Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][N:8]=2)[C:4](=[O:21])[CH2:3]1.[C:23]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:23][N:6]1[C:2]([CH3:22])([CH3:1])[CH2:3][C:4](=[O:21])[N:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][N:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)cn2)N1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1N(c2ccc(C#Cc3ccccc3)cn2)C(=O)CC1(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
(35 mg, 120 μmol) 5,5-Dimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (Example 1, step 4) was dissolved in ACN (2 ml). K2CO3 (33 mg, 240 μmol, 2 equiv.) and iodomethane (22 mg, 156 μmol, 1.3 equiv.) were added and the mixture was stirred for 16 hours at 80° C. The reaction mixture was evaporated and extracted with water and two times with ethyl acetate. The organic layers were extracted with brine, dried with sodium sulfate and evaporated to dryness. The crude product was purified by reverse phase column chromatography. The desired 1,5,5-trimethyl-2-(5-phenylethynyl-pyridin-2-yl)-pyrazolidin-3-one (18 mg, 49% yield) was obtained as a colorless oil, MS: m/e=306.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](=[O:31])[CH:18]([CH:20]([C:26]([O:28]CC)=[O:27])[C:21]([O:23]CC)=[O:22])[CH3:19])=[CH:16][C:11]=2[O:10]C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([NH:8][C:12]1[CH:13]=[CH:14][C:15]([C:17](=[O:31])[CH:18]([CH:20]([C:26]([OH:28])=[O:27])[C:21]([OH:23])=[O:22])[CH3:19])=[CH:16][C:11]=1[OH:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)c1ccc(NCc2ccccc2)c(O)c1)C(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 g (11.4 mmol) diethyl 2-[2-(3-benzyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-1-methyl-2-oxo-ethyl]-malonate are combined with 50 ml of ethanol, then 28 ml 1N sodium hydroxide solution are added and the mixture is stirred overnight at RT. The next day another 28 ml of 1N sodium hydroxide solution are added and the mixture is refluxed for 6 h. After cooling to RT 50 ml 1N hydrochloric acid are added and the mixture is extracted with DCM. The phases are separated using a phase transfer cartridge. The filtrate is evaporated down i. V.
Reaction SMILES: [CH2:1]([N:3]1C=CC(=O)C(OCC2C=CC=CC=2)=C1COC)C.[CH3:21][O:22][CH:23]([C:26]1O[C:28]([CH3:41])=[CH:29][C:30](=[O:40])[C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:24][CH3:25].CN>>[CH3:1][N:3]1[C:28]([CH3:41])=[CH:29][C:30](=[O:40])[C:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:26]1[CH:23]([O:22][CH3:21])[CH2:24][CH3:25]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Reactant: CCC(OC)c1oc(C)cc(=O)c1OCc1ccccc1
Agent: CN
Product: CCC(OC)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Yield: 37.6 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4( 1H)-one using 2-(1-methoxypropyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one 4.32 g (15 mmol, 1 eq.) and 3.49 g (45 mmol, 3 eq.) of 40% aqueous methylamine yielded the title compound (1.7 g, 37.6%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>C(Cl)Cl.O1CCOCC1>[N:11]1([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CCCN3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1nc2c(c(N3CCNCC3)n1)CCCN2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(5,6,7,8-Tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.88 g, 2.75 mmol) in DCM (10 mL) was added HCl in dioxane (4M, 5 mL). The mixture was stirred at RT for 4 hours. The solvent was removed to give 4-Piperazin-1-yl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine as HCl salt (0.80 g, 99%). MS (APCI+) [M+H]+220.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][CH2:11][NH2:12])=[CH:2]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH:12][CH2:11][CH2:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:19]
Reactant: NCCc1c[nH]c2ncccc12
Reactant: COc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)NCCc2c[nH]c3ncccc23)c1
Temperature: 25 °C

