Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:5]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]>CO>[C:1]([CH:4]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][CH:5]1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(O)ccc1/C=C/C(=O)O
Solvent: CO
Product: CC(=O)C1C=C(O)C=CC1/C=C/C(=O)O
Yield: 97.3 %

Procedure:
Some ortho-coumaric acid was acetylated under conventional conditions to obtain ortho-acetyl coumaric acid with a yield of 49% after recrystallisation. 5.54 g (26.9 mmol) o-acetyl coumaric acid was then hydrogenated for 4 h in 50 ml methanol using 0.5 g 10% Pd-C to give 5.45 g (97%) o-acetyl dihydrocoumaric acid in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH3:32][CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[CH2:25][N:34]3[CH2:35][CH2:36][CH2:37][CH:33]3[CH3:32])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccc(F)cc3C=O)ccc2n1
Reactant: CC1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCN1Cc1cc(F)ccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
95 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-5-fluorobenzaldehyde are dissolved in 2 ml of 1,2-dichloroethane and 2 ml of tetrahydrofuran. 34 μl of 2-methylpyrrolidine and 18 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 103 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH3:38])=[O:36])=[CH:31][CH:30]=2)=[C:23]([CH3:39])[CH:22]=1>CC(O)C.Cl>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:36])[NH:37][CH3:38])=[CH:31][CH:30]=3)=[C:23]([CH3:39])[CH:22]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(N)cc2C)cc1
Agent: Cl
Solvent: CC(C)O
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4C(=O)OC)n3)cc2C)cc1
Temperature: 120 °C

Procedure:
A mixture of methyl 2-(2,5-dichloropyrimidin-4-ylamino)benzoate (Step 1, 50 mg, 0.16 mmol) and 4′-amino-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide (Intermediate 31, 46 mg, 0.16 mmol) in 2-propanol is treated with conc. aqueous HCl (4 drops). The mixture is sealed and heated in a microwave at 120° C. for 20 min. The mixture is concentrated, and the residue is partitioned between ethyl acetate and sodium carbonate aqueous solution. The organic layer is concentrated to afford crude methyl 2-(5-chloro-2-(5-methoxy-2-methyl-4′-(methylcarbamoyl)biphenyl-4-ylamino)pyrimidin-4-ylamino)benzoate as a brown solid. The obtained crude product is treated with neat cyclopropylamine (0.5 mL). The mixture is heated in a sealed tube at 110° C. overnight. The mixture is concentrated and the residue is applied to RP-HPLC for purification to afford the 4′-(5-chloro-4-(2-(cyclopropylcarbamoyl)phenylamino) pyrimidin-2-ylamino)-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.75 (m, 1H), 8.49 (m, 1H), 8.15 (s, 1H), 7.91 (d, 2h0, 7.73-7.71 (m, 1H), 7.60 (m, 1H), 7.46 (d, 2H), 7.30-7.26 (m, 1H), 6.98 (s, 1H), 3.88 (s, 3H), 2.96 (s. 3H), 2.90-2.86 (m, 1H), 2.15 (s, 3H), 0.86-0.83 (m, 2H), 0.67-0.65 (m, 2H); ESMS m/z 557.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>C(Cl)(Cl)Cl>[CH3:8][C:9]1([CH3:14])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:11](=[O:12])[CH2:10]1
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)Nc2ccccc21
Temperature: 80 °C

Procedure:
Aniline (7.26 g, 45.2 mmol) and 3-methylbut-2-enoyl chloride (53.2 g, 45.2 mmol) were heated in chloroform at reflux for 2 h. After cooling, the mixture was filtered. The filtrate was concentrated to dryness and dried under vacuum. The crude 3-methyl-but-2-enoic acid phenylamide (ca. 10 g) was dissolved in toluene (50 mL). This toluene solution was added to the stirred AlCl3 powder (27 g) portion-wise. After addition, the resulting dark brown solution was heated at 80° C. for 2.5 h. The warm slurry was poured carefully to stirred crashed ice. The resulting mixture was extracted with EtOAc (3×), washed with sat'd NaHCO3, H2O, brine, and dried over MgSO4. The residue was purified by silica gel flash chromatography (CH2Cl2, then EtOAc) to give 2.2 g of pure 1a and about 4-5 g of less pure portion 1a. LC-MS ESI 176 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1SC.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1
Reactant: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c1=O
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
The mixture of 4-(2-chloro-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (30, 1.50 g, 5.0 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1.500 g, 7.50 mmol) was ground for 5 min and then heated in a tube under nitrogen atmosphere at 130° C. for 14 h. The mixture was separated by silica gel column, and eluted with 10-50% ethyl acetate in petroleum ether to give (R)-tert-butyl 1-(4-(2-chloro-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (31). MS: m/z, 396 (100%, M-56), 398 (35%), 452 (100%, M+1), 454 (35%), 474 (70%, M+23), 476 (25%).
