Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CN(C=O)C>[CH:29]1([CH2:28][O:1][C:2]2[N:7]=[C:6]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(O)n2)CC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(OCC3CC3)n2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Stir tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (0.25 g, 0.90 mmol) in DMF (10 mL) and add cesium carbonate (0.44 g, 1.35 mmol) and (bromomethyl)cyclopropane (0.13 g, 0.99 mmol). Heat the mixture to 30° C. and stir overnight. Quench the reaction with water, and extract three times with EtOAc (20 mL). Combine the organic extracts. Wash the extracts with water then brine; dry over sodium sulphate; collect the filtrate; and concentrate under vacuum to give the crude product. Purify using silica gel normal phase flash column chromatography using a gradient of 0-30% ethyl acetate in petroleum ether to give the title compound (0.28 g, 94%) as a clear oil. MS (m/z): 333 (M+1).
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:14]#[N:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[OH-:19].[Na+]>OS(O)(=O)=O>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:14](=[O:19])[NH2:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:18])[CH3:17]
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N(CCC(C(N)=O)c1ccccc1)C(C)C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
N,N-Diisopropyl-3-cyano-3-phenylpropanamine (11.6 g, 47.5 mmol) was mixed with H2SO4 (90%, 100 mL) and the mixture was stirred at 100° C. for 30 min. The reaction mixture was poured on ice, made alkaline (11 M NaOH) and extracted twice with diethyl ether. The combined organic phases were dried (Na2SO4) and the solvent evaporated, affording the title compound as a colourless oil, 12.4 g (100%); 1H NMR (CDCl3) δ1.26 (m, 12H), 2.14 (m, 1H), 2.60 (m, 1H), 2.73 (t, 2H), 3.31 (m, 2H), 3.86 (t, 1H), 6.06 (br, 2H), 7.51-7.61 (m, 5H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:12][CH:13]=2)[S:6][CH:7]=1)[CH3:2].[CH3:19][O:20][C:21](=[O:34])[C@H:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29](O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=4)=[CH:13][N:12]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH3:23]
Reactant: COC(=O)[C@@H](C)n1ccc2cc(O)ccc21
Reactant: CCc1csc(-c2ccc(OCCCO)nc2)n1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4[C@H](C)C(=O)OC)c3)nc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
A solution of 3-[5-(4-ethyl-thiazol-2-yl)-pyridin-2-yloxy]-propan-1-ol (Example 73, 7.0 g, 0.025 mol), (R)-2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (Example 8, 4.961 g, 0.023 mol), and triphenylphosphine (7.716 g, 0.029 mol) in dichloromethane (60 mL) was treated with a solution of 1,1′-(azodicarbonyl)-dipiperidine (7.423 g, 0.029 mol) in dichloromethane (45 mL) slowly over 25 minutes while maintaining the temperature around 25° C. The resulting suspension was stirred at rt for 18 h. Upon completion, the solvent was removed under vacuum and the crude product was purified by silica gel chromatography using a gradient of 5-35% ethyl acetate/hexanes to give 7.3 g (69%) of the title compound as a beige solid. The product was characterized as in Example 69.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([F:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)Cl>[F:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCC(F)CC1
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCC(F)CC3)c2)CC1
Temperature: 80 °C
Yield: 93 %

Procedure:
A solution of 1-(5-chloro-2-nitro-phenyl)-4-fluoro-piperidine (as prepared in the previous step, 0.44 g, 1.7 mmol) in 4-methylpiperazine (2 mL) was heated to 80° C. for 18.5 h. The solution was cooled to room temperature, diluted with CH2Cl2, and washed with water. The aqueous layer was further extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.51 g, 93%) as a bright yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.04 (d, 1H, J=9.2 Hz), 6.45 (dd, 1H, J=9.2 Hz, J=2.4 Hz), 6.34 (d, 1H, J=2.4 Hz), 4.97-4.79 (m, 1H), 3.38 (app t, 4H, J=5.2 Hz), 3.26-3.15 (m, 4H), 3.07-2.98 (m, 4H), 2.54 (app t, 4H, J=5.2 Hz), 2.35 (s, 3H). LC-MS (ESI, m/z): Calcd. for C16H23FN4O2, 323.2 (M+H), found 323.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.C(OCC)(=[O:18])C.CCCCCC>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:15][C:14](=[O:18])[O:13][C:11](=[O:12])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C2CC(=O)OC(=O)C2)cc1
Yield: 38 %

