Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>ClCCl>[C:20]1([S:26]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.7 %

Procedure:
To a stirred suspension of tert-butyl azetidin-3-ylcarbamate (4.61 g, contaminated with diphenylmethane 1:1, ˜13.39 mmoles) in dichloromethane (150 mL), was added triethylamine (3.73 mL, 26.77 mmoles) and benzenesulfonyl chloride (2.57 mL, 20.08 mmoles). The reaction was stirred at room temperature for ˜4 hours and became a solution. Sat. ammonium chloride was added to the mixture and the aqueous phase was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous magnesium sulphate, filtered and concentrated. The residue was precipitated from dichloromethane/hexanes 1:1 to give the title material (1.073 g, ˜26%) as a solid. The mother liquor was concentrated and the residue was purified on Biotage (0 to 20% acetonitrile in dichloromethane) to afford the title material (2.46 g, ˜58%). 1H NMR 400 MHz CDCl3 δ (ppm): 1.42 (9H, s), 3.60 (2H, br s), 4.06 (2H, dd, J=8.7 and 7.7 Hz), 4.35 (1H, br s), 4.70 (1H, br s), 7.60-7.64 (2H, m), 7.68-7.72 (1H, m), 7.86-7.88 (2H, m).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:48])([CH3:47])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:46])([C@@:13]3([CH3:45])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[C:51]([C:53]1([C:68]([O:70][CH3:71])=[O:69])[CH2:58][CH2:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][CH2:54]1)#[N:52]>>[C:51]([C:53]1([C:68]([O:70][CH3:71])=[O:69])[CH2:58][CH2:57][C:56]([C:7]2[C:8]([CH3:47])([CH3:48])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:46])([C@@:13]4([CH3:45])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:55][CH2:54]1)#[N:52]
Reactant: COC(=O)C1(C#N)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C#N)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 61 %

