Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([CH2:18]OS(C)(=O)=O)[O:15][N:14]=2)=[CH:9][CH:8]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([SH:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CCOCC>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([S:37][CH2:18][C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:9]=[CH:8][N:7]=[CH:12][CH:11]=3)[N:17]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: CS(=O)(=O)OCc1nc(-c2ccncc2)no1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(SCc2nc(-c3ccncc3)no2)CC1
Reaction time: 1.67 h

Procedure:
t-BuOK (92 mg, 823 μmol) and methanesulfonic acid 3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl ester (Preparation 12, 150 mg, 588 μmol) were added to a stirred solution of 4-mercaptopiperidine-1-carboxylic acid tert-butyl ester (191 mg, 881 mol) in anhydrous THF (10 ml). After 100 min, the reaction mixture was diluted with Et2O, before being washed with NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, and concentrated, then the residue was purified by column chromatography (IH-EtOAc, 3:2) to afford the title compound: RT=3.77 min; m/z (ES+)=377.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.[NH2:21][OH:22].[OH-].[K+].CO>C1COCC1>[OH:22][NH:21][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: COC(=O)C=CC=CCSc1ccc2ccccc2c1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C=CC=CCSc1ccc2ccccc2c1)NO
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 6-(naphthalen-2-ylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.505 g, 1.78 mmol) in distilled THF (10 mL) containing 50% aqueous hydroxylamine (1.08 mL, 16.4 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 2.5 ml, 2.5 mmol) over a period of 30 minutes. After stirring the mixture at 0° C. for an additional hour, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The solution was extracted with ethyl acetate (2×50 mL), and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The solid residue was recrystallised from ethyl acetate to give the title compound (0.315 g, 62%) as a white solid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].[CH2:10]([O:28][C:29]1[O:33][CH:32]=[C:31]([C:34](Cl)=[O:35])[CH:30]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1C=CC=CC=1>[CH2:10]([O:28][C:29]1[O:33][CH:32]=[C:31]([C:34]([CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6])=[O:35])[CH:30]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)Cl)co1
Agent: [Na]
Solvent: c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)C(C(C)=O)C(=O)OC)co1

Procedure:
To a cooled mixture of 40.0 g (0.106 mole) of 5-(cis-9-octadecen-1-yloxy)-3-furoic acid in methylene chloride is added 30 ml of thionyl chloride. The mixture is stirred for 5 hours. Then the solvent and excess thionyl chloride is removed under reduced pressure affording the crude 5-(cis-9-octadecen-1-yloxy)-3-furoyl chloride. A mixture of 11.6 g (0.100 moles) of methyl acetoacetate and 2.3 g of sodium in 1 liter of benzene is refluxed for 20 hours, then cooled, and the crude 5-(cis-9-octadecen-1-yloxy)-3-furoyl chloride is added over a two hour period. The mixture is refluxed for 6 hours, cooled by the addition of ice and mixed well. The benzene layer is separated, washed with 5% sodium bicarbonate solution and dried. The benzene is distilled off under reduced pressure yielding 2-[5-(cis-9-octadecen-1-yloxy)-3-furoyl]acetoacetic acid, methyl ester. To a solution of 3.3 g of ammonium chloride in 15 ml of water at 40° C is added 10 g of the above ester maintaining the temperature at 40° C for 15 minutes followed by rapid cooling. The solution is extracted with ether, the extract dried, and evaporated to dryness affording 2-[5-(cis-9-octadecen-1-yloxy)-3-furoyl]acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)([Cl:15])=O.CN(C)C=O>ClCCCl>[Cl:15][C:9]1[C:4]2[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cnc(F)cc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Fc1cc2c(Cl)ncnc2cn1
Yield: 91 %

