Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH:24]([O:27][CH2:28][CH2:29][NH2:30])([CH3:26])[CH3:25]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH2:29][CH2:28][O:27][CH:24]([CH3:26])[CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)OCCN
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Product: CC(C)OCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-isopropoxyethanamine. 1H NMR (400 MHz, DMSO-d6) δ 1.10 (d, J=6.06 Hz, 6H) 3.42 (q, J=5.81 Hz, 2H) 3.48-3.55 (m, 2H) 3.55-3.64 (m, 1H) 7.79 (d, J=8.34 Hz, 2H) 8.15 (br. s., 2H) 8.42 (d, J=7.58 Hz, 1H) 8.68 (br. s., 1H) 8.77 (t, J=5.05 Hz, 1H) 8.92 (s, 1H) 13.54 (br. s., 1H). MS m/z [M+H]+392.1.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:20]1([NH:26][C:27]([O:1][CH2:2][CH:3]([CH2:18][O:19][C:27](=[O:28])[NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][N:5]2[C:27](=[O:28])[NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(C(COC(=O)Nc1ccccc1)COC(=O)Nc1ccccc1)N(C(=O)Nc1ccccc1)CC2

Procedure:
0.01 mole of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline is reacted with 0.03 mole of phenylisocyanate in toluene, as described in Example 22. The aimed compound is obtained, which has the same physical and analytical characteristics as the product of Example 26 (Table 2).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:48][P:49]([C:54]1[CH:59]=[CH:58][C:57]([CH:60]([NH2:67])[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:56][CH:55]=1)(=[O:53])[O:50][CH2:51][CH3:52]>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:67][CH:60]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:57]2[CH:56]=[CH:55][C:54]([P:49]([CH3:48])(=[O:53])[O:50][CH2:51][CH3:52])=[CH:59][CH:58]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: CCOP(C)(=O)c1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h (325.5 mg, 1.5 mmol) in MeCN (10 ml) were added HATU (599 mg, 1.51 mmol), Et3N (159 mg, 1.51 mmol) and ethyl methyl(4-(amino(phenyl)methyl)phenyl)phosphinate (2-d′, 433 mg, 1.5 mmol). The resulting mixture was stirred at room temperature for 2 hour. Then it was concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with saturated NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC to provide the product, 2-4, (159 mg, 22%). 1H NMR (CD3OD, 300 MHz,): δ 8.67 (m, 2H), 8.39 (m, 2H), 7.94 (m, 1H), 7.46 (m, 5H), 7.26 (m, 5H), 6.29 (s, 1H), 3.76 (m, 2H), 1.57 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CCCCCCOc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCCCCCCOc2ccccc2)cc1
Yield: 94.8 %

Procedure:
To a stirred solution of 7.1 (1.19 g, 4.03 mmol) in AcOEt (40 mL) at room temperature was added 10% Pd/C (0.18 g, 15% w/w) and the resulting suspension was hydrogenated (30 psi, 6 h). The catalyst was removed by filtration through celite and the filtrate was evaporated under reduced pressure to give the title compound (8.1) (1.14 g, 95% yield) as a white solid (m p 32-34° C.).
Reaction SMILES: [NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[N:15]=[C:14]([C:24](OCC)=[O:25])[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[C:11]([C:10](=[O:30])[CH:9]=1)=[CH:12][C:13]([F:29])=[C:14]([CH2:24][OH:25])[N:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(CO)c(F)cc12
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
To a 0° C. suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (100.0 mg, 0.25 mmol) in THF (2.5 mL) was added LAH (0.750 mmol, 1M in THF) dropwise over 10 min. After 5 min. the reaction was slowly quenched with EtOAc (10 mL), was left to stir for 15 min and was concentrated in vacuo. The resiude was taken up in CH2Cl2 (10 mL) and 1N HCl (5 mL) and was left to stir for 30 min. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Trituation with Et2O provided 2-anilino-6-fluoro-7-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (55.2 mg, 61%) as a tan solid: LCMS RT: 2.01 min, MH+: 362.3.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:10]([O-])([OH:12])=[O:11].Cl>C(OC(=O)C)(=O)C>[CH3:9][C:7]1[CH:8]=[C:2]([CH3:1])[C:3]([NH2:4])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(N)c(C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
2,4-Dimethylaniline (8.0 g, 66.0 mmol) was dissolved in acetic anhydride (50 mL), and nitric acid (5 mL) was slowly added in drops thereto at 0° C. After stirring for 30 min, the mixture was diluted with ice water (200 mL). Conc. hydrochloric acid (10 mL) was added in drops thereto, and the resulting mixture was stirred under reflux for 4 h. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The residue was diluted with aqueous ammonium hydroxide solution. The resulting orange solid was filtered and dried to give the title compound (10.6 g, Yield 97%).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]2[C@H:15]([CH2:16][CH2:17]O)[O:14][CH2:13][CH2:12][C:11]=2[CH:19]=1.CS(Cl)(=O)=O.CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O.S([O-])(=O)(=O)C.[CH2:51]1[C:61]2=[C:62]3[C:57](=[CH:58][CH:59]=[CH:60]2)[C:56]([N:63]2[CH2:68][CH2:67][NH:66][C@H:65]([CH3:69])[CH2:64]2)=[CH:55][CH:54]=[C:53]3[CH2:52]1>>[CH2:51]1[C:61]2=[C:62]3[C:57](=[CH:58][CH:59]=[CH:60]2)[C:56]([N:63]2[CH2:68][CH2:67][N:66]([CH2:17][CH2:16][C@H:15]4[C:10]5[CH:9]=[CH:8][C:7]([N:3]6[CH2:4][CH2:5][CH2:6][S:2]6(=[O:20])=[O:1])=[CH:19][C:11]=5[CH2:12][CH2:13][O:14]4)[C@H:65]([CH3:69])[CH2:64]2)=[CH:55][CH:54]=[C:53]3[CH2:52]1
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1
Reactant: O=S1(=O)CCCN1c1ccc2c(c1)CCO[C@H]2CCO
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: CS(=O)(=O)[O-]
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CC3)CCN1CC[C@@H]1OCCc2cc(N3CCCS3(=O)=O)ccc21

