Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)=[O:5]
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCl)C(=O)NCc1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52b, 3-chloro-2,2-dimethylpropionyl chloride (27.4 g) in dichloromethane (100 ml) was added to 4-chlorobenzylamine (25.0 g) and triethylamine (24.6 ml) in dichloromethane (400 ml) to give 3-chloro-N-(4-chlorobenzyl)-2,2-dimethylpropionamide, m.p. 97°-98° C.
Reaction SMILES: COS([O-])(=O)=O.C[S+](C)C1C=CC([CH2:15][C:16](O)=[O:17])=CC=1.[NH2:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>O>[C:16]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:17])[CH3:15]
Reactant: C[S+](C)c1ccc(CC(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: COS(=O)(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In 30 ml of water was dissolved 3.1 g of p-dimethylsulfoniophenylacetate methylsulfate prepared in Synthetic Example 3, and 20 ml of an aqueous solution of 1.64 g of phenylalanine and 1.4 ml of triethylamine was dropwise added thereto under stirring at room temperature. The reaction mixture was further stirred for 12 hours at room temperature and adjusted to pH 2 by adding 2% HCl. The aqueous solution was extracted twice with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure, and ether was added to the obtained residue to afford a white crystalline product.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[NH:12][CH:11]=1)=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[NH3:2].[F:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:8][CH:6]1[CH2:7][CH:5]1[CH2:3][N:2]([CH3:1])[CH3:20]
Reactant: CN(C)C(=O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CC1CC1Cc1c[nH]c2ccc(F)cc12
Product: N
Temperature: 25 °C
Yield: 184.5 %

Procedure:
A solution of (−)-trans-2-(5-fluoro-3-indolylcarbonyl)-cyclopropanecarboxylic acid dimethylamide (180 mg, 0.66 mmol) in THF was added dropwise to a suspension of LAH (100 mg, 2.63 mmol) in THF at room temperature with stirring. The reaction was heated to reflux and stirred for 1 h. The reaction was then cooled to room temperature, diluted with ether, and quenched with aqueous NaOH (1 mL of 1 N solution). The resulting precipitate was filtered and washed with ether. The organic filtrate was concentrated in vacuo. The residue was dissolved in methylene chloride, and transferred directly to an SCX resin cartridge. The cartridge was washed with methanol, and then with methanolic ammonia (2.0 M) to give (+)-[2-(5-fluoro-1H-indol-3-ylmethyl)-cyclopropyl-methyl]-dimethylamine [150 mg, 94% yield, optical rotation +19.26° (c=1.38 mg/mL, ethanol, 20° C.)]. 1H NMR (MeOH-d4): δ7.25 (dd, J=8.8, 4.5 Hz, 1H), 7.17 (dd, J=9.9, 2.5 Hz, 1H), 6.82 (dt, J=2.4 Hz, 1H), 2.69 (dd, J=6.5 Hz, 2H), 2.29 (dd, J=4.86 Hz, 1H), 2.20 (s, 6H), 2.15 (dd, J=12.8 Hz, 1H), 0.90 (m, 1H), 0.70 (m, 1H), 0.51 (m, 1H), and 0.39 (m, 1H), FIMS: 247.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:19]([O:18][CH3:17])[CH:20]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(OC)c1OC

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3,4,5-trimethoxyaniline were reacted to produce 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.33 (s, 1H), 9.17 (s, 1H), 8.99 (s, 1H), 8.06 (d, 1H, J=3.3 Hz), 7.27 (d, 1H, J=7.5 Hz), 7.08-7.02 (m, 4H), 6.46 (dd, 1H, J=1.8 and 7.8 Hz), 3.60 (s, 6H), 3.57 (s, 3H); LCMS: purity: 99%; MS (m/e): 387(MH+).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC1CCCNC1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCCC(C)C2)ncn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 99 mg of 3-methylpiperidine was added therein, and the mixture was stirred for 4 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 181 mg of 4-(2-butynyloxy)-6-(3-methylpiperidino) pyrimidine (hereinafter, referred to as Compound (19)).
Reaction SMILES: [C:1](C1C=CC(C(OC)=O)=CC=1)(=O)[CH3:2].COC(OC)N(C)C.CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)=O.[CH:38]([C:41]1[CH:49]=[CH:48][C:44]([C:45]([NH2:47])=[NH:46])=[CH:43][CH:42]=1)([CH3:40])[CH3:39]>C(O)C>[CH:38]([C:41]1[CH:49]=[CH:48][C:44]([C:45]2[N:47]=[C:26]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([O:34][CH2:1][CH3:2])=[O:33])=[CH:30][CH:29]=3)[CH:25]=[CH:24][N:46]=2)=[CH:43][CH:42]=1)([CH3:40])[CH3:39]
Reactant: CN(C)C=CC(=O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: CC(C)c1ccc(C(=N)N)cc1
Agent: COC(OC)N(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccnc(-c3ccc(C(C)C)cc3)n2)cc1

