Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C=C(CCCC#N)CCCC#[N:18].C1C=CC=CC=1>P(=O)(O)(O)O.O>[C:1]1(=[O:6])[NH:18][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: C=C(CCCC#N)CCCC#N
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=P(O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: O=C1NC(=O)c2ccccc21
Temperature: 240 °C
Yield: 199.4 %

Procedure:
225 g (1.52 moles) of phthalic anhydride, 121.5 g (0.75 mole) of 5-methylene-1,9-nonanedinitrile, 300 cc of benzene, 40 g of water and 2 g of phosphoric acid were placed in a 1-liter autoclave. The autoclave was closed, then purged with dry nitrogen. Following purging, the reactor was heated to 240° C for a period of 4 hours. After cooling, the reaction mixture was filtered. The filter solid, after being washed in 300 cc of benzene, filtered and dried, yielded 220 g of phthalimide having a melting point of 234°-238° C. Yield 100 percent.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1([CH3:18])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][S:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[OH-].[K+]>>[CH3:18][C:5]1([CH2:4][C:3]([OH:19])=[O:2])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][S:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Agent: [K+]
Agent: [OH-]
Product: CC1(CC(=O)O)SCCc2c1[nH]c1ccccc21

Procedure:
This ester is then treated with aqueous alcoholic KOH in the manner described for the esters in Example 1 and 2 to afford the title compound, m.p. 147°-149° C., nmr (CDCl3) δ1.86 (S, 3H), 3.06 and 8.12 (6H), 7.35 (multiplet, 4H), 8.71 (1H), 10.31 (1H), after recrystallization from benzene-hexane.
Reaction SMILES: [C:1]1([C:18]([OH:20])=O)[C:14]2[CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([C:15]([OH:17])=O)[C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C=O.S(Cl)(Cl)=O>[C:18]([C:1]1[C:14]2[CH2:13][C:12]3[C:7](=[C:8]([C:15](=[O:17])[C:1]4[CH:14]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1cccc2c1Cc1cccc(C(=O)O)c1C2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1cccc2c1Cc1cccc(C(=O)c3ccccc3)c1C2
Temperature: 60 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A solution of 9,10-dihydro anthracene-1,5-dicarboxylic acid (52, 1 g, 3.73 mmol) in 200 μl of dimethyl formamide and 20 ml of thionyl chloride was refluxed for 3 hours. The resulting solution was evaporated to dryness under vacuum, 60 ml of benzene added, and warmed to 60° C. to obtain a solution. This solution was slowly added to a 250 ml round bottom flask containing a mixture of AlCl3 and 20 ml of benzene. The resulting mixture was stirred for 18 hours at room temperature and poured into 100 ml of an ice/water mixture containing 10 ml of conc. HCl. The organic layer was separated and the aqueous layer was washed twice with 100 ml portions of benzene. After drying over Na2SO4, the combined organic extracts were dried under vacuum to yield a brown colored crude product. This was further purified by flash column chromatography to obtain a dark yellow, oily product (0.39 g, 27%) (According to NMR studies the product is 80+% pure). 1H NMR (300 MHz, CDCl3): δ 4.04 (s, 4H), 7.20-7.86 (m, 16H), 7.51 (d, 2H, J=6 Hz), 7.70 (d, 2H, J=6 Hz), 13.00 (broad s, 2H). 13C NMR (300 MHz, CDCl3): δ 33.95, 125.48, 126.98, 128.51, 128.55, 129.94, 130.30, 133.24, 135.74, 137.88, 197.15.
Reaction SMILES: O[C:2]1([C:12]2[C:21]([OH:22])=[CH:20][C:15]3[N:16]=[C:17]([CH3:19])[S:18][C:14]=3[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].I>O.C(OCC)(=O)C>[OH:22][C:21]1[C:12]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:11])=[CH:13][C:14]2[S:18][C:17]([CH3:19])=[N:16][C:15]=2[CH:20]=1
Reactant: Cc1nc2cc(O)c(C3(O)C(=O)Nc4ccccc43)cc2s1
Agent: I
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2cc(O)c(C3C(=O)Nc4ccccc43)cc2s1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one (4.81 g, 15.4 mmol) and 48% aqueous hydroiodic acid (25 mL) was heated at reflux for 1 h. The reaction mixture was allowed to cool to ambient temperature and was diluted with water (50 mL) and ethyl acetate (50 mL). The mixture was briefly sonicated, causing a precipitate to be deposited. The solid was collected by filtration, washed with water (20 mL) and dried in vacuo to afford 3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one (4.52 g, 99%) as a pale yellow solid: MS (ES+) m/z 297.2 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:8]1[C:7]2[C:12](=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1ccc2c(=O)[nH]cnc2c1
Product: CC(C)c1ccc2c(Cl)ncnc2c1
Yield: 97 %

