Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[C:10]1([C:16]2[C:21]([OH:22])=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[C:18]([CH3:27])[CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=C(C)C=C(C)C=1>[C:10]1([C:16]2[C:21]([O:22][P:2]3[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]3)=[C:20]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH:19]=[C:18]([CH3:27])[CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: CC1(C)COP(Cl)OC1
Reactant: Cc1cc(C2=CCCCC2)c(O)c(C(C)(C)C)c1
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C2=CCCCC2)c(OP2OCC(C)(C)CO2)c(C(C)(C)C)c1
Yield: 57.1 %

Procedure:
4.85 g (29.0 mmol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane are added dropwise over a period of about 15 minutes to a solution of 6.6 g (27.0 mmol) of 6-(cyclohexen-1-yl)-2-tert-butyl-4-methylphenol (compound(102), Example 1)and 4.0 ml (29.0 mmol) of triethylamine in 25 ml of mesitylene (1,3,5-trimethylbenzene). The reaction mixture is then refluxed for 18 hours, cooled, filtered, and the filtrate is concentrated on a vacuum rotary evaporator. Crystallization of the residue from dry acetonitrile gives 5.8 g (57%)of 2-[6-(cyclohexen-1-yl)-2-tert-butyl-4-methyl-phenoxy]-5, 5-dimethyl-1,3,2-dioxaphosphorinane, m.p. 97°-102° C. (compound(201), Table 2).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([C@H:11]1[N:15]([C:16]([C@@H:18]([NH:24][C:25]([CH2:27][NH:28][C:29]([C@@H:31]([NH:42][C:43]([C@@H:45]([NH:53][C:54]([C@@H:56]([NH:64][C:65]([CH:67]([NH:74][C:75]([C@@H:77]([NH:83][C:84]([C@@H:86]([NH:91][C:92]([C@@H:94]([NH:97][C:98]([C@@H:100]([NH:109][C:110]([C@@H:112]([NH:115]C(C)=O)[CH2:113][OH:114])=[O:111])[CH2:101][C:102]2[CH:107]=[CH:106][C:105]([OH:108])=[CH:104][CH:103]=2)=[O:99])[CH2:95][OH:96])=[O:93])[CH2:87][CH2:88][S:89][CH3:90])=[O:85])[CH2:78][CH2:79][C:80]([OH:82])=[O:81])=[O:76])[CH2:68][C:69]2[NH:73][CH:72]=[N:71][CH:70]=2)=[O:66])[CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])[CH2:46][CH2:47][CH2:48][NH:49][C:50]([NH2:52])=[NH:51])=[O:44])[CH2:32]C2C3C(=CC=CC=3)NC=2)=[O:30])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:17])[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:5]([NH2:7])=[O:6])[CH3:3].[OH2:119].C(N([CH2:125][CH3:126])CC)C>C(#N)C>[NH2:115][C@H:112]([C:110]([NH:109][C@H:100]([C:98]([NH:97][C@H:94]([C:92]([NH:91][C@H:86]([C:84]([NH:83][C@H:77]([C:75]([NH:74][C@H:67]([C:65]([NH:64][C@H:56]([C:54]([NH:53][C@H:45]([C:43]([NH:42][C@H:31]([C:29]([NH:28][CH2:27][C:25]([NH:24][C@H:18]([C:16]([N:15]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:9]([NH:8][C@H:4]([C:5]([NH2:7])=[O:6])[CH:2]([CH3:1])[CH3:3])=[O:10])=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:26])=[O:30])[CH2:32][C:126]1[CH:125]=[CH:5][C:4]([OH:119])=[CH:2][CH:1]=1)=[O:44])[CH2:46][CH2:47][CH2:48][NH:49][C:50](=[NH:51])[NH2:52])=[O:55])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:66])[CH2:68][C:69]1[N:73]=[CH:72][NH:71][CH:70]=1)=[O:76])[CH2:78][CH2:79][C:80](=[O:81])[OH:82])=[O:85])[CH2:87][CH2:88][S:89][CH3:90])=[O:93])[CH2:95][OH:96])=[O:99])[CH2:101][C:102]1[CH:103]=[CH:104][C:105]([OH:108])=[CH:106][CH:107]=1)=[O:111])[CH2:113][OH:114]
Reactant: O
Reactant: CCN(CC)CC
Reactant: CSCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(C)=O)C(=O)N[C@@H](CCC(=O)O)C(=O)NC(Cc1cnc[nH]1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(N)=O)C(C)C
Solvent: CC#N
Product: CSCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 66 h

