Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH2:3][OH:4].C(N(C(C)C)CC)(C)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:2]2[CH2:3][O:4][C:23](=[O:25])[NH:1]2)=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C[C@H](N)CO)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C[C@H]2COC(=O)N2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A stirred solution of (2S)-2-amino-3-(4-methylphenyl)propan-1-ol (Step A, 460 mg, 2.79 mmol) in CH2Cl2 (20 mL) at 0° C. was treated with diisopropylethylamine (2.92 mL, 16.74 mmol) and triphosgene (414 mg, 1.39 mmol) under an atmosphere of N2. The reaction stirred at 0° C. for 3 h. The reaction was quenched with sat. NaHCO3 (10 mL) and extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-70% EtOAc/hexanes gradient) to afford (4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as a white solid. LCMS=192.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.17 (d, J=8 Hz, 2H), 7.09 (d, J=7.7 Hz, 2H), 5.39 (br s, 1H), 4.48 (t, J=8.4 Hz, 1H), 4.37 (dd, J=8.6, 5.6 Hz, 1H), 4.11-4.06 (m, 1H), 2.86 (d, J=7.1 Hz, 2H), 2.36 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18](Cl)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][CH:2]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(O)c1cccc2cnccc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(OC(C)=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
The product of Example 70B (1.0202 g, 4.41 mmol) in pyridine (15 mL) was treated with acetyl chloride (0.35 mL, 4.92 mmol) dropwise. The solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was purified by column chromatography (2% methanol/CH2Cl2) to provide the title compound as yellow oil (0.8100 g, 67%). MS (ESI+) m/z 274 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 1.07 (t, J 7.1, 3H), 2.17 (s, 3H), 4.13 (m, 2H), 6.62 (s, 1H), 7.74 (m, 1H), 7.94 (d, J 7.1, 1H), 8.03 (d, J 6.1, 1H), 8.22 (d, J 7.6, 1H), 8.60 (d, J 5.7, 11H), 9.39 (s, 1H).
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])[CH2:9][N:8]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:7][CH2:6]2.[ClH:20]>O1CCOCC1>[ClH:20].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]2
Reactant: COC(=O)CN1CCc2cc(OC)c(OC)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(CC(=O)O)CC2
Yield: 81.2 %

Procedure:
Methyl 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetate (2.5 g, 9.42 mmol) was dissolved in dioxane (20 ml), and aqueous 12M HCl (6 ml, 72.0 mmol) was added. The mixture was stirred under reflux for 8 hours, then the volatiles were removed under vacuum and the resulting solid was suspended in CH3CN and recovered by filtration affording the title compound (2.2 g, 7.65 mmol, 81% yield). MS/ESI+ 252.1 [MH]+.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([CH3:10])([CH2:8][F:9])[C:5](=[O:7])[CH3:6].CCOCC>O>[Br:1][CH2:6][C:5](=[O:7])[C:4]([CH3:10])([CH3:3])[CH2:8][F:9]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CF
Solvent: CCOCC
Solvent: O
Product: CC(C)(CF)C(=O)CBr
Yield: 79.8 %

Procedure:
480 g of bromine were slowly added dropwise to a mixture of 354 g (3 moles) of 3,3-dimethyl-4-fluoro-2-butanone and 2,000 ml of ether at 20° to 30° C., while cooling and stirring. The yellowish solution was subsequently stirred at 20° C. for a further hour, and 500 ml of water were then carefully added. The ether phase was separated off, washed several times with water and dried over sodium sulphate. After distilling off the solvent, the residue was distilled under a waterpump vacuum. 472 g (80% of theory) of 1-bromo-3,3-dimethyl-4-fluoro-2-butanone of boiling point 80° to 90° C./11 mm Hg column were obtained. ##STR14##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:12].Cl.C[CH2:15][O:16]CC>[C-]#N.[Zn+2].[C-]#N>[OH:12][C:4]1[C:5]([CH:15]=[O:16])=[CH:6][C:7]2[CH2:8][CH2:9][O:10][C:11]=2[C:3]=1[O:2][CH3:1]
Reactant: CCOCC
Reactant: COc1c(O)ccc2c1OCC2
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1c(O)c(C=O)cc2c1OCC2
Reaction time: 2 h

Procedure:
A mixture of 2.49 g. (15 mmole) of 2.3-Dihydro-7-methoxy-6-benzofuranol, 5.87 g. (50 mmole) zinc cyanide and 100 ml. of dry ether was saturated with hydrogen chloride for 1 hour at 0°, then for 2 hours at room temperature. The mixture was then allowed to stand overnight at room temperature then concentrated in vacuo and the residue treated with 100 ml. of 0.1N HCl for 1 hour at reflux. After cooling, ether extraction provided the product which was purified by chromatography over silica gel (E. Merck 60), eluting with CHCl3, to yield a colorless solid, m.p. 71°-72°.
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21]C)=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([Br:24])[CH:26]=4)[N:30]([CH3:34])[CH:29]=3)[C:19]([OH:21])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Cn1ccc2cc(Br)ccc21
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Temperature: 80 °C
Yield: 79.4 %

