Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:53][N:54]([CH3:58])[C:55](Cl)=[O:56]>C(Cl)Cl>[CH3:53][N:54]([CH3:58])[C:55]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1)=[O:56]
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 5C (41.5 mg, 0.051 mmol) and DIEA (0.045 mL, 0.256 mmol) in CH2Cl2 (1 mL) at room temperature was added dimethylcarbamic chloride (4.94 μL, 0.054 mmol), slowly, via syringe. The reaction was stirred overnight at room temperature. Volatiles were removed via a stream of nitrogen and TFA (0.5 mL) was added. The mixture was then heated at 60° C. in an oil bath for 4 h. The reaction was then cooled to room temperature and the TFA was removed under reduced pressure. The resulting crude material was diluted with 1 mL of THF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=56.165 min. 6-((trans-4-((dimethylcarbamoyl)amino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide, 2TFA (18 mg, 45.2% yield) was obtained as a white foam. LC/MS, m/z 533.1 (M+1). HPLC Rt=4.200 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.31 (1H, s), 9.82 (1 H, s), 8.73 (1H, d, J=2.47 Hz), 8.51 (1H, t, J=6.05 Hz), 8.44 (1H, d, J=5.22 Hz), 8.34 (1H, d, J=3.85 Hz), 8.12 (1H, s), 7.97 (1H, s), 7.68-7.80 (1H, m), 7.50 (1H, d, J=8.52 Hz), 7.17-7.26 (1H, m), 7.02 (1H, dd, J=6.74, 5.36 Hz), 5.84-5.93 (1H, m), 3.77-3.87 (1H, m), 3.40 (1H, d, J=6.05 Hz), 2.78 (6H, s), 2.06 (2H, s), 1.80 (2H, s), 1.34 (4H, d, J=12.10 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[CH2:11][C:12](=O)[CH3:13]>OS(O)(=O)=O>[CH3:13][C:12]1[C:4]2[C:3](=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[CH3:8])[N:9]=[C:10]([OH:15])[CH:11]=1
Reactant: CC(=O)CC(=O)Nc1cc(C)ccc1C
Agent: O=S(=O)(O)O
Product: Cc1ccc(C)c2c(C)cc(O)nc12
Temperature: 25 °C
Yield: 28 %

Procedure:
A 5.50 g (26.8 mmol) sample of N-(2,5-dimethylphenyl)-3-oxobutanamide in 10.0 mL of H2SO4 was microwaved at 140° C. for 5 minutes. After the reaction was cooled to room temperature it was quenched into ice-H2O. The resulting mixture was basified with saturated NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×20 mL) and the combined organic extracts were washed with H2O (1×15 mL), brine (lx 20 mL), dried over MgSO4 and concentrated to give the desired title compound (1.4 g, 28%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.41 (s, 3 H) 2.69 (d, J=1.17 Hz, 3 H) 2.73 (s, 3 H) 6.48 (s, 1 H) 6.90 (d, J=7.33 Hz, 1 H) 7.19 (d, J=7.62 Hz, 1 H) 8.87 (br. s., 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH:12]1[CH2:20][NH2:21].C([O-])(O)=O.[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:21][CH2:20][CH:12]2[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:11]2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: NCC1Cc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCC2Cc3ccccc3O2)n1
Yield: 74.5 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.41 g, 2.3 mmol), C-(2,3-dihydro-benzofuran-2-yl)-methylamine (0.52 g, 3.47 mmol), and NaHCO3 (0.97 g, 12 mmol) in EtOH (7 mL) is heated to reflux for 3 h. The mixture is diluted with water (8 mL), filtered, washed (water). The solid is dissolved in EtOAc, dried (MgSO4), filtered, and concentrated in vacuo to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,3-dihydro-benzofuran-2-ylmethyl)-amine (0.5 g) as a solid. LCMS: RT=2.59 minutes; MS: 292 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=O)[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]2[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:8]1[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 105 °C
Reaction time: 1.33 h
Yield: 73 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (5.0 g) and phosphorus oxychloride (POCl3)(6.3 ml) was stirred at 100 to 110° C. for 80 minutes. The reaction mixture was concentrated under reduced pressure. The residue was poured into water, neutralized with an aqueous saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave ethyl 2-chloro-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.8 g, 73%) which was then recrystallized from ethyl acetate-hexane. mp. 168°-169° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2.[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl>>[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:1]([CH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([CH3:19])[CH:17]=1)[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2
Reactant: NCCOc1cccc2c1CC(=O)N2
Reactant: Cc1cccc(CCl)c1
Product: Cc1cccc(CN(CCOc2cccc3c2CC(=O)N3)Cc2cccc(C)c2)c1
Yield: 34 %

