Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: [H][H]
Reactant: CC(C)CCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
3-Nitro-1-iso-pentyl-1H-pyrazole (115 mg, 0.63 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-iso-pentyl-1H-pyrazol-3-ylamine (89 mg, 93%) as golden oil: ESI-LRMS m/e calcd for C8H15N3 [M+] 153.1, found 154.3 [M+H+].
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]([OH:11])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:2]1[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCOCC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 17 %

Procedure:
Proceeding as in Example 1, but substituting 2-morpholin-4-ylacetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 155, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-morpholinoacetamido)propanamide (23 mg, 17%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.20 (br s, 1H), 7.98-7.96 (d, 1H), 7.61-7.57 (d, 2H), 7.33-7.26 (m, 5H), 7.23-7.19 (t, 2H), 7.04-6.97 (m, 4H), 4.72-4.67 (m, 1H), 4.52 (s, 2H), 3.78-3.68 (m, 2H), 3.59-3.57 (t, 4H), 2.99 (s, 2H), 2.47-2.42 (m, 4H). MS (EI) for C28H30FN3O5. found 508.0 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH2:1]([N:8]1[C:12]([CH:25]2[CH2:27][CH2:26]2)=[CH:11][C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(Cc2ccccc2)n1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(C2CC2)n(Cc2ccccc2)n1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2.57 g of methyl 1-benzyl-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (7.06 mmol, 1.0 eq.) were dissolved in 51 mL of dry 1,2-dimethoxyethane under nitrogen atmosphere. 1.52 g of cyclopropylboronic acid (17.6 mmol, 2.5 eq.), 2.62 g of sodium carbonate (24.7 mmol, 3.5 eq.) and 408 mg of tetrakis(triphenylphosphin)palladium(0) (0.353 mmol, 0.05 eq.) were added and the mixture was stirred for 24 hours at 75° C. bath temperature. Then the mixture was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue purified by flash chromatography to give 1.61 g (5.39 mmol, 76%) of analytically pure target compound.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH3:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[C:15]([CH3:21])[N:14]=1>O1CCCC1>[CH3:12][C:13]1[C:18]([CH:19]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)[OH:20])=[CH:17][CH:16]=[C:15]([CH3:21])[N:14]=1
Reactant: Cc1ccc(C=O)c(C)n1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cnnn2C)c(C)n1
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 22.5 mL, 56.3 mmol) was added dropwise by syringe to a stirring solution of 1-methyl-1H-1,2,3-triazole (5.00 g, 60.2 mmol, prepared according to PCT Int. Appl., 2008098104) in dry tetrahydrofuran (400 mL) at −55° C. The resulting off-white slurry was stirred at −45° C. for 20 minutes, whereupon a solution of 2,6-dimethyl-pyridine-3-carbaldehyde (8.33 g, 61.7 mmol) in dry tetrahydrofuran (10 mL) was added dropwise by syringe. After 5 minutes, the cooling bath was removed and the reaction mixture was allowed to slowly warm. After 45 minutes, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (100 mL) were added. The mixture was concentrated by rotary evaporation. The residue was dissolved in ethyl acetate (300 mL). The organic solution was washed with saturated aqueous sodium chloride solution (100 mL, containing excess solid sodium chloride). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and the combined solution was concentrated. Ether (100 mL) was added to the residue and the mixture was sonicated for 20 minutes during which time a white solid crashed out. The solids were collected by filtration. Ether (100 mL) was added to the collected solids and the mixture sonicated a second time. After 20 minutes, the mixture was filtered and the solids were collected to provide the title compound as a fine powder.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH:11]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:28][CH:27]=1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C(c1ccc2nc(Oc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 80 °C

Procedure:
A suspension of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine (54 mg, 0.14 mmol), methyl-4-hydroxybenzoate (21.7 mg, 0.14 mmol) and potassium carbonate (21.6 mg, 0.16 mmol) in 1 mL of DMF was heated at 80° C. overnight. The mixture was concentration in vacuo and the residue partitioned between water and DCM. After extracting the aqueous layer, the combined DCM extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified using PTLC and eluting with 5% MeOH (2N NH3)/DCM to provide methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-yl)butyl)benzo[d]thiazol-2-yl)oxy)benzoate. MS (ESI) m/z 451.17 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=2[C:5]([F:19])=[C:4](Cl)[N:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(N(C(C)C)CC)(C)C>CS(C)=O.CC(O)C>[C:31]([O:30][C:29]([NH:28][C@@H:23]1[C@H:22]([NH:21][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:18])[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:6]=3[C:5]=2[F:19])[CH2:27][CH2:26][O:25][CH2:24]1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1Cc2c(F)c(Cl)nc(Cl)c2C1=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 26.4 %

