Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.BrN1C(=O)CCC1=O>C(OCC)(=O)C>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)CCc1cc(C)ccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: Cc1ccc2c(=O)c3ccc(C)cc3ccc2c1
Temperature: 80 °C

Procedure:
10,11-Dihydro-2,8-dimethyl-5H-dibenzo[a,d]cyclohepten-5-one (European Patent, 1993, 0 25 589 322 A1) (6 g) and N-bromosuccinimide (5 g) in ethyl acetate (100 ml) was irradiated with a 500 W halogen lamp. After 5 hours the reaction mixture was cooled and quenched with brine. The organic layer was collected, dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in dry dimethylformamide, treated with 1,5-diazabicyclo[4.3.0]non-5-ene (3.5 ml) and heated at 80° C. for 0.25 hours. The cooled reaction mixture was washed with 2M HCl, brine, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with toluene. Yield 4.5 g.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[OH:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[OH:21])[CH2:34][CH2:33]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Cc1ccc(N2CCNCC2)c(O)c1
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2ccc(C)cc2O)CC1
Yield: 77 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2-hydroxy-4-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C1(C2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][O:17][C:18]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[O:8]2)C=CC=CC=1.[ClH:26]>C(OCC)C>[ClH:26].[C:12]([NH:11][CH2:10][CH:9]([OH:8])[CH2:16][O:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)N1CC(COc2ncccc2C#N)OC1c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)NCC(O)COc1ncccc1C#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To S -2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethylformamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred four hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform exrract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, S -2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution) is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of S -2-(3-tert. butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:26]4[N:30]=[C:29]([C:31]56[CH2:40][CH:35]7[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]7)[CH2:32]5)[CH2:38]6)[O:28][N:27]=4)[CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[C:25]2[C:20](=[C:21]([C:26]3[N:30]=[C:29]([C:31]45[CH2:40][CH:35]6[CH2:34][CH:33]([CH2:39][CH:37]([CH2:36]6)[CH2:38]4)[CH2:32]5)[O:28][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3c(-c4noc(C56CC7CC(CC(C7)C5)C6)n4)cccc32)COC(C)(C)OC1
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: NC(CO)(CO)CN1CCc2c(-c3noc(C45CC6CC(CC(C6)C4)C5)n3)cccc21
Yield: 78 %

Procedure:
When the product of Step C was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 78% yield. 1H-NMR (DMSO-d6) 1.75 (s, 6H); 2.07 (s, 9H); 2.97-3.57 (m, 12H); 6.7 (d, 1H, J=7.6 Hz); 7.12 (tr, 1H); 7.34 (d, 1H, J=7.7 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1>O1CCCC1>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[CH:26]([NH:25][C:10]([C:6]1[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:27]2
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NC1CN2CCC1CC2)c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
Tetrahydrofuran (50 ml) was added to a mixture of indole-5-carboxylic acid (2.42 g, 0.016 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole). The mixture was stirred for 1 hr while nitrogen was bubbled through the solution to remove the carbon dioxide that was evolved. Then 3-aminoquinuclidine (1.89 g, 0.015 mole) was added in one portion, and the mixture was stirred for 60 hr at room temperature. The solid product was collected by filtration to yield 3.75 g (86.8%). Recrystallization from methanol-isopropyl ether (with chilling) gave 1.89 g of the product as an off-white solid; m.p. 293°-295° C. The solid was vacuum dried at 82° C. for 16 hr, m.p. 293°-295° C.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:28](Cl)(=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[C:28]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CCCCCC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCCC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(OC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 23.8 %