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 1-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactants. The product was isolated as a mixture of diasteromers (solid, 61% yield). MS: m/e 762.6 (M+H)+, 3.01 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.34 (d, J=2.0 Hz, 1H), 5.28-5.22 (m, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.60-4.57 (m, 1H), 3.85 (s, 3H), 3.17-3.06 (m, 3H), 2.87-2.78 (m, 2H), 2.84 (s. 3H), 2.74-2.40 (m, 10H), 2.33-0.78 (m, 27H), 1.69 (s, 3H), 1.07 (s, 3H), 1.01-0.93 (m, 6H), 0.96 (s, 3H), 0.85 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][N:14](C)C=O>[C-]#N.[C-]#N.[Zn+2].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:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])#[N:14]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C)c(C#N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of methyl 3-bromo-4-methylbenzoate (compound 1.6, 18 g, 78.58 mmol, 1.00 equiv), Zn(CN)2 (11.1 g, 94.87 mmol, 1.20 equiv), and Pd(PPh3)4 (7.3 g, 6.32 mmol, 0.08 equiv) in N,N-dimethylformamide (250 mL) was stirred under a nitrogen atmosphere at 100° C. overnight. After cooling to room temperature, the reaction was then quenched by careful addition of 200 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×500 mL of ethyl acetate. The combined organic layers were washed with 3×200 mL of brine, dried over (Na2SO4), and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as eluent to yield 11 g (76%) of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16](CP(=O)(OCC)OCC)=[CH:15][CH:14]=2)[N:3]=1.ClC1N=C(Cl)C(C(F)(F)F)=CN=1.[CH2:40]([P:43](C1C=CC(N)=CC=1)([CH2:45][CH2:46][CH3:47])=[O:44])[CH2:41][CH3:42]>>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([P:43]([CH2:45][CH2:46][CH3:47])([CH2:40][CH2:41][CH3:42])=[O:44])=[CH:26][CH:27]=2)[N:3]=1
Reactant: CCCP(=O)(CCC)c1ccc(N)cc1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: CCCP(=O)(CCC)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using 2,4-Dichloro-5-trifluoromethylpyrimidine (101.6 mg, 0.4681 mmol) and 4-(dipropylphosphoryl)aniline (Compound 198B: 116 mg, 0.515 mmol). This was purified on an ISCO Combiflash unit (0-5% MeOH/DCM) to isolate 75 mg of the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.3 Hz, 6H), 1.30 (br. s., 2H), 1.46 (br. s., 2H), 1.76-2.00 (m, 4H), 7.69 (dd, J=10.1, 8.6 Hz, 2H), 7.84 (dd, J=8.7, 1.9 Hz, 2H), 8.87 (s, 1H), 10.89 (s, 1H). MS (ES+): m/z=406.04 (100) 408.01 (35) [MH+]. HPLC: tR=4.01 min (ZQ3, polar—5 min)
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(O)(O)=O>CC#N.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>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=1)[C:3]([CH3:13])=[N:4]2
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (Prepared in Example 85, 0.3361 g, 1.577 mmol), 3-fluorobenzeneboronic acid (0.2428 g, 1.735 mmol), tetrakis(triphenylphosphine)palladium (0.09114 g, 0.07887 mmol), and sodium carbonate anhydrous (0.8360 g, 7.887 mmol) in CH3CN—H2O (3:1) (16.00 mL) was stirred at 100° C. After 3.5 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give red syrup. The red syrup was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 5-chloro-3-(3-fluorophenyl)-2-methylquinoxaline as a solid: 1H NMR (400 MHz, DMF) δ ppm 8.05 (1 H, dd, J=8.4, 1.4 Hz), 8.00 (1 H, dd, J=7.6, 1.4 Hz), 7.83 (1 H, dd, J=8.4, 7.6 Hz), 7.60-7.67 (3 H, m), 7.38-7.46 (1 H, m), 2.74 (3 H, s); LC-MS (ESI) m/z 273.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:38])[C:5]2[N:6]=[CH:7][N:8]([C:36]=2[N:37]=1)[C@@H:9]1[O:35][C@H:26]([CH2:27][O:28][Si](C(C)C)(C)C)[C@@H:18]([O:19][Si](C(C)C)(C)C)[C@H:10]1[O:11][Si](C(C)C)(C)C.Cl[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][OH:48])=[CH:42][CH:41]=1.[H-].[Na+].CO.C(Cl)[Cl:54]>>[Cl:54][C:44]1[CH:45]=[CH:40][CH:41]=[CH:42][C:43]=1[CH2:46][CH2:47][O:48][C:2]1[N:3]=[C:4]([NH2:38])[C:5]2[N:6]=[CH:7][N:8]([C:36]=2[N:37]=1)[C@@H:9]1[O:35][C@H:26]([CH2:27][OH:28])[C@@H:18]([OH:19])[C@H:10]1[OH:11]
Reactant: ClCCl
Reactant: CC(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](C)(C)C(C)C)[C@@H]1O[Si](C)(C)C(C)C
Reactant: OCCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(OCCc2ccccc2Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Yield: 20.8 %

Procedure:
A mixture of 2-chloro-2′,3′,5′-tris-O-(isopropyldimethylsilyl)adenosine (Example 5, 5.0 g, 6.5 mmol) and 15 ml of 2-(4-chlorophenyl)ethyl alcohol was placed under a nitrogen atmosphere and heated to 50° C. Sodium hydride (1.30 g, 60% dispersion in mineral oil, 32.5 mmol) was added at a rate so as to control gas evolution. The reaction was then heated for 48 h at which time LC showed conversion to the fully deprotected coupling product. The reaction was allowed to cool to room temperature, carefully quenched with 40 mL of water and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (120 mL), dried over MgSO4, and concentrated under reduced pressure to afford a clear oil. Chromatography on silica gel eluting with CH2Cl2, 5% MeOH in CH2Cl2, and then 10% MeOH in CH2Cl2 provided 570 mg (20.8%) of the title compound as a white solid. m.p. 158–161° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[C:3]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1CCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Br)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
In a large sealed tube is added 5-bromo-2,4-dichloropyrimidine (3 g, 13.2 mmol) in 100 mL of EtOH. Then cyclopentyl amine (1.95 mL, 19.75 mmol) and N,N′-diisopropylethylamine (3.36 mL, 19.8 mmol) are added to the solution at rt. The solution is then stirred rt overnight. Solvent is evaporated and the crude is purified using silica gel chromatography (15% ethyl acetate/85% hexane) to give (5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine as a white solid (3.25 g, 89%). MS(ESI) m/z 278.4 (M+H)+
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH2:24][SH:25]>>[CH3:28][O:27][C:23](=[O:26])[CH2:24][S:25][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCC2)CC1
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCC2)C2CCC(C)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclopentyl-1-(4-methyl-cyclohexyl)-urea (Example 202) and methyl thioglycolate.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11]([CH3:15])[CH2:12][CH2:13]O>>[CH2:13]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:13][CH2:12][CH:11]([CH3:15])[CH3:10])=[O:6])[OH:3])[CH2:12][CH:11]([CH3:15])[CH3:10]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CC(C)CCO
Product: CC(C)CCOC(=O)CC(O)C(=O)OCCC(C)C
Temperature: 110 °C