Procedure:
A stirred suspension of 30.0 g (182 mmol) of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one in 182 mL of 1,2-dichloroethane was treated successively with 182 mL of thionyl chloride, then ca. 1 mL of N,N-dimethyl-formamide. The mixture was heated at reflux for 2.5 hours, then concentrated to a solid that was coevaporated twice with 1,2-dichloroethane. The residual dark brown solids were dissolved in dichloromethane, and the solution was filtered through a short pad of silica gel eluting with dichloromethane. Concentration of product fractions afforded 30.5 g (91%) of pure product after drying. Crystallization of a small sample from tert-butyl methyl ether gave product of mp 75-76° C. 1H NMR (CDCl3): δ9.29 (s, 1H, 9.16 (s, 1H), and 7.65 (dd, J=0.7 Hz, 2.0 Hz, 1H).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C=O>O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:1][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C=CC(=O)N1c1ccc(O)cc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
In a reactor, 30.0 g (0.275 moles of p-aminophenol, 29.7 g (0.303 moles) of maleic anhydride, 39.0 g (0.275 moles) of phosphorus pentoxide and 100 g of dimethylformamide were charged and stirred at 15° C. for 2 hours. The reaction mixture was then gradually heated to 60° C., at which temperature the reaction was further continued for 2.5 hours. After cooling to room temperature, the resulting reaction mixture was admixed with water to precipitate N-(p-hydroxyphenyl)maleimide in the form of crystals. The crystals were separated by filtration, washed with water and then dried to obtain 25.1 g (0.133 moles) of N-(p-hydroxyphenyl)maleimide (yield 48.2%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[N:10]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:10]1([C:15]([N:2]2[CH2:3][CH:4]3[CH2:8][C:7](=[O:9])[CH2:6][CH:5]3[CH2:1]2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=C1CC2CNCC2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC2CN(C(=O)N3CCCC3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (478 mg, 2 mmol) was dissolved in 20 mL dichloromethane, and pyrrolidine-1-carbonyl chloride (0.276 mL, 2.5 mmol) and triethylamine (0.84 mL, 6 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, 10% citric acid solution was then added to the mixture to adjust to pH 4. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(pyrrolidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 8a (0.26 g, yield 58.5%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2.F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[CH2:8][CH2:7]2
Reactant: N#Cc1cccc(F)c1
Reactant: Clc1ccc2c(c1)CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cccc(N2CCc3cc(Cl)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A slurry of 2.64 g (0.11 mole, 1.1 equivalents) sodium hydride in 15.36 g (0.1 mole) 5-chloroindoline and 50 ml sieve dried DMSO was permitted to stir at room temperature under nitrogen for 2 hours. While cooling in an ice bath, a solution of 12.11 g (0.1 mole) 3-fluorobenzonitrile in 15 ml sieve dried DMSO was then added dropwise over 15 minutes. At the end of the addition, the ice bath was removed and the reaction mixture was permitted to warm to room temperature and stir overnight (20 hours). The product was poured onto ice and then extracted twice with CHCl3. The combined organic portions (400 ml) were washed four times with water (400 ml portions), 4 N HCl (three 300 ml portions) brine (300 ml), dried over Na2SO4, and concentrated to give 28.03 g (25.47 g theory) of a solid. Recrystallization from hot absolute ethanol containing 5-10% CHCl3 afforded 11.12 g (43.66% overall) of 3-(5-chloro-1-indolinyl)benzonitrile, m.p. 120°-121° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Sn]([N:29]=[N+:30]=[N-:31])(CCCC)CCCC)CCC>O1CCOCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:31][N:30]=[N:29][N:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.513 g of N-Boc 4-cyanopiperidine in 5 mL of dioxane was added 0.71 mL of tri-n-butyl tin azide. The reaction was heated at 100° C. for 4 days and was then evaporated to a viscous oil. The residue was taken up in 5 mL of ether and treated with 10 mL of 2N hydrochloric acid in ether. The reaction was stirred for 1 hour and then the precipitate was filtered, washed well with ether and dried to afford 0.54 g the title compound as a tan solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][CH:30]([C:27]4[CH:26]=[CH:25][C:24]([NH2:23])=[CH:29][CH:28]=4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: Nc1ccc(C2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 4-(4-aminophenyl)piperidine, hydrochloride, preparative HPLC (Method C) (30%, light yellow crystals). HPLC-MS m/z=458.2 (M+1), Rt: 3.42 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:32].[Na+].CC(=O)CC>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][I:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: BrCC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: ICC(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Yield: 91.2 %

