Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:5].[CH3:28][C:29]1[O:33][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:31][C:30]=1[CH2:40][O:41][C:42]1[CH:52]=[CH:51][C:45]2[CH:46]=[C:47]([CH:49]=O)[O:48][C:44]=2[CH:43]=1.Cl>CN(C)C=O.O1CCCC1.[C].[Pd]>[C:4]([CH2:6][CH2:7][CH2:8][CH2:49][C:47]1[O:48][C:44]2[CH:43]=[C:42]([O:41][CH2:40][C:30]3[N:31]=[C:32]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[O:33][C:29]=3[CH3:28])[CH:52]=[CH:51][C:45]=2[CH:46]=1)#[N:5]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(C=O)oc2c1
Reactant: N#CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCCCC#N)oc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
Sodium hydride (60%, oily, 0.20 g) was gradually added to a solution of 3-cyanopropyltriphenylphosphonium bromide (2.07 g) in N,N-dimethylformamide (30 ml) at room temperature, followed by stirring for 1 hour. 6-(5-Methyl-2-phenyl-4-oxazolylmethoxy)benzofuran-2-carboaldehyde (1.40 g) was added, followed by stirring at 70° to 80° C. for 2 hours. The reaction mixture was poured over ice water and neutralized with 2N hydrochloric acid, followed by extraction with ethyl acetate (200 ml). After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:2, v/v), an oily substance was obtained, which was dissolved in tetrahydrofuran (40 ml). To this solution, palladium-carbon (5%, 0.70 g) was added, followed by catalytic reduction at room temperature and under an atmospheric pressure of 1 atm. The catalyst was filtered off, the filtrate was concentrated; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:3, v/v), crystals of 2-(4-cyanobutyl)-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (0.97 g, 60%) were obtained, which was then recrystallized from diethyl ether-hexane to yield colorless prisms having a melting point of 87° to 88° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[F:18])(=[O:7])[CH3:6]>CN(C)C=O.C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[CH:11][C:10]=1[F:18])(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1F
Temperature: 25 °C

Procedure:
2.90 ml of thionyl chloride was added to 2.50 g (12.6 mM) of 4-acetoxy-3-fluorobenzoic acid. Under stirring at room temperature, two drops of N,N-dimethylformamide (DMF) was added thereto, followed by refluxing for 40 minutes. After the reaction, dry benzene was added to the reaction mixture, followed by two times of distilling-off of excessive thionyl chloride under reduced pressure to obtain 4-acetoxy-3-fluorobenzoyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])([CH2:13][OH:14])[CH2:9]1)=O)(C)(C)C.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[OH:14][CH2:13][C:10]1([NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CCCCc1nnc(C(=O)NC2(CO)CCN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NC2(CO)CCNC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-{[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (55 mg) in DCM (2 mL) was added 4 N HCl in dioxane (1.0 mL) at 0° C., and the reaction was stirred for 1 h at room temperature. The volatiles were removed under reduced pressure, and the residue was triturated with anhydrous ethyl ether and dried under high vacuum to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (3-hydroxymethyl-pyrrolidin-3-yl)-amide dihydrochloride.
Reaction SMILES: O=O.[CH3:3][C:4](C)([O-])C.[K+].[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].C(I)C>C1COCC1.O>[CH2:3]([CH:10]([C:11](=[O:12])[CH3:13])[C:9]([O:15][CH3:16])=[O:14])[CH3:4]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCI
Product: CCC(C(C)=O)C(=O)OC
Reaction time: 1 h
Yield: 60 %