Procedure:
Utilizing 4-(2-amino-ethoxy)-1,3-dihydro-indol-2-one prepared in example 2 and reacting with 3-methylbenzyl chloride in the same manner as described for intermediate 15 above to afford the title compound as a crystalline solid in 34% yield, mp 162-164.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([CH2:14][CH3:15])=[CH:12][C:11]([C:16](=[O:18])[CH3:17])=[C:10]([OH:19])[CH:9]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:16]([C:11]1[C:10]([OH:19])=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:22])[CH3:21])=[C:13]([CH2:14][CH3:15])[CH:12]=1)(=[O:18])[CH3:17]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCN
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCc1cc(C(C)=O)c(O)cc1OCCCCCNC(C)=O

Procedure:
In a manner analogous to that taught in Example 77, 265 mg of the amine from Example 137 was acylated with acetyl chloride and pyridine to provide 158 mg of the desired title product, m.p.=115°-116° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]#[N:19])=[N:9]1)([CH3:4])([CH3:3])[CH3:2].CCO.[CH2:24](N)[CH2:25][NH2:26]>C(O)(=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[N:9]=[C:10]([C:18]3[NH:26][CH2:25][CH2:24][N:19]=3)[C:11]=12
Reactant: NCCN
Reactant: CC(C)(C)OC(=O)Cn1nc(C#N)c2c(N)ncnc21
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1nc(C2=NCCN2)c2c(N)ncnc21
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of (4-amino-3-cyano-pyrazolo[3,4-d]pyrimidin-1-yl)-acetic acid tert-butyl ester (80 g, 0.291 mol) and EtOH (800 mL) in an ice water bath was added acetic acid (67 mL) and then ethylenediamine (195 mL). The resulting mixture was refluxed for 90 min, cooled to room temperature and filtered. The solid was suspended in water (1 L), filtered and dried in vacuo to give of tert-butyl 2-(4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate (84.6 g, 90% yield). MS (ES) m/z 318.1 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:24][CH:23]=[CH:22][CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[CH3:16][C:8]1[N:9]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[S:11][C:7]=1[C:6]1[CH:5]=[C:4]([S:17]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)(=[O:19])=[O:18])[S:3][CH:2]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CC=CC3)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCCC3)c2)s1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
N-{5-[2-Bromo-5-(2,5-dihydro-pyrrole-1-sulfonyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (612 mg; 1.21 mmol; 1 eq), is dissolved in anhydrous THF (50 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (15.5 ml; 1.6 M; 9.69 mmol; 8 eq) is added dropwise. The reaction is stirred 2 hours and is quenched with water. The solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (42) as white-off solid (36 mg; 8%).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH:19]=[CH:20][CH:21]([OH:28])[CH:22]([F:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]>[C:1]([O:9][CH:10]1[CH2:18][CH:13]2[O:14][C:15](=[O:17])[CH2:16][CH:12]2[CH:11]1[CH2:19][CH2:20][CH:21]([OH:28])[CH:22]([F:27])[CH2:23][CH2:24][CH2:25][CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(F)C(O)C=CC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCC(F)C(O)CCC1C(OC(=O)c2ccccc2)CC2OC(=O)CC21
Yield: 94 %

Procedure:
To 1.1 g of platinum in 50 ml of ethyl acetate was added a solution of 11 g of (0.028 mol) of [3aR-[3a alpha,4alpha(1E,3R*,4S*),5beta,6a alpha]]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxy-1-octenyl)hexahydro-2H-cyclopenta[b]furan-2-one in 110 ml of ethyl acetate. The mixture was then hydrogenated until the theoretical uptake of hydrogen was complete and then filtered through a bed of Celite. The solvent was then removed under reduced pressure and the residue chromatographed over 250 g of silica gel (toluene -.varies. 30% by volume ethyl acetate/70% by volume toluene) to afford 10.7 g of [3aR-[3a alpha,4alpha(3R*,4S*),5beta,6a alpha)]-5-(benzoyloxy)-4-(4-fluoro-3-hydroxyoctyl)hexahydro-2H-cyclopenta[b]furan-2-one (94% yield) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br>[OH-].[Na+]>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH:10]=1
Reactant: Cc1coc2cc(O)ccc12
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Product: Cc1coc2cc(OCCCBr)ccc12
Temperature: 80 °C
Yield: 169.6 %

