Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]>C1COCC1.[Cl-].[Na+].O>[C:3]([CH:2]([CH2:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC(=O)C(F)(F)F)C(C)=O
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl acetoacetate (3.98 mL) in THF (dry) (50 mL) was added NaH (1.571 g) at 0° C., and the mixture was stirred for 30 min at the same temperature. To the mixture was added 3-bromo-1,1,1-trifluoroacetone (5 g) 0° C., and the mixture was stirred for 3 h. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.570 g).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7].C([Li])CCC.C(O)(=[O:35])C.OO>O1CCCC1>[F:1][C:2]1[CH:26]=[CH:25][C:24]([OH:35])=[CH:23][C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(I)ccc1F
Reactant: CC(=O)O
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(O)ccc1F
Temperature: -78 °C
Yield: 43 %

Procedure:
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2-fluoro-5-iodo-benzyl) ester (8.9 g, 18 mM) was dissolved in tetrahydrofuran (150 mL), trisopropylborate (6.7 g, 36 mM) was added and the mixture was cooled to −78° C. At this low temperature n-butyllithium (16.9 mL, 1.6N) was added drop by drop with stirring. The mixture was stirred for 45 min at −78° C., for another 45 min at −50° C. and for 15 min at 0° C. Acetic acid (9.5 mL, 50%) was added slowly with stirring (0–5° C.), followed by hydrogen peroxide (2.75 mL, 35%). Stirring continued with cooling for another 45 min and for 1 h at room temperature. The mixture was partitioned between water and diethylether, organic phases were pooled, washed with water, sodium thiosulfate solution (5%), brine and dried with Na2SO4 to yield after evaporation a light yellow oil (8.5 g). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate 1:1) to yield 3.0 g (43%) of the product as a yellowish oil. MS (ISP): 400.5 (M+NH4)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.Cl[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[O:22].CCN(C(C)C)C(C)C>>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)=[O:22])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)cc1
Yield: 45.2 %

Procedure:
Methyl 4-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)amino]carbonyl}benzoate was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.05 g, 0.17 mmol), methyl 4-(chlorocarbonyl)benzoate (0.05 g, 0.25 mmol) and DIPEA (0.05 mL, 0.25 mmol). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were lyophilized, neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.035 g, 45%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.22 (s, 1H), 7.98-8.06 (m, 2H), 7.92-7.98 (m, 2H), 7.80 (s, 1H), 7.60 (d, 1H), 7.45 (s, 1H), 7.38 (t, 1H), 7.25 (s, 1H), 7.23 (d, 1H), 4.47 (d, 2H), 3.86 (s, 3H). MS: m/z 455.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[C:38](=[O:40])[NH:27][C:16]=2[CH:17]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (20.0 g, 53.27 mmol, 1.0 equiv; example 1/step 4) in toluene (200 mL) and N-ethyldiisopropylamine (17.21 g, 133.17 mol, 2.5 equiv) was added a solution of triphosgene (18.97 g, 63.92 mmol, 1.2 equiv) in toluene (200 mL) and the reaction mixture stirred at 70° C. for 1.5 h. The solvent was evaporated, the residue diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water and a sat. solution of NaCl, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was further washed with a mixture of hexane/ethyl acetate (95:5) to yield 15.5 g (73%) of the title product as wvhite solid. 1H NMR (400 MHz, DMSO): δ 1.43 (s, 9H), 1.72 (d, J=10.8, 2H), 2.17-2.23 (m, 2H), 2.88 (br s, 2H), 4.09 (d, J=8.6 Hz, 2H), 4.38 (t, J=12.2 Hz, 1H), 4.77 (d, J=5.3 Hz, 2H), 5.26 (d, J=10.4 Hz, 1H), 5.40 (dd, J=17.2 Hz, J=1.4 Hz, 1H), 5.99-6.09 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.69-7.71 (m, 1H), 11.17 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 28.04, 28.43, 50.32, 64.78, 78.79, 108.13, 109.18, 117.70, 121.69, 121.71, 122.67, 128.20, 132.81, 133.39, 153.78, 153.82, 165.36. MS (ISP): 402.2 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][S:4][C:3]1=2.N1C2CCC3C=CC=CC=3C(=O)C=2S[CH:17]=1.IC>C1COCC1>[CH3:17][C:5]1[S:4][C:3]2[C:2](=[CH2:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:7]=2[N:6]=1
Reactant: O=C1c2ccccc2CCc2ncsc21
Reactant: C=C1c2ccccc2CCc2ncsc21
Solvent: C1CCOC1
Solvent: CI
Product: C=C1c2ccccc2CCc2nc(C)sc21
Reaction time: 0.08 h