Procedure:
Diisoamyl-DL-malate was prepared using a procedure similar to that in Example 4. To the reaction flask, DL-malic acid (87.54 g), 3-methyl-1-butanol (285 mL) and Amberlyst®15 ion exchange resin (11.9 g) were added. The mixture was placed under nitrogen and heated to reflux. At 109° C., two phases started to collect in the Dean-Stark trap. The reaction was maintained at 110° C. for 8 hr, during this time water was continuously removed. The product was dissolved in diethyl ether and separated from the catalyst via filtration over a bed of silica. The organic layer was washed with saturated sodium bicarbonate a number of times, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Diisoamyl-DL-malate was obtained as a low viscosity, clear colorless liquid with a slight odor (130 g, 72% yield) after pumping on the sample in vacuo to remove residual 3-methyl-1-butanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH:19]=[CH2:20])[C:9](=[O:11])[CH3:10].CCN(CC)CC.O>CN(C=O)C.Cl[Pd]Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]=[CH:19][C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:8]([C:9](=[O:11])[CH3:10])[CH2:7][C:6]=2[CH:21]=1
Reactant: C=Cc1cc(Cl)ccc1N(Cc1cc(Br)ccc1I)C(C)=O
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1Cc2cc(Br)ccc2C=Cc2cc(Cl)ccc21
Temperature: 60 °C
Yield: 44.1 %

Procedure:
To a stirred solution of N-(5-Bromo-2-iodo-benzyl)-N-(4-chloro-2-vinyl-phenyl)-acetamide (0.55 g, 1.5 mmol) and Et3N (0.63 mL, 4.5 mmol) in DMF (25 mL) was added PdCl2 (40 mg, 0.23 mmol) and the reaction was heated to 60° C. When the reaction was complete by HPLC the mixture was poured into H2O and extracted with Et2O. The Et2O layer was washed with H2O (2×20mL) and brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography eluting with CH2Cl2 to give 1-(8-Bromo-2-chloro-6H-dibenzo[b,f]azocin-5-yl)-ethanone (0.24 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([O:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]=1[Cl:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c(=O)c1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccccc2c(OCc2ccccc2)c1Cl
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (1.1 g) in DMF (30 mL) were added benzyl bromide (0.57 mL) and potassium carbonate (720 mg) at room temperature, followed by stirring for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=85/15) to obtain ethyl 4-(benzyloxy)-3-chloroquinoline-2-carboxylate (1.24 g).
Reaction SMILES: [Cl:1][C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1.Cl>O1CCOCC1>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:33][C:31]4[CH:30]=[N:29][N:28]([CH2:27][CH2:26][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:32]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17].[ClH:1].[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:33][C:31]4[CH:30]=[N:29][N:28]([CH2:27][CH2:26][N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:32]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Nc1cnn(CCN2CCCC2)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cnn(CCN5CCCC5)c4)nc23)cc1

Procedure:
219 c) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine was synthesized from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1.5-a]pyridine (0.150 g, 0.487 mmol) and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine (0.105 g, 0.585 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. The isolated pure product was treated with 2N hydrogen chloride in dioxane. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine hydrochloride was isolated as a light green solid (70 mg, 30%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)=[CH:3][CH:2]=1.O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:21]1([NH:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[N:8][CH:9]=2)=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:20]=1
Reactant: O=C(O)c1cnc(-c2ccncc2)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(-c2ccncc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.9 %