Procedure:
2-[(1S)-6-(1,1-Dioxido-2-isothiazolidinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethanol was reacted with methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate. The resultant crude mesylate was then condensed with (3R)-1-(1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine, as described for Example 1b), to yield the title compound. M+H=532.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[N:9]([CH3:10])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1.C(OC(=O)C)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[ClH:24].[CH3:1][O:2][CH2:3][C@H:4]1[CH2:5][NH:6][CH2:7][CH2:8][N:9]1[CH3:10]
Reactant: COC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC[C@H]1CNCCN1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl (3R)-3-(methoxymethyl)-4-methylpiperazine-1-carboxylate (220 mg) and ethyl acetate (2.33 mL) was added a 4 M hydrogen chloride ethyl acetate solution (2.19 mL), followed by stirring at room temperature overnight. The reactant was concentrated under reduced pressure to obtain (2R)-2-(methoxymethyl)-1-methylpiperazine dihydrochloride (218 mg) as a white solid.
Reaction SMILES: CC1[O:3][CH2:4][C:5]([CH3:16])([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.[OH-].[K+].O>C(O)C>[NH2:6][C:5]([CH3:16])([CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][OH:3]
Reactant: CC1=NC(C)(COCc2ccccc2)CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(N)(CO)COCc1ccccc1

Procedure:
2,4-Dimethyl-4-benzyloxymethyloxazoline (80 grams, prepared by a similar method to that described in Example 1) and potassium hydroxide (100 grams) in aqueous ethanol were heated together under reflux for 4 days. The volume of the reaction mixture was reduced under reduced pressure and water (300 milliliters) was then added. The aqueous mixture was extracted with ether (3 × 250 milliliters) and the extracts dried and the solvent removed under reduced pressure. The residue was distilled under reduced pressure to give 2-amino-3-benzyloxy-2-methylpropanol as a colorless liquid, boiling point 128°-129°C at 1.1 Torr.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)#[N:6].[CH3:17]O>>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]#[N:6])=[CH:12][CH:11]=1
Reactant: CO
Reactant: N#Cc1ccc(CC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.1 mL, 15.07 mmol) was added to cool MeOH (70 mL) at 0° C. After 5 min 2-(4-cyanophenyl)acetic acid (1 g, 6.21 mmol) was added. After 30 min, cooling was removed and the mixture stirred for 21 h at RT. The solvent was removed and toluene was added and evaporated 3 times to give a sticky yellow solid. The product was used crude for the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:10])[C:7]=1[NH:8][CH3:9].[Cl:11][CH2:12][C:13](O)=O.[OH-].[Na+].[ClH:18]>>[Cl:18][C:2]1[C:7]2[N:8]([CH3:9])[C:13]([CH2:12][Cl:11])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCl
Reactant: Cl
Reactant: CNc1c(N)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCl)nc2cccc(Cl)c21
Temperature: 90 °C
Yield: 40 %

