Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:15]([CH3:26])([CH3:25])[CH2:16][C@@:17]([C:21]([F:24])([F:23])[F:22])([OH:20])[CH2:18]O)[CH:14]=1.CS(Cl)(=O)=O>C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([C:15]([CH3:26])([CH3:25])[CH2:16][C@:17]2([C:21]([F:24])([F:23])[F:22])[CH2:18][O:20]2)[CH:14]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CO)C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (8.2 mL, 58.8 mmol) was added to a solution of (2R)-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-(trifluoromethyl)-1,2-pentanediol (3.4 g, 10.9 mmol) in DCM (34 mL). This solution was then cooled to 0° C. and neat methanesulphonyl chloride (1.1 mL, 15.3 mmol) was added over 5 min keeping the temperature at 0-5° C. The resulting suspension was stirred at 0-5° C. for 15 min before warming to 20° C. The reaction mixture was then left to stir overnight. Further neat methanesulphonyl chloride (0.84 μL, 0.1 eq) was added at room temperature and the mixture stirred for 15 min. The reaction mixture was then washed successively with 1M HCl (3×12 mL), 9% aqueous sodium bicarbonate (12 mL) and water (12 mL) before evaporating to dryness to afford the title compound, 3.08 g.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:20])[C@H:6]([CH3:19])[NH:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1>O.O1CCOCC1>[F:16][C:14]1[CH:15]=[C:10]([CH2:9][C:8]([NH:7][C@H:6]([C:5]([OH:20])=[O:4])[CH3:19])=[O:18])[CH:11]=[C:12]([F:17])[CH:13]=1
Reactant: COC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Yield: 97.2 %

Procedure:
To a stirred solution of 3,5-difluorophenylacetic acid (6.02 g, 34.97 mmol), L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in dichloromethane (200 mL) under nitrogen at 0° C. was added NMM (8.84 g, 87.39 mmol) and EDAC-HCl (7.38 g, 38.49 mmol). The mixture was allowed to warm gradually to ambient temperature and stir overnight. The reaction was diluted with ethyl acetate and extracted sequentially with aqueous sodium bicarbonate, 1N aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes:ethyl acetate to afford N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.91 g, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (d, 3H, J=7.0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, 1H), 6.02 (br 1H), 6.67-6.87 (m, 3H). MS APCI, m/z=258 (M+1). LC/MS: 1.68 min. Lithium hydroxide (1.40 g, 33.33 mmol) in water (60 mL) was added dropwise to a solution of N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.79 g, 30.28 mmol) in 1,4-dioxane (150 mL). After 2 h the solvent was evaporated. The residue was dissolved in water and the solution extracted with diethyl ether. The aqueous phase was acidified with 1N aqueous HCl and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried, filtered and evaporated to afford the title compound (7.16 g, 97% yield) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.28 (d, 3H, J=7.4 Hz), 3.51 (s, 2H), 4.20 (m, 1H), 6.93-7.12 (m, 3H), 8.44 (d, 1H, J=7.0 Hz), 12.46 (br, 1H). HPLC Method A: 2.12 min.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[Na].[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21](OCC)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH3:11][C:12]1[N:17]2[N:18]=[CH:19][C:20]([C:21]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:22])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnn2c(C)cccc12
Reactant: O[C@H]1CN2CCC1CC2
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cccc2c(C(=O)O[C@H]3CN4CCC3CC4)cnn12
Reaction time: 2.5 h
Yield: 10.2 %

Procedure:
After a suspension of 90 mg (0.71 mmol) of (R)-(-)-3-quinuclidinol, which had been prepared in accordance with the procedure disclosed in "Eur. J. Med. Chem.", 14, 111-114 (1979), in 15 ml of benzene was refluxed for 1.5 hours by using a Dean-Stark apparatus, 0.05 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2.5 hours. Unreacted sodium was removed and 100 mg (0.49 mmol) of ethyl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform:methanol=10:1), whereby 15 mg (0.05 mmol) of the title compound were obtained as white crystals (yield: 12%).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:35])=[O:5])[S:12][CH:13]=2)=[CH:29][CH:30]=1
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
2-[(4-{2-[(4-Bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (350 mg) obtained in Example 402-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (240 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:24][C:17]=12.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:24][C:17]=12
Reactant: CN1CCC(c2cc3c(-c4cc(NC(=O)OC(C)(C)C)ccc4F)ccnc3[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2cc3c(-c4cc(N)ccc4F)ccnc3[nH]2)CC1
Reaction time: 2 h

