Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1)#[CH:2].Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[N:17]=1.C(N(CC)CC)C.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:8]1[C:3]([C:1]#[C:2][C:20]2[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:16][N:17]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[CH:29][CH:28]=3)[N:19]=2)=[N:4][CH:5]=[N:6][CH:7]=1)[CH3:14]
Reactant: C#Cc1ncncc1CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cncnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To a nitrogen de-gassed solution of ethyl 2-(4-ethynylpyrimidin-5-yl)acetate (I110) (0.146 g, 0.766 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (0.250 g, 0.547 mmol) in dry DMF (15 mL) were added triethylamine (0.305 mL, 2.19 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.016 g, 0.055 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.019 g, 0.027 mmol) and Cu(I)I (0.010 g, 0.055 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated in vacuo to give a brown gum. The crude material was purified by silica gel chromatography (Isolera Biotage, 40 g Si cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I111) (0.093 g, 27% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.50 (s, 1H), 9.23 (s, 1H), 8.97 (s, 1H), 8.88 (s, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.14-4.04 (m, 4H), 3.96 (s, 2H), 2.81 (br s, 2H), 2.70-2.61 (m, 1H), 1.75 (d, J=11.9 Hz, 2H), 1.53-1.37 (m, 11H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.64 min; m/z 609.2 [M−H]−.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C[N:9](C)[CH2:10][CH2:11][NH2:12].CN1CCOCC1>ClCCl>[CH:3]([CH2:2][C:1]([NH:9][CH2:10][CH2:11][NH2:12])=[O:6])([CH3:5])[CH3:4]
Reactant: CN(C)CCN
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(=O)NCCN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Isovaleroyl chloride (5 g, 38 mmole) in dichloromethane was added dropwise to a stirred solution of N,N-dimethylethylene diamine (3,38 g, 38 mmole) and NMM (7.75 g, 76.7 mmoles) in CH2Cl2 at 0° C. The reaction mixture was stirred at room temperature for four hours when the solvent was evaporated. The residue was taken up in 5 M NaOH (50 ml) and extracted with ethyl acetate (2×100 ml). The ethyl acetate was washed with a saturated aqueous solution of sodium chloride, dried (Na2SO4) and evaporated. The residue was dissolved in diethyl ether and 5 M HCl in ethyl acetate (10 ml) added. The resulting solid was filtered, washed with diethyl ether (5+10 ml) and dried under high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][N:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[N:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cn4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cn4)cnc32)cc1
Yield: 91.6 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(5-(piperazin-1-yl)pyridin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg. 0.164 mmol) was alkylated using (S)-2-methyloxirane (18 mg, 0.329 mmol), DIPEA (58 μL, 0.329 mmol) and ethanol (10 mL) to get 100 mg (91.7%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([O:20]CC)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CC(C)=O>[CH2:11]([N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1])[CH3:12].[CH3:23][C:11]1[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc2ccccc2s1
Solvent: CC(C)=O
Product: CC[n+]1c(C)sc2ccccc21
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
2-Methylbenzothiazole (300 pbw) and ethyl p-toluenesulfonate (440 pbw) are heated with stirring to 150° C., the temperature rising to about 200° C. due to the exothermic reaction. After 10 minutes, the mixture is poured into 2000 pbw of acetone, and the product that precipitates is removed by filtration with suction, washed with acetone and dried over phosphorous pentoxide.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[C:23]([CH:30]=O)=[CH:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[CH3:34][NH2:35]>CO>[CH3:34][NH:35][CH2:30][C:23]1[C:22]2[C:26](=[CH:27][CH:28]=[CH:29][C:21]=2[C:18]2[N:17]=[C:16]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])=[C:3]([C:2]([F:33])([F:32])[F:1])[CH:4]=3)[O:20][N:19]=2)[NH:25][CH:24]=1
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4[nH]cc(C=O)c34)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: CN
Solvent: CO
Product: CNCc1c[nH]c2cccc(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole-3-carboaldehyde (150.0 mg) in CH3OH (1.5 ml) was added a 40% CH3OH solution of CH3NH2 (74.5 mg) at 0° C. After warming to room temperature, the solution was stirred at room temperature for 3 hours. After confirming the production of an iminium salt, the organic solvent was evaporated under reduced pressure. The residue was dissolved in EtOH (1.5 ml). To this was added NaBH4 (12.09 mg) at 0° C. After warming to room temperature, the solution was stirred at room temperature for 15 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, chloroform:CH3OH=100:0 to 90:10) to obtain N-methyl-1-(4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)methanamine (87.4 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[N:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31][CH2:30]3)[C:21]2=[O:37])[CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC([O-])(C)C.[Na+].O>COCCOC.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[N:20]3[C:21](=[O:37])[C:22]4[C:27]([C@H:28]3[CH2:14][CH2:13][CH2:12]2)=[C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH2:34]2)[CH:25]=[CH:24][CH:23]=4)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN1CCN(c2cccc3c2CN(C(CCCOS(C)(=O)=O)c2ccc(OC)c(OC)c2)C3=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOC
Product: CCN1CCN(c2cccc3c2[C@H]2CCC[C@H](c4ccc(OC)c(OC)c4)N2C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 4-(3,4-dimethoxy-phenyl)-4-[4-(4-ethyl-piperazin-1-yl)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyl ester (112 mg, 0.211 mmol) was dissolved in DME (0.80 mL), and a 4 M solution of NaOtBu in THF (0.5 mL) was added. The resulting mixture was stirred at 60° C. for 1 hour and then allowed to cool to room temperature. The resulting mixture was then poured into water (10 mL) and extracted with EtOAc (2 times, 15 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuum to yield a residue. The residue was purified using prep-HPLC 5-90 gradient water (0.2% TFA buffer)/acetonitrile (0.15% TFA buffer) to yield the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.[BH4-].[Na+]>CO>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: COc1ccccc1C=O
Reactant: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Yield: 85.4 %