Procedure:
Using ethyl 3-(4-methoxyphenyl)-2-propenoate, the title compound was synthesized in the same manner as in Reference Example 5. Yield 38%. mp. 144–149° C. (ethyl acetate-hexane).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:31][CH2:32][CH:33]([OH:45])[CH2:34][N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36]1>C(Cl)Cl>[CH2:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:43][CH2:44][N:35]1[CH2:34][CH:33]([OH:45])[CH2:32][NH:31][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C(O)c1ccccn1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of picolinic acid (100 mg, 0.81 mmol) in DCM (10 mL), was added EDCI (187 mg, 0.97 mmol) and HOBT (132 mg, 0.98 mmol), which was stirred at 25° C. for 0.5 h before 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (167 mg, 0.81 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The solution was concentrated in vacuo and the residue was purified by prep-HPLC to provide the title compound (68 mg, Yield 26.9%). 1H NMR (CD3OD, 400 MHz): δ 8.61 (d, J=3.9 Hz, 1H), 8.49 (brs, 1H), 8.10 (d, J=7.8 Hz, 1H), 8.01-7.92 (m, 1H), 7.56 (dd, J=5.1, 6.8 Hz, 1H), 7.31-7.20 (m, 3H), 7.19-7.13 (m, 1H), 4.44-4.27 (m, 3H), 3.66-3.47 (m, 4H), 3.31-3.12 (m, 4H). LCMS (m/z): 312.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OCc2ccc(F)c(F)c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(F)c(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.7 %

Procedure:
To a stirred solution of methyl 3-chloro-4-[(3,4-difluorobenzyl)oxy]benzoate (Preparation 10, 10.86 g, 34.7 mmol) in methanol (700 mL) and water (150 mL) was added sodium hydroxide (6.946 g, 173.7 mmol) and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, diluted with water (285 mL), adjusted to pH 3 with hydrochloric acid and the resulting precipitate collected by filtration, washed with water and the azeotroped with toluene in vacuo twice to yield the title compound as a solid (6.5 g, 62% over 2 steps).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Br)([CH3:25])([CH3:24])[CH3:23].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:22]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C2CN(CCCC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
2-(4-Octyloxy-phenyl)-morpholine (1.50 g; 5.2 mmol), 4-bromo-butyric acid tert-butyl ester (1.38 g; 6.2 mmol) (prepared according to C. Morin, M. Vidal Tetrahedron, 1992, 48(42), 9277), potassium iodide (1.03 g; 6.2 mmol), K2CO3 (1.42 g; 10.29 mmol), and CH3CN (15 mL) were mixed and heated under reflux for 2 hours. After cooling to RT the reaction mixture was concentrated in vacuo, dissolved in EtOAc, washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester (1.90 g), TLC (SiO2 Rf. 0.20 EtOAc:hexanes 1:1)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([NH:17][C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:20])[CH3:19])=[O:16])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>CN(C=O)C>[Si:40]([O:39][CH2:38][CH2:37][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([NH:17][C:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:20])[CH3:19])=[O:16])[S:2]([CH3:1])(=[O:3])=[O:4])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(NC(=O)c1cccc(-c2ccncc2NS(C)(=O)=O)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a mixture containing 3-(3-(methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (0.20 g, 0.50 mmol), potassium carbonate (0.30 g, 2.0 mmol) and DMF (1.6 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (0.10 mL, 0.50 mmol) in a steady stream via syringe. The mixture was stirred at 80° C. for 4 h, cooled to room temperature, filtered, concentrated and purified on silica gel (0-10% methanol/dichloromethane, 60 min gradient) to afford 3-(3-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a brown oil. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.75 (s, 1H), 8.64 (d, J=4.88 Hz, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=7.94 Hz, 1H), 7.77 (d, J=7.93 Hz, 1H), 7.52-7.60 (m, 2H), 7.40 (d, J=7.32 Hz, 2H), 7.28 (t, J=7.63 Hz, 2H), 7.17 (t, J=7.32 Hz, 1H), 3.42-3.50 (m, 1H), 3.25 (s, 3H), 3.03 (s, 1H), 1.64-1.71 (m, 6H), 0.71-0.78 (m, 9H), −0.12-−0.06 (m, 6H). LCMS: retention time: 2.497 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 568 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:15]([CH2:18][C:19](=[O:21])[CH3:20])(=[O:17])[CH3:16].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[C:18]([C:19](=[O:21])[CH3:20])[C:15](=[O:17])[CH3:16]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: C1CCCCC1
Product: COc1cc(C=C(C(C)=O)C(C)=O)cc(OC)c1OC
Reaction time: 8 h