Procedure:
6-Chloro-N1-methylbenzene-1,2-diamine (800 mg, 5 mmol) and 2-chloroacetic acid (700 mg, 8 mmol) were dissolved in HCl 2N (5.7 mL). The resulting solution was heated at 90° C. for 18 h. The aqueous layer was neutralized by 3N NaOH. After extraction with EtOAc (3*10 mL), the organic layer was washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt:70/30 as eluent) to afford 478 mg of 7-chloro-2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (Yield: 40%) as a pink solid
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylate (1.017 g) in MeOH (3 mL) and dioxane (3 mL) was added 1N NaOH aq solution (5.8 mL), and the mixture was stirred at ambient temperature for 2 hours. To the mixture was added 1N NaOH aq solution (5-8 mL) and heated at 50° C. for 2 hours. The pH value of the mixture was adjusted to 7 with 1N HCl, and the solvent was removed in vacuo. Obtained solid was suspended in toluene and the residual water was geotropically removed to give (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid and the crude product was used in next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C:5](=[O:18])[C:6]#[C:7][C:8]([CH3:17])([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:9])[CH3:2].C1(C2C[S:31][C:30](=[S:33])[S:29]2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C:5]([C:6]1[S:31][C:30](=[S:29])[S:33][C:7]=1[C:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([CH3:17])[CH3:9])=[O:18])[CH3:2]
Reactant: CCOC(OCC)C(=O)C#CC(C)(C)OC1CCCCO1
Reactant: S=C1SCC(c2ccccc2)S1
Solvent: ClCCl
Product: CCOC(OCC)C(=O)c1sc(=S)sc1C(C)(C)OC1CCCCO1
Temperature: 130 °C

Procedure:
A mixture of 1,1-diethoxy-5-methyl-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-yn-2-one 3 (1.5 g, 5.0 mmol) and 4-phenyl-1,3-dithiolane-thione (5.3 g, 25.0 mmol) was heated under N2 at 130° C. for 1 hour. The reaction was monitored by thin layer chromatography using silica gel as the stationary phase and dichloromethane as the mobile phase. The color of the reaction mixture changed from yellow to dark orange. After completion of the reaction, as evidenced by TLC, the reaction was stopped, cooled, and the target compound 4 was purified by radial chromatography using silica gel as the stationary phase. The target compound 4 eluted as the third fraction with a mixture of dichloromethane and hexanes (60:40). The first band was the excess 4-phenyl-1,3-dithiolane-thione, and the second band yielded 2,2-diethoxy-1-(5-(2-(tetrahydro-2H-pyran-2-yloxy)propan-2-yl)-2-thioxo-1,3-dithiol-4-yl)ethanone 5 which was further converted to 4-(diethoxymethyl)-4-hydroxy-6,6-dimethyl-4,6-dihydro-[1,3]dithiolo[4,5-c]furan-2-thione 4.
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH:4]([OH:6])[CH:3]=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.N1C=CC=CC=1.O1CCCC1>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:6][C@@H:4]1[CH2:5][C@H:1]([OH:7])[CH:2]=[CH:3]1
Reactant: OC1C=CC(O)C1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a solution of 5.0 g of 2-cyclopentene-1,4-diol in 300 ml of methylene chloride was added 5 ml of a solution of p-toluenesulfonic acid in tetrahydrofuran (1 millimole/100 ml). A solution of 4.2 g of 2,3-dihydropyran in 30 ml of methylene chloride was then added dropwise with stirring over a period of 1 hour. After stirring overnight at room temperature, 8 drops of pyridine were added. The methylene chloride was evaporated and the residue was dissolved in diethyl ether, washed with water and dried. The residual obtained by evaporating the solvent was chromatographed on silica gel (200 g) using chloroform as an eluent. First, the diether product flowed out. The subsequent effluent was treated in a customary manner to afford 6.6 g of cis-4-tetrahydropyranyloxy 2-cyclopentenol as colorless oily substance boiling at 84° C. (0.7 mmHg).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]1[CH2:8][N:7]([C@@H](C2C=CC=CC=2)C)[C:6](=[O:17])[CH2:5]1)[CH3:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:1][C@H:2]([C@H:4]1[CH2:8][NH:7][C:6](=[O:17])[CH2:5]1)[CH3:3]
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)[C@H]1CNC(=O)C1
Reaction time: 1.5 h

Procedure:
A solution of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one (500 mg, 2.1 mmol) in TFA (3.6 mL) was heated to 150° C. in a microwave reactor. After 90 min, the resulting mixture was diluted with DCM and concentrated in vacuo. The resulting residue was dissolved in DCM (15 mL) and water (20 mL). The phases were separated, and the organic phase was extracted with water (4×20 mL). The combined aqueous phase was concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (10% to 30% MeOH in DCM) to afford (R)-4-((S)-1-hydroxyethyl)pyrrolidin-2-one 1.18.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[C:6]=2[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1.[C:28]1(B(O)O)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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>[OH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:6]3[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=[C:2]([C:36]4[C:37]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:33]=[CH:34][CH:35]=4)[C:7]=3[N:8]=[C:9]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc(Cl)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2cccc3ccccc23)c2nc(N3CCOCC3)nc(-c3cccc(O)c3)c2n1