Procedure:
Under nitrogen atmosphere free of water and oxygen, to a three-necked flask equipped with a dropping funnel were successively added 0.15 mol of potassium tert-butoxide and 150 ml of THF, then stirrer was started. 0.12 Mol of methyl acetoacetate was slowly dropped to the reactor cooled in an ice-water bath. Upon completion of the dropping, the reaction was continued at room temperature for further 1 hr. Then 0.18 mol of ethyl iodide was slowly dropped at room temperature, and then the reaction was heated to reflux for 6 hrs. At the end of the reaction, solvent was evaporated by using a rotatory evaporator, and saturated saline was added to just dissolve the solid. Organic phase was separated, and aqueous phase was extracted with a suitable amount of diethyl ether for three times. The combined organic phase was washed well with saturated saline, then dried over anhydrous sodium sulfate. Solvent was removed by using a rotatory evaporator, and the residue was distilled under reduced pressure to give 0.072 mol of product. Yield 60%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:40])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37](O)=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:50]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.O>[C:37]([C:21]1[C:22]2[NH:23][C:24]3[C:29]([C:30]=2[C:18]([C:14]2[C:13]([CH3:40])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:17]=[CH:16][CH:15]=2)=[CH:19][N:20]=1)=[CH:28][CH:27]=[C:26]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH:25]=3)(=[O:38])[NH2:50]
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A homogeneous, burgundy solution of 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b] indole-1-carboxylic acid (0.2860 g, 0.533 mmol), ammonium chloride (0.114 g, 2.132 mmol), BOP (0.306 g, 0.693 mmol), DIPEA (0.447 ml, 2.56 mmol) and N-methylmorpholine (0.229 ml, 2.079 mmol) in DMF (Volume: 3.33 ml) was stirred. After 1 hr, water (35 mL) was added and the mixture was stirred at room temperature for 30 min. The precipitate was filtered, washed with water, dried over Drierite to give the desired product (0.274 g, 0.511 mmol, 96% yield) as a tan solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[C:16]1([S:22]([N:9]2[C:10]3[C:6](=[C:5]([C:4]([F:3])([F:14])[F:15])[CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(C(F)(F)F)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
370 mg of NaH at 60% in oil are added to a solution of 0.85 g of 4-trifluoromethyl-1H-indole in 15 ml of tetrahydrofuran, under an inert atmosphere. The reaction mixture is stirred at ambient temperature for one hour and then 0.88 ml of benzenesulfonyl chloride is added dropwise and the stirring is continued for 16 hours. The reaction mixture is then poured into a 10% ammonium chloride solution, extracted with ethyl acetate and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and diisopropyl ether (98/2, then 95/5: v/v), so as to give 1.08 g of 1-benzenesulfonyl-4-trifluoromethyl-1H-indole in the form of a pale yellow oil which is used as it is in the next step.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23].Br[CH2:30][CH2:31][CH2:32][OH:33]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:30][CH2:31][CH2:32][OH:33])=[CH:14][CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[NH:19][C:20](=[O:28])[C@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)c2ccc(O)cc2)cc1Cl)C(F)(F)F
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)c2ccc(OCCCO)cc2)cc1Cl)C(F)(F)F
Reaction time: 0.25 h

Procedure:
Sodium hydride (0.06 g of a 60% dispersion in oil) was added to a solution of (R)-N-[2-chloro-4-(4-hydroxyphenylsulphinyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 89) (0.5 g) in DMF (5 ml) at 0° C. The mixture was stirred for 15 minutes then 3-bromopropanol (0.12 ml) was added as a solution in DMF (3 ml). The mixture was stirred at ambient temperature for 16 hours. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-10% methanol/DCM to give the title compound (0.34 g) as a gum. NMR (CDCl3): 1.25 (dd, 2H), 1.7 (s, 3H), 1.8 (s, 1H), 3.8-3.9 m, 2H), 4.1-4.2 (m, 2H), 5.1 (s, 1H), 6.95 (d, 2H), 7.4 (d, 1H), 7.5 (d, 2H), 7.6-7.65 (m, 1H), 8 45-8.55 (m, 1H), 9.3 (s, 1H); MS (ESP−): 464.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:21]=2[CH2:20]1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:31])[CH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][C:28]([O:30][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[CH:29][C:21]=2[CH2:20]1)[CH3:15]
Reactant: CCOC(=O)CC1CCCc2ccc(O)cc2C1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Product: CCOC(=O)CC1CCCc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2C1