Procedure:
Add 1.2 equiv of n-BuLi-hexanes dropwise to a solution of 4-methylene-9,10-dihydro-4H-3-thia-1-aza-benzo[f]azulene (prepared from 9,10-dihydro-3-thia-1-aza-benzo[f]azulen-4-one (see Scheme XIII(b) as in Preparation 23) in THF (0.08 M) at −78° C. under Ar. Stir the resultant dark green solution for 5 min before adding 1.2 equiv of iodomethane in THF. Allow to warm and stir at room temperature for 18 h before quenching with excess water. Separate layers and extract the aqueous layer with diethyl ether (3×) and then dry (MgSO4) and concentrate the combined organic layers under reduced pressure. Use in the next step without further purification: 1H NMR (CDCl3, 400 MHz) δ 2.60 (s, 3 H), 3.03-3.13 (m, 4 H), 5.34 (s, 1 H), 5.53 (s, 1 H), 7.20-7.28 (m, 3 H), 7.33 (m, J=7.2 Hz, 1 H). TLC Rf=0.30 (10% EtOAc:hexanes).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:2]([CH2:3][CH2:4][C:5]([N:14]2[CH2:21][CH2:20][CH2:19][C@H:15]2[C:16]([OH:18])=[O:17])=[O:7])=[O:1])[CH:9]=1
Reactant: O=C(O)CCC(=O)c1cccnc1
Reactant: O=C(O)[C@@H]1CCCN1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1cccnc1

Procedure:
As for Example 11, γ-oxo-3-pyridinebutyric acid is coupled to L-proline to give 1-[3-(3-pyridylcarbonyl)propionyl]-L-proline.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2.IC1C=C2C(=CC=1)[NH:24][CH:23]=C2>>[C:23]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2)#[N:24]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: Ic1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1

Procedure:
When the product of Step B was substituted for 5-iodoindole in Example 7, Step A, the similar process afforded the title compound in 85%, as colourless solid, after purification by FCC (SiO2; CH2Cl2). 1H-NMR (CDCl3) 1.49 (s, 9H); 4.56-4.72 (m, 4H); 7.32-7.37 (m, 1H); 7.49-7.56 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(NS(C)(=O)=O)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NS(C)(=O)=O)cc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 27.5 %

Procedure:
(S)—N-(3-Methyl-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (110 mg, 0.16 mmol) was treated with trifluoroacetic acid (2 ml, 26 mmol) and a solution of ammonia (7N in methanol, 2 ml, 90 mmol) according to the method described in Example 27 to give 25 mg (28% yield) of the title compound. Purity 98%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][CH:10]2[CH:15]([N:16]=1)[CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11]2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1=CC2N=C(N3CCC[C@@H]3C)C(=O)NC2C=C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-((S)-2-methylpyrrolidin-1-yl)-2-oxo-1,2,4a,8a-tetrahydroquinoxaline-6-carboxylate (140.0 mg, 0.48 mmol) in dichloromethane (50 mL) was added pyridine (152 mg, 1.92 mmol) and Tf2O (271 mg, 0.96 mmol), and the reaction mixture was stirred overnight under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3×15 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (195 mg, crude), which was used in the next step directly.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1)/[C:13]([OH:15])=O.[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH:39]([NH2:41])[CH3:40].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C.O.C(Cl)CCl.CN(C=O)C>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH:39]([NH:41][C:13](=[O:15])/[C:12](=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1)/[CH2:11][CH2:10][CH2:9][Cl:8])[CH3:40]
Reactant: CC(N)c1ccc(F)cc1F
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(/C=C(\CCCCl)C(=O)NC(C)c2ccc(F)cc2F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a DMF (5 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (250 mg) obtained in Example 418 and 1-(2,4-difluorophenyl)ethylamine (CAS#603951-43-5, 141 mg), IPEA (0.5 mL), EDC (430 mg) and HOBT (303 mg) were added one by one, and the reaction solution was agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system). (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid [1-(2,4-difluorophenyl)ethyl]amide was obtained. Sodium hydride (40% mineral oil content, 20 mg) was added to a DMF (5 mL) solution of this compound, and that reaction solution was agitated at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) 151 mg of (E)-1-(1-(2,4-difluorophenyl)ethyl)-3-(3-methoxy-4-(methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one racemate was obtained. This compound (25 mg) was separated in CHIRALPAK™ AD-H available from Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase; hexane:ethanol=7:3), and the title optically active substance with a retention time of 25 minutes (Example 620: 11.8 mg; >99% ee) and the title optically active substance with a retention time of 45 minutes (Example 621: 11.2 mg; >99% ee) were obtained. The physical properties of the title optically active compound with a retention time of 25 minutes are as follows.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][C@H:9]3[CH2:13][N:12](CC4C=CC=CC=4)[CH2:11][C@@H:10]3[O:21][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:22]>CO>[ClH:22].[F:1][C:2]1[C:7]2[CH2:8][C@H:9]3[CH2:13][NH:12][CH2:11][C@@H:10]3[O:21][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1C[C@H]1CN(Cc3ccccc3)C[C@@H]1O2
Agent: Cl
Solvent: CO
Product: Fc1cccc2c1C[C@H]1CNC[C@@H]1O2