Procedure:
A mixture of tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (1.24 g, 3.85 mmol), tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (1.00 g, 4.62 mmol), diisopropylethylamine (3.36 mL, 19.27 mmol) in DMSO (10 mL) and 2-propanol (40 mL) were heated to 100° C. in an oil bath for 20 h. The reaction was repeated on the same scale and both reaction solutions were combined and concentrated. The mixture was purified via silica gel flash chromatography eluting with EtOAc and hexanes (10-50% EtOAc gradient) to give the title compound as a pale pinkish-white solid (510 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (s, 9H), 1.50 (s, 3H), 1.59-1.61 (m, 1H), 1.97-1.99 (m, 1H), 1.97-1.99 (m, 1H), 3.46-3.49 (m, 2H), 3.80-3.83 (m, 3H), 4.31-4.33 (m, 1H), 4.73 (s, 1H), 6.59 (d, J=7.30 Hz, 1H), 7.43 (d, J=7.30 Hz, 1H). [M+H] calc'd for C22H30ClFN4O6, 501; found, 501.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.N1(O)C2C=CC=CC=2N=N1.[N:51]12[CH2:58][CH2:57][CH:54]([CH2:55][CH2:56]1)[C@@H:53](O)[CH2:52]2>C1COCC1>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:18][C@@H:53]2[CH:54]3[CH2:57][CH2:58][N:51]([CH2:56][CH2:55]3)[CH2:52]2)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(Nc1ccccc1)c1ccc(OCc2ccccc2)nc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 12 %

Procedure:
To a solution of 2-(6-(benzyloxy)pyridin-3-yl)-2-(phenylamino)acetic acid (I52) (460 mg, 1.38 mmol) in THF (20 ml), were added DCC (341 mg, 1.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (223 mg, 1.65 mmol), and (R)-quinuclidin-3-ol (210 mg, 1.65 mmol). The resulting reaction mixture was stirred at room temperature for 15 hours, and then the solvent was evaporated. DCM is added, the insoluble was filtered off and the organic phase was washed twice with Na2CO3 and brine, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography (DCM/MeOH=95/5 to 97/3), recovering first diastereomer 1 of C53 (71 mg, 12% yield), then a mixture of diastereomers of C53 (84 mg, 14% yield) and finally diastereomer 2 of C53 (21 mg, 4% yield).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[NH2:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([NH:16][C@H:17]([C:19]2[N:23]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:22]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=3[N:20]=2)[CH3:18])[N:11]=[CH:10][N:9]=1.OO>CS(C)=O>[NH2:7][C:8]1[C:13]([C:14]([NH2:15])=[O:2])=[C:12]([NH:16][C@H:17]([C:19]2[N:23]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:22]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=3[N:20]=2)[CH3:18])[N:11]=[CH:10][N:9]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cccnc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](Nc1ncnc(N)c1C(N)=O)c1nc2ccc(F)cc2n1-c1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of potassium carbonate (0.027 g, 0.19 mmol) and (S)-4-amino-6-(1-(6-fluoro-1-(pyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethylamino)pyrimidine-5-carbonitrile (0.060 g, 0.16 mmol) in DMSO (1.60 mL) was added hydrogen peroxide (31.3% in water, 0.078 mL, 0.80 mmol) dropwise under nitrogen atmosphere. The solution was stirred at 0° C. for 1 h then was partitioned between water and EtOAc. Organic extracts were concentrated under reduced pressure then purified by MPLC (eluted with a gradient of 0-10% MeOH in DCM) to afford 4-amino-6-(((1S)-1-(6-fluoro-1-(3-pyridinyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarboxamide as an off-white foam. 1H NMR (400 MHz, DMSO-d6) d ppm 1.48 (d, J=6.85 Hz, 3H) 5.26 (quin, J=6.94 Hz, 1H) 6.57 (s, 2H) 6.98 (dd, J=8.90, 2.45 Hz, 1H) 7.14 (ddd, J=9.78, 8.80, 2.54 Hz, 1H) 7.46 (s, 2H) 7.65-7.70 (m, 1H) 7.74 (dd, J=8.80, 4.89 Hz, 1H) 7.77 (s, 1H) 7.94 (d, J=7.63 Hz, 1H) 8.05-8.12 (m, 1H) 8.78 (dd, J=4.79, 1.47 Hz, 1H) 8.82 (d, J=2.15 Hz, 1H). LC-MS (ESI) m/z 393.2 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:18](OCC)[O:17][C:16](=O)[CH2:15]1)[CH:5]=[CH2:6].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH2:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:18]=[N:3][NH:2][C:16](=[O:17])[CH2:15]1)[CH:5]=[CH2:6]
Reactant: C=CCOc1ccccc1C1CC(=O)OC1OCC
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCOc1ccccc1C1C=NNC(=O)C1