Procedure:
The title compound is prepared according to the procedure of Example 19 except that (4-bromo-butyl)-carbamic acid tert-butyl ester is used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (3-hydroxy-6,7,8,9-tetrahydro-5H-benzo-cyclohepten-6-yl)-acetic acid ethyl ester is used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalen-2-yl)-acetic acid ethyl ester.
Reaction SMILES: [Mg].[Cl-].[Li+].Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].C(O[CH2:17][CH:18]=[CH2:19])(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:19]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[CH:18]=[CH2:17]
Reactant: COc1ccccc1Br
Reactant: C=CCOC(C)=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: C=CCc1ccccc1OC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under protective gas, 63 mg of magnesium turnings, 126 mg of anhydrous lithium chloride, 4 ml of dry tetrahydrofuran and 2.4 mmol of 2-bromoanisole were reacted at room temperature to give the Grignard compound. Then the dark-colored solution formed was cooled to 0° C. and a solution of 35.3 mg of iron(III) acetylacetonate (5 mol %) in 2 ml of dry tetrahydrofuran was added and the mixture was stirred for five minutes. Then 2 mmol of allyl acetate were added dropwise and the reaction mixture was stirred for 2 h. For workup, hydrolysis was effected with 5 ml of saturated sodium hydrogencarbonate solution and the mixture was extracted three times with 10 ml each time of ethyl acetate. The combined organic phases were dried over magnesium sulfate, concentrated and purified by column chromatography on silica gel (eluent: cyclohexane-ethyl acetate). 95% of theory of 2-allylanisole was isolated.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:10](Cl)=[O:11])=[N:7][C:8]=1[CH3:9].[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[CH:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:14].[H-].[Na+].O1CCCC1>CCCCCC.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:26])[C:17]([C:10]([C:6]1[CH:5]=[CH:4][C:3]([CH3:2])=[C:8]([CH3:9])[N:7]=1)=[O:11])=[CH:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:14]
Reactant: Cc1ccc(C(=O)Cl)nc1C
Reactant: CCOC(=O)C=CNc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1ccccc1)C(=O)c1ccc(C)c(C)n1

Procedure:
Compound 2e was prepared following the procedure outlined in Step 1 of Example 6 using 2.28 g (11.0 mmol) of 5,6-dimethyl-pyridine-2-carbonyl chloride hydrochloride (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351), 1.91 g (10.0 mmol) of 3-phenylamino-acrylic acid ethyl ester, 1.08 g (27.0 mmol) of 60% sodium hydride and 25 mL tetrahydrofuran. Flash chromatography using 10-80% ethyl acetate in hexane yielded 575 mg of the product as yellow solid. LC-MSD, m/z for C19H20N2O3 [M+H]+=325.5, HPLC retention time: 1.9 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[OH:8].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[O:8][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Reactant: COCCOCCl
Product: COCCOCOc1c(Br)cc(CC(=O)OC)cc1C=O

Procedure:
Proceeding as in Reference 12, but substituting methyl 3-bromo-5-formyl-4-hydroxyphenylacetate (27.32 g, 0.10 mole) and 2-methoxyethoxymethyl chloride (0.125 mol, 14.3 mL), gave methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-phenylacetate (31.4 g (87%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:26][CH:25]([S:22]([NH:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][C:35](=[O:37])[CH3:36])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)(=[O:24])=[O:23])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CCN)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccc(-c2ccc([C@@H]3CCC[C@H]3NS(=O)(=O)C(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(+,−) Trans propane-2-sulfonic acid {2-[4′-(2-amino-ethyl)-biphenyl-4-yl]-cyclopentyl}-amide (prepared in example 9) was dissolved in 20 mL of dry methylene chloride and triethylamine added (0.275 mL, 1.98 mmol). To this stirred mixture was added acetyl chloride (0.084 mL, 1.19 mmol). The reaction was stirred at room temperature for 3 days. The reaction was concentrated in vacuo and chromatographed on a Chromatotron® eluting with 98:2 methylene chloride:methanol which afforded 150 mg (64% 2 steps) of the title compound. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9]([Cl:19])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][CH2:34][CH3:35])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CC(CC)=O>[CH2:34]([N:33]([CH:30]1[CH2:29][CH2:28][N:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:32][CH2:31]1)[C:5](=[O:6])[C:4]1[CH:8]=[C:9]([Cl:19])[C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:11][C:3]=1[O:2][CH3:1])[CH3:35]
Reactant: CCNC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(NC(=O)C(F)(F)F)c(Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCN(C(=O)c1cc(Cl)c(NC(=O)C(F)(F)F)cc1OC)C1CCN(Cc2ccccc2)CC1
Reaction time: 48 h
Yield: 68.3 %