Procedure:
The product of Example 91E (100 mg, 0.5313 mmol) in phosphorous oxychloride (2 mL) was heated under a nitrogen atmosphere at reflux for one hour. The reaction was cooled and concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (50 mL) and washed sequentially with saturated aqueous sodium hydrogencarbonate (2×25 mL), water (25 mL), and brine (25 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as a yellow oil (107 mg, 0.5177 mmol, 97%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J=6.99 Hz, 6 H) 3.14-3.29 (m, 1 H) 7.86 (dd, J=8.64, 1.65 Hz, 1 H) 7.93 (s, 1 H) 8.22 (d, J=8.46 Hz, 1 H) 9.07 (s, 1 H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17](OCC)=O)[N:11]=1)[CH3:8].C1C[O:25]CC1>>[CH2:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([OH:25])[CH3:17])[N:11]=1)[CH3:8]
Reactant: CCNc1cccc(CC(=O)OCC)n1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCNc1cccc(C(C)O)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mechanically stirred solution of LiAlH4 in THF( 1.0 M, 20 mL, 20.4 mmol) was added dropwise a solution of ethyl 2-(ethylamino)-6-pyridylacetate (1 g, 4.1 mmol) in THF (30 mL). After the addition was completed, the reaction mixture was heated to reflux. After 5 hr, the reaction was cooled to 0° C. and quenched with 10% NaOH solution. The solids were removed by filtration, and the filtrate was concentrated in vacuum. The residue was dissolved in CH2Cl2, and the solution was dried (MgSO4) and concentrated. Reconcentration from toluene (3×) gave the title compound as a colorless oil: MS (ES) 167 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:7]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1)(=[O:5])=[O:4].O1CC[CH2:19]OO1>CS(O)(=O)=O.FC(F)(F)C(O)=O>[F:15][C:13]1[CH:12]=[CH:11][C:8]2=[C:7]3[C:14]=1[CH2:1][N:2]([CH3:19])[S:3](=[O:4])(=[O:5])[C:6]3=[CH:10][S:9]2
Reactant: C1COOOC1
Reactant: CNS(=O)(=O)c1csc2ccc(F)cc12
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(F)ccc3scc(c23)S1(=O)=O
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
0.37 g of 5-fluoro-benzo[b]thiophene-3-sulphonic acid-methylamide are dissolved in 5.9 ml of methanesulphonic acid at 35° C. and combined with a solution of 0.06 g of trioxane in 1.8 ml of trifluoroacetic acid. After 2.5 h stirring at 35° C. the reaction mixture is poured onto 100 ml of ice water and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried with Na2SO4, evaporated down in vacuo and then purified by chromatography. Yield: 0.22 g. M.p.: 175° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[S:12])[S-:11])[CH:6]=[CH:5][CH:4]=1)[CH3:2].C([NH+](CC)CC)C.Cl[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C(#N)C>[CH2:23]([C:22]1([OH:25])[CH2:21][S:12][C:10](=[S:11])[N:9]1[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=1)[CH3:24]
Reactant: CCC(=O)CCl
Reactant: CCc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: CCc1cccc(N2C(=S)SCC2(O)CC)n1
Reaction time: 4 h
Yield: 57.9 %

Procedure:
The procedure of Example 4 is followed but starting with triethylammonium (6-ethylpyrid-2-yl)dithiocarbamate (72.0 g) and 1-chlorobutan-2-one (25.5 g) in anhydrous acetonitrile (400 cc) at a maximum temperature of 25° C. The reaction is continued for 4 hours at 20°-25° C. The product is purified by chromatography over silica (470 g; 0.063-0.200 mm) contained in a column 3.8 cm in diameter, eluting with chloroform (5 liters). The chromatographed product (43.0 g) is recrystallised from ethanol (120 cc) to give 4-ethyl-3-(6-ethylpyrid-2-yl)-4-hydroxythiazolidine-2-thione (37.2 g) melting at 84° C.
Reaction SMILES: O[C@H:2]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@H:2]([CH2:35][O:36][Si:37]([CH:44]([CH3:45])[CH3:46])([CH:38]([CH3:39])[CH3:40])[CH:41]([CH3:42])[CH3:43])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Temperature: 70 °C
Reaction time: 72 h
Yield: 104.6 %