Procedure:
Part A. A solution of methyl 4-acetylbenzoate (1.00 g, 5.61 mmol) and dimethylformamide dimethyl acetal (746 μL, 5.61 mmol) in ethanol (5 mL) is heated to reflux for 12 h. The solution is cooled and evaporated, and the residue is separated by column chromatography to afford the product as a mixture of methyl and ethyl esters of 4-(3-dimethylamino-acryloyl)benzoic acid (679 mg). A portion of this material (121 mg) is dissolved in ethanol (5 mL) and treated with 4-isopropyl-benzamidine (81 mg). The solution is heated to reflux for 12 h., cooled, filtered through celite, and evaporated. The residue is separated by column chromatography (silica gel, 1:4 ethyl acetate-hexane) to afford the product, ethyl 4-[2-(4-isopropyl-phenyl)-pyrimidin-4-yl]-benzoate.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH4+:9].C(O)(=O)CCC(O)=O.[OH-].[Na+]>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C\C(=O)O
Reactant: [NH4+]
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 0.67 h

Procedure:
Monoammonium maleate (3.00 g of 94% wet salt, 0.0212 mole) and succinic acid (.[.0,278.]. 0.278 g, 0.0024 mole) were thoroughly mixed together and then were reacted as in Example 2 and 3 by heating in a convection oven at .[.230°240°.]. 230°-240° C. for 40 minutes. A brittle, red-brown solid was obtained which weighed .[.2,204.]. 2.204 g. Hydrolysis of this product with sodium hydroxide produced an aspartic acid copolymer having molecular weights by GPC of Mw 1717, Mn 1016, Mw/Mn 1.69.
Reaction SMILES: [CH3:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH:21]=[O:22])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:23].O[C@@:25]1(C)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C=O)C(=CC(=O)CC1)C=C3.O[C@@]1(C#CC)CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C=O)C(=CC(=O)CC1)C=C3.C[C@]12CC[C@H]3[C@@H](C=CC4[C@]3(C=O)CCC(=O)C=4)[C@@H]1CCC2=O>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][CH2:17][C@@:16]2([CH2:21][OH:22])[C:3]=1[CH2:4][C@@H:5]([CH3:25])[C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:23]
Reactant: C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@@]21C
Reactant: CC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C=O)CCC1=O
Agent: CC#C[C@]1(O)CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C=O)[C@H]3CC[C@@]21C
Agent: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C=O)[C@@H]1CCC2=O
Product: CC1=C2C[C@@H](C)[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CC[C@@H]1O

Procedure:
Substituting 4-methyl-4,6-androstadiene-3,17,19-trione, 17β-hydroxy-17α-methyl-4,6-androstadiene-3,19-dione and 17β-hydroxy-17α-propinyl-4,6-androstadiene-3,19-dione for the 4,6-androstadiene-3,17,19-trione above results in the formation of 4,7α-dimethyl-4-androstene-3β,17β,19-triol, 7α,17α-dimethyl-4-androstene-3β,17β,19-triol and 7α-methyl-17α-propinyl-4-androstene-3β,17β,19-triol, respectively.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][C:8]([C:16]2[N:17]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:18]3[C:23]([C:24]=2C)=[CH:22][C:21]([CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:40].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][C:8]([C:16]2[N:17]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:40]
Reactant: Cc1c(-c2cc(OCC3CO3)c(Cl)c3c2C(=O)NC3)n(C(=O)OC(C)(C)C)c2ccc(CN3CCCCC3)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCC3CO3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 79.2 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-5-(2,3-epoxypropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)methylindol-2-yl]isoindolinone (77.1 mg, 0.211 mmol) was dissolved in acetonitrile (2.3 mL), and the solution was treated with Compound BD (151 mg, 0.383 mmol), palladium acetate (3.8 mg, 0.017 mmol), tri(o-tolyl)phosphine (10.3 mg, 0.034 mmol) and triethylamine (0.294 mL, 2.11 mmol), followed by purification by slurry using diisopropylether to obtain 4-chloro-5-(2,3-epoxypropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (92.3 mg, yield 79%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32]C)=[O:31])[O:18][N:17]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:20]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([OH:32])=[O:31])[O:18][N:17]=1
Reactant: COC(=O)Cc1ccccc1OCc1cc(OCCc2nc(-c3ccccc3)sc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1CCOc1cc(COc2ccccc2CC(=O)O)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a mixture of methyl 2-[2-[[3-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-isoxazolyl]methoxy]phenyl]acetate (0.77 g), tetrahydrofuran (5 mL) and methanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 3 hrs. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration and dried with air to give crystals (0.71 g, 96%) of 2-[2-[[3-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy]-5-isoxazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 159-160° C.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[CH2:34][C@H:33]([CH3:35])[N:32]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[CH2:34][C@H:33]([CH3:35])[N:32]([C:36]3[S:37][C:38]([C:42]([NH2:7])=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 197-198° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.37-7.17 (m, 6H), 4.57-4.51 (m, 1H), 4.42 (d, J=5.4 Hz, 2H), 3.60 (dd, J=9.0, 9.0 Hz, 1H), 3.03 (dd, J=9.0, 3.4 Hz, 1H), 2.46 (s, 3H), 1.38 (d, J=6.2 Hz, 3H); MS (ES+) m/z 348.9 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>CC#N.C([O-])([O-])=O.[Na+].[Na+]>[N:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[C:12]([NH2:11])[CH:13]=[CH:14][CH:15]=2)[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: Brc1cnc2ccccn12
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1cccc(-c2cnc3ccccn23)c1
Temperature: 80 °C
Yield: 66.3 %

