Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.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]>[C:21]([O:20][C:16](=[O:19])[CH:17]=[CH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(C=CC(=O)OC(C)(C)C)cn12
Temperature: 95 °C

Procedure:
A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (500 mg, 1.86 mmol), tert-butyl acrylate (408 uL, 2.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (51 mg, 0.056 mmol), [(t-Bu)3PH]BF4 (27 mg, 0.093 mmol) and N,N-dicyclohexylmethylamine (738 uL, 3.48 mmol) in anhydrous 1,4-dioxane (5 mL) was heated at 95° C. overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated and the crude product was purified by silica chromatography to yield ethyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (70). MS m/z 317.14 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[O:37][CH3:38]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Product: COC(=O)c1cc(COc2ccc(-c3ccc(OC)cc3OC)cc2)c(C)o1

Procedure:
Compound (139) was prepared from compound (119) and 1-bromo-2,4-dimethoxy-benzene by adapting the procedure of Example 31(a). LC/MS System A; Rt=4.09 mins.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[CH2:12]([N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1)[CH3:13].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:12][CH3:13])[CH2:15][CH2:16]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: CCN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a mixture of 4-amino-3-chloro-benzoic acid (Fluorochem; 2.575 g, 15 mmol) and 1-ethylpiperidin-4-amine (Fluorochem; 2.12 g, 16.5 mmol) in DMF (50 mL), was added DIPEA (5.2 mL, 30 mmol). The mixture was cooled with an ice-bath. HATU (6.27 g), added and the reaction mixture stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL), and Ethyl Acetate (4×50 mL). The organic extracts were washed with brine (2×75 ml), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated to give the crude product as a gum, which was triturated with ether to yield the title compound as a tan solid (3.54 g, 84%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH2:9])[C:7]#[N:8].C(N(CC)CC)C.[CH3:17][C:18]1[S:19][C:20]([C:24](Cl)=[O:25])=[C:21]([CH3:23])[N:22]=1.Cl.C(N(CC)CC)C>C(OC(=O)C)C.O>[C:7]([CH:6]([NH:9][C:24]([C:20]1[S:19][C:18]([CH3:17])=[N:22][C:21]=1[CH3:23])=[O:25])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)#[N:8]
Reactant: Cc1nc(C)c(C(=O)Cl)s1
Reactant: N#CC(N)c1ccco1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C)c(C(=O)NC(C#N)c2ccco2)s1
Yield: 90 %

Procedure:
In 120 ml of ethylacetate were dissolved 6.2 g of alpha-(2-furyl)-alpha-aminoacetonitrile and 6.0 g of triethylamine, and with stirring, the 2,4-dimethylthiazole5-carboxylic acid chloride was added dropwise to the solution, and the mixture was stirred at room temperature for 1 hour. Water (150 ml) was added, and the precipitated triethylamine hydrochloride was dissolved. The ethyl acetate layer was separated, washed with water, and dried over sodium sulfate. The dried ethyl acetate layer was distilled under reduced pressure to remove the solvent. The residue was recrystallized from isopropyl ether to give 11.65 g (yield 90.0%) of the desired N-(alpha-cyanofurfuryl)-2,4-dimethylthiazole-5-carboxylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=2)[NH:21][CH:20]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:11][CH2:10]1
Reactant: Fc1ccc2[nH]cc(CCCCl)c2c1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Product: Fc1ccc2[nH]cc(CCCN3CCN(c4cccc(Cl)c4Cl)CC3)c2c1

Procedure:
from 1-(2,3-dichlorophenyl)piperazine and 3-(3-chloropropyl)-5-fluoro-1H-indole. Mp 147–148° C. 1H NMR (DMSO-d6): 1.75–1.85 (m, 2H); 2.30–2.45 (t, 2H); 2.45–2.60 (m, 2H); 2.70 (t, 2H); 3.00 (b s, 4H); 3.35 (b s, 2H); 6.85–6.95 (m, 1H); 7.05–7.15 (m, 1H); 7.20 (s, 1H); 7.20–7.35 (m, 4H); 10.85 (b s, 1H). Ms m/z: 406 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:14][C:15]([C:17]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[CH2:21][CH2:20][N:19]([C:10](=[O:11])[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: COc1cccc(N=C=O)c1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2cccc(OC)c2)C1