Procedure:
To a solution of 3-methyl-1-benzofuran-6-ol (0.20 g, 1.35 mmol) in NaOH (6 M aqueous solution, 0.25 mL) was added 1,3-dibromopropane (0.48 mL, 0.46 mmol), and the mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to rt, and NaOH (6 M aqueous solution, 0.11 mL) was added. The reaction mixture was heated at 80° C. for 1 h, cooled to rt, and partitioned between CH2Cl2 and NaHCO3 (saturated aqueous solution). The organic layer was dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc/hexane (v/v)=1:19) to give 210 mg (58%) of the title compound containing minor impurities. This material was used in next step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.38 (d, 1H), 7.32 (s, 1H), 7.0 (s, 1H), 6.88 (dd, 1H), 4.14 (t, 2H), 3.62 (t, 2H), 2.40-2.28 (m, 2H), 2.20 (s, 3).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>>[CH3:12][C:11]1[C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:21][CH2:22]2)=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: Cc1nc2ccccc2nc1Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2ccccc2nc1N1CCN(Cc2ccccc2)CC1
Temperature: 125 °C

Procedure:
2-Chloro-3-methylquinoxaline (1.0 g, 5.6 mmol) and N-benzylpiperazine (2.9 ml, 16.8 mmol) were mixed and heated to 125° C. for 18 h. Saturated aqueous sodium hydrogen carbonate was added and the product was extracted with chloroform. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give a dark red oil. The crude product was purified by flash chromatography using silica gel eluting with methanol:dichloromethane (15:85) to give the pure product as a red oil which solidified upon standing (1.63 g, 94%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][N:35]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:34][CH2:33]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(COc2ccc(C3CCNCC3)c(OCc3ccccc3)c2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
In a 25 ml round-bottomed flask, 0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine in 10 ml of tetrahydrofuran is dissolved in the presence of 0.26 ml of N,N-diisopropylethylamine. 0.17 ml of benzoyl chloride is added and the mixture is then stirred for 24 hours at ambient temperature. The reaction mixture is extracted with ethyl acetate and then the organic phases are combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 0.5 g of [4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is obtained. Yield=80%.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([NH:8][OH:9])=[NH:7])[CH3:2].[CH2:14](OC(=O)C1C=C(C)N=C(C(C)C)C=1)C>>[OH:9][NH:8][C:6](=[NH:7])[C:5]1[CH:10]=[C:11]([CH3:13])[N:12]=[C:3]([CH:1]([CH3:14])[CH3:2])[CH:4]=1
Reactant: CCOC(=O)c1cc(C)nc(C(C)C)c1
Reactant: CCc1cc(C(=N)NO)cc(C)n1
Product: Cc1cc(C(=N)NO)cc(C(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-ethyl-N-hydroxy-6-methyl-isonicotinamidine starting from 2-isopropyl-6-methyl-isonicotinic acid ethyl ester; LC-MS: tR=0.42 min, [M+1]+=194.08; 1H NMR (D6-DMSO): δ 1.22 (d, J=7.0 Hz, 6H), 2.44 (s, 3H), 2.91-3.02 (hept, J=7.0 Hz, 1H), 5.91 (s, 2H), 7.32 (s, 2H), 9.88 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
To a solution of (2R, 4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (3.17 g: 12.9 mmole) in dichloromethane (16 ml) in a nitrogen atmosphere under ice cooling, triethylamine (2.15 ml: 15.5 mmole) and methanesulfonyl chloride (1.19 ml: 15.5 mmole) are added. The mixture is stirred to react for 30 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as oil (4.13 g). Yield: 99%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)[CH3:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]=[C:24]([C:9]2[CH:10]=[CH:11][C:6]([CH:4]([C:3]([O:2][CH3:1])=[O:13])[CH3:5])=[CH:7][CH:8]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C(C)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(C)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Under inert gas atmosphere 3.43 g (2.97 mmol) Pd(PPh3)4 are added to 17.2 g (59.4 mmol) 2-(4-iodo-phenyl)-propionic acid methyl ester (Bioorg. Med. Chem. Lett. 2010, 20, 896), 20.2 g (65.3 mmol) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 18.9 g (178 mmol) sodium carbonate in 200 mL 1,2-dimethoxyethane and 30 mL water. The mixture is stirred for 2 h at 100° C. and for additional 12 h at 80° C. After that time, water is added and the mixture is extracted with EtOAc (3×). The combined organic layers are washed with water (2×) and brine and dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel; heptane:EtOAc gradient 100:0->60:40).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@H:2]([C@@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].OS(O)(=O)=O.[CH2:16](O)[C:17]([F:20])([F:19])[F:18]>>[C:6]([C@H:4]([C@@H:2]([C:1]([O:10][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:9])[OH:3])[OH:5])([O:8][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:7]
Reactant: OCC(F)(F)F
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=S(=O)(O)O
Product: O=C(OCC(F)(F)F)[C@@H](O)[C@H](O)C(=O)OCC(F)(F)F
Temperature: 25 °C
Yield: 33 %