Procedure:
A solution of 2-methoxy-4-trifluoroacetylamino-5-chlorobenzoyl chloride (17.4 g; 0.055 moles) dissolved in anhydrous ethyl methyl ketone (75 ml) was added little by little to another solution of 1-benzyl-4-ethylamino-piperidine (10.9 g; 0.05 moles) and triethylamine (7.0 ml; 0.05 moles) in anhydrous ethyl methyl ketone (75 ml) at room temperature. On completion of the addition, the mixture was left at room temperature and stirred for 48 hours, and then the mixture was concentrated at reduced pressure, poured into water, and extracted with chloroform. The organic solution was dried (Na2SO4) and the solvent removed in vacuo. The residue was recrystallized from a mixture of methanol and diethyl ether to give N-ethyl-N-(1-benzylpiperid-4-yl)-2-methoxy-4-trifluoroacetylamino-5-chlorobenzamide (17 g), m.p. 198°-200° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.Cl[C:15]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([N+:28]([O-:30])=[O:29])=[CH:17][N:16]=1.O>CN(C=O)C>[N+:28]([C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][C:15]([O:3][C:4]2[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)=[N:16][CH:17]=1)([O-:30])=[O:29]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccccc3)c([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 16.24 g, 406 mmol) was suspended in DMF (800 mL) and solid N-(3-hydroxyphenyl)acetamide (61.0 g, 406 mol) was added portionwise over 1 h (warming and frothing occurs). After the final addition the product from Step 4 (101.2 g, 406 mmol) was added as a solid, portionwise, over 10 min and the resulting mixture was heated to 60° C. overnight. Water (800 mL) was carefully added dropwise to the still warm reaction mixture over 1 h to give a fine yellow precipitate. The mixture was then cooled to 0° C., filtered and the resulting solid was washed with cold H2O and hexane to give the title compound (143.3 g, 97%) as a yellow solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 10.06 (s, 1H), 9.80 (s, 1H), 8.91 (s, 1H), 7.44-7.49 (m, 3H), 7.37 (dd, 2H, 1.26 Hz, 8.6 Hz), 7.29-7.33 (m, 3H), 6.76-6.80 (m, 1H), 6.22 (s, 1H), 2.04 (s, 3H). MS (ES+) m/e 365 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1ccccc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-Bromoanisole (1.87 g, 10.0 mmol) in 10 mL THF under Argon was added n-butyllithium (4.0 mL 2.5M in hexane, 10.0 mmol) cooled to -78° C. The solution was stirred 10 min. at -78° C., and a solution of 1,4-Cyclohexanedione mono-ethylene ketal (1.56 g, 10.0 mmol) in 10 mL THF was added slowly. The solution was warmed to r.t. and stirred for 60 min., then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude solid was crystallized with hexane/diethylether 2:1 to give 8-(2-Methoxy-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[C:10]=1[O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.[ClH:37].CCOCC.B(Br)(Br)Br>>[ClH:37].[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([O:21][C:22]2[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3F)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3F)ccc2c1
Yield: 48 %

Procedure:
Using the procedure demonstrated in Example 10, react 1-(2-{4-[2-(2,3-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine (622 mg, 1.27 mmol), 2M HCl in ether (1.3 mL, 2.6 mmol) and boron tribromide (0.60 mL, 6.4 mmol) to give 309 mg (48%) of the title compound: mass spectrum (ion spray) 476.4 (M−Cl).
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Sn:2]([CH3:4])([CH3:3])[CH3:1])=[CH:10][CH:9]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: C[Sn](C)(C)Cl
Solvent: C1CCOC1
Product: COc1ccc([Sn](C)(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To trimethyltin chloride (1.71 g, 8.58 mmol, 1.00 equiv) in THF (50 mL) at 23° C. was added 4-methoxyphenylmagnesium bromide (0.50 M in THF, 34.3 mL, 17 mmol, 2.0 equiv). After stirring for 1.0 hr at 60° C., the reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl (50 mL), and Et2O (50 mL) was added. The phases were separated and the aqueous phase was extracted with Et2O (2×50 mL). The combined organic phases were washed with brine (100 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by fractional distillation to afford 1.86 g of the title compound as a colorless oil (80% yield).
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH3:15][NH:16]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:5]1([C:15]#[N:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CNCCNC
Reactant: Brc1cccc2ccccc12
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cccc2ccccc12
Temperature: 110 °C
Reaction time: 24 h
Yield: 70.2 %

Procedure:
An oven dried screw cap test tube was charged with NaCN (127 mg, 2.592 mmol), dried KI (72 mg, 0.434 mmol, 20 mol %) and CuI (41 mg, 0.215 mmol, 10 mol %), evacuated and backfilled with argon three times. 1-Bromonaphthalene (300 μL, 2.157 mmol), N,N′-dimethylethylenediamine (230 μL, 2.16 mmol) and anhydrous toluene (1.4 mL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25 ° C. for 10 min, then the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate (3×2 mL). The combined organic layers were washed with 5 mL of water and dried over MgSO4. The solvent was removed at reduced pressure. Purification of the residue by flash chromatography on silica gel (2×15 cm; hexane/ethyl acetate 10:1) provided 232 mg (70% yield) of the title compound as a colorless oil.