Procedure:
Add three-angstrom molecular sieves to a stirred solution of 6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide (0.1000 g, 0.3887 mmol) (compound of example 33), 2-methoxybenzaldehyde (0.047 mL, 0.39 mmol), and methanol (5 mL). Agitate the reaction for 18 h on a platform shaker at room temperature. Add sodium borohydride and agitate for 1 h at room temperature. Filter to remove the molecular sieves and load the reaction mixture directly onto a 10 g prepacked SCX cartridge. Flush with methanol (150 mL) and elute the product off the SCX cartridge with 2 M ammonia in methanol (50 mL). Concentrate on a rotary evaporator to give 0.1253 g (85%) of 6-{4-[2-(2-methoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 4.14 minutes, Purity: 97.9%; mass spectrum (ion spray): m/z=378.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3]C(O)=O.[N:7]1([C:15]([O:17]CC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=O.[CH3:32][NH2:33]>C(O)C.O>[NH2:1][C@H:2]([C:15]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([NH:33][CH3:32])=[O:11])=[O:17])[CH3:3]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CN
Reactant: NCCC(=O)O
Solvent: CCO
Solvent: O
Product: CNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N

Procedure:
In a similar manner, the chromophore DNP and β-alanine were coupled to Fmoc-Pro-Lac-pins prepared as described in Example 4. This was cleaved from the pin by reaction with 150 μl of a 50:50 mixture of saturated methylamine in ethanol and water at room temperature for 2.5 hrs to yield DNP-β Ala-Pro-NH-CH3. The solution was evaporated to dryness to remove excess methylamine. FIG. 9b is the HPLC analysis of the cleavage product and again demonstrates that it is of excellent purity.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH:10]=[CH:11][N:12]([CH3:14])C)[CH:5]=[CH:6][C:7]=1[CH3:8].N[C:17]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=C[NH:19][N:18]=1>C(O)(=O)C>[C:4]1([C:9]2[N:19]3[N:18]=[CH:17][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)C=CN(C)C)cc1C
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(C)c(C)c3)ccnc12