Procedure:
To a solution of Example 179C (102 mg, 0.24 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred for 2 hours. Concentration and purification by HPLC (Zorbax XDB C-18 (32) using a gradient of 5-40% acetonitrile/water (containing 0.1% trifluoroacetic acid) afforded the title compound. LCMS: 325 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([OH:23])[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([O:23][CH3:26])[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1CC(O)(c2cc(F)cc(OCc3ccccc3)c2)CCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(OCc3ccccc3)c2)CCOC(C)C1
Reaction time: 0.75 h
Yield: 71 %

Procedure:
A mixture of (2RS, 4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-hydroxy-2-methyltetrahydropyran (0.45 g) and dimethylformamide (5 ml) cooled in an ice bath, sodium hydride (0.068 g of a 55% w/w dispersion in mineral oil) was added and the mixture was stirred for 45 minutes. Methyl iodide (0.11 ml) was added and the mixture was stirred for 15 minutes. The ice bath was removed and the mixture was stirred at ambient temperature for 30 minutes. The mixture was poured into water (15 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 10:1 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained as an oil, (2RS, 4SR)-4-(3-benzyloxy-5-fluorophenyl)-4-methoxy-2-methyltetrahydropyran (0.33 g, 71%);
Reaction SMILES: [CH2:1]([N:7]([C:14]1[C:15](OCC)=[N:16][S:17](=[O:20])(=[O:19])[N:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:24]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH2:31])([CH3:27])([CH3:26])[CH3:25]>CCO>[C:24]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH:31][C:15]1[C:14]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:18][S:17](=[O:19])(=[O:20])[N:16]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1OCC
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CCO
Product: CCCCCCN(CCCCCC)C1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of 4-(N,N-di-n-hexylamino)-3-ethoxy-1,1-dioxo-1,2,5-thiadiazole (400 mg, 1.02 mmol) and L-tyrosine t-butyl ester (261 mg, 1.1 mmol) in EtOH (10 mL) was stirred at room temperature for 36 hrs. The solvent was removed under reduced pressure residue purified by flash column chromatography (silica, hexane:EtOAc 3:1 then 1:1) to give the title compound as a white waxy solid (400 mg, 73%).
Reaction SMILES: COC1C=CC2SC3C(=CC=CC=3)NC=2C=1.O.[C:18]1([CH3:45])[CH:23]=[CH:22][C:21]([C:24]([C@@:26]([C:42]([OH:44])=[O:43])([OH:41])[C@@:27]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[O:33])([OH:31])[C:28]([OH:30])=[O:29])=[O:25])=[CH:20][CH:19]=1>C(O)C>[C:18]1([CH3:45])[CH:23]=[CH:22][C:21]([C:24]([C:26]([C:42]([OH:44])=[O:43])([OH:41])[C:27]([C:32]([C:34]2[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=2)=[O:33])([OH:31])[C:28]([OH:30])=[O:29])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: COc1ccc2c(c1)Nc1ccccc1S2
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)C(O)(C(=O)O)C(O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 134.5 %

Procedure:
(±)-10-(3 Dimethy]amino-2-methylpropyl)-2-methoxyphenothiazine (16.5 g; 0.05 mole), (-)-di(p-toluoyl)-L-tartaric acid monohydrate (10.15 g; 0.025 mole) and ethanol (75 cc) are introduced into a 250-cc three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser and a nitrogen inlet. The stirred mixture is heated to 60° C. until a homogeneous solution is obtained. The mixture is cooled to 50° C. and crystallization is then seeded by adding a few crystals of the neutral salt of (-)-di(p-toluoyl)tartaric acid and the dextrorotatory base. While stirring is maintained, the mixture is kept for 1 hour at 50° C., cooled to 20° C. in the course of 2 hours, and maintained at 20° C. for 1 hour. The crystals obtained are separated by filtration, washed with ethanol (2×30 cc) and then dried. The neutral salt (12.99 g) of (-)-di(p-toluoyl)tartaric acid and dextrorotatory 10-(3-dimethylamino-2-methylpropyl) -2-methoxyphenothiazine is thereby obtained.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1/[N:17]=[CH:18]/[N:19](C)C)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])N>C(#N)C.C(O)(=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([NH:2][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:17]=[CH:18][N:19]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)N1CCc2c(oc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Yield: 32.1 %