Procedure:
To a solution of 2-(4-methoxybenzyl)phenyl β-D-glucopyranoside (0.10 g) in 2,4,6-trimethylpyridine (2 mL) was added hexanoyl chloride (0.072 g) at 0° C., and the mixture was stirred for 3 hours. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-(4-methoxybenzyl)phenyl 6-O-hexanoyl-β-D-glucopyranoside (0.030 g).
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CO>ClCCl>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CN1C(=O)CCN1C(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CN1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To a solution of 1,1-dimethylethyl 2-methyl-3-oxo-1-pyrazolidinecarboxylate (0.98 g, 4.89 mmol) in dry dichloromethane was added borane dimethyl sulfide complex (1.16 ml, 12.24 mmol). The mixture was stirred at rt overnight. LCMS indicated ˜40% starting material left. Another portion of borane dimethyl sulfide complex (0.5 ml, 5.28 mmol) was added, and stirring continued overnight. Methanol was added dropwise to the reaction mixture until bubbling ceased. Water (1 ml) was then added, and the mixture was refluxed for 1 h. After cooling to rt, the mixture was concentrated to dryness under vacuum. The residue was taken up in water (30 ml) and dichloromethane (45 ml), the organic layer was separated, and the aqueous layer was extracted with dichloromethane (45 ml). The combined organic solution was dried (Na2SO4), filtered and concentrated to provide 1,1-dimethylethyl 2-methyl-1-pyrazolidinecarboxylate (0.48 g, 52.7%). LCMS: (2M+H)+ 372.9.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([C:11]([C:21]4[CH:26]=[CH:25][N:24]=[C:23](S(C)(=O)=O)[N:22]=4)=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[NH2:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>C(#N)C>[CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([C:11]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[N:22]=4)=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(CN)CO
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3c(CC4CC4)nccn23)n1
Solvent: CC#N
Product: CC(C)(CO)CNc1nccc(-c2c(-c3ccc(F)cc3)nc3c(CC4CC4)nccn23)n1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A solution of 8-cyclopropylmethyl-2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)imidazo[1,2-a]pyrazine (3.00 g, 7.08 mmol) and 3-amino-2,2-dimethylpropan-1-ol (TCI-US, 3.65 g, 35.4 mmol) in ACN (100 mL) was heated at about 85° C. for about 2 d. After cooling to ambient temperature, a precipitate formed, which was filtered off, washed with ACN, dried in vacuo and purified by silica gel chromatography with heptane/EtOAc (gradient 50-100% EtOAc, then isocratic 100% EtOAc). After concentration, the residue was three times re-dissolved in DCM and re-concentrated, resulting in a colorless foam, which was dried in a vacuum oven for about 16 h at about 55° C. and about 21 Torr to give 1.809 g (56%) of the title compound as a colorless solid: LC/MS (Table 1, Method g) Rt=3.01 min; MS m/z: 447.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([N:18]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24].CO>>[ClH:24].[NH:8]1[CH2:11][CH:10]([C:12]2[C:17]([N:18]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:9]1
Reactant: CC1CCN(c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CO
Product: CC1CCN(c2nccnc2C2CNC2)C1
Yield: 99 %

Procedure:
A solution of 3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidine-1-carboxylic acid tert-butyl ester (43) (191 mg, 0.6 mmol) in 4N HCl/MeOH (13 mL) was stirred at RT for 30 min. The reaction mixture was concentrated to give 2-azetidin-3-yl-3-(3-methyl-pyrrolidin-1-yl)-pyrazine hydrochloride (44)
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:3]=1.BrC1C(OC)=CC(NCC2C=CC3N=C(SC)SC=3C=2)=C([N+]([O-])=O)C=1>>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([S:11][CH3:12])[S:10][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:3]=1
Reactant: CSc1nc2c(Br)cc(CNc3ncccc3[N+](=O)[O-])cc2s1
Agent: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Product: CSc1nc2c(Br)cc(CNc3ncccc3N)cc2s1

Procedure:
N2-((4-Bromo-2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine was synthesized as a red solid (120 mg) using a procedure analogous to that described in Step 2 of Example 41, substituting N-((4-bromo-2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine from the previous step for 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline used in Example 41. LCMS (ESI) m/z 380, 382 (M+H)+.
Reaction SMILES: [CH2:1]1[O:16][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH2:5]2)[O:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH2:2]1[O:3][C:4]2([CH2:5][CH2:6][CH:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH2:8][CH2:9]2)[O:16][CH2:1]1
Reactant: C1=C(c2cccnc2)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: c1cncc(C2CCC3(CC2)OCCO3)c1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A mixture of 4-(3-pyridyl)cyclohex-3-en-1-one ethylene acetal (4.80 g, 22.1 mmol) in EtOAc (50 mL) containing 10% Pd/C (458 mg) was hydrogenated under atmospheric pressure for 3 h. After filtration of the catalyst, the solution was concentrated in vacuo, to yield 4-(3-pyridyl)cyclohexanone ethylene acetal (4.81 g, 99%) as yellow solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:14]1.C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a mixture di-tert-butyl [{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]piperidin-1-yl}methylylidene]biscarbamate 64 (2.30 g, 4.71 mmol) in a solution of DCM (40 mL) and ethanol (6 mL) was added hydrazine hydrate (0.270 mL, 4.71 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 65 (0.72 g, 43%) as a white foam.
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH3:11][C:12]([O:15][C:16]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:17])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.[I-].[Li+]>[C:22]([O:21][C:19]([N:18]([C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Temperature: 70 °C
Reaction time: 22 h
Yield: 91 %