Procedure:
A mixture of 3-bromo-imidazo[1,2-a]pyridine (2.7 g, 13.7 mmol) and 3-aminobenzeneboronic acid (2.4 g, 17.5 mmol) in CH3CN (20 ml) and 2N aqueous Na2CO3 (20 ml) was deoxygenated by evacuation then refill with N2 (×3). PdCl2dppf (500 mg, 0.68 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 80° C. for 8 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O and then filtered through Celite®. The Celite® was washed with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (100% CH2Cl2→2% 2M NH3-MeOH/CH2Cl2) to give the title compound (1.9 g, solid). MS: [M+H]+ 210
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[O:30][C:31](Cl)=[O:32]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[O:30][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)Oc1ccc2ccccc2c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)Oc1ccc2ccccc2c1

Procedure:
According to the general method of Example 7, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and chloroformic acid 2-naphthyl ester were combined to provide 2-naphthyl N-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a white powder, m.p. 154.0–155.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.08 (d, J=7.4 Hz, 1H), 7.94–7.86 (m, 4H), 7.64 (dd, J=8.3, 1.0 Hz, 1H), 7.56–7.43 (m, 4H), 7.30 (m, 1H), 7.20 (dd, J=8.8, 2.3 Hz, 1H), 6.61 (broad s, 2H), 4.65 (t, J=6.9 Hz, 2H), 3.14 (q, J=6.4 Hz, 2H), 1.94 (m, 2H), 1.56 (m, 2H); MS (El) m/e 426.1927 (426.1930 calcd for C25H23N5O2).
Reaction SMILES: C[C:2]1[C:3]([CH2:11][CH2:12][CH2:13][CH:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([CH:8]=[CH:9][CH:10]=1)C([O-])=O.OCCCC1C=CC([C:30]([O:32][CH3:33])=[O:31])=CC=1.C(CC(OCC)=O)#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12][CH2:11][C:3]1[CH:2]=[CH:10][C:9]([C:30]([O:32][CH3:33])=[O:31])=[CH:8][CH:4]=1)#[N:21]
Reactant: CCOC(=O)C(C#N)CCCc1c(C)cccc1C(=O)[O-]
Reactant: COC(=O)c1ccc(CCCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(=O)CC#N
Product: CCOC(=O)C(C#N)CCCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
Preparation of methyl-(4-cyano-4-ethoxycarbonylbutyl)benzoate ##STR21## To a 250 mL flame dried round bottom flask were charged 10.0 g (51.5 mmol) of methyl 4-(-hydroxypropyl)benzoate and 5.48 mL (51.5 mmol) of ethyl cyanoacetate dissolved in 40 mL of anhydrous tetrahydrofuran (THF). To this solution was then added dropwise to a solution of 20.2 g (77 mmol) of triphenylphosphine and 12.1 mL (77 mmol) of diethyl azodicarboxylate dissolved in 60 mL of anhydrous THF. After the addition, the reaction was stirred at ambient temperature for 1.5 hours. The volatiles were removed in vacuo and the crude oil was dissolved in 300 mL of EtOAc, washed with brine, dried over Na2SO4, and removed in vacuo. This crude oil was then purified on silica gel using a Waters Prep LC 2000 eluting with a gradient of 1:1 MeCl2 /Hex to 100% MeCl2 to give 6.0 g (40%) of methyl 4-(4-cyano-4-ethoxycarbonylbutyl)benzoate as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[Zn](CC)[CH2:14][CH3:15]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:14]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])[CH3:15]
Reactant: CC[Zn]CC
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCc1ccc(C(=O)O)cc1OC
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-3-methoxy-benzoic acid (2.49 g, 10.9 mmol) and Pd(dppf)Cl2 (158 mg, 0.216 mmol) were stirred in dioxane (25 mL) and Et2Zn (22 mL, 1 M in hexanes, 22 mmol) was added. The reaction mixture was heated at 70° C. for 1 h. The mixture was cooled to room temperature and was quenched with MeOH (1.1 mL). The solution was diluted with ethyl acetate (20 mL) and was washed with 1 N HCl (10 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness to give 4-ethyl-3-methoxybenzoic acid. ESI-MS m/z calc. 180.1, found 179.1 (M−1)−; Retention time: 1.77 minutes (3 min run).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[CH3:12][CH:13]1[CH2:15][N@@:14]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CN(CCN(C)C)C>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:14][C@H:13]([CH2:15][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH3:12])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)[N@]2CC2C)cc1