Procedure:
The title compound was prepared according to the method described for Preparation using 3-methoxy phenyl isocyanate and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford a racemate as a colourless liquid (230 mg, 80%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH:10]([CH3:33])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](COCC1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@@H](COCC1CC1)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 0.325 g (0.73 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one (Example 68, Step B) and iodomethane (0.055 mL, 0.874 mmol) in THF (7.0 mL) was added lithium bis(trimethylsilyl) amide (1M solution in THF, 0.8 mL, 0.8 mmol) at −78° C. The reaction was allowed to warm to R.T., then was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography on silica gel, eluting with a gradient of 10% to 30% EtOAc in hexane, to provide the title compound as a mixture of C-3 stereoisomers, as indicated by *.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].CI.[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:13]([O:15][C:16]([C:18]1([CH3:1])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (15% solution in n-hexane; 82 mL, 0.19 mol) is added to a stirred solution of diisopropyl amine (28.75 mL, 0.20 mol) in tetrahydrofuran (400 mL) at −70° C. under an atmosphere of nitrogen and stirred for 30 minutes. A solution of piperidine-1,4-dicarboxylic acid-1-tert-butyl ester 4-ethyl ester (30 g, 0.12 mol) in tetrahydrofuran (80 mL) is introduced at −70° C. Hexamethyl phosphoramide (45 mL) is added and reaction mixture is allowed to stir till the temperature reaches at −45° C. Reaction mixture again cooled to −70° C., methyl iodide (39.3 mL, 0.60 mol) is added and stirred for 1 hour. Saturated aqueous solution of ammonium chloride (100 mL) is added slowly into the reaction mixture at 0° C. and stirred for 10 minutes. It is extracted with ethyl acetate (3×200 mL). Combined organic layer is washed with brine solution (1×100 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400, n-hexane:ethyl acetate, 9:1) to furnish 4-methyl piperidine-1,4-dicarboxylic acid-1-tert-butylester-4-ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[N:10][N:11]([CH2:13][C:14]([O:16]CC)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)=[N:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2nn(CC(=O)O)cc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
To a solution of ethyl [4-(4fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl]acetate from Step 1 (1.05 g, 2.6 mmol) in THF (20 mL) was added 3.0 mL of aqueous 1N lithium hydroxide at 25° C. under nitrogen and the mixture stirred at 25° C. for 24 hours. The mixture was acidified with 2N HCl, extracted with two portions ethyl acetate and the organic layer separated, washed with brine, dried over MgSO4 and concentrated in vacuo. Chromatographic purification on silica gel using 20% ethanol/79% chloroform/1% acetic acid as the eluant gave [4-(4-Fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazol-1-yl]acetic acid as a white solid (0.58 g, 60%). Elemental analysis . for C18H15N2FSO4 +0.8 CH3CO2H Calc'd: C, 55.73, H, 4.34, N, 6.63, S, 7.59. Found: C, 55.72, H, 4.35, N, 6.74, S, 7.72.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:13])[C:11]#N)=[CH:4][CH:3]=1.[CH3:14][OH:15].Cl.C[OH:18]>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:13])[C:11]([O:15][CH3:14])=[O:18])=[CH:4][CH:3]=1
Reactant: CO
Reactant: COc1nc(Cl)ccc1C(C)C#N
Agent: Cl
Product: COC(=O)C(C)c1ccc(Cl)nc1OC
Yield: 67 %

Procedure:
To a stirred solution of 2-(6-Chloro-2-methoxypyridin-3-yl)propanenitrile (1850 g, 9439 mmol) in MeOH (20 L) was added MeOH/HCl (about 2 M) at r.t. After the addition, the resulting mixture was heated at reflux for 12 hours. The reaction mixture was evaporated to move most of MeOH, and the residue was diluted with H2O (6 L) and basified to pH=9˜10 with solid NaHCO3. The aqueous layer was extracted with CH2Cl2 (15 L). The organic layer was washed with water (10 L) and brine (10 L), dried over Na2SO4 and concentrated to dryness. The crude residue was purified by column chromatography (petroleum ether/EtOAc=100:0˜80:20) to afford methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (1450 g, 67%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.44 (d, 3H), 3.67 (s, 3H), 3.91 (q, 1H), 3.95 (s, 3H), 6.89 (d, 1H), 7.45 (d, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn](CCCC)(CCCC)[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([C:31]2[CH:30]=[N:29][CH:28]=[N:33][CH:32]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2cncnc2)c1
Yield: 77.9 %