Procedure:
Ethyl 3-cyano-2-{[(1E)-(dimethylamino)methylidene]amino}-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 37A (1.00 g, 4.14 mmol) and 3,4-dichloroaniline (1.12 g, 6.89 mmol) were heated in a mixture of acetonitrile (20 mL) and acetic acid (2 mL) for 20 h under reflux. The mixture was then half-concentrated in vacuo and heated for further 20 h. Subsequently, it was diluted with water, basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was triturated with methanol. The precipitate was collected by suction filtration to yield 542 mg (34%) of the title compound. A second batch of 50 mg (4%) was obtained from the mother liquor after purification by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH2:19][CH3:20]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH2:19][CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCBr
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 70.5 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (7.12 g, 32.9 mmol), NaH (900 mg, 37.5 mmol) and propylbromide (4.05 g, 32.9 mmol) were reacted in DMF (64 mL) to give 2-acetoxy-2-acetyl-pentanoic-acid-tert-butylester (250h) (6.00 g, 23.2 mmol, 71%) as a slightly yellow oil after Kugelrohr distillation at 160° C. and 1.0 mbar. Then, 250h (6.00 g, 23.2 mmol) and 393 mg (2.07 mmol) p-TsOH.H2O were stirred in 60 mL benzene according to decarboxylation method A. Kugelrohr distillation at 1.0 mbar and 150° C., followed by column chromatography (diethylether:petroleum ether=1:8) gave 251h (2.00 g, 12.6 mmol, 54%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[S:25](Cl)(=[O:27])=[O:26]>O1CCCC1.C(OCC)(=O)C.O>[F:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[S:25]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: Oc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Oc1ccc(Cl)cc1)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a stirred solution of 4-chlorophenol (13.94 g, 108 mmol) in tetrahydrofuran (400 mL) at ambient temperature was added triethylamine (30.2 mL, 216 mmol). The mixture was stirred at ambient temperature for 10 minutes and cooled to 0° C. 2,4,5-Trifluorobenzenesulfonyl chloride (25.00 g, 108 mmol) was added and the reaction mixture was stirred for 1 h at ambient temperature and diluted with ethyl acetate (600 mL) and water (200 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford 4-chlorophenyl 2,4,5-trifluorobenzenesulfonate as a colorless liquid in 98% yield (34.4 g): 1H NMR (300 MHz, DMSO-d6) δ8.18-7.96 (m, 2H), 7.50 (d, J=7.2 Hz, 2H), 7.19 (d, J=7.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](O)=O)=[C:6]([CH3:15])[CH:5]=1.C(Cl)(=O)C(Cl)=O.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)CC(CC(O)=O)([C:34]([OH:36])=[O:35])O.C(N(CC)CC)C>ClCCl.CN(C=O)C.C(#N)C.O.C([O-])(=O)C1C=CC=CC=1.[Ag+].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:34]([OH:36])=[O:35])=[C:6]([CH3:15])[CH:5]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COC(=O)c1ccc(CCC(=O)O)c(C)c1
Agent: [Ag+]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
4-(2-Carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (500 mg, 2.25 mmol) was dissolved in dry dichloromethane (10 ml) and a few drops of DMF. Oxalyl chloride (0.393 ml, 4.5 mmol) was added dropwise and the mixture was stirred for 1 h at room temperature. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in acetonitrile (20 ml) and cooled to 0° C. A solution of 2M (trimethyl-silyl)diazomethane in hexanes (2.25 ml, 4.5 mmol) was added dropwise and the reaction mixture was stirred for 5 h at 0° C. then 20 h at room temperature. Ethyl acetate then 10% citric acid solution were added and the layers were partitioned. The organic layer was washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% ethyl acetate:50% cyclohexane). The product obtained was dissolved in a mixture of acetonitrile and water. A solution of silver benzo-ate (103 mg, 0.45 mmol) in triethylamine (1.25 ml, 9 mmol) was added gradually while the mixture was sonicated in an ultrasound bath. After 30 min at room temperature, solvents were removed in vacuo. Ethyl acetate and 10% aqueous citric acid solution were added and the layers were partitioned. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% cyclohexane) to yield the title compound (378 mg, 71%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCCCCC>C1COCC1.CN1CCCC1=O.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 67 h
Yield: 37 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 10 min. The solution was cooled to 0° C., then treated with a solution of ZnBr2 (0.923 g; 4.10 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then 1-methyl-2-pyrrolidinone (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0564 g; 10 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in 1-methyl-2-pyrrolidinone (2 ml). The reaction mixture was then heated to 65° C. and stirred for 67 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 0.74 mmol (37% yield) of diphenylacetylene and 0.97 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH:28]=O.C([O-])(=O)C.[NH2+]1CCCCC1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:9](=[CH:28]\[C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=1)/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)/C(=C/c1ccc2ccccc2c1)C(=O)c1ccccc1O
Temperature: 22 °C
Reaction time: 168 h
Yield: 58.3 %

