 hours in a sealed tube. The reaction mixture was cooled to room temperature and treated with 1 N HCl solution (5 mL) and stirred for 20 min. The reaction was basified with 2 N NaOH solution (25 mL) and product was extracted into CH2Cl2 (3×20 mL) and the combined organic fractions were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude product was purified by column chromatography on silica gel (2 N NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 4 (0.44 g, 89%) as a syrup. 1H NMR (DMSO-d6) δ 6.38 (s, 1H), 6.30-6.23 (m, 2H), 4.31 (brs, 2H), 4.01-3.92 (m, 1H), 3.14 (t, 2H, J=8.1 Hz), 2.68 (t, 2H, J=8.1 Hz), 2.56-2.50 (m, 3H), 2.37-2.29 (m, 1H), 2.21 (s, 3H), 2.02-1.90 (m, 1H), 1.76-1.66 (m, 1H); ESI-MS (m/z, %): 218 (MH+, 100).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.[N+:13]([CH:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:16])#[C-:14].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:16][C:15]1[N:13]=[CH:14][O:8][C:7]=1[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][CH:5]=1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(F)(F)F)nc1
Yield: 88.3 %

Procedure:
6-(trifluoromethyl)nicotinaldehyde (7 g, 40 mmol), 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (8.41 g, 40.0 mmol) and K2CO3 (6.63 g, 48.0 mmol) were heated to reflux in methanol (200 mL) overnight. The solution was cooled and the solvents removed in vacuo. The orange semi-solid was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and the solvents removed in vacuo. The crude product was purified by column chromatography with 10% to 45% ethyl acetate/hexanes as eluent to afford 8.06 g (88% yield) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 9.01 (d, J=2.03 Hz, 1H), 8.08 (dd, J=7.97, 1.86 Hz, 1H), 7.93 (s, 1H), 7.77 (d, J=8.48 Hz, 1H), 2.51 (s, 3H,). MS (ESI+) m/z 229 (M+H)+.
Reaction SMILES: [I:1]I.[CH2:3]([CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12]O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[I:1][CH2:12][CH:11]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: II
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCCCCCCCCC(CI)CCCCCCCC
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Iodine (12.25 g, 48.3 mmol) was added to a solution of 2-octyl-1-dodecanol (12.42 g, 41.6 mmol), triphenylphosphine (13.17 g, 50.2 mmol), and imidazole (3.42 g, 50.2 mmol) in 80 mL dichloromethane at 0° C. After stirring for 30 min, the reaction mixture was allowed to warm to room temperature over 4 h before 12 mL of saturated Na2SO3 (aq) was added. The organics were concentrated by evaporation and the mixture taken up in 500 mL pentane, washed three times with 200 mL water, and once with 150 mL brine. The mixture was then passed through a 3 cm silica gel plug, and dried over Na2SO4. The organics were concentrated by evaporation to give a colorless oil (15.78 g, yield 92.9%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[C:11]1([S:21](Cl)(=[O:23])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:21]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)(=[O:23])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 1-naphthalenesulfonyl chloride (2.27 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 3% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (2.15 g, 68%). 1H-NMR (300 MHz, CDCl3) δ 8.79 (d, J=8.5 Hz, 1H), 8.14 (d, J=7.0 Hz, 2H), 7.98 (d, J=8.4 Hz, 1H), 7.78 (t, J=8.5 Hz, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.46 (s, 1H), 6.34 (s, 1H), 6.17 (s, 1H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C@@H:12]3[CH:16]([OH:19])[CH:17]([OH:18])[C@@H:5]([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.I([O-])(=O)(=O)=O.[Na+]>C(O)C>[CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]([CH:16]=[O:19])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([CH:17]=[O:18])[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)[C@@H]1c3ccccc3[C@H]2C(O)C1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCO
Product: Cc1ccc2c(c1)C(C=O)c1ccccc1C2C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2.5 g. portion of cis-2-methyl-9,10-dihydro-9,10-ethanoanthracene-11,12-diol [obtained above as yellow crystals (m.p. 227°-228° C.)] is suspended in 100 ml. of an aqueous solution containing 2.14 g. of sodium periodate and one ml. of ethanol. The mixture is stirred at room temperature for 2 hours and the solid is collected by filtration, washed with water and dried giving the desired product as a pale yellow solid, m.p. 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:11](=[O:22])[CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[C:10]1[S:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]1=[O:22]
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C1CSC(c2cccc(Cl)c2)N1CCCN1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1C(=Cc2cccc(Cl)c2)SC(c2cccc(Cl)c2)N1CCCN1CCCCC1
Temperature: 60 °C

Procedure:
2-( 3-Chlorophenyl)-3-(3-piperidin-1-ylpropyl)-thiazolidin-4-one (3 mm, 1 g), 3-chlorobenzaldehyde (4.5 mm, 0.51 mL), and potassium t-butoxide (4.5 mm, 0.5 g) are mixed in 50 mL toluene with molecular sieves and heated at 60° C. for 4 hours. The molecular sieves are removed by filtration, and the solvent is concentrated to dryness. Pure Compound 2 (0.5 g) is isolated by column chromatography (5% MeOH/CH2Cl2). MS: m/z (APCI, AP+) 462 [M]+. MP 137-139° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)(C(C)(C)C)(C)C.O[C@@H:22]([CH2:35][CH:36]1[CH2:39][CH2:38][CH2:37]1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:24]>>[CH:9]([C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([C@H:22]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[O:24])[CH2:11]1)=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: COc1ccc(COC(=O)[C@@H](O)CC2CCC2)cc1
Product: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1

Procedure:
The title compound was prepared from 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) and 4-(methoxy)benzyl 2-(S)-hydroxy-3-(cyclobutyl)propanoate (from EXAMPLE 19, Step E) using procedures analogous to those described in EXAMPLE 1, Steps G-I.