Procedure:
A solution of Example 1 (0.42 g) in methanol (10 mls) was treated with excess hydrogen chloride in methanol and the solution was evaporated to dryness. The residue was redissolved in methanol and was hydrogenated over 10% palladium on charcoal (50 mg) at 40°-50° until reaction was complete. The solvent was evaporated, the product was treated with hydrogen chloride in ethanol, evaporated to dryness and the solid was triturated with isopropyl alcohol to give the title compound (0.25 g). M.p. 220°-2°. NMR (DMSOd6) δ 9.72 (2H, Br-s, NH2+), 7.22 (1H, q, 6-H), 6.9-6.7 (2H, m, 5-H, 7-H), 4.21 (1H, d of t, 3a-H), 3.78-2.6 (6H, m, 3-H2, 1-H2, 9-H2), 2.22 (1H, m, 9a-H).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.NCCCCCCN[C:18]1[C:19]2[C:24]([N:25]=[C:26]3[C:31]=1[CH:30]=[CH:29][CH:28]=[CH:27]3)=[CH:23][CH:22]=[CH:21][CH:20]=2.CO>C(Cl)(Cl)Cl>[CH:20]1[C:19]2[C:24](=[N:25][C:26]3[C:31]([CH:18]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][CH:21]=1
Reactant: NCCCCCCNc1c2ccccc2nc2ccccc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: c1ccc2nc3ccccc3cc2c1
Reaction time: 1 h

Procedure:
To a solution of 76 mg (0.168 mmol) of TFP ester 4 in 3 mL of chloroform was added 94 μL of triethylamine (0.67 mmol). 1.23 ml of a 50 mg/mL solution of 9-(6-aminohexylamino)acridine dihydrochloride in methanol (61.5 mg, 0.168 mmol) was added to the stirred solution. HPLC analysis after 1 hour showed complete reaction of the starting TFP ester. The reaction mixture was partitioned between 15 mL of methylene chloride and 10 mL of water. The organic phase was washed with 10 mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was chromatographed on silica gel and the desired product was eluted with a gradient of 90:5:5-methylene chloride: triethylamine:methanol in hexanes. Removal of solvents gave the desired product 5 as a red solid: TLC (90:5:5-methylene chloride: triethylamine:methanol) Rf =0.79; 1H NMR (CDCl3) δ 8.12 (d, 2H, J=8.8 Hz,), 8.07 (d, 2H, J=8.8 Hz), 7.68 (t, 2H, J=6.9 Hz), 7.37 (t, 2H, J=7.4 Hz), 5.60 (s, 1H), 5.2 (br s, 1H), 3.82 (t, 2H, J=7.1 Hz), 3.21 (q, 2H, J=6.6 Hz), 2.54 (m, 2H), 2.2 (m, 10H), 1.98 (s, 3 H), 1.8-1.65 (m, 6H), 1.5-1.3 (m, 6H).
Reaction SMILES: OC[C:3]1[O:7][C:6]([CH:8]=[CH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5][CH:4]=1>C(O)C>[O:7]1[CH:3]=[CH:4][CH:5]=[C:6]1[CH:8]=[CH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC(=O)C=Cc1ccc(CO)o1
Solvent: CCO
Product: CCCCCCCCC(=O)C=Cc1ccco1

Procedure:
1-Furan-2-yl-undec-1-en-3-one was prepared using a procedure similar to that described for the synthesis of 1-(5-Hydroxymethyl-furan-2-yl)-undec-1-en-3-one using either ethanol as solvent or using no solvent.
Reaction SMILES: C(O)=O.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=O.[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1.Cl>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:9][CH:21]1[C:22](=[O:23])[O:24][C:17]([CH3:25])([CH3:16])[O:18][C:19]1=[O:20]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
Under ice-cooling, to formic acid (20 mL) was added dropwise triethylamine (29.6 mL). Then, 3,4-dimethoxybenzaldehyde (9.22 g) and Meldrum's acid (8.00 g) were added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was poured into a mixture of ice (80 g) and 1 mol/L hydrochloric acid (50 mL), and the precipitate was collected by filtration to give the title compound (14.4 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=O.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[N:13]1([C:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]2=[O:1])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1CCCCC1C(=O)N1CCCCC1
Yield: 96.5 %