Reaction SMILES: C([CH2:3][O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=1)#N.C(N(CC)CC)C>CO>[C:25]1([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[CH:10]=[CH:11][C:6]([C:5]([O:4][CH3:3])=[O:31])=[N:7][CH:8]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#CCOC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Heat at reflux 4 gm. (0.01 mole) of cyanomethyl-5-(triphenylmethyl)picolinate and 2 ml. triethylamine in 50 ml. methanol for 4 hr. Remove methanol under reduced pressure. Triturate solid residue with water and recrystallize from ethylacetate - isopropyl ether, to obtain the product of this example, m.p. 160°-164°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[CH:16][C:15]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:23][CH:24]=2)=[CH:16][C:15]=1[C:29]([F:30])([F:31])[F:32]
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to those described for E1 starting from 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol.
Reaction SMILES: C(OC(=O)CC(C)=O)C.N1CCCCC1.[CH2:16]([O:18][C:19](=[O:30])[C:20]([C:27](=[O:29])[CH3:28])=[CH:21][CH:22]([CH3:26])[CH2:23][CH2:24][CH3:25])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:19]([C:20]1[CH2:21][C:22]([CH3:26])([CH2:23][CH2:24][CH3:25])[O:29][C:27]=1[CH3:28])([O:18][CH2:16][CH3:17])=[O:30]
Reactant: CCCC(C)C=C(C(C)=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Product: CCCC1(C)CC(C(=O)OCC)=C(C)O1
Temperature: 120 °C

Procedure:
4-Carbethoxy-2,5-dimethyl-2-propyl-2,3-dihydrofuran was prepared by the acid-catalyzed rearrangement of ethyl-2-acetyl-4-methyl-2-heptenoate. The ethyl-2-acetyl-4-methyl-2-heptenoate was obtained by reacting 390 grams (3 moles) ethylacetoacetate with 300 grams (3 moles) 2-methylvaleradehyde in the presence of a small amount (10.2 grams; 0.12 mole) piperidine. For the rearrangement, 100 grams (0.47 mole) of the ethyl-2-acetyl-4-methyl-2-heptenoate was combined with 4.4 grams (0.023 mole) p-toluenesulfonic acid and 100 mls toluene. The mixture was heated at reflux (120° C.) for about 2 hours and worked up in accordance with the procedure of Example XXIV. Short path distillation of the crude product yielded 4-carbethoxy-2,5-dimethyl-2-propyl-2,3-dihydrofuran (B.P. 98°-100° C. at 2.5 mm Hg). The product had a pleasing cis-jasmine-like (jasmone, celery, jasmine absolute) odor. The structure ##STR25## was confirmed by infrared and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([NH:8][C:9]([C@@H:11]([NH:23][C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:14])=[O:10])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:7]=[C:6]1[C:2](=[O:1])[CH2:3][CH:4]([NH:8][C:9]([C@@H:11]([NH:23][C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:14])=[O:15])=[O:10])[CH2:5]1
Reactant: O=C(NC1CC(O)C(O)C1)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CC(NC(=O)[C@H](CS(=O)(=O)Cc2ccccc2)NC(=O)N2CCOCC2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of morpholine-4-carboxylic acid [(R)-1-(3,4-dihydroxy-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide (670 mg, 1.47 mmol) in methylene chloride (40 ml) was treated with Dess-Martin periodinane (624 mg, 1.47 mmol) and the reaction stirred at room temperature overnight. More Dess-Martin periodinane (642 mg, 1.51 mmol) was added and the reaction stirred at room temperature for 6 hours and then overnight. The reaction mixture was washed with a solution of Na2S2O3 in water (0.26M), then with saturated aqueous bicarbonate solution, then with water, then dried over Na2SO4 and then evaporated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane, then with ethyl acetate to give morpholine-4-carboxylic acid [(R)-1-(3,4-dioxo-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide as an off white solid (45 mg). 1H NMR (CDCl3): 7.50–7.38 (m, 5H), 6.62 (m, 1H), 5.91 (d, J=5 Hz, 1H), 4.81 (m, 1H), 4.58–4.35 (m, 3H), 3.73–3.61 (m, 5H), 3.44–3.32 (m, 4H), 3.22 (m, 1H), 2.72–2.12 (m, 4H). MS: 452 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.C(O)(=O)C.