Azzindani/Open_Reaction_Data huggingface dataset:
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:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[O:1][N:2]=1
Reactant: C#Cc1cccnc1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: c1cncc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 3-ethynylpyridine (Aldrich, 0.52 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.77 (dd, J=7.9, 5.2 Hz, 1H), 7.92 (s, 1H), 8.55 (dt, J=7.9, 1.8 Hz, 2H), 8.76-8.98 (m, 3 H), 9.32 (d, J=1.2 Hz, 2H) ppm; MS (DCI/NH3) m/z 225 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][CH3:18])=[O:6].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:18][O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:5]([N:4]1[CH2:3][CH2:2][O:1][C:21]1([CH3:23])[CH3:22])=[O:6]
Reactant: COC(C)(C)OC
Reactant: COc1ccc2ccccc2c1C(=O)NCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ccccc2c1C(=O)N1CCOC1(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of Example 175A in anhydrous N,N-dimethyl formamide (10 mL) was added 2,2-dimethoxypropane (0.62 mL, 5.0 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol). The resulting mixture was stirred under a N2 atmosphere at 60° C. for 16 h. Additional 2,2-dimethoxypropane (0.3 mL, 2.4 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) were added, and the mixture was stirred at 60° C. for 6 h. The mixture was partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (3×50 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using a solvent gradient of 50-65% ethyl acetate in hexane. The title compound was obtained as a colorless, crystalline solid (0.44 g, 62% for two steps). 1H NMR (300 MHz, CDCl3) δ 1.83 (s, 3 H), 1.88 (s, 3 H), 3.13 (m, 1 H), 3.40 (m, 1 H), 3.92 (m, 2 H), 3.98 (s, 3 H), 7.28 (m, 1 H), 7.37 (m, 1 H), 7.49 (m, 1 H), 7.71 (m, 1 H), 7.80 (m, 1 H), 7.86 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH2:7]O.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH2:7][N:30]=[N+:31]=[N-:32]
Reactant: OCc1cc(Cl)ccc1OCC(F)(F)F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)-5-chlorobenzyl alcohol (1.9 g, 7.9 mmol) in THF (20 mL) at 0° C. was added diphenyl phosphoryl azide (2.2 mL, 10.2 mmol) followed by DBU (1.5 mL, 10.0 mmol). The reaction mixture was allowed to warm to room temperature overnight following which the solvent was removed under reduced pressure. The residue was partitioned between ether and water and the organic layer dried over sodium sulfate. Filtration, concentration and purification by flash chromatography (19:1 hexane/ether) gave the azide as a white solid: 1H NMR (CDCl3) δ7.31 (m, 2H), 6.82 (d, J=8.8 Hz, 1H), 4.40 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH:17](O)[C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH2:14]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1.C(N(S(F)(F)[F:36])CC)C>ClCCl>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH:17]([F:36])[C:16]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[CH:15][CH2:14]3)=[N:9][C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)C(O)C2)ncn1Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=c1nc(N2CC=C(c3ccc(F)cc3)C(F)C2)ncn1Cc1ccc(Cl)cc1
Yield: 42.2 %

Procedure:
To a dichloromethane solution (1.0 mL) of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (15 mg, 0.04 mmol) synthesized in Synthesis Example 90, (diethylamino)sulfur trifluoride (10 μL, 0.04 mmol) was added at 0° C. and the resultant mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, dichloromethane was added to the reaction solution and the resultant reaction solution was washed with saturated sodium bicarbonate water and brine. The resultant organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. To the resultant residue, silica gel was added and the mixture was filtered, followed by washing the mixture with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the title compound (7 mg, yield: 46%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:46][O:47][C:48]1[C:49]2[N:62]=[C:61]([NH2:63])[S:60][C:50]=2[C:51]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[N:52][CH:53]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:63][C:61]2[S:60][C:50]3[C:51]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[N:52][CH:53]=[C:48]([O:47][CH3:46])[C:49]=3[N:62]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COCCOc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1

Procedure:
From 4-(2-methoxy-ethoxy)-benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 445 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:18])=[C:11]([F:10])[CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)c(F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1ccc(Nc2nc(Cl)ncc2F)cc1F

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoroaniline gave 2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.10 (d, 1H, J=2.1 Hz), 7.72 (m, 1H), 7.22 (m, 2H), 6.95 (bs, 1H); LCMS: purity: 93%; MS (m/e): 260 (M+).