Procedure:
First, 6 g of 2,2-bis(6-benzyloxyhexyl)ethyl bromide, 2.19 g of sodium iodide, and 150 ml of 2-butanone were placed in a 300 ml flask. The mixture was stirred under reflux for 16 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene) to obtain 6 g of 2,2-bis(6-benzyloxyhexyl)ethyl iodide (Y: 91.2%). The compound thus obtained had a purity of 95.3% by HPLC.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]([NH:36]C(=O)OC(C)(C)C)[CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]([NH2:36])[CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)NC1CCCCNC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCCCC(N)C5)n4)n[nH]c3cn2)cn1
Yield: 58.6 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl azepan-3-ylcarbamate were reacted. The product was deprotected to give 226 as a white solid (58.6% over two steps). 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 7.94 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.4 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 4.18 (d, J=12 Hz, 1H), 4.13-4.06 (m, 1H), 3.90 (s, 3H), 3.54 (m, 1H), 3.36 (d, J=8.8 Hz, 1H), 3.32 (s, 1H), 2.05-1.95 (m, 1H), 1.84-1.69 (m, 3H), 1.53-1.41 (m, 1H), 1.40-1.27 (m, 1H); 2 protons not seen. LC/MS: m/z 389.2 [M+1]
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=1>>[CH3:30][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:11][CH2:12][N:13]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH2:14][CH2:15]3)=[CH:8][CH:9]=2)=[O:3])=[CH:24][CH:23]=1
Reactant: CC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CCC(=O)c2ccc(N3CCN(c4ccncc4)CC3)cc2)cc1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 39, but using as starting material 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine in place of 1-(4-formylphenyl)-4-(4pyridyl)piperazine and 4-tolualdehyde in place of 4-methylacetophenone, was prepared 1-[4-(4-methylphenylpropionyl)-phenyl]-4-(4-pyridyl)piperazine (27% yield), m.p. 130-132° C.
Reaction SMILES: [BH4-].[Na+].CCO.[CH2:6]([O:8][C:9](=[O:35])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1/[CH:23]=[CH:24]/[C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:35])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C@@H:17]1/[CH:23]=[CH:24]/[CH:25]([OH:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH3:7]
Reactant: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Yield: 80.4 %

Procedure:
Sodium borohydride (10 mg, 0.26 mmol) followed by EtOH (0.25 mL) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo -piperidin-1-yl}-butoxy)-acetic acid ethyl ester (110 mg, 0.25 mmol) in CH2Cl2 (1.0 mL) at 0° C. After 1 h at 0° C. the reaction was quenched with 1 N aqueous HCl. The reaction mixture was extracted with CH2Cl2 (3×10 mL), then the combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2 →2% MeOH/CH2Cl2) afforded 88 mg (80%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][OH:33])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[CH3:34]I.[H-].[Na+]>CN(C=O)C.FC1C=CC=CC=1COC1C=CC([C@@H]2N(C(OC(C)(C)C)=O)[C@](CO)(C(OC)=O)CC2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][O:33][CH3:34])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: CI
Reactant: COC(=O)[C@]1(CO)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@]1(C(=O)OC)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 109.7 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate (D66, 480 mg, 1.04 mmol) and methyl iodide (130 μl, 2 mmol) in dry DMF (5 ml) at 0° C. was added sodium hydride (60 mg, 1.5 mmol, 60% dispersion in mineral oil) and the mixture was stirred for 1.5 h from 0° C. to r.t. A second batch of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate (D62, 46 mg, 0.1 mmol) was dissolved in dry DMF (0.5 ml) and methyl iodide was added. The mixture was cooled at 0° C. and sodium hydride (6 mg, 0.15 mmol, 60% dispersion in mineral oil) was added and the mixture was stirred for 1.5 h from 0° C. to r.t. The reactions were quenched with brine/ice and the two mixtures were combined and extracted with ethyl acetate. The organic layer was washed three times with ice cold brine, dried (Na2SO4) and evaporated to afford the title compound as a colourless oil (540 mg); Rt (HPLC): 6.89 min; MS: (ES/+) m/z: 496 [M+Na] C26H32FNO6 requires 473; 1H NMR (400 MHz, CDCl3) δ(ppm): 7.48-7.59 (m, 1H); 7.42-7.48 (m, 2H); 7.28-7.36 (m, 1H); 7.13-7.21 (m, 1H); 7.03-7.13 (m, 1H); 6.89-7.00 (m, 2H); 5.13 and 5.16 (s, s, 2H); 4.94-5.06 and 4.74-4.83 (m, m, 1H); 4.09-4.19 (m, 1H); 3.78-3.96 (m, 1H); 3.83 (s, 3H); 3.41 (s, 3H); 2.44-2.70 (m, 1H); 2.17-2.36 (m, 2H); 1.69-1.87 (m, 1H); 1.11 and 1.40 (s, s, 9H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][CH2:19][OH:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21]I.[H-].[Na+]>CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][CH2:19][O:20][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 42.1 %