Procedure:
3-(3,4,5-trimethoxybenzylidene)-2,4-pentanedione (hereinafter “HSS”) was prepared by the condensation of 3,4,5-trimethoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol. The typical yield of HSS is about 68% with a purity, as determined by GC, of 99.1%. HSS is an off-white free-flowing powder with a melting point of 83-86° C. with a λmax at 319 nm.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[C:6]([S:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13]CC)=[O:12])=[N:7][N:8]=1>C1COCC1.CO>[Br:3][C:4]1[N:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[C:6]([S:9][C:10]([CH3:17])([CH3:16])[C:11]([OH:13])=[O:12])=[N:7][N:8]=1
Reactant: CCOC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
Lithium hydroxide solution (1M aqueous, 358 μL, 0.358 mmol, 3 eq) was added to a solution of ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (55 mg, 0.119 mmol) in THF (1 mL) and methanol (0.5 mL), and the mixture stirred for 2 hours at room temperature. The crude reaction mixture was then concentrated, acidified with HCl (1N) and sonicated to break up solids. Filtration gave 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as an off-white solid (39 mg, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:53][CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=1)=[C:5]2[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:53][CH2:54][N:55]2[CH2:59][CH2:58][CH2:57][CH2:56]2)=[CH:30][CH:31]=1
Reactant: OCCN1CCCC1
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(O)cc3)c2cc1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OCCN4CCCC4)cc3)c2cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 6-bromo-4-(4-hydroxy-benzyl)-7-methoxy-3-(4-trifluoromethyl-phenyl)-chromen-2-one (0.70 g, 1.4 mmol) and triphenylphosphine (0.73 g, 2.8 mmol) in THF (40 mL) were sequentially added 1-(2-hydroxylethyl)pyrrolidine (0.65 mL, 5.6 mmol) and diisoproyl azodicaroxylate (0.55 mL, 2.8 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. Organic extracts were combined and washed with water and saturated sodium chloride in succession, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel flash column chromatography (10% methanol in CH2Cl2) provided the title compound as a solid (0.44 g, 53%). MS (ESI) m/z 602.3 (M+1)+, 604.3 (M+1+2)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#N)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.CO.[OH:21]S(O)(=O)=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]=[O:21])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc2nc(-c3ccc(C#N)cc3)cn2c1
Solvent: CO
Solvent: c1ccccc1
Product: Cc1ccc2nc(-c3ccc(C=O)cc3)cn2c1
Reaction time: 2.5 h

Procedure:
1.0 g of 6-methyl-2-(4'-cyanophenyl)imidazo[1,2-a]-pyridine in 20 ml dry benzene was treated with Dibal (5.5 ml of 1M solution). After stirring for 2-3 hrs, methanol 15 ml was added, followed by 10 ml of 10% H2SO4. The precipitate was filtered, dissolved in water and basified with 15% NaOH. The collected precipitate was recrystallized from ethanol. Yield 0.68 g (68%); mp 210°-211° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[C:13]1([C:19]2[C:20](=[O:30])[NH:21][C:22](=[O:29])[N:23]3[CH2:28][CH2:27][CH2:26][S:25][C:24]=23)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:2]([N:21]1[C:20](=[O:30])[C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:24]2[S:25][CH2:26][CH2:27][CH2:28][N:23]2[C:22]1=[O:29])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCI
Reactant: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2
Yield: 64.6 %

Procedure:
1-Iodopentane (2.29 g), potassium carbonate (1.28 g) and 9-phenyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (2 g) in DMF (30 ml) were stirred at 100° C. for 15 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography on silica gel. The obtained crude crystals were recrystalized from ethyl acetate-hexane to give colorless crystals (1.64 g, 65%).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+].CO>O>[OH:14]/[N:13]=[C:1]1\[CH2:2][CH2:3][CH2:4][C:5]2[C:10]\1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCCc2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O/N=C1\CCCc2ccccc21