Procedure:
To the solution of 3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (400 mg, 1.1 mmol) in toluene (10 mL) was added tetrekis(triphenylphosphine)palladium (40 mg, 1%) and tributyl(pyrimidinyl)tin (0.51 g, 1.38 mmol). The mixture was stirred and heated under reflux for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 2:1) to afford an oil (335 mg, 80%): 1H NMR (CDCl3, 300 MHz) δ 1.40 (s, 9H), 1.85-2.00 (m, 2H), 2.00-2.10 (m, 2H), 3.38 (m, 1H), 4.00 (m 1H), 4.14 (m, 1H), 4.24 (m, 1H), 7.40 (s, 1H), 8.20 (d, 1H, J=3.0 Hz), 8.88 (s, 2H), 9.28 (s, 1H); MS (CI/NH3) m/z 277 (M+H)+.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16]2)=[O:9])([CH3:6])[CH3:5].CO.O>C1COCC1>[CH3:6][C:4]([O:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16]2)=[O:9])([CH3:3])[CH3:5]
Reactant: CCOC(=O)c1cc2cccc(NC(=O)OC(C)(C)C)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Lithium hydroxide (0.196 g, 8.18 mmol) was added to a solution of ethyl 7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.249 g, 0.818 mmol) in THF:MeOH:water/3:1:1 (5 mL). The mixture was stirred at RT overnight. The solvent was evaporated and the residue was dissolved in water, acidified with 6N aqueous HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.206 g, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.36 (s, 1H), 9.29 (s, 1H), 7.28-7.53 (m, 2H), 7.14-7.28 (m, 2H), 6.97-7.13 (m, 1H), 1.41-1.80 (m, 9H). MS m/z 277 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].I[CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:39][CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(O)cc(Br)c2)c1CCC(=O)OCC
Reactant: ICC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC3CCCC3)c2)c1CCC(=O)OCC
Yield: 71458.6 %

Procedure:
A similar procedure as described in Example 43, step 3 was used, starting from 4-[3-[6-(3-bromo-5-hydroxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (600 mg, 1.03 mmol), iodomethylcyclopentane (260 mg, 1.24 mmol), and potassium carbonate (356 mg, 2.57 mmol) to afford 4-[3-[6-(3-bromo-5-cyclopentylmethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (487 g, 73%) as a colorless viscous oil: EI(+)-LRMS m/e calcd for C35H49BrO7 (M+H)+ 663.45. found 663.5.
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][C@H:13]([C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[CH:14]([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+]>CO>[I:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:13]([OH:12])[CH:14]([CH3:15])[CH3:16])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: CC(C)[C@H](OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)[C@H](O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100.5 %

Procedure:
(S)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.288 g, 0.57 mmol) was dissolved in hot methanol (40 mL) and K2CO3 (0.15 g, 1.1 mmol) was added. The mixture was heated to reflux for one hour, cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield (S)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol (0.184 g, 100%) as a light yellow oil. 1H NMR was identical to that of the racemic alcohol.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=1[CH2:7][N:8]=[N+]=[N-])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:6]=1[CH2:7][NH2:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(OC)cc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccc(OC)cc1CN
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.2 %

Procedure:
Step AS (4). To a solution of 2-allyloxy-5-methoxybenzyl azide (4.5 g, 21 mmol) in 150 mL of anhydrous THF was added triphenylphosphine (10.8 g, 41 mmol) and 0.5 mL of water. The mixture was stirred at rt for 7 h. The reaction was concentrated under vacuum and the residue was partitioned between Et2O and 2 N HCl. The aqueous layer was basified with 2 N NaOH to pH 10 and extracted with EtOAc (3×40 mL). The organic layers were combined and washed with brine then dried over magnesium sulfate. After concentration, the residue was purified by silica gel chromatography, eluting with a mixture of 30% 2N ammonia in methanol and 70% EtOAc to yield 2-allyloxy-5-methoxybenzylamine as colorless oil (2.2 g, 55%). LC-MS (M+H)+=194; 1H NMR (400 MHz, CD3OD) δ ppm 3.75 (s, 3H) 4.08 (s, 2H) 4.60 (d, J=5.29 Hz, 2H) 5.22-5.30 (m, J=10.58 Hz, 1H) 5.35-5.44 (m, J=17.37 Hz, 1H) 6.01-6.15 (m, 1H) 6.89-6.96 (m, 2H) 6.96-7.02 (m, 1H).
Reaction SMILES: [OH2:1].[H-].[Na+].[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)([O:6][C:7]([CH3:10])(C)C)=[O:5]>CCOC(C)=O.C(Cl)Cl>[C:4]([NH:11][C@H:12]([C:4]([OH:6])=[O:5])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:1])=[CH:18][CH:19]=1)([O:6][CH2:7][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCBr
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reaction time: 16 h