Reaction SMILES: [OH-].[Na+].CC(O)C.[CH:7]1([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>C(OCC)(=O)C>[CH:7]1([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(OC2CCCCC2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(OC2CCCCC2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
10% Sodium hydroxide aqueous solution 0.25 mL was added to a suspension of 2-propanol 2.0 mL of methyl 4-(cyclohexyloxy)-2-(4-fluoroanilino)benzoate 40 mg at room temperature, and it was heated and refluxed for 5 hours. After the reaction mixture was cooled to room temperature,1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and solid matter was filtrated to give 4-(cyclohexyloxy)-2-(4-fluoroanilino)benzoic acid 8 mg of white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16]O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[Br:38][CH2:16][C@H:13]1[CH2:14][CH2:15][C@H:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][CH2:12]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CBr)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5.00 g (20.55 mM) of trans-4-[N-(tert-butoxycarbonyl)aminomethyl]cyclohexane-1-methanol and 6.42 g (24.48 mM) of triphenylphosphine in methylene chloride (30 ml) was added 13.63 g (41.1 mM) of carbon tetrabromide at 0° C. and the mixture was stirred at room temperature for 20 hours. This reaction mixture was purified by column chromatography (ethyl acetate-hexane: 10%) to provide the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].[C-]#N.[Na+].CI>CO>[Br:1][C:2]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#CSc1ccc(N)c(Br)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1ccc(N)c(Br)c1

Procedure:
A solution of 2-bromo-4-thiocyanoaniline (11.5 g., 0.05 mole) and sodium cyanide (1.23 g., 0.025 mole) in methanol (100 ml.) is stirred at room temperature overnight. Sodium cyanide (0.025 mole) is then added and the reaction heated at reflux 2 hours and then cooled (0°-5° C.). Methyl iodide is added and stirring continued. Thin layer chromatography shows one product spot. Product is recovered by extraction with methylene chloride, 8.4 g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>C1COCC1>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ClCCCCCCOCc1ccccc1
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirred solution of 6-chloro-1-hexanol (15.0 g, 0.110 mol) and benzyl bromide (18.8 g, 0.110 mol) in dry THF (200 ml) at room temperature under argon was slowly added (over 30 min.) sodium hydride powder (2.899 g, 0.121 mol). The solution was left overnight and the solids filtered off. The solvent was removed under reduced pressure, the residues taken up into dichloromethane (100 ml) and washed (2×20 ml water). The solution was dried over MgSO4 and the solvent removed to yield an orange oil which was subsequently distilled (160° C., 0.5 mBar) to yield the title compound (17.5 g, 70%) as a colourless oil. C13H19OCl requires 226. Found DCl: MNH4+, 244. δH (CDCl3) 1.49 (4H, m, (CH2)2(CH2)2Cl), 1.70 (2H, p, CH2CH2O), 1.83 (2H, t, CH2CH2Cl), 3.54, 3.56 (4H, 2×t, CH2CH2O, CH2Cl), 4.56 (2H, s, CH2Ph), 7.40 (5H, m, Ph). δC (CDCl3) 25.3 (1C, CH2(CH2)2Cl), 26.4 (1C, CH2(CH2)3Cl), 29.3 (1C, CH2(CH2)2O), 32.3 (1C, CH2CH2Cl), 44.8 (1C, CH2Cl), 69.9, 72.6 (2C, CH2O), 127.2 (1C, CH(CH2)2C), 127.3 (2C, CHC), 128.1 (2C, CHCHC), 138.4 (1C, CCH2O).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[C:37]([F:38])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[F:27][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:26])[N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=1)[C:4]([C@@H:2]([NH:1][C:29]1[C:30]3[C:37]([F:38])=[CH:36][NH:35][C:31]=3[N:32]=[CH:33][N:34]=1)[CH3:3])=[N:5]2
Reactant: Fc1c[nH]c2ncnc(Cl)c12
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]cc(F)c12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (76 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.4 mL) at 23° C. was added 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (38 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 43 mg of the title compound (42% yield).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[N:9]1[C:15](=[O:30])[C@@H:16]([C@@H:21]([C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[OH:22])[CH2:17][CH2:18][C:19]#[CH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])(=O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[N:9]1[C:15](=[O:30])[C@@H:16]([C@H:21]([O:22][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:17][CH2:18][C:19]#[CH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a stirred solution of 29.7 g (71.9 mmol) of (4S)-4-benzyl-3-{(2R)-2-[(S)-(6-chloropyridin-3-yl)(hydroxy)methyl]hex-5-ynoyl}-1,3-oxazinan-2-one from Step B and 15.0 mL (126 mmol) of 2,6-lutidine in 300 mL of anhydrous dichloromethane at 0° C. under an atmosphere of nitrogen was added 22 mL (94 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate at a rate slow enough to keep the internal temperature below 3° C. The reaction mixture was stirred for 16 h at 0° C. then evaporated in vacuo to remove all volatiles. The residue was diluted with 400 mL of water and extracted with diethyl ether (3×300 mL). The combined organics were washed sequentially with a 0.5 M aqueous hydrochloric acid solution (100 mL), water (100 mL) brine (100 mL) then dried over magnesium sulfate. After filtration and evaporation in vacuo the residue was purified by silica gel chromatography eluting with a 5-8% ethyl acetate in hexanes gradient to afford the title compound as a colorless foam (37 g, 97%). LC-MS: m/z (ES) 527.3 (MH)+.
