Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH3:5].O.[OH-].[Li+].Cl>CO.O>[OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[CH3:5]
Reactant: COC(=O)c1ccc(C(C)CCO)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CCO)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.8 %

Procedure:
To the solution of methyl 4-(4-hydroxybutan-2-yl)benzoate (354 mg, 1.7 mmol) in methanol (30 mL) and water (5 mL) was added lithium hydroxide hydrate (150 mg, 3.6 mmol) were added. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrochloric acid aqueous solution (1N) to adjust pH=6 and extracted with dichloromethane (10 mL×3). The organic layers were combined and concentrated to give 4-(4-hydroxybutan-2-yl)benzoic acid (290 mg, 88%).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[O:37][CH3:38])[C:5](=[O:27])[N:6]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19](C)[CH:18]=2)[C:7]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)#[N:2].[CH3:39][S:40]([O:43][CH2:44][CH2:45][CH2:46]OS(C)(=O)=O)(=[O:42])=[O:41].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:39][S:40]([O:43][CH2:44][CH2:45][CH2:46][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:7]2[N:6]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[C:5](=[O:27])[N:4]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[C:3]=2[C:1]#[N:2])=[CH:9]1)(=[O:42])=[O:41]
Reactant: COc1ccc(Cn2c(C#N)c(-c3c[nH]c4ccccc34)n(-c3cn(C)c4ccccc34)c2=O)c(OC)c1
Reactant: CS(=O)(=O)OCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(C#N)c(-c3cn(CCCOS(C)(=O)=O)c4ccccc34)n(-c3c[nH]c4ccccc34)c2=O)c(OC)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution 0.15 g (0.298 mmol) of the product from step b) in 2 ml of DMF was 0.40 g (1.72 mmol) of 1,3-propandiol bismethansulfonate and 0.50 g (3.62 mmol) of K2CO3. The mixture was stirred at 70° C. overnight and partitioned between EtOAc and water. The organic phase was washed with water and brine and finally evaporated. The residue was purified by chromatography on silica furnishing 0.11 g (59%) of the sub-title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH2:51][CH3:52])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C1COCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH2:51][CH3:52])[CH2:45][N:46]2[CH2:47][CH:48]([OH:50])[CH2:49]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CC[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
DIPEA (0.52 mL, 3.0 mmol) was added to a stirred suspension of 4-bromobenzoic acid (462 mg, 3.0 mmol) and TBTU (963 mg, 3.0 mmol) in THF (15 mL) at rt. After 10 min was (S)-1-(2-(methylamino)butyl)azetidin-3-ol (Compound M12) (475 mg, 3.0 mmol) added, followed by addition of DIPEA (0.52 mL, 3.0 mmol). The reaction was stirred at rt for 4 h. The mixture was concentrated under reduced pressure and the residue dissolved in DCM (60 mL). The organic phase was washed with NaHCO3 (aq., 60 mL). The aqueous layer was extracted with DCM (15 mL). The combined organic layers were washed with NaHCO3 (8% aq., 60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (577 mg, 56%). Mixture of rotamers: 1H NMR (500 MHz, DMSO-d6) δ 0.82, 1.43-1.54, 2.43, 2.54-2.62, 2.70-2.80, 3.39-3.51, 4.18, 4.88, 7.33, 7.63. Total number of protons: 20. There is one additional very broad proton signal between 4.2 and 3.1 ppm. HRMS (M+H)+: calculated 341.0865. found 341.0870.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.[CH:24]1([NH:30][C:31]2[C:36]([C:37]([O:39]CC)=O)=[CH:35][N:34]=[C:33]([NH:42][C:43]([NH:45][CH2:46][CH3:47])=[O:44])[CH:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[CH:50]=1>CN(C=O)C.O>[CH:24]1([NH:30][C:31]2[C:36]([C:37]([NH:48][C:49]3[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=3)=[O:39])=[CH:35][N:34]=[C:33]([NH:42][C:43]([NH:45][CH2:46][CH3:47])=[O:44])[CH:32]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCNC(=O)Nc1cc(NC2CCCCC2)c(C(=O)OCC)cn1
Reactant: Cc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1cc(NC2CCCCC2)c(C(=O)Nc2cccc(C)c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.8 %