Procedure:
A mixture of Example 9 (145 mg; 0.37 mmol), 1-naphthylboronic acid (142 mg; 0.82 mmol), cesium carbonate (489 mg; 1.50 mmol) and Pd(PPh3)4 (87 mg; 0.07 mmol) in DMF (4 mL) was stirred at 150° C. for one hour (microwave heating) then concentrated in vacuo. The residue was partitioned between EA and aq. citric acid and the two phases separated. The aqueous layer was dried over magnesium sulfate and concentrated in vacuo. Precipitation from EA/Et2O afforded the title compound as a yellow solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)#[CH:12].N>>[F:20][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: C#Cc1ccc(F)c(F)c1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: Fc1ccc(-c2cc(-c3cnccn3)no2)cc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 4-ethynyl-1,2-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.38-7.54 (m, 2H), 7.74-7.84 (m, 1H), 7.90 (ddd, J=11.1, 7.5, 2.0 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.4, 1.6 Hz, 1H), 9.29 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=O)=[CH:10][CH:9]=1>C1(OC)C=CC=CC=1>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S+:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)O
Reactant: COc1ccc(S(=O)c2ccc(OC)cc2)cc1
Solvent: COc1ccccc1
Product: COc1ccc([S+](c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Product: CS(=O)(=O)[O-]
Temperature: 80 °C
Yield: 227.1 %

Procedure:
A mixture of 192.22 g of methane sulfonic acid, 54.46 g of bis-(4-methoxyphenyl)sulfoxide and 500 ml of anisole was heated at 80° C. for 22 hours. The mixture was poured into 1000 g of ice water and extracted three times with 500-ml portions of ether. The aqueous phase was neutralized with 50 percent aqueous sodium hydroxide and extracted five times with 500-ml portions of chloroform. The combined chloroform phases were dried with magnesium sulfate and the chloroform was removed on a rotary evaporator to give 105.76 g of tris-(4-methoxyphenyl)sulfonium methane sulfonate with residual chloroform of solvation.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])C.[CH3:27][C:28]1([CH3:38])[O:33][CH2:32][C:31]([CH3:37])(C(O)=O)[CH2:30][O:29]1>>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH2:12][C:9]2([C:28]([O:29][CH2:30][CH3:31])=[O:33])[CH2:10][CH2:11][N:6]([C:4]([C:31]3([CH3:37])[CH2:30][O:29][C:28]([CH3:27])([CH3:38])[O:33][CH2:32]3)=[O:5])[CH2:7][CH2:8]2)(=[O:14])=[O:15])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2CCN(C(=O)OCC)CC2)cc1
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Yield: 131.8 %

Procedure:
Ethyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5-trimethyl-1,3-dioxan 5-yl)carbonyl]-4-piperidinecarboxylate was prepared according to the general method as outlined in Example 30 (step 8). Starting from 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]piperidinecarboxylic acid ethyl ester (0.333 g, 0.8 mmol) and 2,2,5-trimethyl-(1,3)dioxane-5-carboxylic acid (0.168 g, 0.96 mmol), 0.339 g (79%) of the desired product was isolated as a white solid. Electrospray Mass Spec: 536.1 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: c1cscn1
Reactant: COC(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C., stirred solution of thiazole (270 μL, 3.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (2.6 mL of a 1.6 M solution in hexanes, 4.2 mmol). After 30 min, zinc chloride (11.4 mL of a 1.0 M solution in diethyl ether, 11.4 mmol) is added. The reaction mixture is warmed to 0° C. and methyl 4-iodobenzoate (1 g, 3.8 mmol) and palladium(0)tetrakis(triphenylphosphine) (530 mg, 0.4 mmol) are added. The reaction mixture is heated at 70° C. for 20 h under argon, cooled to room temperature, and then partitioned between ethyl acetate and water. The organic layer is washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) yields the title compound. 1H NMR (300 MHz, CDCl3) δ 8.14-8.03 (m, 4H), 7.93-7.92 (m, 1H), 7.42-7.41 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc(OCCCN2CCCCC2)nc1
Solvent: CO
Product: Nc1cnc(OCCCN2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
5-nitro-2-(3-piperidin-1-yl-propoxy)pyrimidine (100 mg, 0.38 mmol) was dissolved in a mixed solvent of methanol (2 mL) and distilled water (2 mL), sodium dithionite (Na2S2O4) (655 mg) was added, and the mixture stirred for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, methanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated, and the target compound (60 mg, 68%) was obtained as a yellow oily residue.