Procedure:
To a mixed solution of [2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]amine (580 mg) and 3-methoxybenzoic acid (658 mg) in tetrahydrofuran (5 mL) and N,N-dimethylformamide (3 mL), 1-hydroxy-7-azabenzotriazole (HOAt) (588 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride (826 mg) were added, followed by stirring at room temperature until materials disappear. To the reaction mixture, ice water and an aqueous saturated sodium hydrogen carbonate solution were sequentially added and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:8) to obtain the titled compound having the following physical properties (612 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[N:4]([CH2:9][C:10]([O:12]C)=[O:11])[N:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[N:4]([CH2:9][C:10]([OH:12])=[O:11])[N:3]=1
Reactant: COC(=O)Cn1nc(C)n(C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(CC(=O)O)c(=O)n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
593 mg of methyl (3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetate (Va-6) are dissolved in 5 ml of tetrahydrofuran, and 134 mg of lithium hydroxide in 2 ml of water are added. The mixture is stirred at room temperature for 16 hours, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. This gives 167 mg of (3,4-dimethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:21][CH:22]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH3:23]>O1CCCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:23])[CH3:21])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) in tetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide in tetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with ether, and the resulting solution was washed twice with water. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 10% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[CH:22]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:23]([F:26])([F:25])[F:24])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CCO>[Cl:1][C:2]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[CH:22]([C:27]2[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:23]([F:25])([F:26])[F:24])[CH:17]=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 80 °C
Yield: 100 %

Procedure:
To a stirred solution of (E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g, 7.6 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a gummy liquid (0.3 g), which was carried on to the next step without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH2:9][CH:10](Cl)[Cl:11].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:11][CH2:10][CH2:9][CH2:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCC(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: ClCCCOc1ccccc1

Procedure:
A two-phase mixture of phenol (5 g, 53 mmol), dichloropropane (32 ml), tetrabutylammonium hydrogen sulphate (0.3 g, 1 mmol), and sodium hydroxide solution (25 ml, 3M) was refluxed for 3 h. The organic layer was separated, dried (MgSO4), washed through a plug of silica with dichloromethane (200 ml), and concentrated in vacuo. The residues were distilled to give the title compound as a colourless, viscous oil (8.0 g, 88%) bp 110° C. at 0.1 mm Hg. NMR (CDCl3, 250 MHz) δ=2.26 (2H,q,J=6 Hz), 3.77 (2H,t,J=6 Hz), 4.13 (2H,t,J=6 Hz), 6.90-7.00 (3H,m), 7.26-7.34 (2H,m).
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:5][CH2:4][CH:3]([OH:6])[CH2:2][F:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)CF
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(O)CF)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-fluoropropane-1,2-diol (from Sigma, 0.750 g, 7.97 mmol) and triethylamine (1.39 mL, 9.96 mmol) in DCM (20 mL) was added p-toluenesulfonyl chloride (1.60 g, 8.37 mmol). The reaction was stirred at RT for 2 h. The mixture was concentrated to dryness and used in next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CS(O[CH:12]1[CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)[CH2:13]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:12]2[CH2:13][C:14]3([CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[CH2:15]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC(OS(C)(=O)=O)C2)C1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC2(CC(n3cc(Br)cn3)C2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (210 mg, 1.428 mmol, 1.2 equiv) and tert-butyl 2-(methylsulfonyloxy)-6-azaspiro[3.5]nonane-6-carboxylate (380 mg, 1.19 mmol, 1.0 equiv) in DMF (2.5 mL) was added Cs2CO3 (465 mg, 1.428 mmol, 1.2 equiv). The mixture was stirred at 80° C. for 3 hrs. It was concentrated by rotary evaporator to give the residue which was purified by CombiFlash (25 g silica gel column, EtOAc/Hex: 0-40%) to afford 110 mg (yield 25%) of tert-butyl 2-(4-bromo-1H-pyrazol-1-yl)-6-azaspiro[3.5]nonane-6-carboxylate (cis and trans isomers) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:2]=1>C(O)C.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([S:7]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)(=[O:8])=[O:9])[CH2:2]1
Reactant: O=S(=O)(c1cccnc1)N1CCOCC1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: O=S(=O)(C1CCCNC1)N1CCOCC1
Reaction time: 70 h
Yield: 22.2 %