Procedure:
3-(Bromomethyl)benzonitrile (5 g, 25.5 mmoles) and di-tert-butyliminodicarboxylate (5.54 g, 25.5 mmoles) were dissolved in anhydrous THF (50 mL) and cesium carbonate (16.62 g, 25.5 mmoles) and lithium iodide (1 70.5 mg, 1.275 mmoles) were added. The mixture was stirred at 70° C. for 22 h and the reaction was worked up as described in Preparative Example 89, Step B above. The residue was chromatographed on a silica gel column (60×5 cm) using 5% ethyl acetate in hexane as the eluant to give 3-(di-tert-butoxycarbonylamino)benzonitrile (7.39 g, 87%): FABMS: m/z 333.2 (MH+); HRFABMS: m/z 333.1815 (MH+); Calcd. for C18H25N2O4: m/z 333.1814; δH (CDCl3) 1.52 (18H, s, —COOC(CH3)3), 4.84 (2H, s, CH2), 7.48 (1H, m, Ar—H), 7.60 (2H, m, Ar—H) and 7.65 ppm (1H, m, Ar—H); δC (CDCl3) CH3: 28.1, 28.1, 28.1, 28.1, 28.1, 28.1; CH2: 48.4; CH: 129.2, 131.0, 131.0, 131.9; C: 83.2, 83.2, 112.5, 118.8, 140.1,152.5, 152.5.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:34])[C@H:23]([CH2:25][CH2:26][C:27](=[O:33])[O:28]C(C)(C)C)[NH2:24])[CH:16]=1)=[CH:8][CH:7]=2)(=[O:3])[NH2:2].Cl>C(Cl)Cl.O1CCOCC1>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:34])[C@H:23]([CH2:25][CH2:26][C:27](=[O:28])[OH:33])[NH2:24])[CH:16]=1)=[CH:8][CH:7]=2)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)Nc1cccc(COc2ccc3[nH]c(C(N)=O)cc3c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1cc2cc(OCc3cccc(NC(=O)[C@@H](N)CCC(=O)O)c3)ccc2[nH]1
Reaction time: 1 h
Yield: 51 %