Procedure:
A mixture of 3,4-dihydro-1-(2H)-naphthalenone (72.4 g, 0.495 mol), hydroxylamine hydrochloride (139 g, 1.98 mol), sodium acetate (162 g, 1.98 mol), methanol (500 mL) and water (100 mL) was refluxed for 6 hours. The reaction mixture was diluted with water (2 L), and extracted with ether (800 mL). The organic layer was washed with water, dried and concentrated. The residue was crystallized from ether/hexane to give the title compound: LCMS m/z=162.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([NH:13][CH2:14][C:15]1[NH:16][C:17](=[O:25])[C:18]2[CH2:24][O:23][CH2:22][CH2:21][C:19]=2[N:20]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH2:33][CH2:32][CH2:31]2>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:10]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][C:2]([NH:13][CH2:14][C:15]3[NH:16][C:17](=[O:25])[C:18]4[CH2:24][O:23][CH2:22][CH2:21][C:19]=4[N:20]=3)=[O:1])[CH2:5][CH2:6]1)=[O:12])[CH2:33][CH2:32][CH2:31]2
Reactant: O=C(CN1CCC(C(=O)O)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: COc1ccc2c(c1)CCCN2
Product: COc1ccc2c(c1)CCCN2C(=O)C1CCN(CC(=O)NCc2nc3c(c(=O)[nH]2)COCC3)CC1
Yield: 22.6 %

Procedure:
The title compound (56 mg, 22% yield) was prepared following the general procedure of Example 1 from 1-(2-oxo-2-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)ethyl)piperidine-4-carboxylic acid (250 mg, 0.50 mmol) and 6-methoxy-1,2,3,4-tetrahydroquinoline (82 mg, 0.50 mmol). 1H NMR (400 MHz, CDC3) δ 10.68 (br. s., 1H), 8.12 (br. s, 0.5H), 6.97 (br. s., 0.5H), 6.73-6.80 (m, 2H), 4.58 (s, 2H), 4.38 (d, J=5.6 Hz, 2H), 3.97 (t, J=5.6 Hz, 2H), 3.63-3.89 (m, 5H), 3.10 (br. s., 2H), 2.89 (br. s., 3H), 2.71 (t, J=5.3 Hz, 4H), 2.15 (br. s., 2H), 1.82-2.09 (m, 5H), 1.68 (br. s., 1H). HRMS calculated for C26H33N5O5 496.2560. found (ESI, [M+H]+), 496.2561. Retention time=1.29 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:23](=[O:24])[CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:26][CH3:27])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1Cc1cnc(N)s1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C(=O)Nc1ncc(Cc2cccnc2OC)s1)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine (44 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (15 mg, 0.041 mmol, 21%). ESI-MS m/z calc. 367.1, found 368.1 (M+1)+ Retention time 3.24 minutes.
Reaction SMILES: CC[C:3]1[C:8]([C:9]#[N:10])=[C:7]([NH:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:5][N:4]=1.[O-][CH2:17][CH3:18].[Na+]>CCO.O>[CH2:17]([O:15][C:13]([C:12]1[NH:11][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:8]=2[C:9]=1[NH2:10])=[O:14])[CH3:18]
Reactant: CC[O-]
Reactant: CCc1nccc(NCC(=O)O)c1C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2ccncc2c1N
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of ethyl-4-(3-cyanopyridine)glycinate (2.47 g, 12.1 mmol) under nitrogen in EtOH (60 mL) was added sodium ethoxide (0.90 g, 13.3 mmol) and the mixture was heated at reflux for 1 hour. The mixture was allowed to cool to ambient temperature then quenched by the addition of water (3 mL) and saturated ammonium chloride solution (5 mL). The solvent was concentrated in vacuo, to provide a residue that was diluted with water (30 mL), and extracted with EtOAc (2×40 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound as a brown solid (1.35 g, 55%). LCMS (method B): RT=0.61 min, M+H+=206.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:20]([N:22]=[C:23](SC)[S:24][CH3:25])#[N:21]>CC#N.CCN(CC)CC>[C:20]([N:22]=[C:23]([NH:1][C@@H:2]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[S:24][CH3:25])#[N:21]
Reactant: CSC(=NC#N)SC
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSC(=NC#N)N[C@@H](CC1CCCCC1)CN(C)C(=O)OC(C)(C)C
Yield: 30.5 %

Procedure:
To a solution of (S)-tert-butyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (1.08 g, 4 mmol) in CH3CN (15 mL) and Et3N (3 mL) was added dimethyl cyanocarbonimidodithioate (642 mg, 4.4 mmol). The mixture was heated to reflux for 4 h. The reaction mixture was concentrated to give the residue, which was purified by column to give (S)-tert-butyl 2-((cyanoimino)(methylthio)methylamino)-3-cyclohexylpropyl(methyl)carbamate (450 mg, 31%).