Procedure:
Into 1 ml of stirred solution of 1 mg of α-MSH in a 8:2 mixture of acetonitrile and water placed in a polyethylene test tube under Ar and containing 0.07 mg of triethylamine (TEA), 2.15 mg of NHS-Chlidea (prepared in Example 14a) in a small volume (about 0.2 ml) of acetonitrile was added and shortly sonicated. The reaction mixture, sealed under Ar, was stirred at room temperature in the dark for 66 hrs. In the course of the reaction, aliquots of 15 μl were taken from the reaction mixture, after 0, 3, 19, 45 and 66 hrs from the beginning of the reaction, and were subjected to HPLC analysis.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][NH:3]1.S(=O)(=O)(O)[OH:17]>>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([NH2:9])=[O:17])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][NH:3]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(=O)[nH]nc1-c1ccccc1
Product: NC(=O)c1cc(=O)[nH]nc1-c1ccccc1
Reaction time: 24 h

Procedure:
2,3-Dihydro-3-oxo-6-phenyl-5-pyridazinecarbonitrile (10.0 g) is added to cold (0°-5° C.) concentrated sulfuric acid (50 ml) and the resulting solution is kept at 0°-5° C. for 24 hours and then poured onto crushed ice and the solid product is collected and recrystallized from aqueous ethanol to give 2,3-dihydro-3-oxo-6-phenyl-5-pyridazinecarboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH2:17][CH3:18].[Cl-].[Na+]>CN(C)C=O.O>[CH2:16]([NH:19][C:13]([C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:15])[CH2:17][CH3:18]
Reactant: CCCN
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitro-1H-indole-2-carboxylic acid (6.95 g, 33.7 mmol) in N,N-dimethylformamide (DMF)/pyridine (1/1, 150 ml) N,N′-carbonyl-diimidazole (5.47 g, 33.71 mmol) was added. The mixture was stirred at 80° C. for 1 h. At 0° C. propylamine (9.96 g, 168.56 mmol) was added. The mixture was stirred at 0° C. for 1 h and then at room temperature for 16 h. The solution was diluted with water (2 I). After addition of sodium chloride the product precipitated. After filtration the residue was washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as a yellow powder.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][C:45]1[S:49][C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)=[N:47][CH:46]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][CH2:44][C:45]1[S:49][C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:53]=[N:52]2)=[N:47][CH:46]=1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: COCc1cnc(Cn2ncc(N)n2)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cnc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (61.0 mg, 0.28 mmol) in CH2Cl2 (1.5 mL) was treated at rt with DMAP (8.5 mg, 0.07 mmol), HOBt (45.6 mg, 0.34 mmol), EDC (135 mg, 0.70 mmol) and DIPEA (0.19 mL, 1.12 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 2-((5-(methoxymethyl)thiazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (63 mg, 0.28 mmol) in CH2Cl2 (1.5 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (5.0 mL), the layers were separated and the org. phase was washed with water (5.0 mL) dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil: TLC: rf (4:6 hept-EA)=0.29. LC-MS-conditions 07: tR=0.92 min, [M+H]+=425.09.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[C:7]1=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O.B(F)(F)F.CCOCC.CS(O)(=O)=O.C([SiH](CC)CC)C>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:9]2[CH:23]=[CH:24][CH:25]=[CH:26][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCC1(C(=O)OCC)CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1=O
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Agent: FB(F)F
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)CCCC1(C(=O)OCC)CCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc2C1
Temperature: 5 °C
Yield: 52.6 %