Procedure:
EDCI.HCl (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 0.092 g, 0.480 mmol) and 1-hydroxybenzotriazole monohydrate (0.073 g, 0.480 mmol) were added to a stirred solution of ethyl 4-(cyclohexylamino)-6-(3-ethylureido)nicotinate iii (0.100 g, 0.320 mmol) in DMF (3 mL) at room temperature. After 15 min, m-toluidine (0.052 g, 0.480 mmol) was added and the reaction mixture stirred at room temperature for 24 h. The mixture was treated with water (5 mL) and the resulting colourless precipitate filtered, washed with water, air-dried and recrystallized from EtOH to afford Compound 3 (0.030 g, 0.076 mmol, 29%) as colourless microcrystals. 1H NMR (300 MHz, DMSO-d6): δ 10.00 (1H, s), 9.01 (1H, s), 8.44 (1H, s), 8.28 (1H, br), 8.10 (1H, d, J 9.0), 7.52 (1H, s), 7.42 (1H, d, J 9.0), 7.20 (1H, t, J 6.0), 6.90 (1H, d, J 6.0), 6.66 (1H, s), 3.25-3.13 (3H, m), 2.29 (3H, s), 1.94-1.91 (2H, m), 1.67-1.57 (3H, m), 1.42-1.23 (5H, m), 1.08 (3H, t, J 7.2); [M+H]+ m/z=396.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:6][CH:7]([CH2:28][CH:25]3[CH2:24][CH2:23][N:22]([CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:27][CH2:26]3)[C:8](=[O:14])[C:9]2=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2

Procedure:
As it was disclosed in Example 3 and 4 of JP-A 64-79151(1989), indanone derivative was produced by reacting 5,6-dimethoxy-1-indanone with 1-benzyl-4-formylpiperidine in the presence of strong base such as lithium diisopropylamide (Example 3), followed by reduction (Example 4) for example. According to this method, yield for Donepezil through Example 3 and 4 was 50.8% (62%×82%).
Reaction SMILES: [CH3:1][Li].Br[CH2:4][C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1>C(OCC)C.[Cu]I>[CH2:4]([C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH3:1]
Reactant: Cc1cc(F)cc(CBr)c1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: CCc1cc(C)cc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Methyllithium (40 ml, 64 mmol) was added dropwise at 0° C. to a slurry of copper(I)iodide (6.42 g, 33.6 mmol) in diethyl ether (20 ml). After being stirred at 0° C. for 30 minutes, the clear colorless homogeneous cuprate solution was cooled to −78° C. where 3-bromomethyl-1-fluoro-5-methylbenzene (5.15 g, 25.4 mmol) in 10 ml diethyl ether was added. The temperature was allowed to rise slowly. The reaction was quenched at −50° C. with NH4Cl/NH3-buffer (50 ml). Extraction with diethyl ether (3×50 ml), brine (1×100 ml). The organic layer was dried over MgSO4, filtered and the solvents were removed to yield 3.3 g (94%) of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:12]C1C=CC=C(C(OO)=O)C=1.C(Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[C:9]([OH:11])[N:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=c1[nH]ccc2cccnc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Oc1nccc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In accordance with Scheme 3, the compound of formula X, 1-oxy-7H-[1,7]naphthyridin-8-one can be prepared as follows: The compound of formula IX, 7H-[1,7]naphthyridin-8-one (which can be prepared from commercially available starting product in accordance with literature Chemical & Pharmaceutical Bullentin (1985), 33(2), 626-33) was stirred for about 70 hours at room temperature in chloroform with 3-chloroperbenzoic acid to obtain the compound of formula X. To a suspension of 1-oxy-7H-[1,7]naphthyridin-8-one in dry N,N-dimethylformamide was added drop wise oxalyl chloride at 0° C. After completed addition, the mixture was allowed to warm to room temperature and stirred for about 30 minutes to obtain the compound of formula XI, 2-chloro-[1,7]naphthyridin-8-ol. To a solution of 2-chloro-[1,7]naphthyridin-8-ol in pyridine was added trifluoromethanesulfonic anhydride at about −10° C. The reaction mixture was allowed to warm to room temperature and stirred for about 1 hour to obtain the compound of formula XII, trifluoro-methanesulfonic acid 2-chloro-[1,7]naphthyridin-8-yl ester. Furthermore, the compound of formula XII and a compound of formula R2NH2, for example 2-amnio-4-methylthiazole are dissolved in dry dioxane. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, cesium carbonate and tri(dibenzylideneacetone)dipalladium chloroform complex are added and the reaction mixture is stirred for about 20 hrs at about 130° C. to obtain a compound of formula XIII. The desired compound of formula I can be prepared as follows: To a compound of formula XIII in dry tetrahydrofuran were added tetrakis(triphenylphosphine)palladium and a about 1.0 M solution of diethylzinc in n-hexane. The reaction mixture was heated at reflux for about 1 hour to obtain a compound of formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:39](=[O:50])[CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47](Cl)=[O:48])[CH2:43][CH2:42]2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:47]([N:44]4[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)=[O:50])[CH2:46][CH2:45]4)=[O:48])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C(Cl)N1CCN(CC(=O)N2CCOCC2)CC1
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (90 mg, 0.24 mmol) (from Example 25a supra) in tetrahydrofuron (3 mL) was added triethyl amine (60 mg, 0.60 mmol) (Aldrich), followed by the addition of 4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl chloride (99 mg, 0.36 mmol) (from Example 48a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-{1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-piperidine-3-yl}-1,3-dihydro-indol-2-one as a white solid. (Yield 70 mg, 47.6%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: N#CCCCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: N#CCCCN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A mixture of 5 parts of 4-chlorobutanenitrile, 10 parts of (4-fluorophenyl)(4-piperidinyl)methanone, 10 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The reaction mixture was filtered and the filtrate was evaporated. The oily residue was crystallized from 2,2'-oxybispropane. The product was filtered off and recrystallized from 2,2'-oxybispropane, yielding 6.1 parts of 4-(4-fluorobenzoyl)-1-piperidinebutanenitrile; mp. 100° C. (5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][CH2:8][C:9]3([O:16]2)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:5][C:4]=1[NH2:19].CS([C:23]1[N:28]=[CH:27][C:26]2=[CH:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])[N:25]2[N:24]=1)=O>>[CH3:1][O:2][C:3]1[CH:18]=[C:17]2[C:6]([CH2:7][CH2:8][C:9]3([O:16]2)[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)=[CH:5][C:4]=1[NH:19][C:23]1[N:28]=[CH:27][C:26]2=[CH:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])[N:25]2[N:24]=1
Reactant: COc1cc2c(cc1N)CCC1(CCN(C)CC1)O2
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4OC)n3n1)CCC1(CCN(C)CC1)O2
Yield: 0.2 %