Reactant: C#C[Si](C)(C)C
Agent: CN(C)CCN(C)C
Agent: Cc1ccc(S(=O)(=O)[N@@]2CC2C)cc1
Agent: [Li]CCCC
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)CC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(Trimethylsilyl)acetylene (5.8 mL, 41.65 mmol) was dissolved in 15 mL dry TMEDA and cooled to 0° C. n-BuLi (12.50 mL, 31.24 mmol) was added dropwise via an addition funnel and the resulting mixture was stirred for 20 min at RT. The solution was recooled to 0 ° C. and cannulated to a 0° C. solution of (S)-2-methyl-1-(4-methylbenzenesulfonyl)aziridine (2.2 g, 10.4 mmol) in 15 mL TMEDA . The resulting solution was stirred for 20 h at RT. The reaction mixture was cooled to 0° C. and quenched with sat. NH4Cl and the organic solvent removed. The residue was partitioned between EtOAc and H2O. The organic layer was washed with sat. NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 (90% hexanes: 10% acetone) to afford the title compound. MS (m/z): 310.2 (M+H) (Calc'd for C15H23NO2SSi: 309.5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:21]1[CH2:25][CH2:24][NH:23][CH2:22]1.C(Cl)CCl>CN(C)C1C=CN=CC=1.ClCCl.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:10](=[O:12])[N:23]1[CH2:24][CH2:25][S:21][CH2:22]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(=O)O
Reactant: C1CSCN1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a mixture of 2-tert-butoxycarbonylamino-3-(2-fluoro-phenyl)-propionic acid (0.50 g, 1.77 mmol), thiazolidine (0.15 mL, 1.94 mmol) and 4-dimethylamino-pyridine (0.21 g, 1.77 mmol) in dichloromethane (15 mL) was added EDC (0.44 g, 2.31 mmol). The reaction mixture was stirred at room temperature overnight, diluted with chloroform, washed with 2 N HCl, water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (30% acetone in hexanes) and obtained as a colorless solid (0.39 g, 62%, mp 133-134° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])#[N:2].[NH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36]([N:40]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:35][CH:34]=[CH:33]2.O.[C:56]([OH:60])(=[O:59])[CH:57]=O>>[C:51]([O:50][C:48]([N:40]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[C:36]1[C:37]2[C:32](=[CH:31][C:30]([NH:29][CH:57]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C:5]4[CH:6]=[CH:7][C:8]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[C:3]([C:1]#[N:2])[CH:4]=4)=[CH:21][CH:22]=3)[C:56]([OH:60])=[O:59])=[CH:39][CH:38]=2)[CH:33]=[CH:34][N:35]=1)=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: O=CC(=O)O
Solvent: O
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1C#N
Yield: 86 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 26B (225 mg, 0.57 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 26C (374 mg, 86%) as a yellow solid. MS (ESI) m/z 773.86 (M+H)+.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.[CH:31](Cl)(O)[CH:32]([Cl:34])[Cl:33].C(Cl)(Cl)[Cl:38]>CN(C1C=CN=CC=1)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:31][C:32]([Cl:34])([Cl:38])[Cl:33])=[O:4]
Reactant: OC(Cl)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: ClC(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(Cl)(Cl)Cl

Procedure:
Boc-Pro-OH (6.46 g, 30.0 mmol) in a 300 ml short neck flask was dissolved in distilled CHCl3 (80 ml). DCC (6.82 g, 33.0 mmol) dissolved in advance in a minimum quantity of distilled CHCl3 in ice bath with stirring was added thereto, and trichloroethanol (3.50 ml, 37.0 mmol) and DMAP (0.38 g, 3.0 mmol) was further added, and the mixture was stirred in an ice bath for 2 hours and at room temperature all day. After filter-out of DCUrea, the filtrate was subjected to vacuum concentration. The residue was dissolved in AcOEt, was sequentially washed with a 10% aqueous citric acid solution, water, a saturated aqueous NaHCO3 solution, water, and saturated saline, and was dried with Na2SO4. The filtrate was subjected to vacuum concentration to yield an oil-form product.