Procedure:
1-Benzhydryl-3-(2-hydroxyethyl)azetidine (1.58 g, 5.91 mmol) was suspended in DMF (30 mL), and under a nitrogen stream, methyl iodide (0.37 mL, 5.91 mmol) and 60% sodium hydride (355 mg, 8.87 mmol) were added at 0° C. with stirring. The reaction mixture was stirred for two hours at the same temperature and then poured onto ice water, and the mixture was extracted with ethyl acetate. The combined extract was washed with ice water and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40M, ethyl acetate:n-hexane=5:95), to obtain the title compound (700 mg, 42%) as an oily matter.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=CC=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:6]=CC=CC=1.O=C(CC)CC#[N:30]>>[CH2:1]([C:7]1[CH:20]=[C:25]([NH2:30])[N:9]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:8]=1)[CH3:6]
Reactant: CCC(=O)CC#N
Reactant: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Product: CCc1cc(N)n(-c2ccc3ncccc3c2)n1
Yield: 85.3 %

Procedure:
Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and 3-oxo-pentanenitrile (1.3 g, 1.1 eq) were combined to yield 5-ethyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (2.5 g, 85% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.87 (dd, J=7.8, 1.8 Hz, 1H), 8.39 (dd, J=8.4, 1.5 Hz, 1H), 8.12 (s, 1H), 8.06-8.03 (m, 2H), 7.54 (dd, J=8.4, 1.2 Hz, 1H), 5.46 (br s, 2H), 5.40 (s, 1H), 2.49 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 239.2 (M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23][CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=3)[C:8]3[S:23][CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Reactant: Nc1ccc(CCO)cc1
Product: OCCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Yield: 87.5 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.120 g; 0.29 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.044 g, 0.32 mmol) to afford the title compound (0.101 g, 87%) as a white solid. MW=397.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.20-8.17 (m, 2H), 8.16-8.12 (m, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.51-7.46 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.63 (t, J=5.5 Hz, 1H), 3.65-3.59 (m, 2H), 3.20-3.16 (m, 2H), 2.90 (t, J=6.0 Hz, 2H), 2.73 (t, J=7.0 Hz, 2H), 2.22-2.15 (m, 2H); APCI MS m/z 398 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:23][CH:22]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(Br)cc4)cc3=O)ccc2nn1C
Reaction time: 17 h
Yield: 39.3 %

Procedure:
To a solution of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (150 mg) in tetrahydrofuran (3 ml) were added (4-bromophenyl)methanol (110 mg), bis(2-methoxyethyl)azodicarboxylate (179 mg) and triphenylphosphine (200 mg) at room temperature, and the mixture was stirred at the same temperature for 17 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (98 mg).