Procedure:
Hydrazine hydrate (2.8 ml) was added to a solution of 4-(2-allyloxyphenyl)-5-ethoxydihydro-2-furanone (9.8 g) in acetic acid (30 ml) and water (27 ml). The solution was refluxed for 90 minutes, poured into aqueous sodium bicarbonate, extracted into diethyl ether, evaporated under reduced pressure and the resultant solid recrystallised from benzene to afford 5-(2-allyloxyphenyl)-4,5-dihydro-3[2H]-pyridazinone (6.5 g) as white crystals, m.p. 93°-95° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:28]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]1[CH2:37][CH2:36][N:35]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)(=[O:21])=[O:20])=[CH:17][CH:18]=3)=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)N3CCOCC3)cc2)c1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)c2)CC1
Yield: 72 %

Procedure:
The title compound was prepared from 1-(3-cyanophenyl)-3-(4-(morpholinosulfonyl)phenyl)urea following procedure C and using 2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:9][C:10]1[CH:22]=[CH:21][C:13]([CH:14]=[CH:15][C:16](OCC)=[O:17])=[CH:12][CH:11]=1>C[O-].[Na+]>[O:4]=[C:3]1[CH2:5][C:16](=[O:17])[CH2:15][CH:14]([C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:22][CH:21]=2)[CH:2]1[C:1]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)C=Cc1ccc(C)cc1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1C(=O)CC(=O)CC1c1ccc(C)cc1

Procedure:
To a cooled solution of sodium methoxide (from 2.3 g., sodium and absolute methanol, 40 ml.) was added with shaking methyl acetoacetate (11.8 g.). When homogeneous the mixture was treated with ethyl p-methylcinnamate (19. g.) and then heated under reflux for 18 hrs. After cooling the precipitated sodium enolate salt (formula III) was collected by filtration and washed with acetone. This enolate salt was then converted to the corresponding dione of formula II by dissolving in cold water followed by acidification with 2-N-hydrochloric acid, which afforded crystalline methyl 2,4-dioxo-6-p-tolylcyclohexanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COc1ccc(Cl)cc1C=O
Yield: 923.5 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (3.1 g, 2 mmol), 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (5.46 g, 24 mmol), K2CO3 (5.5 g, 40 mmol) and KI (0.1 g) were mixed in DMF (20 mL). Then the mixture was irradiated under microwave at 150° C. for 1 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (Yield: 5 g, 92.5%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH:3]=[CH:4]3)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: Cn1ccc2cc(CN)ccc21
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(ccn2C)c1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (1-methyl-1H-indol-5-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.76 min.; [M+H]+: 379.12 g/mol.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH3:17])=[C:11]([CH2:14][CH3:15])[CH:12]=2)[C:6](=[O:7])[O:5]1)#[N:2].C[O-].[Na+]>Cl>[C:1]([CH:3]1[C:6](=[O:7])[C:8]2[C:13](=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH2:16][CH3:17])[CH:9]=2)[C:4]1=[O:5])#[N:2]
Reactant: CCc1cc2c(cc1CC)C(=CC#N)OC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1cc2c(cc1CC)C(=O)C(C#N)C2=O
Yield: 77.8 %