Procedure:
Prepared according to general procedure B using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (259 mg, 1.1 mmol), 2-naphthaldehyde (172 mg, 1.1 mmol), 12.0 mL toluene, piperidinium acetate (2.2 mL, 0.025M in toluene) and sodium sulfate (2.3 g), stirred at 22° C. for 7 d. Purified via recrystallization from hexanes/CH2Cl2, yielding 240 mg (58%) of beige crystals. mp=111-112° C.; IR (film) 2978.0; 1712.8; 1624.1; 1154.1 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.97 (bs, 1H); 8.02 (s, 1H); 7.91 (s, 1H); 7.79 (d, J=7.6 Hz, 1H); 7.78 (d, J=7.3 Hz, 1H); 7.70 (d, J=8.5 Hz, 1H); 7.58 (dd, J=8.0, 2.5 Hz, 1H); 7.51-7.46 (m, 3H); 7.37 (dd, J=8.5, 1.5 Hz, 1H); 7.05 (d, J=8.2 Hz, 1H); 6.81 (t, J=7.3 Hz, 1H); 1.44 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 201.9, 163.9, 162.9, 142.4, 137.3, 134.1, 133.2, 132.05, 132.03, 131.6, 130.6, 129.0 (x2), 128.0, 127.9, 127.0, 125.9, 120.3, 119.6, 118.6, 82.8, 28.2; LRMS (electrospray): Mass calculated for C24H22O4 [M]+, 374.14. Found [M+23]+, 397.2.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH3:26])[CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].Br[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:28][CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH2:22]3)[CH2:18]2)[CH3:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: Fc1ccccc1OCCBr
Reactant: CN(CCN1CC2CNCC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(CCN1CC2CN(CCOc3ccccc3F)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 160 °C
Yield: 58 %

Procedure:
To 4-cyano-N-methyl-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide dihydrochloride (0.127 g, 0.30 mmol, prep I above), 1-(2-bromo-ethoxy)-2-fluoro-benzene (0.069 g, 0.315 mmol;) and potassium carbonate (0.145 g, 1.05 mmol) was added acetonitrile (4 mL) and water (0.1 mL). The mixture was heated by microwave irradiation (10 minutes, 160° C.) and was then filtered and evaporated. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 85 mg (58.0%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C[O-].[Na+].ClC1C=CC=CC=1.Cl[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40]>CO>[CH2:37]([N:38]([CH2:41][CH3:42])[CH2:39][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1)[CH3:36]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccc(N2c3ccccc3CCC2c2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1ccc(N2c3ccccc3CCC2c2ccc(Cl)cc2)cc1

Procedure:
A procedure was followed similar to that described in Example 1 but using 18 g. 1-(4-hydroxyphenyl)-2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline, 3.8 g. sodium methoxide, 160 ml. chlorobenzene, 15 ml. dry methanol and 8.8 g. N-(2-chloroethyl) diethylamine. The crude material was chromatographed on 700 g. activated magnesium silicate (60-100 mesh) using benzene, benzene containing increasing amounts of ether, and ether as eluants and there was thus eluted with 7 - 50% ether in benzene and with ether 15 g. 1-{4-[2-(diethylamino)ethoxy]phenyl}-2-(4-chlorophenyl)-1,2,3,4-tetrahydroquinoline which was converted to the cyclohexanesulfamate salt; m.p. 161°-163°C. (isopropyl alcohol).