Procedure:
Compound 29 (4.76 g, 9.48 mmol) was dissolved in 45 mL of dry 1,2-dichloroethane, cooled to 5° C., and treated with trifluoroacetic acid (1.3 mL), BF3.Et2O (1.4 mL), anhydrous methanesulfonic acid (3.2 mL) and triethylsilane (5.7 mL). The reaction was allowed to slowly warm to room temperature over 18 hours. The reaction was cooled to 5° C. and cautiously quenched with saturated aqueous NaHCO3 (100 mL). The reaction mixture was extracted with ethyl acetate (100 mL) and the ethyl acetate extract was extracted with saturated aqueous NaHCO3, water, brine (2×), dried over Na2SO4, and concentrated in vacuo to give an oil. This oil was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (17:3) to give 2.43 g (53%) of compound 30 as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH2:3][C:4](=[O:6])[OH:5].CC(C)=O.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>O.[OH-].[Na+]>[C:22]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12]([OH:14])=[O:13])=[O:8])[CH2:3][C:4](=[O:5])[OH:6])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A suspension of 20 g (0.081 mols) of α-aspartylaspartic acid in 80 ml of water was dissolved in a 27-% sodium hydroxide aqueous solution until the pH reached 11, and 40 ml of acetone were added thereto. To the solution were added dropwise 17.7 g (0.081 mols) of lauroyl chloride over a period of 1 hour. When adding lauroyl chloride, the temperature was maintained at 10° C., and 27-% sodium hydroxide was added dropwise simultaneously to keep the pH at 11. After the addition of lauroyl chloride, the reaction solution was warmed at 30° C., and allowed to stand for 30 minutes. Subsequently, the pH was adjusted to 1 with the addition of conc. hydrochloric acid. The solid precipitate was separated by filtration, and dried to obtain 31.7 g of N-(N'-lauroyl-α-aspartyl)aspartic acid in a yield of 91%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,640 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.CO.[C:12](O)(=O)[CH3:13].C(C=O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[C:4]([N:3]=1)=[N:9][CH:12]=[CH:13][N:8]=2
Reactant: CC(=O)O
Reactant: Nc1ncc(Br)nc1N
Agent: O=CC=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Brc1cnc2nccnc2n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 50 mg (0.27 mmol) of 5-bromopyrazine-2,3-diamine in 2 mL of a 10:1 solution of methanol/acetic acid was added 0.046 mL (0.40 mmol) of glyoxal solution (40 wt. % in water) and the resulting solution was stirred at 50° C. for 4 h. The reaction mixture was cooled to ambient temperature, diluted with 10 mL of ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (5 mL each). The organic phase was then dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to yield the title compound as a tan crystalline solid which was used without further purification. LC/MS 211.1, 213.1 (M+1, M+3).
Reaction SMILES: [NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:15][CH2:14]2)[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:37].C([O:40][C:41](=[O:55])[CH2:42][N:43]1[CH2:48][CH2:47][N:46]([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:45][CH2:44]1)C>>[NH2:1][C:2]1[C:32]([C:33]([F:35])([F:34])[F:36])=[CH:31][C:5]([CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:15][CH2:14]2)[C:8]([N:52]2[CH2:51][CH2:50][CH:49]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([OH:40])=[O:55])[CH2:48][CH2:47]3)[CH2:54][CH2:53]2)=[O:9])=[CH:4][C:3]=1[Cl:37]
Reactant: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(CC(=O)O)CC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 16.4 from 108 mg (0.20 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 51 mg (0.20 mmol) ethyl(4-piperidin-4-yl-piperazin-1-yl)-acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:34])[C:12](=[O:33])[C:13]([CH3:32])=[C:14]2[C:19]=1[C:18](=[O:20])[NH:17][C:16](=[O:21])[N:15]2[C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1.[CH2:35]([O:42][CH2:43][CH2:44][CH2:45][CH2:46]O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C.O>[CH2:35]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][N:17]1[C:18](=[O:20])[C:19]2=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])[N:11]([CH3:34])[C:12](=[O:33])[C:13]([CH3:32])=[C:14]2[N:15]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=2)[C:16]1=[O:21])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(=O)Nc1cccc(-n2c(=O)[nH]c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Reactant: OCCCCOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(-n2c(=O)n(CCCCOCc3ccccc3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Yield: 77 %

Procedure:
Under argon atmosphere, to a suspension of N-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 89 (75.0 mg), 4-benzyloxybutyl alcohol 90 (25.0 μl) and triphenylphosphine (37.0 mg) in tetrahydrofuran (1.00 ml) was added diisopropyl azodicarboxylate (28.0 μl) with stirring under ice cooling. The mixture was stirred at the same temperature for 2 hrs, and 4-benzyloxybutyl alcohol (13.0 μl), triphenylphosphine (19.0 mg) and diisopropyl azodicarboxylate (14.0 μl) were added. The mixture was stirred at the same temperature for 1 hr, and water and ethyl acetate were added to allow partitioning. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:ethyl acetate=2:1→1:1) and thin layer chromatography (hexane:acetone=1:1) for further purification to give N-{3-[3-(4-benzyloxybutyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 91 (74 mg, yield 77%) as a pale-yellow amorphous form.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)=[N:27][CH:28]=1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:35][CH:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([CH3:22])=[CH:28][N:27]=3)[CH2:34][CH2:33]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1ccc(N2CCC(N)CC2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)nc1
Temperature: 120 °C
Yield: 43.5 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (97 mg, 0.324 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 1-(5-Methylpyridin-2-yl)piperidin-4-amine dihydrochloride (86 mg, 0.327 mmol) was added followed by TEA (33 g, 0.324 mmol). The reaction mixture was heated in a microwave reactor for at 120° C. for 25 mins. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3-solution and water. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (64 mg, 43.5%). 1H NMR (500 MHz, CDCl3): δ 1.33-1.41 (m, 2H), 1.71-1.74 (m, 1H), 2.17 (s, 3H), 2.38-2.43 (m, 2H), 3.08-3.15 (m, 1H), 3.95-3.99 (m, 2H), 5.23 (d, 1H), 6.51 (d, 1H), 7.26 (dd, 1H), 7.43-7.45 (m, 3H), 7.53-7.55 (m, 2H), 7.96 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 17.51, 27.84, 32.05, 44.64, 50.68, 61.78, 107.10, 107.50, 122.63, 125.39, 128.91, 130.11, 131.90, 134.20, 138.65, 147.86, 157.77, 159.91; Mass Spectrum: M+H+ 455.0.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH2:13]1CC[CH:16]([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:15][CH2:14]1>>[CH2:22]([NH:21][C@H:2]([C:1]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:1][CH2:2][CH2:3][CH3:4].[NH2:21][C:20]1[CH:13]=[CH:14][CH:15]=[CH:16][N:19]=1
Reactant: CCCCCCCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCCCCCN[C@@H](Cc1ccccc1)C(=O)O
Product: Nc1ccccn1