Procedure:
Following a procedure analogous to 251c, 7-methoxy-1′-methyl-3,4-dihydrospiro[chromene-2,4′-piperidin]-6-amine (0.15 g, 57 mmol) and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (55 mg, 19 mmol) were converted to the title compound (15 mgs, 13%) isolated as a TFA salt. H-NMR (DMSO-d6) δ 9.47 (broad s, 1H), 8.91 (s, 1H), 7.85-7.80 (m, 2H), 7.48-7.42 (m, 2H), 7.21 (d, J=9.2 Hz, 1H), 7.13-7.09 (m, 1H), 6.97-9.92 (m, 2H), 6.54 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.39-3.32 (m, 2H), 3.23-3.13 (m, 2H), 2.85 (s, 3H), 2.59-2.55 (m, 2H), 1.95-1.77 (m, 65H); LC/MS (ESI+): 486.18 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39]Cl>C(Cl)Cl>[CH3:22][O:21][C:9]1[C:8]([CH3:23])=[C:7]2[C:3]([C:4](=[O:24])[O:5][CH2:6]2)=[C:2]([O:1][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[C:10]=1[CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COCCOCCl
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1c(C/C=C(\C)CCC(=O)OC)c(OC)c(C)c2c1C(=O)OC2

Procedure:
To methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (61.0 g) in methylene chloride (1000 ml) at 0° C. was added diisopropylethylamine (30.4 g) and methoxyethoxymethyl chloride (29.2 g). After 31/2 hours the solution was washed with dilute hydrochloric acid, dried and evaporated to give methyl (E)-6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate as an oil.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C[C@H](N)c2ccccc2)CC1
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To a solution of 160 mg of ethyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}piperidine-4-carboxylate in 1.5 mL of dichloromethane was added 0.7 mL of trifluoroacetic acid, followed by stirring for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium carbonate solution and a chloroform-methanol mixed solution were added thereto in this order to carry out a layer separation operation. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 120 mg of ethyl 1-[(2R)-2-amino-2-phenylethyl]piperidine-4-carboxylate.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#N.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([Li])=[O:16]>>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)=[O:16]
Reactant: Cc1ccnc(C#N)c1
Reactant: [Li]C(=O)c1ccco1
Product: Cc1ccnc(C(=O)c2ccco2)c1