Procedure:
4-(Pyridine-3-sulfonyl)-morpholine (25 mmol, 5.7 g) was shaken with platinum (IV) oxide (500 mg) in ethanol (50 mL) at 60° C. under hydrogen at 50 psi for 16 h. Reduction was incomplete so the catalyst was removed by filtration, the solvent evaporated under vacuum and the residue dissolved in a mixture of water (50 mL) and acetic acid (10 mL) with warming. Platinum (IV) oxide (1 g) was added and hydrogenation at 50 psi was continued for a further 70 h at 60° C. The catalyst was removed by filtration and the solvent was evaporated under vacuum to give an orange gum which was redissolved in water and the solution (pH 4-5) was extracted with dichloromethane (×3). The aqueous layer was evaporated to a small volume under vacuum, made strongly basic by the addition of 4 M sodium hydroxide solution, xylenes were added and the solvents were removed under vacuum. The residue was agitated with dichloromethane and anhydrous sodium sulfate, the solids removed by flitration through Celite® and the filtrate evaporated under vacuum to give 4-(piperidine-3-sulfonyl)-morpholine as a waxy orange solid (1.3 g, 22%).
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OC)=O.[CH2:17]([O:24][C:25]([NH:27][C@H:28]1[CH2:34][CH2:33][C@@H:32]2[CH2:35][C@H:29]1[CH:30](O)[N:31]2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([O:24][C:25]([NH:27][C@H:28]1[CH2:34][CH2:33][C@@H:32]([NH:31][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][C@H:29]1[CH:30]=[CH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CC(C)(C)OC(=O)N1C(O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred suspension of NaH (60% in mineral oil, 160 mg) in tetrahydrofuran (3 mL) on an ice bath was treated dropwise over 10 min with tert-butyl dimethylphosphonoacetate (0.796 mL). The mixture was stirred at rt for 15 min, then was cooled again on an ice bath and treated with a solution of (1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-hydroxy-6-aza-bicyclo[3.2.1]octane-6-carboxylate (432 mg) in tetrahydrofuran (3 mL). The mixture was stirred at rt for 3 h. The mixture was treated with saturated aqueous NH4Cl and diluted with ethyl acetate. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate to provide tert-butyl 3-((1S,2S,5R)-2-(benzyloxycarbonylamino)-5-(tert-butoxycarbonylamino)cyclohexyl)acrylate as a white glassy foam (308 mg). MS found: (M+H)+=475.5.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[CH2:12][CH2:11]1)=[O:9])(C)(C)C.Cl>O1CCOCC1>[Br:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][C:6]([OH:25])=[O:5])[CH2:11][CH2:12]1)=[O:24]
Reactant: CC(C)(C)OC(=O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1
Yield: 87.1 %

Procedure:
A solution of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid tert-butyl ester (400 mg, 0.97 mmol) in dioxane.HCl (4 mL) was stirred at 0° C. for 30 minutes. The reaction mixture was concentrated to afford 300 mg of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionic acid. LCMS: 356.02 (M+1)+, 96.9%, H1NMR: (DMSO-d6): δ 12.6 (s, 1H), 7.7 (d, 1H), 7.54-7.32 (m, 3H), 3.7-3.4 (m, 8H), 3.2-3.06 (m, 2H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[CH3:7][C:5]1[N:6]=[C:2]([C:11]#[C:10][CH2:9][CH2:8][N:12]2[N:13]=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=[N:16]2)[S:3][CH:4]=1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Cc1csc(Br)n1
Product: Cc1csc(C#CCCn2nc3ccccc3n2)n1
Yield: 26.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-4-methylthiazole (100 mg, 0.56 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example 109(D)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 40 mg (0.15 mmol, 27%) of 2-(4-(4-methylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a white solid (M.P.=78-80° C.).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:5][CH:6]=1.[Cu](C#N)[C:12]#[N:13].N>CN(C)C=O>[CH3:9][C:8]([CH3:10])=[CH:7][C:4]1[S:3][C:2]([C:12]#[N:13])=[CH:6][CH:5]=1
Reactant: N#C[Cu]C#N
Reactant: CC(C)=Cc1ccc(Br)s1
Agent: N
Solvent: CN(C)C=O
Product: CC(C)=Cc1ccc(C#N)s1
Reaction time: 2 h
Yield: 34 %

