Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[C:6](=[O:15])[C:7](=[O:14])[NH:8]2.I[CH3:17].Cl>C1COCC1>[CH3:17][N:8]1[C:9]2[C:5](=[C:4]([Cl:3])[CH:12]=[C:11]([Cl:13])[CH:10]=2)[C:6](=[O:15])[C:7]1=[O:14]
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(=O)c2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 60% NaH (20.5 mg), 4,6-dichloroisatin (947 mg), and iodomethane (0.328 mL) in THF (20 mL) were stirred overnight at room temperature, poured into 1 N hydrochloric acid, and extracted with ethyl acetate. The extracts were washed with sat. aqueous NaCl, dried over MgSO4, and concentrated. The residue was washed with hexane to give the title compound (849 mg, 84%).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[I-:19]>CC(=O)CC>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][I:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCC(c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCCC(c1ccccc1)c1ccccc1

Procedure:
A mixture of 1,1-diphenyl-4-bromobutane (2.5 g, 12 mmol) and NaI (11.9 g, 80 mmol) in 2-butanone (70 ml) was heated for 4 hours at reflux. The solvent was removed in vacuo and the residue was taken up in Et2O (100 ml). The organic layer was washed with aqueous Na2SO3 (10%) and with brine, dried (Na2SO4), and concentrated in vacuo. The oil was distilled under high vacuum to obtain the title compound, bp 150° C./0.1 mm.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[CH2:20][C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]([C:21](=[O:22])[CH2:20][C:13]2[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:12]=2[F:11])[C:4](=[O:9])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1cc(F)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)Cc2cc(F)c(F)cc2F)C(=O)O1
Yield: 95.9 %

Procedure:
2,2-Dimethyl-[1,3]dioxane-4,6-dione (5.69 g, 39.5 mmol) was dissolved in 400 mL of dichloromethane under stirring, followed by addition of 2,4,5-trifluorophenyl acetic acid 1a (7.15 g, 37.6 mmol) and 4-dimethylaminopyridine (7.35 g, 60.2 mmol) in an ice-water bath. Then a suspension of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.28 g, 43.2 mmol) in 250 mL of dichloromethane was added dropwise slowly. After stirring at room temperature for 36 hours, the reaction mixture was washed with the solution of 5% potassium bisulfate (250 mL×7) and saturated brine (250 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2,2-dimethyl-5-[2-(2,4,5-trifluorophenyl)-acetyl]-[1,3]dioxane-4,6-dione 1b (11.4 g, yield 96%) as a white solid. MS m/z (ESI): 315.5 [M−1].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[N:8]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccc(C(F)(F)F)cc2)sc2ccccc12
Yield: 15.7 %

Procedure:
A mixture of 4-trifluoromethylbenzonitrile (2.00 g, 12 mmol), methyl thiosalicylate (3.93 g, 23 mmol), triethylamine (2.40 g, 24 mmol) and toluene (10 ml) was heated and refluxed for 25 hours under a nitrogen flow. The reaction solution was concentrated under reduced pressure and the residue was applied to column chromatography using silica gel (100 g). Fractions eluted with hexane-ethyl acetate (5:1, v/v) were concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (0.58 g, 16%) as crystals.
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>COCCOC.[Ag]=O>[CH2:22]([O:21][C:19]([N:13]1[CH2:14][CH2:15][N:16]([C:7]2[C:6](=[O:12])[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:10]=3[C:9](=[O:11])[CH:8]=2)[CH2:17][CH2:18]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C1C=CC(=O)c2ncccc21
Agent: O=[Ag]
Solvent: COCCOC
Product: CCOC(=O)N1CCN(C2=CC(=O)c3ncccc3C2=O)CC1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
A mixture of 1.1 g of 5,8-quinolinedione in 100 ml of 1,2-dimethoxyethane was added dropwise to a solution of 2.37 g of 1-piperazinecarboxylic acid, ethyl ester in 25 ml of 1,2-dimethyoxyethane with stirring. Stirring was continued for 30 minutes, then 1 g of silver oxide was added and this mixture was stirred overnight. The mixture was filtered and the solid washed with dichloromethane. The filtrate and wash were combined, evaporated, triturated with ethyl acetate and the solid collected. This solid was chromatographed, eluting with dichloromethane, then ethyl acetate. The active fractions were combined and evaporated, giving 817 mg of the desired product, mp 192°-194° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:24]([C:26]([O:28]CC)=[O:27])[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH:4]=[CH:5][N:6]=1.[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[C:24]([C:26]([OH:28])=[O:27])[S:25][C:17]3=4)=[CH:14][CH:15]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCn3ccnc3C)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nccn1CCOc1ccc(-n2c(=O)ccc3c(-c4ccccc4)c(C(=O)O)sc32)cc1