Procedure:
2-Cyano-4-methylpyridine is reacted in an inert atmosphere with an ethereal solution of freshly prepared 2-furoyl-lithium followed by acid hydrolysis to form 2-(2-furoyl)-4-methylpyridine which is then reacted with methyl iodide to form 2-(2-furoyl)-1,4-dimethylpyridinium iodide. Both furoyl compounds exhibit thermal and chemical analgesic properties.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[C@@H:4]2[CH2:16][C:15](=[O:17])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8].[BH4-].C[N+](C)(C)C.C(O)(=O)C>C(Cl)Cl>[OH:18][CH:3]1[C@@H:4]2[CH2:16][C:15](=[O:17])[N:5]2[C:6]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])=[C:2]1[CH3:1]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@H]2C1=O
Agent: C[N+](C)(C)C
Agent: [BH4-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C[C@H]2C1O
Reaction time: 0.5 h

Procedure:
Freshly prepared 2,2,2-trichloroethyl 2-methyloxocarbapen-2-em-3-carboxylate, made from 100 mg. (0.317 mmole) of the precursor oxide according to Example 11, was taken up in 2 ml. of methylene chloride and cooled to -78° C. Tetramethylammonium borohydride (23 mg., 0.079 mmole) was added. After 30 minutes, ir spectral analysis (1775 cm-1) indicated a satisfactory reduction. The reaction was quenched with acetic acid (0.58 equivalent, 10 microl.), extracted twice with aqueous buffer solution (pH 7), dried over anhydrous magnesium sulfate and filtered to yield a solution of 2,2,2-trichloroethyl 1-hydroxy-2-methylcarbapen-2-em-3-carboxylate. If desired, this product is further isolated by evaporation to dryness in vacuo at reduced temperature.
Reaction SMILES: [SH:1][C:2]1[N:3]=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.[CH3:22]I.[OH-].[Na+]>C(O)C>[CH3:22][S:1][C:2]1[N:3]=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[N:7]=1
Reactant: CI
Reactant: Fc1ccc(-c2nnc(S)nc2-c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1

Procedure:
3-Mercapto-5,6-bis(4-fluorophenyl)-1,2,4-triazine, 16.6 g. (0.05 mole), was reacted with 7 g. (0.05 mole) of methyl iodide in 75 ml. of ethanol containing 2 g. (0.05 mole) of sodium hydroxide by the method of Example 4(B). The yield was 13.2 g. of 3-methylthio-5,6-bis(4-fluorophenyl)-1,2,4-triazine, mp about 132°-135°C., after crystallization from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)cc1

Procedure:
A solution of 4-methoxyphenylacetic acid (2 g) and para-toluensulfonic acid (230 mg) in 30 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is suspended in a saturated aqueous solution of sodium hydrogencarbonate and extracted twice with ethyl acetate. The organic extracts are collected, washed with water and dried over sodium sulfate to give, after evaporation of the solvent under reduced pressure, 2.14 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3cc(Cl)ccc3nc2OC)CC1
Yield: 77 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 77%). 1H NMR (300 MHz, CDCl3): δ 3.10-3.17 (m, 4H), 3.80-3.89 (m, 6H), 4.08-4.15 (m, 4H), 6.88-7.07 (m, 4H), 7.20-7.32 (m, 1H), 7.41-7.44 (m, 1H), 7.50-7.68 (m, 1H), 7.82 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([NH2:12])[CH2:5]2.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[N:23]([CH2:27][CH2:28][CH2:29]Cl)[CH2:22][C@@H:21]1[CH3:31])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[N:23]([CH2:27][CH2:28][CH2:29][NH:12][CH:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[O:8][CH2:7]2)[CH2:22][C@@H:21]1[CH3:31])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: NC1COc2ccc(Br)cc2C1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCNC1COc2ccc(Br)cc2C1
Temperature: 150 °C
Yield: 99.1 %

Procedure:
A mixture of 6-bromo-chroman-3-ylamine (0.105 g, 0.46 mmol, 1 eq), (2S,5R)-4-(3-chloro-propyl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.133 g, 0.46 mmol, 1 eq), K2CO3 (0.127 g, 0.92 mmol, 2 eq), and Kl (0.017 g, 0.10 mmol, 0.2 eq) in DMF (0.5 mL) was heated in a microwave reactor at 150° C. for 25 min. The reaction mixture was partitioned between EtOAc (3 mL) and 10% aqueous NaHCO3 (3 mL). The organic layer was separated and aqueous layer was extracted with EtOAc (2 mL×3). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give 0.22 g (100%) of (2S,5R)-4-[3-(6-bromo-chroman-3-ylamino)-propyl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil. The material was carried on to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[CH3:20][C:21](CBr)=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][CH2:21][CH3:22])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.2 %

Procedure:
A mixture of the product from Example 232b (56 mg, 0.17 mmol), 2-methyl-3-bromo propene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmole) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (55 mg, 100%).