Procedure:
The acylated phenylalanine anilide imprint molecule was synthesized in three steps. (1) N-α-t-BOC-L-phenylalanine was coupled with 2-aminopyridine using DCC to give N-α-t-BOC-L-phenylalaniine-2-aminopyridine. (2) The a-amine was then deprotected with TFA to give N-α-L-phenylalanine-2-aminopyridine. (3) To create a compound having the properties of a surfactant, the free amine was then acylated with decanoic acid using DCC to give N-α-decyl-L-phenylalanine-2-aminopyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[C:4]([Cl:25])[CH:3]=1.[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]([C:32](Cl)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)C(C)C)(C)C.O>ClCCl>[CH:15]1[C:13]2[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([NH:1][C:32]([C:27]4[C:26]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:33])=[CH:3][C:4]=3[Cl:25])=[O:7])[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[O:11][C:12]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
A mixture of 0.263 g of 10,11-dihydro-10(4-amino-2-chlorobenzoyl)dibenz[b,f][1,4]oxazepine, 0.195 g of [1,1'-bipheny]-2-carbonyl chloride and 0.116 g of N,N-diisopropylethylamine in 7 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N Na2CO3, water, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate (pad washed with dichloromethane). The filtrate is concentrated to dryness to give a yellow solid. The solid is purified by chromatography on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give 0.12 g of a yellow glass, m.p. 145° C.-188° C.: Anal.found: C, 73.6; H, 4.6; N,5.0; Cl, 6.4.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[C:4]([CH3:20])=[N:3]1.[OH-:21].[Na+]>OS(O)(=O)=O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:9]([C:11]([NH2:12])=[O:21])[CH:10]=[C:5]2[C:4]([CH3:20])=[N:3]1
Reactant: [OH-]
Reactant: Cc1nn(C)c2nc(CCN3CCCC3)c(C#N)cc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nn(C)c2nc(CCN3CCCC3)c(C(N)=O)cc12
Temperature: 60 °C
Reaction time: 48 h

Procedure:
1,3-Dimethyl-6-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile was dissolved in concentrated H2SO4 (55 mL) and the solution stirred at 60° C. for 2 days. The mixture was cooled to 0° C., treated with 6N NaOH to pH 14, and extracted with ethyl acetate. The organic extract was evaporated under reduced pressure and the residue washed with ether to give 1,3-dimethyl-6-[2-(pyrrolidin-1-yl)ethyl)-1H-pyrazolo [3,4-b]pyridine-5-carboxamide (2.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C1COCC1>[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](=[O:6])[NH2:7])[CH:3]=1)=[O:22]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 3-aminobenzamide (310 mg, 2.3 mmol) in 7.6 mL of THF at 0° C. was added triethyl amine (0.63 mL, 4.6 mmol) followed by 2-bromobenzoylchloride (500 mg, 2.3 mmol). The reaction was stirred at 0° C. for 15 minutes and partitioned between water and dichloromethane. The layers were separated, the organics dried and solvent removed to give 2-bromo-N-(3-carbamoylphenyl)benzamide which was used for coupling without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][F:17])[N:11]=1)(=O)=O.[CH3:18][NH2:19]>>[F:17][CH2:16][C:12]1[N:11]=[C:10]([C:9]#[C:8][CH2:7][CH2:6][NH:19][CH3:18])[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCCC#Cc1cccc(CF)n1
Reactant: CN
Product: CNCCC#Cc1cccc(CF)n1
Yield: 15 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(C), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 11 mmol) and N-methylamine 40% in aqueous solution (20 mL). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH: from 90/10 to 90/10 with TEA as eluent) to afford 324 mg of 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine as a pale oil (Yield: 15%).