Procedure:
To a solution of the compound of Example 91 (134 mg, 0.27 mmol) in EtOH (0.5 mL) and water (0.73 mL) was added sodium hydroxide (0.27 mL of a 1M solution, 0.27 mmol) and the mixture heated at reflux for 5 h. The reaction was freeze dried to give 7-{4-[2-(2-Methyl-1H-imidazol-1-yl)ethoxy]phenyl}-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylic acid as a solid. LCMS (ES+) RT 2.34 minutes, 472 (M+H)+. This compound was dissolved in DMF (2 mL) and thionyl chloride (30 μL, 0.405 mmol) was added and the reaction stirred at r.t. for 5 mins. Aqueous ammonia (2 mL of a 25% solution) was added and the reaction stirred for 30 mins. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined EtOAc extracts were washed with water (2×10 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a solid (104 mg, 82%). δH (CDCl3) 7.52–7.48 (3H, m), 7.37–7.33 (2H, m), 7.29–7.26 (2H, m), 7.20–7.18 (1H, m), 7.01–6.96 (3H, m), 6.90–6.88 (2H, m), 6.50 (1H, d, J 9.6 Hz), 4.23–4.20 (4H, m), 2.42 (3H, s). LCMS (ES+) RT 2.28 minutes, 471 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)OC(CO)CO2
Reaction time: 24 h
Yield: 84.8 %

Procedure:
(7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol (1.0 g, 4.7 mmol) was dissolved in methanol (30 ml) and palladium on activated carbon was added (0.10 g, 5% wt). The mixture was shaken on a parr shaker under H2(g) atmosphere (60 psi) for 24 hours. The mixture was filtered through celite and evaporated to give 722 mg of material as a white solid (86%), which was used as such for the next step. M/z=182 (m+1). Lc: 0.82 minutes.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15](OC)=[O:16])[CH:12]=[C:13]([SH:14])[N:8]2[N:7]=1)(=O)C.[NH2:20][OH:21]>CO>[OH:21][NH:20][C:15]([C:11]1[CH:12]=[C:13]([SH:14])[N:8]2[N:7]=[C:6]([CH2:5][OH:4])[N:19]=[C:9]2[N:10]=1)=[O:16]
Reactant: NO
Reactant: COC(=O)c1cc(S)n2nc(COC(C)=O)nc2n1
Solvent: CO
Product: O=C(NO)c1cc(S)n2nc(CO)nc2n1
Yield: 74 %

Procedure:
Methyl 2-(acetoxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-5-carboxylate (80 mg) (0.28 mmol) are dissolved in 3 ml of absolute methanol. 188 mg (5.7 mmol) of hydroxylamine are added within 4 days while stirring. The product is precipitated (pH 6) with 3N aqueous hydrochloric acid, filtered off under suction and washed with methanol. After crystallization from methanol there are obtained 50 mg of N-hydroxy-2-(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-5-carboxamide as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[Li]CCCC>C1COCC1.Cl>[C:7]1([C:3]2[O:4][CH:5]=[CH:6][C:2]=2[B:13]([OH:18])[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccoc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccoc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a mixture of 3-bromo-2-phenylfuran (6.70 g, 30.0 mmol) and B(Oi-Pr)3 (10.4 mL, 45.0 mmol) in THF (67 mL) was added n-BuLi (1.65 M in hexane, 36.4 mL, 60 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. The mixture was diluted with 1 M HCl aqueous solution at 0° C., extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and triturated with EtOAc/hexane to yield the title compound (2.23 g, 40% yield) as a green solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.64 (1H, d, J=1.4 Hz), 7.21-7.45 (3H, m), 7.69 (1H, d, J=1.6 Hz), 8.00-8.08 (2H, m).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].I[C:14]1[CH:19]=[CH:18][C:17](/[C:20](/[CH3:24])=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1>>[OH:23][CH2:22]/[CH:21]=[C:20](/[C:17]1[CH:18]=[CH:19][C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:15][CH:16]=1)\[CH3:24]
Reactant: C/C(=C\CO)c1ccc(I)cc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2ccc(/C(C)=C/CO)cc2)cc1

Procedure:
The pale yellow solid, (E)-1-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-ethanone was prepared from 4-acetylphenyl boronic acid and (E)-3-(4-iodophenyl)-but-2-en-1-ol by a procedure analogous to that described in example 54a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH2:24][CH2:25][NH2:26])(=[O:23])=[O:22])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:26][CH2:25][CH2:24][S:21](=[O:23])(=[O:22])[NH:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:11]([CH3:12])[CH3:13])[CH2:15][CH2:16]1)=[O:7]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Reactant: O=C(O)c1cccc(Cl)c1
Product: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2cccc(Cl)c2)CC1