Procedure:
N-{(2S)-2-Hydroxy-3-[(triisopropylsilyl)oxy]propyl}-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (177 mg, 0.262 mmol) synthesized in Example (35b) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (70.0 mg, 0.402 mmol) and triethylamine (0.22 mL, 1.58 mmol) were added, followed by stirring at 70° C. for 3 days under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-60%) to afford the desired product (180 mg, yield ˜100%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:32]=[CH:33][N:34]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[CH:17]=[C:12]([NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[N:7]=3)[C:13]3[N:14]([CH:32]=[CH:33][N:34]=3)[N:15]=2)[CH2:19]1
Reactant: COc1ccc(Nc2cc(N3CCCC(NC(=O)OC(C)(C)C)C3)nn3ccnc23)nc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2cc(N3CCCC(N)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamate (300 mg, 0.64 mmol) and TFA (5 mL) in dichloromethane (5 mL) was stirred at 25° C. for 6 h. The residue was concentrated to give the crude 6-(3-aminopiperidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine trifluoroacetate salt (350 mg, crude) as a brown liquid that was used directly without further purification. LC-MS: 370 [M+1]+, tR=1.09 min
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:5]=[CH:4][N:3]=1.[NH3:13]>CO>[N:8]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:13])[CH:7]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: N
Reactant: Clc1cc(-n2ccnc2)ncn1
Solvent: CO
Product: Nc1cc(-n2ccnc2)ncn1
Temperature: 65 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
4-Chloro-6-(1H-imidazol-1-yl)pyrimidine (4.0 g, 22.1 mmol) was split into two equal portions and separately placed into two sealed tubes with a solution of 7 N ammonia in methanol (40 mL). The tubes were sealed and heated at 65° C. for 20 h, then allowed to stand at room temperature for 3 days. The reactions were combined, concentrated and purified by flash chromatography on a 240 g silica gel cartridge with 40 to 100% EtOAc in hexane, then 0 to 50% MeOH in EtOAc to yield 6-(1H-imidazol-1-yl)pyrimidin-4-amine (1.43 g, 40%). LCMS: RT=0.39 min, MH+=162.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:14])=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:14])=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1F
Product: CC(=O)Nc1cc(C(=O)C=CN(C)C)ccc1F
Yield: 78.5 %

Procedure:
3.3 g (16.9 mmol) of N-(5-acetyl-2-fluoro-phenyl)-acetamide were dissolved in 8.36 ml (7.49 g) (62.89 mmol) of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 6.5 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was crystallized from ethyl acetate. 3.32 g of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-acetamide as a yellowish-white solid were obtained (yield 78.6%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[NH:11][C:12](SC)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[NH:18]([C:22]1[S:23][CH:24]=[C:25]([CH2:27][S:28][CH2:29][CH2:30][NH2:31])[N:26]=1)[C:19]([NH2:21])=[NH:20]>N1C=CC=CC=1>[NH:18]([C:22]1[S:23][CH:24]=[C:25]([CH2:27][S:28][CH2:29][CH2:30][NH:31][C:12]2[NH:11][C:10](=[O:17])[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:14][N:13]=2)[N:26]=1)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CSc1ncc(Cc2ccc(C)nc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)cn1

Procedure:
Equimolar amounts of 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone and 2-(2-guanidino-4-thiazolylmethylthio)ethylamine are refluxed together with pyridine for 48 hours to give 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30](=[O:37])[CH2:31][CH:32]([CH3:36])[C:33](O)=[O:34]>CC(N(C)C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:37])[CH2:31][CH:32]([CH3:36])[C:33]1=[O:34]
Reactant: CC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (1.09 g, 3.4 mmol) and diisopropylethylamine (0.98 g, 5.7 mmol) were added sequentially to a stirred solution of N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-methylsuccinamic acid (1 g, 2.6 mmol) in dimethylacetamide (5 ml), the mixture was stirred at ambient temperature for 15 minutes, then it was poured onto water (50 ml) and allowed to stand at ambient temperature for 20 hours. The resulting solid was collected by filtration, washed with hexane (20 ml) and dried in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-methylpyrrolidine-2,5-dione (0.654 g) as a beige solid, m.pt. 171–172° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.4 (d, 3H) (CH3), 2.6–2.7 (m, obscured by DMSO signal, 1H) (—CHMe-), 3.05–3.3 (m, 2H) (—CH2CHMe-), 4.5 (s, 2H) (ArCH2—), 7.3–7.55 (m, 2H) (2×ArH), 7.6–7.7 (m, 1H) (ArH), 7.9–8.2 (m, 3H) (3×ArH), 8.4 (d, 1H) (ArH), 12.8 (s, 1H) (CONH); m/z (M+H)+ 366, 98% purity.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([OH:9])[CH2:2]2.C[O:11][C:12]([C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.[H-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([O:9][C:12]([C:14]1([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:11])[CH2:2]2
Reactant: COC(=O)C1(c2ccccc2)CCCCCC1
Reactant: O[C@@H]1CN2CCC1CC2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O[C@@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A solution of (S)-(+)-3-quinuclidinol (299 mg) and 1-phenyl-cycloheptanecarboxylic acid methyl ester (Example 14d) (455 mg) in 6.5 mL dry toluene under nitrogen was treated with a 60% dispersion of sodium hydride (94 mg) and the mixture was heated to reflux for 24 h then cooled to room temperature and allowed to stand over the weekend. EtOAc and sat. NaHCO3 (aq) were added and the phases separated. The aqueous phase was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried (MgSO4) and evaporated to afford the crude product. Purification was achieved by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the sub-titled compound (384 mg) as a yellow oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][CH:34]=1)[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][C:10]2([F:36])[F:35])(=O)=O.[Cl-].[Li+].[CH2:41]([Sn](CCCC)(CCCC)C=C)[CH2:42]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:10]1([F:36])[C:9]2[C:32](=[CH:33][CH:34]=[C:7]([CH:41]=[CH2:42])[CH:8]=2)[C:13]2=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:25])([F:23])[F:24])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)=[C:12]2[CH2:11]1
Reactant: O=S(=O)(Oc1ccc2c(c1)C(F)(F)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)C(F)(F)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 100 °C
Yield: 64.3 %