Reaction SMILES: [O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:9])[NH2:8])[CH3:6])[OH:3].[NH:10]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17].C(O)C>C(OCC)(=O)C>[NH:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=[O:17].[O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:8])[NH2:9])[CH3:6])[OH:3]
Reactant: O=C1CCC(C(=O)O)N1
Agent: CN(CC(=O)O)C(=N)N
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CC[C@@H](C(=O)O)N1

Procedure:
According to a preferred embodiment, the aforementioned salt can be prepared by reacting creatine with an equimolar amount of D,L-pyroglutamic acid in ethyl acetate (or in a mixture of equal parts ethyl acetate and ethanol) until complete formation of the salt. The solution can be optionally concentrated and, upon cooling, the crystallized salts are filtered and washed with ethyl acetate (or a mixture of ethyl acetate and ethanol). Alternatively, the procedure can be carried on by reacting excess D,L-pyroglutamic acid with creatine in ethyl acetate (or a mixture of ethyl acetate and ethanol).
Reaction SMILES: Cl.[F:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[C:8]([NH:15][CH2:16][C:17](O)=[O:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(N(CC)CC)C>[F:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:17](=[O:18])[CH2:16][NH:15][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: F[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CC[C@H](F)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
(S)-3-Fluoropyrrolidine hydrochloride (535 mg), N-Boc glycine (746 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.41 g), 1-hydroxybenzotriazole (993 mg), and triethylamine (1.19 mL) were dissolved in tetrahydrofuran (5 mL), and the solution was stirred at 70° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and aqueous saturated sodium bicarbonate (20 mL) was added to the residue, followed by extraction with ethyl acetate (10 mL). The organic layer was washed sequentially with 0.1N HCl (10 mL) and saturated brine (10 mL) and dried over sodium sulfate, followed by concentration under reduced pressure, to thereby yield compound 20a (98.1 mg, yield: 9.3%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:10][CH2:11][CH2:12][C:13]1([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:17]CCO1.[CH3:24][CH:25]1[CH:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][CH:28]([CH3:38])[CH2:27][NH:26]1>CN(C)C=O>[CH:18]1([C:13](=[O:17])[CH2:12][CH2:11][CH2:10][N:26]2[CH2:27][CH:28]([CH3:38])[CH2:29][CH:30]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[CH:25]2[CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: ClCCCC1(C2CCCCC2)OCCO1
Reactant: CC1CNC(C)C(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC(c2ccc(O)cc2)C(C)N(CCCC(=O)C2CCCCC2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
0.96 g (9 mmol) of sodium carbonate, 1.35 g (9 mmol) of sodium iodide and 2.1 g (9 mmol) of 2-(3-chloropropyl)-2-cyclohexyl-1,3-dioxolane were added to a solution of 1.7 g (8.3 mmol) of 2,5-dimethyl-3-(4-hydroxyphenyl)piperidine in 10 ml of dimethylformamide and the resulting reaction mixture was stirred at a temperature of 80° C. for 16 hours. After cooling, the reaction mixture was poured on ice and extracted three times with ethyl acetate. After evaporating the organic layer under reduced pressure, the residue was dissolved in a mixture of 20 ml of dimethylformamide and 40 ml of 2N hydrochloric acid and stirred for 1 hour so as to split the dioxolane group present. The solution was then extracted three times with diethyl ether, rendered basic by the addition of concentrated ammonia and extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with a concentrated saline solution, dried on sodium sulphate an evaporated under reduced pressure. The resulting crude product (2.3 g) was purified by means of flash chromatography over 75 g of silicagel (Merck, grain size 0.040-0.063 mm) using a mixture of dichloromethane, methanol and concentrated ammonia (95:4.5:0.5) as an eluent. After combining and evaporating the desired fractions, totally 1.2 g (46%) of 1-(4-cyclohexyl-4 -oxobutyl)-2,5-dimethyl-3-(4-hydroxyphenyl)piperidine were obtained (compound no. 1).