Procedure:
3-Chloro-N-[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-benzamide was prepared by an analogous procedure as described in example 9 starting from 104 mg (1.1 equiv.) 3-chloro-benzoic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 3-chloro-N-[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-benzamide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:10][C:9]2[C:8]([CH3:24])([CH3:23])[CH2:7][CH2:6][C:5]([CH3:26])([CH3:25])[C:4]=2[CH:3]=1.[Li]CCCC.[CH:32](N1CCCCC1)=[O:33]>O1CCCC1>[CH:32]([C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])=[CH:10][C:9]2[C:8]([CH3:24])([CH3:23])[CH2:7][CH2:6][C:5]([CH3:25])([CH3:26])[C:4]=2[CH:3]=1)=[O:33]
Reactant: O=CN1CCCCC1
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C=O)cc21
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 14 g (32 mmol) of 2-bromo-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 200 mL of dry tetrahydrofuran at −78° C. was added 24.9 mL (64 mmol) of n-BuLi (2.5 M in hexane) via syringe under N2 atmosphere. The reaction mixture was stirred at this condition for 1 hour. Then it was quenched with a solution of 7 mL (64 mmol) of N-formyl piperidine in 10 mL of dry tetrahydrofuran. The resulting solution was stirred for an additional 30 minutes, when it was quenched with 100 mL of NH4Cl solution. The reaction mixture was extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 30% ethyl acetate/hexanes) to afford 11.1 g (90%) of 2-formyl-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene. (M+=386).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.O>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:24][CH:25]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cccc2c3c([nH]c12)CCN(C)C3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc2c3c(n(CCc4ccc(C(F)(F)F)nc4)c12)CCN(C)C3
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in NMP (2.5 ml), powdered KOH (561 mg, 10 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added slowly to the above solution and stirred for 16 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude and extracted with the ethyl acetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 40 mg (8.2%) of 5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole as TFA salt.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCCl>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:11]=[C:12]([F:16])[CH:13]=[CH:14][C:15]=2[S:18]([Cl:17])(=[O:20])=[O:19])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(Cc2cccc(F)c2)CC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCCl
Product: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-ethyl-4-(3-fluorobenzyl)piperidine (Intermediate 179, 0.210 g) in DCE (1 mL) was added to chlorosulfonic acid (2 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The resultant mixture was added carefully to ice/water and extracted with DCM. The organic layer was dried (Na2SO4) and filtered and the filtrate was evaporated to dryness to give 2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonyl chloride (0.290 g) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[K+].[Br-]>>[CH:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:25])([O:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[C:4]([OH:3])=[O:26])=[CH:8][CH:9]=3)[N:37]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 50. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 2H, J=8.8 Hz), 7.16 (d, 2H, J=8.8 Hz), 6.95 (d, 2H, J=8.4 Hz), 6.78 (d, 2H, J=8.4 Hz), 4.11 (t, 2H, J=6.2 Hz), 3.24 and 3.15 (d of ABq, 2H, J=13.8 Hz), 2.95 (t, 2H, J=6.2 Hz), 2.85 (tt, 1H, J=11.6, 3.4 Hz), 2.30 (s, 3H), 2.03-1.95 (m, 2H), 1.83-1.74 (m, 2H), 1.73-1.68 (m, 1H), 1.58-1.47 (m, 1H), 1.49 (s, 3H), 1.38-1.17 (m, 4H). IR (KBr) 3400, 2937, 1735, 1614, 1513, 1328 cm−1. HRMS (ES+) m/z exact mass calcd for C29H33NO5F3 532.2311, found 532.2332.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](Cl)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:18][CH3:17])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Cl[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Reactant: CN
Solvent: CCO
Product: CN[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Crude 4-[(2R)-2-(4-Bromophenyl)-2-chloroethyl]morpholine (34.5 g) was dissolved in 200 mL of EtOH at room temperature with magnetic stirring. The resulting solution was cooled to 0° C. and treated with MeNH2 (71 mL, 33 wt % in EtOH) under N2. The reaction flask was capped with a rubber septum and the reaction mixture maintained at room temperature for 48 h. The mixture was then concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated to yield the title compound as a yellow solid (32 g, 93%). MS (ES) m/e 300 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=2)[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=2)[C:18]([N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)c1cccc(NC2CCN(Cc3ccccc3)CC2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)c1cccc(N(c2ccccc2)C2CCN(Cc3ccccc3)CC2)c1
Temperature: 110 °C
Yield: 117.8 %