Procedure:
A mixture of 5,5-difluoro-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl trifluoromethanesulfonate (Preparation 66E, 0.024 g, 0.042 mmol) and lithium chloride (2.60 μL, 0.127 mmol) in dioxane (5.0 mL) was degassed with nitrogen for 15 minutes. To the reaction mixture was added tributyl(vinyl)stannane (0.015 g, 0.047 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (4.90 mg, 4.24 μmol) at room temperature. The resulting reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and filtered. The brownish residue was washed with ethyl acetate (3×10 mL), and the combined filtrates were concentrated in vacuo. The residue was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM) to yield 5,5-difluoro-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.012 g, 0.027 mmol, 63.7% yield) as a tan viscous liquid. The product had an HPLC ret. time=3.77 min. (condition B). LC/MS M+1=444.20. 1H NMR (500 MHz, CD3OD) δ ppm 7.75 (1H, d, J=7.93 Hz), 7.55-7.68 (2H, m), 7.38-7.57 (4H, m), 7.18-7.38 (1H, m), 6.63 (1H, dd, J=17.70, 10.99 Hz), 5.75 (1H, d, J=17.70 Hz), 5.19 (1H, d, J=10.99 Hz), and 2.85-3.02 (2H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[N:14]#[C:15]Br>C(Cl)Cl.O>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15]#[N:14])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CN1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-piperidinemethanol (140 g, 1.22 mol) in CH2Cl2 (1 L) was treated with a slurry of NaHCO3 (205 g, 2.44 mol) in water (1.4 L) at 0° C. The mixture was stirred at 0° C. for 15 min, and then charged with a solution of cyanogen bromide in CH2Cl2, (1.34 mol) at 0° C. The reaction mixture was stirred and allowed to warm to ambient temperature, and stirred overnight. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and the filtrate was concentrated. The crude product was combined with other batches made similarly and purified by chromatography on a silica gel column to give 300 g of 4-(hydroxymethyl)-1-piperidinecarbonitrile.
Reaction SMILES: [C:1]1([C:7]2N=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C#[C:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([O:22][C:20]([C:19]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][O:10][CH:9]=1)=[O:21])[CH3:24]
Reactant: c1ccc(-c2cocn2)cc1
Reactant: CCOC(=O)C#Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cocc1-c1ccccc1
Temperature: 220 °C
Yield: 78.4 %

Procedure:
Mix 4-Phenyl oxazole (3.33 g, 23.0 mmol) and ethyl phenylpropiolate (4.0 g, 23.0 mmol) in a sealed tube and heat at 220° C. for 20 hours. Perform flash-chromatography on silica gel eluting with 4:1 Hex/ethyl acetate to afford 3.9 g of 4-phenylfuran-3-carboxylic acid ethyl ester as a yellow oil. MS: m/e=217 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=1[O:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3([CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[O:30][CH3:31])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCC1(c2noc3cc(Cl)ccc23)CCNCC1
Yield: 98.2 %

Procedure:
A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 benzisoxazole (4.6 g, 19 mmol), l-[4-(2-chloroethoxy)-3- methoxyphenyl]ethanone (4.3 g, 19 mmol), K2CO3 (2.8 g), a few crystals of KI and acetonitrile (120 ml) was refluxed for 16 hours. The reaction was filtered and the filtrate was concentrated to yield 8.0 g of yellow solid. The solid was chromatographed on a Waters Prep 500 LC (silica columns, eluting with methylene chloride/methanol, 5%). Concentration of the appropriate fractions yielded 3.2 g of a light yellow solid, which upon recrystallization from ethyl acetate afforded 2.3 g (28%) of 1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone as a pale yellow solid, m.p.=133°-135° C.