Procedure:
H2O (1.5 g, 4.29 mmole) was dissolved in EtOAc/CH2Cl2, dried over MgSO4, filtered and evaporated. The residue was dissolved in DMF and treated with NaH (50% dispersion in oil, 0.43 g, 8.96 mmole) for 1 hour. N-BOC-8-amino-1-bromooctane (1.33 g, 4.34 mmole) was added and the reaction was stirred for 16 hours. The DMF was removed in vacuo, the residue dissolved in water, acidified to pH 3 and extracted with EtOAc. The EtOAc layers were combined, dried and concentrated. Column chromatography (SiO2, 97:3:1 CHCl3 /MeOH/HOAc) gave 2-5.
Reaction SMILES: C(N1CCOCC1)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.C(Cl)(=O)C(Cl)=O.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1)OCc1ccccc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
4-Formylmorpholine (50 μL) was added to a stirred solution of 4-bromophenylacetic acid (5.00 g, 23.3 mmol) and oxalyl chloride (5.89 g, 4.05 mL, 46.6 mmol) in dichloromethane (30 mL) under nitrogen at room temperature. When gas evolution ceased the volatiles were evaporated and the residue was taken up in dichloromethane (30 mL). Benzyl alcohol (2.52 g, 2.41 mL, 23.3 mmol) was added in one portion and stirring was continued under nitrogen for 2 h. The volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and saturated sodium hydrogen carbonate solution (50 mL). The phases were separated and the aqueous phase was washed with dichloromethane (2×50 mL). The organic layers were combined, dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (20% diethyl ether: cyclohexane) to give the title compound as a white solid (6.76 g, 95%). LC/MS: 3.57 min; z/e 322 and 324, calcd (M+18) 322 and 324. 1H NMR (400 MHz: CDCl3): 7.45 (2H), 7.30 (5H), 7.15 (2H), 5.15 (2H), 3.60 (2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][NH2:14])[N:12]=2)=[CH:4][CH:3]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][NH:14][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:32])([F:31])[F:15])[O:21][N:20]=4)[CH:23]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: NCc1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCc1coc(-c2ccc(F)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 26 %

Procedure:
This compound was synthesized from (2-(4-fluorophenyl)oxazol-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (65 mg, yield 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.35-9.32 (m, 1H), 8.60 (t, J=1.5 Hz, 1H), 8.25-8.19 (m, 2H), 8.12 (m, 1H), 8.04-8.00 (m, 2H), 7.77-7.73 (t, J=7.8 Hz, 1H), 7.41-7.36 (m, 2H), 4.48-4.47 (d, J=5.2 Hz, 2H). MS (ESI) m/z: Calculated for C20H12F4N4O3: 432.08. found: 433.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH:18]=O)[CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[K+].CS(C)=O>O>[S:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH:26]=[CH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]=[CH:16]2
Reactant: Cc1nc2ccccc2s1
Reactant: O=Cc1ccc2cc(N(c3ccccc3)c3ccccc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C(=Cc1nc2ccccc2s1)c1ccc2cc(N(c3ccccc3)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A mixture of N,N-diphenyl-6-amino-2-naphthaldehyde (4.8 g, 0.015 mol.), 2-methyl benzothiazole (3.0 g, 0.020 mol.), powdered potassium hydroxide (18.0 g, 0.32 mol.) and DMSO (30 ml) was stirred at room temperature for 1 hour, poured into water, and the solids which separated were collected by filtration. These solids were purified by column chromatography on alumina using 1:3 toluene-heptane as the eluent, to give 3.6 g. of product (53% yield) m.p. 181.1-184.8° C. Recrystallization from 1:1 toluene-ethyl acetate raised the m. p. to 201.8-203.8° C. Mass Spec: m/z 454, (M+). Analysis calculated for C31H22N2S: C, 81.92; H, 4.88; N, 6.16; S, 7.04. Found: C, 81.82; H, 4.93; N; 6.04, and S; 6.91.