Procedure:
A mixture of 3-[N-(1-benzyl-piperidin-4-yl)-amino]-N,N-diethyl benzamide (compound 10) (360 mg, 0.98 mmol), Ph3Bi (1.10 g, 2.50 mmol), and Cu(OAc)2 (0.45 g, 2.48 mmol) in toluene (10 mL) was heated at 110° C. for 12 h. Another portion of Cu(OAc)2 (0.45 g) was added and the mixture was heated at 110° C. for an additional 12 h and allowed to cool to room temperature. Water (10 mL) was added and the mixture filtered through Celite®. The layers in the filtrate were separated, and the organic phase was washed with water, brine, dried over Na2SO4 and concentrated. Chromatography of the residue (9:1 EtOAc/heptane) gave the tide compound 11 (255 mg, 59%) as a pale yellow thick oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1.[CH2:21]([NH2:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:21]([NH:23][CH2:17][C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:19])[O:3][C:2]2([CH3:20])[CH3:1])[CH:13]=[N:14][CH:15]=1)[CH3:22]
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCNCc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.133 g, 0.49 mmol) (Example 9a) in dichloroethane (2 mL) is added ethylamine (0.37 mL, 0.738 mmol) and sodium triacetoxyborohydride (0.313 g, 1.477 mmol). The reaction mixture is stirred at 50° C. for 5 h. The mixture is cooled to room temperature, washed with saturated aqueous sodium bicarbonate and is extracted with ethyl acetate. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is dissolved in methanol (5 mL) and purified by reverse phase HPLC to give 4-(5-ethylaminomethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one; HRMS (ESI) m/z 300.1705 [(M+H)+: Calcd for C17H22N3O2: 300.1712]; 1H NMR (400 MHz, MeOD) of the TFA salt δ ppm 1.27 (s, 3 H), 1.46 (t, J=6.8 Hz, 3 H), 1.59 (s, 3 H), 3.35-3.40 (m, 2 H), 4.65 (br. s, 2 H), 5.82 (s, 1 H), 7.51 (br. s, 1 H), 7.64 (d, J=7.3 Hz, 1 H), 7.75 (td, J=7.8, 1.0 Hz, 1 H), 7.84 (td, J=7.6, 1.3 Hz, 1 H), 7.92 (br. s, 1 H), 8.30 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([F:25])([F:24])[C:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])([CH3:17])[CH3:16])(=O)=O)=CC=1.C(N(C(C)C)CC)(C)C.[I-:35].[Na+]>CC(C)=O>[CH2:22]([O:21][CH:19]([O:18][C:15]([CH3:17])([CH3:16])[C:14]([F:25])([F:24])[CH2:13][CH2:12][I:35])[CH3:20])[CH3:23]
Reactant: [I-]
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(C)OC(C)(C)C(F)(F)CCI
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 3.50 g (0.0087 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol 1-(4-methylbenzenesulfonate), 40 mL of acetone, 0.5 mL of diisopropylethylamine and 13.10 g (0.087 mol) of sodium iodide was stirred at 25° C. for 64 hr. The mixture was evaporated to dryness. The residue was partitioned between 5% aqueous sodium sulfite solution and methylene chloride. The organic phase was washed with saturated aqueous sodium bicarbonate solution. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was chromatographed on 0.06-0.20 mm silica gel to yield 4-(1-ethoxyethoxy)-3,3-difluoro-1-iodo-4-methylpentane. NMR (CDCl3) δ4.98 (quartet, 1, J=7 Hz), 3.50 (quartet, 2, J=7 Hz), 3.28 (multiplet, 2), 2.60 (multiplet, 2), 1.32 (triplet, 6, J=1 Hz), 1.28 (doublet, 2, J=7 Hz), and 1.18 ppm (triplet, 3, J=7 Hz).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:4])[NH2:3].C(N(CC)CC)C.[C:20]([C:23]1[C:24](=[O:34])[O:25][C:26]([OH:33])=[C:27]([C:30](=O)[CH3:31])[C:28]=1[OH:29])(=[O:22])[CH3:21]>CO>[C:20]([C:23]1[C:24](=[O:34])[O:25][C:26](=[O:33])[C:27](=[C:30]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([O:5][C:2](=[O:4])[NH2:3])=[CH:7][CH:8]=2)[CH3:31])[C:28]=1[OH:29])(=[O:22])[CH3:21]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: NC(=O)Oc1ccc(N)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(OC(N)=O)cc2)C(=O)OC1=O

Procedure:
A solution of 1.88 g. (0.01 m.) of p-carbamoyloxyaniline hydrochloride and 1.0 g. (0.01 m.) of triethylamine in 50 ml. of methanol is added to a hot solution of 2.21 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol. The resulting mixture is refluxed for two hours, cooled and the filtered solid recrystallized to give 5-acetyl-3-[1-(p-carbamoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 213°-215° C.