Procedure:
A mixture of 3-cyanomethylene-5,6-diethylphthalide (4.7 g; 0.021 mole) and methanolic sodium methoxide (from sodium [0.48 g] and methanol [21 ml]) was refluxed for 20 mins., cooled, and the red solution poured into 5N hydrochloric acid (100 ml). The precipitated yellow solid was filtered off and dried in vacuo over P2O5 /NaOH to yield 3.711 g (79%) of material of m.p. 172°-173° C (d). (Found; C, 73.60; H, 5.94; N, 6.13; C14H13NO2 requires; C, 73.99; H, 5.77; N, 6.16%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.[NH:19](/[C:23](/[CH3:29])=[CH:24]\[C:25](OC)=[O:26])[C:20]([CH3:22])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:25](=[O:26])[CH:24]=[C:23]([CH3:29])[N:19]=[C:20]2[CH3:22])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(N2CCCCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCCCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
To a solution of 3-fluoro-4-(piperidin-1-yl)aniline (10.00 g, 51 mmol) in anhydrous CH2Cl2 (100 mL) was added trimethylaluminum (155 mL, 155 mmol, 1.0 M in toluene) under N2. The mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (9.72 g, 62 mmol) in anhydrous CH2Cl2 (20 mL). The reaction mixture was stirred at rt for 5 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a pale yellow solid (11.02 g, 71%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=O.[C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])#[N:16].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1/[CH:4]=[CH:5]/[CH:6]=[C:17]([C:15]#[N:16])[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=CC=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)=C/C=C/c1cc([N+](=O)[O-])ccc1Cl

Procedure:
15 g (70 millimoles) of 2-chloro-5-nitrocinnamaldehyde (mp. 115°-117° C.) and 10 g (0.1 mole) of methyl cyanoacetate in 200 ml of toluene were heated under a water separator in the presence of 1 g of ammonium acetate and 1 ml of acetic acid until water no longer distilled over. The product crystallized out on cooling. After the usual working up procedure, 58% of the product of melting point 193°-194° C. remained.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+]([O-])=O)[CH:9]=1)(=[O:4])=[O:3].[Br:17]C1C=C(CCO)C=CC=1>>[CH3:1][S:2]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:17])[CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Reactant: OCCc1cccc(Br)c1
Product: CS(=O)(=O)OCCc1cccc(Br)c1
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield using a similar procedure to description D4 starting from 2-(3-bromophenyl)ethanol.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[C:14]2=[O:21])[CH:10]=[CH:11][CH:12]=1>C(OC(=O)CC)(=O)CC.O>[C:17]([NH:6][C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:19])([CH3:20])[C:14]2=[O:21])[CH:10]=[CH:11][CH:12]=1)(=[O:18])[CH2:16][CH3:15]
Reactant: CC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Agent: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)Nc1cccc(N2C(=O)CC(C)(C)C2=O)c1

Procedure:
Five and one half g. of propionic anhydride containing one drop of concentrated sulfuric acid was mixed at ambient temperature with 8.7 g. of N-m-aminophenyl-2,2-dimethylsuccinimide in a small beaker. The mixture became very hot and on cooling was poured into water and extracted with methylene chloride, which was dried and stripped under vacuum yielding 9.5 g. of a glassy product. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11](O)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:31]([NH2:39])[C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33].C(Cl)(Cl)Cl.CO>C(#N)C>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C@H:2]([C:11]([NH:39][CH2:31][C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: NCC(=O)NCC(=O)O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
FMOC-Tyr-gly-gly was coupled to ADR as in Section 7.1.1. for gly-ADR. Yield of FMOC-tyr-gly-gly-ADR was 95%; melting point 150°-153° C.; Rf: 0.63 [chloroform/methanol 8:2 (silica); Rf: 0.68 [acetonitrile/0.1% aqueous TFA 1:1 (reverse phase)]. Elemental analysis for C55H54N4O17H2O; calculated: C,62.25; H, 5.32; N, 5.30; observed: C, 62.17; H, 5.92; N, 5.09. The protecting FMOC moiety removed from the product as described in Section 7.1.1. for gly-ADR. Yield of the product tyr-gly-gly-ADR.HOAc was 68 mg (80%); melting point, 165.C (dec.); Rf: 0.10 [chloroform/methanol 8:2 (silica)]; Rf: 0.53 [acetonitrile 0.1% aqueous TFA 1:1 (reverse phase)]. Elemental analysis for C42H48N4O17.2H2O; calculated: C, 55.01; H, 5.72; observed: C, 55.15; H, 5.54.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][NH:17][CH3:18])=[CH:10][CH:9]=1>C(OCC)C>[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:18])=[CH:10][CH:9]=1
Reactant: CNCCCc1ccncc1
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)CCN(C)CCCc1ccncc1
Reaction time: 8 h

Procedure:
15.1 g of ethyl acrylate are added portionwise to a solution of 22.5 g (0,15 Mol) of N-[3-(pyrid-4-yl)propyl]-N-methyl-amine in 50 ml of diethyl ether. The clear solution formed is allowed to stand overnight. The solvent is evaporated off. Ethyl 3-{N-[3-(pyrid-4-yl)propyl]-N-methyl-amino}-propionate is thus obtained as an oil.