Procedure:
A mixture of 4.06 g. of 3',4'-dimethyl-3-dimethylaminoacrylophenone and 3.10 g. of ethyl 3-aminopyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 6 hours. The desired compound is recovered as in previous examples except that the compound as first observed is amorphous and then crystallizes on standing in the crystallization solvent, m.p. 187°-188° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH2:6][C:7]([O:9][CH:10]([CH3:13])[CH2:11]C)=[O:8])=[O:5])[CH3:2].[ClH:21].[Cl:22][O-].[Na+]>>[Cl:21][C:6]([Cl:22])([P:4]([O:3][CH2:1][CH3:2])([N:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[O:5])[C:7]([O:9][CH:10]([CH3:13])[CH3:11])=[O:8]
Reactant: [O-]Cl
Reactant: CCOP(=O)(CC(=O)OC(C)CC)N(C(C)C)C(C)C
Reactant: Cl
Agent: [Na+]
Product: CCOP(=O)(N(C(C)C)C(C)C)C(Cl)(Cl)C(=O)OC(C)C
Reaction time: 0.75 h

Procedure:
To 100 ml of 5.25 percent sodium hypochlorite solution (Clorox®) was added 6.0 g of 1-methylpropyl 2-[ethoxy di(1-methylethyl)aminophosphinyl]acetate dropwise. The pH was maintained at 10.5-11.0 by simultaneous addition of 1 N HCl solution. The reaction mixture was stirred an additional 45 minutes then extracted with methylene chloride. The methylene chloride solution was dried and stripped in vacuum to give 6.2 g of 1-methylethyl 2,2-dichloro-2-[ethoxy di(1-methylethyl)aminophosphinyl]acetate as an acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>CCCCCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccccc1Oc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Oc2ccc(Cl)cn2)nc1

Procedure:
A mixture of 1.5 grams (0.0068 mole) 2-(5-chloropyridin-2-yloxy)phenol, 1.3 grams 2-chloro-5-nitropyridine, 1.0 grams potassium carbonate, and 40 ml of methyl ethyl ketone was heated at reflux overnight. Excess water was added and the aqueous mixture extracted with 200 ml of ethyl ether. The ether extract was washed with saturated NaHCO3, H2O, brine, dried (MgSO4), filtered, and the solvent was evaporated to yield a solid which was suspended in hexane and filtered. Yield 1.4 grams, m.p. 82°-84°; ir (Nujol): 6.15, 6.25 (C=N, NO2), 13.30 (broad), 13.70 microns; NMR (CDCl3): δ6.55 (s, ArH), 6.75 (d, ArH), 6.95 (s, ArH), 7.35 (s, 4H, ArH), 7.40-7.65 (m, ArH), 8.05 (d, ArH), 8.40 (AB quartet, ArH), 8.95 (d, ArH).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[C:1]([CH:9]=[CH:10][C:11]([Cl:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=CC(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(Cl)C=CC(=O)c1ccccc1

Procedure:
3-Benzoylacrylic acid (3 g.) was refluxed for 2 hours with 100 ml. of methylene chloride and 10 ml. thionyl chloride. Concentration to dryness gave 3-benzoylacrylyl chloride. Methanol (15 ml.) was added and the resulting solution stirred for 0.5 hour. Ether (35 ml.) was added. The resulting organic mixture was washed in sequence with 15 ml. of water, 15 ml. of 1 N sodium hydroxide and twice with 15 ml. of water, concentrated to an oil, the oil triturated with 25 ml. of hot hexane, decanted from insolubles and the hexane concentrated to yield methyl 3-benzoylacrylate (1.9 g., oil, m/e 190).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: Cc1cccc(C)c1O
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: Cc1cccc(C)c1Oc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2