[N-:24]=[C:25]=[O:26].[K+]>O>[N+:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH2:24])=[O:26])=[CH:19][C:6]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.75 g. of 5-amino-2-nitro-3-phenylbenzofuran in 5 ml. of glacial acetic acid and 3 ml. of water is added an equimolar amount of potassium isocyanate dissolved in 5 ml. of warm water. The reaction is stirred at about 20° C. for 30 minutes then filtered to separate the solid product. The solid is recrystallized from aqueous methanol to provide yellow crystals of 2-nitro-3-phenyl-5-ureidobenzofuran, m.p. 230°-232° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([Li])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([N:14]([CH2:28][CH3:29])[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[CH:20][CH:19]=1)[CH3:13].[Cl-].[NH4+]>CCOCC>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:24]([CH2:25][CH3:26])([OH:27])[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:14]([CH2:28][CH3:29])[CH2:12][CH3:13])=[CH:23][CH:22]=1
Reactant: [Li]c1cccc(C(F)(F)F)c1
Reactant: CCC(=O)c1ccc(OCCN(CC)CC)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCN(CC)CCOc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 250 ml. of a 0.4 molar solution of 3-trifluoromethylphenyl-lithium in ether a solution of 6.3 g. of 4'-[2-(diethylamino)-ethoxy]-propionphenone in 60 ml. of dry ether is added dropwise, under argon atmosphere, at -30° C., and the reaction mixture is stirred at room temperature for two hours. After cooling the reaction mixture is decomposed with a saturated, aqueous ammonium chloride solution, and the aqueous phase is extracted with ether. The ethereal phases are combined, washed to neutral with water and dried over anhydrous magnesium sulfate. Ether is distilled off under reduced pressure. The residue is chromatographed on a silica gel column with a 7:3 mixture of benzene and ethyl acetate. The solvent mixture is distilled in vacuo, and the residue is crystallized from n-hexane. 3.2 g. of the title compound are obtained, melting at 74° to 75° C.
Reaction SMILES: C1[C@H](NCC2[C:12]3[C:13]([N:15]=[C:16]([NH2:18])[NH:17][C:11]=3[N:10]([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)C=2)=[O:14])[C@@H](O)[C@@H](O)C=1.NC1N=C2N=CC(C#N)=C2C(=O)N=1.ClC(CC#N)=O.ClCC#N.C(OC)=O>>[NH2:18][C:16]1[NH:15][C:13](=[O:14])[CH:12]=[C:11]([NH2:10])[N:17]=1
Reactant: Nc1nc(=O)c2c(CN[C@H]3C=C[C@H](O)[C@@H]3O)cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Agent: N#CC1=C2C(=O)N=C(N)N=C2N=C1
Agent: N#CCC(=O)Cl
Agent: N#CCCl
Solvent: COC=O
Product: Nc1cc(=O)[nH]c(N)n1

Procedure:
A 2-amino-4-oxo-5-cyanopyrrolo[2,3-d]pyrimidine(III) was prepared according to the method reported by Migawa, et al., “A Two Step Synthesis of the Nucleoside q Precursor 2-amino-5-cyanopyrrolo[2-3-d]pyrimidine-4-one” Syn. Comm. 26:3317(1996) which involved the synthesis of chloroformylacetonitrile (110) from chloroacetonitrile (109) and methyl formate as shown in FIG. 19. Cyclocon-densation of compound 10 with 2,6-diamino-4-oxopyrimidine afforded to the key intermediate in 65-70% overall yield. Reductive amination of the 5-nitrile with the appropriate anilines or ethyl-p-aminobenzoyl-L-glutamate in the presence of Raney nickel and hydrogen at 50 psi for 5-6 hours afforded the desired analogues which were purified by column chromatography and were obtained in 20-62% yield. This yielded the product generally represented by compound 112. For the classical analogue, compound 407, which is the compound 112 where R2 is p-benzoyl-L-glutamate, saponification of the chromatographically purified ester afforded the desired product. This method was used to synthesize compounds 407-415, which are generally represented by compound 112 in FIG. 19 with the following substitutions:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:39][CH2:40][OH:41]>>[OH:41][CH2:40][CH2:39][C:31]1[N:30]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([CH3:22])([CH3:23])[CH2:20][OH:21])[CH2:15][CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:3]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1