Reaction SMILES: [K].[CH2:2]([O:4][C:5](=[O:18])/[C:6](/[O-:17])=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:3].[K+].[C:20]([O:23][C@@H:24]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:29]([O:35][C:36](=[O:38])[CH3:37])[C@@H:28]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[O:27][C@@H:25]1O)(=[O:22])[CH3:21]>CN(C=O)C>[C:36]([O:35][C@@H:29]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:24]([O:23][C:20](=[O:22])[CH3:21])[C@@H:25]([O:17]/[C:6](/[C:5]([O:4][CH2:2][CH3:3])=[O:18])=[CH:7]\[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[O:27][C@H:28]1[CH2:39][O:40][C:41](=[O:43])[CH3:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)/C([O-])=C/c1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccccc1[N+](=O)[O-])O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
A solution of the potassium salt of 2-nitrophenylpyruvate B2 (100 mg, 0.36 mmol) in dry DMF (3 mL) was added dropwise over a period of 15 min, to a pre-cooled stirred solution of 2,3,4,6-tetra-O-acetyl-α-D-glucose (149 mg, 0.36 mmol) in dry DMF (2 mL) at 0° C. under nitrogen atmosphere. The temperature was gradually raised to room temperature. Reaction mixture was allowed to stir for 15 h, and the reaction was quenched with chilled, saturated aq. NaCl (25 mL). Extraction with ethyl acetate (3×30 mL), drying (MgSO4), concentration under reduced pressure, and purification by flash chromatography (SiO2, hexane-benzene-acetone-methanol, 5:4:5:1) to isolate the pure resultant compound C2 in 40% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4](C)[CH:3]=1.BrC1C=CC(C=C)=C([Cl:21])C=1.B1C2CCCC1CCC2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([Cl:21])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1Cl
Reactant: Cc1cc(Br)ccc1CCO
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc(Br)cc1Cl
Yield: 54 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 61A (5 g, 23 mmol) was heated in a pressure vessel with 9-BBN at 100° C. for 10 h and worked up as in 30B to yield 61B (2.9 g, 54%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.95 (t, J=6.59 Hz, 2 H) 3.85 (t, J=6.59 Hz, 2 H) 7.14 (d, J=7.91 Hz, 1 H) 7.33 (dd, J=8.13, 1.98 Hz, 1 H) 7.52 (d, J=2.20 Hz, 1 H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)[C@@H]1CCCN1C1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product containing N,N-dimethyl-L-prolinamide hydrochloride obtained in B) (10.5 g) and triethylamine (13.6 g) in ethanol (100 mL) was added 4-thioxothiazolidin-2-one (6.0 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. The obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (4.3 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH:16]=[CH2:17])[O:13][N:12]=2)=[CH:3]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C.ClCCl>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:13][N:12]=2)=[CH:3]1
Reactant: C=Cc1nc(-c2cn(C)c3ccccc23)no1
Reactant: C1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: Cn1cc(-c2noc(CCN3CCCCC3)n2)c2ccccc21
Reaction time: 0.17 h

Procedure:
2[3-(1-Methylindol-3-yl)-1,2,4-oxadiazol-5-yl]ethene (0.4 g) was partially dissolved in ethanol. Piperidine (2 ml) was added to the mixture and this was stirred for 10 minutes. Ethanol was evaporated under reduced pressure and excess piperidine was removed by heating under high vacuum. The residual oil crystallised upon refrigeration. The crude oil was converted to the monooxalate salt by treatment with 1 equivalent of oxalic acid in dichloromethane which afforded a white amorphous powder. This was recrystallised from ethanol yielding the title compound, m.p. 186°-188° C. Found: C, 59.85; H, 6.10; N, 13.95; C18H22N4O. (COOH)2 requires C, 59.99; H, 6.04; N, 13.99%; δH (360 MHz, D2O) 1.48-2.06 (8H, m, CH2 pip: NCH2CH2 ×2+NCH2CH2CH2), 3.00-3.08 (2H, m, NCH2) 3.50 (2H, t, J=9 Hz, CH2CH2N), 3.58-3.70 (4H, m, CH2CH2N+NCH2CH2 pip, overlapping), 3.87 (3H, s, NCH3), 7.36 (dt, 1H, J=7.2, 1.1 Hz, H-5 or H-6), 7.42 (1H, d, J=7.2, 1.1 Hz, H-5 or H-6) 7.58 (1H, d, J=8.2 Hz, H-7), 7.89 (s, 1H, H-2), 8.00 (1H, d, J=7.5 Hz, H-4); m/z (CI+) 311 (M+ +1, 100%), 226 (30), 157 (70), 98 (90).