Procedure:
2-Carbamoyl-5-[3-(O-tert-butyl-α-glutamylamino)benzyloxy]-1H-indole (0.29 g; 0.62 mmol) in solution in CH2Cl2 (2 ml) was treated under argon with HCl (2N) in dioxan (4 ml). The mixture was stirred for one hour, evaporated and the residue was purified on OASIS resin, eluting with H2O/CH3CN 80/20 to give 2-carbamoyl-5-[3-(α-glutamylamino)benzyloxy]-1H-indole.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:45])[C@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:10][C:11](=[O:40])[CH:12]([CH2:21][P:22]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:39])([O:24]C)=[O:23])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.Cl>[C:1]1([NH:7][C:8](=[O:45])[C@H:9]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:10][C:11](=[O:40])[CH:12]([CH2:21][P:22]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:39])([OH:24])=[O:23])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COP(=O)(CCCCN1Cc2ccccc2C1=O)CC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)C(CCc1ccccc1)CP(=O)(O)CCCCN1Cc2ccccc2C1=O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
(2-(((4-(1,3-Dihydro-1-oxo-2H-isoindol-2-yl)butyl)methoxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine N-phenylamide (0.31 g, 0.49 mmol) from Step C was dissolved in methanol (10 mL). The solution was cooled in an ice bath and 2N aqueous sodium hydroxide (5 mL, 10 mmol) was added. The solution was allowed to warm to room temperature and was stirred for an additional 12 h before being diluted with 2N aqueous hydrochloric acid (40 mL) and extracted with ethyl acetate (75 mL). The organic extract was washed with saturated aqueous sodium chloride (25 mL), dried (sodium sulfate), and evaporated. The crude product was purified by high pressure liquid chromatography on a.22 mm×25 cm reverse phase column (Whatman ODS-3, Partisil 10) eluting with 45% acetonitrile/55% water/0.05% trifluoroacetic acid (flow rate of 20 mL/min, detection at 250 nm). Evaporation of appropriate fractions gave 264 mg the desired product (88% yield) as a colorless brittle foam.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=2[C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[CH:6][C:5]=1[O:27][CH3:28].[OH-].[Na+]>C1COCC1>[NH2:26][C:23]1[N:22]=[CH:21][C:20]([C:19]#[C:18][C:11]2[C:12]([CH2:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([O:27][CH3:28])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: CCc1nccc(-c2ccc(C(=O)OC)c(OC)c2)c1C#Cc1ccc(N)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nccc(-c2ccc(C(=O)O)c(OC)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 1.07 g (2.77 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-methoxy-benzoic acid methyl ester (A-41) using 2.4 mL (2.4 mmoL) 1N NaOH in 30 mL THF. The reaction mixture is stirred over night, after complete consumption of the starting material the pH is adjusted to 4 (using 1N HCl). As no precipitate is formed, the aqueous phase is extracted with DCM. However, the product precipitates upon addition of DCM and is collected by filtration. Additional product is precipitated from the mother liquid by adjustment of the pH to 6 (using 1N NaOH). Yield of the combined fractions: 990 mg (96%).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:14])=O>>[C:1]([Cl:14])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C=Cc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The cinnamic acid (5 g, 19.7 mmol) and thionyl chloride (5 eq) were put in MC and stirred at 60° C. overnight. Then, the reaction mixture was removed of the unreacted thionyl chloride and the solvent under vacuum to obtain cinnamoyl chloride.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[OH2:23]>C(OC(=O)C)(=O)C>[F:1][C:2]([F:21])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:6](=[O:23])[CH:5]=[C:4]([CH3:20])[O:18][C:16]=3[CH3:17])=[CH:11][CH:10]=2)=[CH:19][CH:20]=1
Reactant: O
Reactant: CC(=O)Cc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2)c(C)o1
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of polyphosphoric acid (60 g) and acetic anhydride (26 ml) at 90° was added over 15 min a solution of 4-(4-trifluoromethoxyphenoxy) phenylpropan-2-one (9.3 g) in acetic anhydride (30 ml). The mixture was stirred for a further 30 min at 90° then poured into water (1 liter) and extracted with toluene (2×500 ml). The combined extracts were washed with water then satd. aq. sodium bicarbonate and dried over magnesium sulphate. Concentration in vacuo gave an orange oil which was chromatographed on silica gel, eluting with dichloromethane then 1:19 methanol/dichloromethane, to give the title compound as an oil (4.1 g), NMR δH (CDCl3) 6.9-7.4 (8H, m), 6.16 (1H, s), 2.24 (3H, s), 2.16 (3H, s).
Reaction SMILES: [C:1]1(=[C:11]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[O:14][C:12]2=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:23]1[CH2:24][CH2:25][N:20]([C:15]([CH2:16][CH2:17][CH2:18][C:11](=[C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH2:2]2)[C:12]([OH:14])=[O:13])=[O:19])[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: O=C1CCCC(=C2CC=Cc3ccccc32)C(=O)O1
Solvent: ClCCl
Product: O=C(O)C(CCCC(=O)N1CCOCC1)=C1CC=Cc2ccccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.9 %

Procedure:
To a solution of 4.4 g (16.5 mmole) of 2-(1-naphthylidene)adipic anhydride (prepared as described above) dissolved in 80 ml of methylene chloride were added 1.58 ml (18.2 mmole) of morpholine, and the mixture was stirred at room temperature for 14 hours. At the end of this time, the reaction mixture was washed, in turn, with a 5% w/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The mixture was then freed from the solvent by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: a 30: 1 by volume mixture of methylene chloride and methanol), to afford 1.12 g of 5-morpholinocarbonyl-2-(1-naphthylidene)pentanoic acid.