Procedure:
2-Bromo-5-(2-methylpropenyl)-thiophene described in Preparation Example 143 (60 mg, 0.27 mmol) was dissolved in N,N-dimethylformamide (1 mL), copper cyanide (62 mg, 0.69 mmol) was added at 160° C., and the solution was stirred for 2 hours. The reaction solution was cooled, then, concentrated aqueous ammonia (5 mL) was added, and the solution was extracted with diethyl ether (10 mL). The organic layer was washed, dried over anhydrous magnesium sulfate, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5), and the title compound (15 mg, 0.092 mmol, 34%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:17]([C:19]3[N:20]=[C:21]([CH3:31])[S:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:18])=[CH:7][C:6]=2[CH:32]=1.CC1C(S([O-])(=O)=O)=CC(OC)=[C:36]([N:46]=NC2C(O)=CC=C3C=2C=CC(S([O-])(=O)=O)=C3)C=1.[Na+].[Na+].[Cu]C#N>>[C:36]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:17]([C:19]3[N:20]=[C:21]([CH3:31])[S:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:18])=[CH:7][C:6]=2[CH:32]=1)#[N:46]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2cc3cc(Br)ccc3o2)c(-c2ccc(F)cc2)s1
Reactant: COc1cc(S(=O)(=O)[O-])c(C)cc1N=Nc1c(O)ccc2cc(S(=O)(=O)[O-])ccc12
Agent: N#C[Cu]
Agent: [Na+]
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3cc(C#N)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (19 mg) was prepared from (RS)-1-[2-(5-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E129 (420 mg) and copper(I) cyanide according to a procedure similar to that described for Example 67.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[CH:4][CH:3]=1.II.[CH3:17][OH:18]>>[CH3:17][O:18][C:8](=[O:12])[CH:7]([O:6][C:5]1[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][CH2:10][OH:9]
Reactant: O=C1OCCC1Oc1ccc(Cl)cc1
Reactant: CO
Agent: II
Product: COC(=O)C(CCO)Oc1ccc(Cl)cc1
Yield: 33 %

Procedure:
3-(4-chlorophenoxy)dihydrofuran-2(3H)-one, (Example 473a), 1.136 g), iodine (30.0 mg) and methanol (28.9 mL) were stirred at 65° C. for 24 hr. The reaction mixture was concentrated in vacuo. Exces of iodine was eliminante by adding an aqueous solution of sodium sulfite (10% w/w, 15 mL). The mixture was extracted with ethyl acetate. The organic layers were washed with brine (10 mL), dried over sodium sulfate and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (433 mg; 33%). MS (ESI): m/z=244 [M]+.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC([C@H]1[C@@H]2[C@@H]3[C@@](C)(CC[C@@]2(CO)CC1)[C@@]1(C)[C@@H]([C@]2(C)[C@@H](CC1)C(C)(C)[C@@H:49]([OH:62])[CH2:48]C2)CC3)=C>>[CH3:3][C:2]([CH:4]1[CH:8]2[CH:9]3[C:22]([CH3:25])([CH2:23][CH2:24][C:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C:21]1([CH3:26])[CH:12]([C:13]2([CH3:30])[CH:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[CH:16]([O:29][C:49]([CH3:48])=[O:62])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)C1CCC2(C(=O)O)CCC3(C)C(CCC4C5(C)CCC(OC(C)=O)C(C)(C)C5CCC43C)C12

Procedure:
The method of claim 12 wherein the overall yield of the α-isomer of betulinic acid from betulin is greater than 50%.
Reaction SMILES: O([CH2:9][C:10]1[CH:14]=[CH:13][O:12][C:11]=1[CH2:15][CH2:16]O)[Si](C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[CH2:32]([NH2:35])[CH:33]=[CH2:34]>ClCCl.C(OCC)(=O)C>[CH2:32]([N:35]1[CH2:16][CH2:15][C:11]2[O:12][CH:13]=[CH:14][C:10]=2[CH2:9]1)[CH:33]=[CH2:34]
Reactant: C=CCN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccoc1CCO
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCN1CCc2occc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude 2-(3-hydroxymethylfuran-2-yl)ethanol and 1.74 ml (9.96 mmol) of N,N-diisopropylethylamine in 50 ml of dichloromethane, 0.71 ml (9.13 mmol) of methanesulfonyl chloride was added dropwise under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and then saturated sodium chloride. After which it was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 50 ml of ethanol, 0.36 g (6.22 mmol) of allylamine and 2.38 ml (13.7 mmol) of N,N-diisopropylethylamine were added, followed by overnight stirring at 80° C. The solvent was distilled off under reduced pressure from the reaction mixture; the resulting crude product was purified by silica gel column chromatog-raphy (hexane/ethyl acetate=9/1 to 6/1) to yield 5-allyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32]Cl)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[CH2:34]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37]>>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[C:8]([CH2:32][N:38]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C(CCl)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)CC1=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1

Procedure:
A mixture of 10 parts of 3β-acetoxy-6-(chloromethyl)cholest-5-ene and 8 parts of dibutylamine is heated at 90°-95° for 3 hours, whereupon excess amine is removed by vacuum distillation and the residue is extracted with hexane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation, affording 3β-acetoxy-6-(dibutylaminomethyl)cholest-5-ene as the residue.