Procedure:
d-Tartaric acid (23; 25 g, 0.17 mol), trifluoroethanol (200 ml) and H2SO4 (59 mL) were magnetically stirred and heated under reflux for 22 h. The solution was cooled to room temperature, partitioned between H2O and CH2C2. The H2O layer was extracted with CH2Cl2 (2×150 mL). The combined organic layers were washed with saturated aqueous NaHCO3, and brine, then filtered through a bed of Celite and evaporated in vacuo. The residue was dissolved in ethyl ether and filtered through a plug of silica. The silica was rinsed with ca. 600 mL. The ether was removed in vacuo and the residue was recrystallized from ether/hexane to yield 34 (17.3; 33%) as white crystals: mp 77-79° C.; 1H NMR (300 MHz, CDCl3) δ3.13 (two singlets, 2H), 4.6 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1>>[N:16]1([CH2:15][C@@H:11]2[CH2:12][CH2:13][CH2:14][N:10]2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:22][C:23]3[CH:24]=[N:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)=[CH:3][CH:4]=2)=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(OCc2ccc(C(F)(F)F)nc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-(chloromethyl)-6-(trifluoromethyl)pyridine. MS (ES+) 434.2
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:13]=1)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH3:29][CH2:30][N:31]([CH2:34][CH2:35]Cl)[CH2:32][CH3:33]>C(#N)C>[CH2:30]([N:31]([CH2:34][CH3:35])[CH2:32][CH2:33][N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([C:2](=[O:1])[CH:3]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH3:5])=[CH:22][CH:21]=1)[CH3:29]
Reactant: CCC(C(=O)c1ccc(NS(C)(=O)=O)cc1)c1ccccc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(C(=O)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1)c1ccccc1
Yield: 58 %

Procedure:
4'-(1-Oxo-2-phenylbutyl)methanesulfonanilide (31.7 g., 0.100 mole), potassium carbonate (13.8 g., 0.100 mole), and 2-chlorotriethylamine (13.6 g., 0.100 mole) are mixed together in 1 liter of acetonitrile and refluxed 18 hr. The reaction mixture is clarified by filtration and concentrated under reduced pressure. The residual oil is dissolved in ethyl ether and the product extracted therefrom with 1.5N HCl. The aqueous acid extract is washed with ethyl ether and then basified with 50% NaOH. The organic material which separates is extracted into ethyl ether and the extracts are washed with water and brine, and the solution dried (MgSO4). The ether is evaporated and the solid residue is crystallized from hexane to yield 24.1 g. (58% yield), m.p. 76°-77°C.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].[C:14](#[N:17])[CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:16][CH:15]([C:1](=[O:9])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:14]#[N:17]
Reactant: CCOC(=O)c1cccnc1
Reactant: CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C#N)C(=O)c1cccnc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under a N2 atmosphere ethyl nicotinate (3 g, 0.02 mol) and NaH (1.6 g, 0.04 mol) were suspended in toluene (30 mL) and heated to 90° C. Propiononitrile (2.2 g, 0.04 mol) was added dropwise and the reaction was stirred at 90° C. overnight. After cooling to room temperature, the solid was filtered and collected. The solid was dissolved in water (50 mL) and washed with ethyl acetate (30 mL). The aqueous layer was adjusted to pH=6 with 2M HCl and extracted again with ethyl acetate (30 mL×2). The combined ethyl acetate extracts were combined and dried over Na2SO4, filtered and concentrated in vacuo to give the desired product: 1HNMR (400 MHz, CDCl3) δ 9.25 (d, 1 H, J=1.2 Hz), 8.90 (d, 1 H, J=4.8 Hz), 8.33 (d, 1 H, J=8.0 Hz), 7.54 (dd, 1 H, J=1.2 Hz, J=8.0 Hz), 4.37-4.39 (m, 1 H), 1.71 (d, 3 H, J=7.2 Hz).