Procedure:
Ethyl 2-oxocyclohexane-carboxylate (5.3 g, 31 mmol, 5.0 mL) DMAP (1.05 g, 9.4 mmol) and piperidine (5.3 g, 63 mmol, 6.2 mL) in toluene (100 mL) were heated at reflux for 4 days. The reaction was allowed to cool and the reaction was concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (20-80% (B), 100 g, 8 CV, 85 mL/min) to afford 6.26 g (96%) of 2-(piperidine-1-carbonyl)-cyclohexanone (19) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 23.5, 24.5, 25.5, 26.2, 27.1, 30.4, 41.9, 42.9, 46.8, 54.2, 167.6, 207.6.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]([OH:13])[CH2:11][OH:12].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:12][CH2:11][CH2:10][O:13][CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)OC(=O)CCOCCO
Temperature: 25 °C
Reaction time: 96 h
Yield: 22.4 %

Procedure:
tert-Butyl acrylate (5.72 mL, 39.0 mmol) was added to a mixture of ethylene glycol (2.42 g, 39.0 mmol), tetrabutylammonium bromide (377 mg, 1.17 mmol) and potassium hydroxide (77 mg; purity, 85%; 1.17 mmol), and the mixture was stirred at room temperature for 4 days. The reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1, v/v) to give the title compound (1.66 g; yield, 22%) as a colorless oily substance.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:32])[C:26]=2[CH:25]=[CH:24]1.Cl>CCO.C(Cl)Cl.N.CO>[N:16]1[C:8]([C:7]2[C:2]([NH:32][C:27]3[C:26]4[CH:25]=[CH:24][NH:23][C:31]=4[CH:30]=[CH:29][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[C:9]2[C:13]([NH:12][CH:11]=[N:10]2)=[N:14][CH:15]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: c1cnc(Nc2cccc3[nH]ccc23)c(-c2ncnc3[nH]cnc23)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 5.5 %

Procedure:
6-(2-Fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (115.0 mg, 0.3842 mmol) and 1H-indol-4-amine (Aldrich, St. Louis, Mo., 70.7 mg, 0.535 mmol) were suspended in EtOH (1.8 mL) and aqueous hydrochoric acid (5.0 M, 0.090 ml, 0.45 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.), and the reaction was stirred for 3 hours. Then, the reaction was cooled to room temperature and diluted with DCM, 2N ammonia in MeOH, EtOH, and MeOH and concentrated. The residue was treated with MeOH and filtered. Neither the filtrate nor the solid contained pure material, so they were combined, concentrated, treated with DMF, and filtered. The filtrate was concentrated and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min). The fractions with product were collected, concentrated, and filtered through a silica gel plug (about 1 inch, 50:1 DCM/2N ammonia in MeOH to 20:1 DCM/2N ammonia in MeOH to 5:1 DCM/2N ammonia in MeOH) to afford N-(3-(9H-purin-6-yl)pyridin-2-yl)-1H-indol-4-amine (6.9 mg, 5% yield). MS (ESI pos. ion) m/z: 328, (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.90 (s, 1H), 11.16 (s, 1H), 9.87 (d, J=7.82 Hz, 1H), 9.24 (s, 1H), 8.73 (s, 1H), 8.43 (dd, J=4.69 Hz, 1.96 Hz, 1H), 8.28 (dd, J=4.6 Hz, 3.81 Hz, 1H), 7.38-7.35 (m, 1H), 7.09 (s, 1H), 7.08-7.06 (m, 1H), 7.04 (dd, J=7.82 Hz, 4.69 Hz, 1H), 6.79-6.76 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(O)(C)C>[N+:8]([C:7]1[C:2]([N:14]2[CH2:15][CH2:16][NH:11][C:12](=[O:17])[CH2:13]2)=[N:3][CH:4]=[CH:5][N:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1nccnc1Cl
Reactant: O=C1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C1CN(c2nccnc2[N+](=O)[O-])CCN1
Reaction time: 20 h
Yield: 54.7 %

Procedure:
A solution of 2-chloro-3-nitropyrazine (9.1 g, 57 mmol) in chloroform (100 ml) was added dropwise over 45 minutes to a cooled solution of piperazine-2-one (5.71 g, 57 mmol) and triethylamine (8.0 ml, 57 mmol) in isopropanol (120 ml). After addition was complete, the reaction mixture was allowed to warm to 20°-25° and was stirred at this temperature for 20 hours. The precipitate was removed by filtration and recrystallized from methanol-ethyl acetate-hexane to give 6.96 g (54.7%) of product, m.p. 178°-179°.