Reactant: OCCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol and 2-(1H-benzo[d]imidazol-2-yl)ethanol were reacted to give 427. LCMS m/z: 550.3 (MH+)
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[CH:20]([N:26]([CH:28]4[CH2:30][CH2:29]4)[CH3:27])[CH2:19][CH2:18][C:17]([CH3:32])([CH3:31])[C:16]=3[CH:15]=2)=[CH:8][CH:7]=1)[CH3:5].[OH-].[K+].Cl>CO.O1CCCC1>[CH:28]1([N:26]([CH3:27])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:31])([CH3:32])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:33])=[O:2])=[CH:11][CH:10]=4)[CH:23]=[C:22]([O:24][CH3:25])[C:21]2=3)[CH2:29][CH2:30]1
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C#Cc2ccc(C(C)C(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A solution of 2-{4-[5-(cyclopropyl-methyl-amino)-4-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-propionic acid methyl ester (Intermediate 84, 0.115 g, 0.26 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 8% methanol in ethyl acetate as the eluent to afford the title product as a yellow solid (0.062 g, 56%).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN.[CH2:19]([N:21]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O.CN(C)C=O>[CH3:19][NH:21][C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a solution of methyl 4-carboxycinnamate (160 mg) in methylene chloride was added methylamine hydrochloride (58 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (140 mg) at ambient temperature, and the mixture was stirred for 2 hours. To this suspension was added 1-hydroxybenzotriazole (137 mg) and dimethylformamide (2 ml), and the mixture was stirred for 14 hours at same temperature. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give methyl 4-(methylcarbamoyl)cinnamate (82 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][O:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH2:12][O:11][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: COCC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.3 g, 2.3 mmol) was reacted with 4-methoxy-3,3-dimethyl-butyraldehyde (0.3 g, 2.3 mmol) in CH2Cl2 at room temperature for 18 h to give [4-methoxy-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.56 g, 100%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH:25]([O:27][CH2:28][CH3:29])[CH3:26].[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:26][CH2:25][O:27][CH2:28][CH3:29])=[C:18]([F:23])[N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(C)Br
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(OCCOCC)c(F)n2)cc1

Procedure:
A mixture of 0.1 mol of 2C, 0.1 mol of 1-bromoethoxyethane, 0.1 mol of sodium hydroxide, 20 ml of ethanol and 50 ml of water is heated at the boil for 2 hours. The mixture is cooled, dilute hydrochloric acid is added, and the aqueous phase is extracted with dichloromethane. The solvent is removed under reduced pressure, and the residue is purified by column chromatography, giving the product 2-(4-octyloxyphenyl)-5-(2-ethoxyethoxy)-6-fluoropyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][Cl:41].O>CN(C)C=O>[Cl:41][CH2:40][CH2:39][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:23]([C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(O)cc3)c2cc1OC
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(OCCCl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methyl-phenyl]-(4-hydroxy-phenyl)-methanone (compound 188) (128 mg) was dissolved in N,N-dimethylformamide to prepare a solution. Potassium carbonate (215 mg) and 1-bromo-2-chloroethane (134 mg) were then added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (99 mg, yield 69%).