Procedure:
The title compound was prepared from 2,6-dimethylphenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 252.7-258.6° C. 1H NMR (acetone-d6/300 MHz) 7.88 (s, 1H), 7.71 (s, 1H), 7.22 (m, 3H), 6.04 (s, 1H), 5.77 (q, 1H, J=7.0 Hz), 2.13 (s, 6H). 19F NMR (acetone-d6/282 MHz)−79.6 (d, J=7.2 Hz). FABLRMS m/z 397 (M−H). ESHRMS m/z 397.0450 (M−H, Calc'd 397.0454). Anal. Calc'd for C19H14ClF3O4: C, 57.23; H, 3.54; Cl, 8.89. Found: C, 57.21; H, 3.56; Cl, 8.98.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: COc1ccc(F)c(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 3.4 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 2-fluoro-5-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (6 mg, 3.4%) which was obtained as a white solid. MS (ESI): m/e=350.0 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:71]1[CH2:76][CH2:75][CH:74]([C:77]([O:79][CH2:80][CH2:81][CH2:82][CH:83]2[O:87][CH2:86][CH2:85][O:84]2)=[O:78])[CH2:73][CH2:72]1>CN(C=O)C.C(OCC)(=O)C>[C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:71]3[CH2:76][CH2:75][CH:74]([C:77]([O:79][CH2:80][CH2:81][CH2:82][CH:83]4[O:84][CH2:85][CH2:86][O:87]4)=[O:78])[CH2:73][CH2:72]3)=[O:18])=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCCCC1OCCO1)C1CCNCC1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)N3CCC(C(=O)OCCCC4OCCO4)CC3)cc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid (0.300 g, 0.57 mmol) in DMF (2.5 mL) was added di-iso-propylethylamine (0.40 mL, 2.29 mmol) and HATU (0.262 g, 0.69 mmol) and the mixture stirred at RT for 30 minutes. To the resultant solution was added a solution of 3-(1,3-dioxolan-2-yl)propyl piperidine-4-carboxylate hydrochloride (0.241 g, 0.86 mmol) in DMF (1.8 mL). The mixture was stirred at RT for 18 hours. The mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate, brine (×2), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used directly in the next step with no further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(CCCI)OC(C)=O
Yield: 97.5 %

Procedure:
A mixture of 1-chloro-4-acetoxynonane (Ex. 1, Step B-3) (35.3 g., 0.16 mole) and sodium iodide (120 g., 0.8 mole) in acetone (350 ml.) is stirred and heated at reflux with exclusion for light for 10 hours. The resulting suspension is filtered and the collected sodium chloride washed with acetone. The combined filtrate and washings are evaporated in vacuo leaving a residual mass which is partitioned between ether and water. The organic extract is washed with dilute aqueous sodium thiosulfate and water, dried over sodium sulfate and evaporated in vacuo providing the title compound as a colorless liquid (48.7 g., 98%), pmr (CDCl3) δ 2.0 (s, 3H), 3.18 (t, 2H) and 4.98 (m, H).
Reaction SMILES: C([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])CCC.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[CH2:17]([CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:23]=3)[CH:13]=2)[CH:9]1[N:8]=[S:5](=[O:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1Cc2cc(-c3ccc(=O)n(Cc4ccccc4)n3)ccc2C1N=S(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 183.5 %

Procedure:
To 1.0 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane dissolved in 30 ml of dimethylformamide were added 828 mg of potassium carbonate and 547 mg of benzyl bromide, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and crude crystals precipitated were collected by filtration, dried and then recrystallized from ethanol to obtain 1.15 g of 2-n-butyl sulfonylamino-5-[2-benzylpyridazin-3(2H)-on-6-yl]indane. This compound had the same physical property values as those of the compound obtained in Example 85.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)(C)C.O>[CH3:11][N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:23][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH2:20][CH2:19]2)[CH2:16][CH2:17]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: CN1CCC(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1

Procedure:
4-Fluoronitrobenzene (3 g, 21.3 mmol), 1-(1-methylpiperidin-4-yl)piperazine (3.9 g, 21.2 mmol) and triethylamine (3.30 mL, 23.7 mmol) are stirred in anhydrous isopropanol (10 mL) for 10 min at 160° C. in the microwave. The reaction mixture is diluted with water (10 mL), the precipitate is filtered off washed with 50% water in isopropanol and dried in vacuo at 45° C. Yield: 5.14 g