Procedure:
A mixture of 2-pyridin-4-yl-pyrimidine-5-carboxylic acid (100 mg, 0.5 mmol), 1-hydroxybenzotriazole (76.1 mg, 0.56 mmol) and PS-DCC (539 mg, 1.25 mmol/g, 0.66 mmol) in DMF (8 mL) is shaken at room temperature for 15 min, and aniline (31 mg, 0.33 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (398 mg, 3.75 mmol/g, 1.49 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-4-yl-pyrimidine-5-carboxylic acid phenylamide (15 mg, 16%) as solid. MS: 277 (M+H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:10][CH2:9]2)C=CC=CC=1.Cl.[H][H]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Temperature: 45 °C

Procedure:
100 g (219.5 mmol) N-[4-(1-diphenylmethylpiperidin-4-yl)-butyl]-3-(pyridine-3-yl)-propionamide (substance 100) are dissolved in 500 ml ethanol and mixed with 8.0 g palladium (5%) on activated carbon (moistened with 40 ml water) and 25 ml conc. hydrochloric acid. The mixture is heated to ca. 45° C. and stirred under hydrogen atomosphere until consumption of the theoretical amount of hydrogen to be taken up (ca. five hours). After cooling, the catalyst is filtered and the solvent is removed under vacuum. The residue is taken up in 200 ml water and washed three times with a total of 200 ml CHCl3. The organic phases are discarded and the aqueous phase is made alkaline with 11 g sodium hydroxide and extracted three times, each with 100 ml CHCl3. After washing the organic phase with 30 ml water, the solvent is removed under vacuum. The oily residue is filtered over silica gel with CHCl3/CH3OH/NH4OH (80/20/2). Yield of the gradually hardening resin 53.0 g (83%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 70 °C
Yield: 88 %

Procedure:
2-Chloro-5-nitropyridine (800 mg, 5.05 mmol) was dissolved in dioxane (20 mL) and then 1-ethylpiperazine (1.7 g, 15.15 mmol) and N,N-diisopropylethylamine (927 mL, 5.05 mmol) were added. The reaction mixture solution was stirred at 70° C. for a day. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then washed with brine. The organic layer was concentrated by drying with magnesium sulfate. The target compound (1.05 g, 87% yield) was used in the following reaction without purification.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N(C(C)(C)C#N)=N[C:11](C)(C)[C:12]#N.[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:22]([C:23]1[CH:28]=[CH:27][C:26]([CH:11]=[CH2:12])=[CH:25][CH:24]=1)=[CH2:21]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CCCCCCCC
Solvent: O
Solvent: C=Cc1ccccc1
Product: C=Cc1ccc(C=C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 g of the amphiphilic macromolecule reversible addition-fragmentation chain transfer agent and 80 g of deionized water were formulated into an aqueous solution as an aqueous phase, which was added and uniformly mixed with an oil phase consisting of 6 g of styrene, 12 g of p-vinyl benzene, 0.1 g of azobisisobutyronitrile and 9 g of n-octane, and prepared by an ultrasonic crasher into a miniemulsion under the effect of a high shear field. The miniemulsion was transferred to a reactor and subjected to the reaction at a temperature of 80° C. which stopped after 4 hours, and then cooled to the room temperature and discharged to yield polymeric nanocapsules with highly crosslinked shells which were formed by the polymerization of styrene and p-divinyl benzene, wherein the polymeric nanocapsules have an average diameter of 90 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12]2)[N:4]=1.CO.[O-][Cl:24].[Na+]>ClCCl>[Cl:24][C:11]1([C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[O:12]1
Reactant: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Reactant: [O-]Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)nc(C2(Cl)OC(=O)c3ncccc32)n1

Procedure:
A mixture of 490 mg of 5-(4,6-dimethoxy-2-pyrimidinyl)furo[3,4,b]pyridine-7(5H)one and 50 ml of methanol is heated at 55° for 1/2 hour or until a homogeneous solution is formed. 2.6 g of NaOCl (common house bleach) is added dropwise. The mixture is taken up in dichloromethane an the organic phase separated and evaporated to dryness to yield the title compound, mp 146°-148° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]([CH3:22])[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: CNC
Product: CN(C)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.283 g, 1.1 mmol) and dimethylamine (2.7 mL, 2M solution in THF, 5.4 mmol) gives the title compound.