Procedure:
2.6-Dimethylpyridine (0.75 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from Example 61(c), 1.75 g, 6.43 mmol) and 5-bromo-1-methylindole (from step (a), 1.35 g) in anhydrous dimethylformamide (10 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated to 80° C. for 8 hours. The reaction mixture was partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using 50% dichloromethane and 50% hexane as eluant) to give the subtitle compound as a colourless oil (1.98 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CN1CCCC1=O.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>C(#N)C>[C:22]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(OCCCO)c1ccc(O)cc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: C=C(C)C(=O)OCCCOC(=O)c1ccc(O)cc1
Temperature: 0 °C

Procedure:
To a solution of 23 g of 4-hydroxybenzoic acid (3-hydroxypropyl)ester in 100 ml of acetonitrile was added 20 ml of N-methylpyrrolidone with stirring, followed by 16 g of methacryloyl chloride. After the mixture was reacted with stirring at 35° C. for 8 hours, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate/n-hexane to give 4-hydroxybenzoic acid (3-methacryloyloxypropyl)ester (Ph-1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[C:12]([NH:16][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1F
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a suspension of 4-chloro-2-fluorobenzoic acid (0.3494 g, 2.00 mmol) in methylene chloride (10 ml) were added t-butylamine (0.32 ml, 3.05 mmol) and HOBt (0.3248 g, 2.40 mmol), and then WSC HCl (0.4596 g, 2.40 mmol) was added and stirred for 3 hours. The reaction mixture was added into water and extracted three times with ethyl acetate. The combined extracts were dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (0.4403 g; 96%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH:4]([C:6]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])O.C(O)(=O)C>[Pd].CO>[NH2:17][C:15]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([CH2:4][C:3]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:2]=2[F:1])[CH:16]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1C(O)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(N)cc1Cc1ccc(F)cc1F
Reaction time: 9 h
Yield: 69.3 %

Procedure:
A mixture of 2'-(2,4-difluoro-α-hydroxybenzyl)-4'-nitromethanesulfonanilide (5.3 g), 10% palladium on carbon (1 g) and acetic acid (6 ml) in methanol (60 ml) was shaken under hydrogen atmosphere for 9 hours. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with a saturated solution of sodium bicarbonate, dried, and evaporated. The sirupy residue was recrystallized from ethanol to give crystals of 4'-amino-2'-(2,4-difluorobenzyl)methanesulfonanilide (3.2 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][NH:16][C:15](=[O:23])[C:11]=3[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:24])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44]Br>CN(C=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44][N:16]1[CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[N:6]3[C@@H:7]([CH3:9])[CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]3=[C:12]([O:13][CH3:14])[C:11]=2[C:15]1=[O:23]
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]cc(C(=O)OC)c32)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)cc(C(=O)OC)c32)C1=O
Temperature: -25 °C
Reaction time: 0.42 h

Procedure:
To a cold (−25° C.) solution of methyl (6S)-8-ethyl-10-(methoxy)-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate (0.29 g, 0.87 mmol) in anhydrous DMF (15 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 0.96 mmol) was added. The reaction mixture was stirred at −25° C. for 25 minutes and treated with 3-chloro-4-fluorobenzyl bromide (0.27 g, 1.2 mmol; passed through activated basic alumina). The reaction mixture was stirred at 0° C. for 40 minutes and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the titled product.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[O:15]1[CH2:39][CH:16]1[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([CH:28]2[CH2:33][CH2:32][CH:31]([O:34][CH2:35][CH:36]3[O:38][CH2:37]3)[CH2:30][CH2:29]2)([CH3:27])[CH3:26])[CH2:21][CH2:20]1>>[OH:15][CH:16]([CH2:39][N:11]1[C:10]([CH3:13])([CH3:12])[CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3][C:2]1([CH3:14])[CH3:1])[CH2:17][O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([CH:28]2[CH2:29][CH2:30][CH:31]([O:34][CH2:35][CH:36]([OH:38])[CH2:37][N:11]3[C:2]([CH3:14])([CH3:1])[CH2:3][C:4]4([O:5][CH2:6][CH2:7][O:8]4)[CH2:9][C:10]3([CH3:13])[CH3:12])[CH2:32][CH2:33]2)([CH3:27])[CH3:26])[CH2:23][CH2:24]1
Reactant: CC(C)(C1CCC(OCC2CO2)CC1)C1CCC(OCC2CO2)CC1
Reactant: CC1(C)CC2(CC(C)(C)N1)OCCO2
Product: CC(C)(C1CCC(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)CC1)C1CCC(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)CC1
Temperature: 120 °C

Procedure:
A mixture of 8.8 g of 7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]decane and 7.0 g of 2,2-bis[4-(2,3-epoxypropoxy)cyclohexyl]propane was heated at 120° C. for 30 hours. After completion of the reaction, the reaction mixture was purified by column chromatography through silica gel eluted with ethyl acetate. The desired Compound No. 207 was obtained in the form of a pale yellow oil which after being kept at ambient temperature, turned to a solid melting at 48°-50° C.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33]([O:40][C@@H:41]3[O:49][C@H:48]([CH2:50][OH:51])[C@@H:46]([OH:47])[C@H:44]([OH:45])[C@H:42]3[OH:43])=[N:34][NH:35][C:36]=2[CH:37]([CH3:39])[CH3:38])=[C:27]([CH3:52])[CH:26]=1)[C:17](=[O:19])[NH2:18])=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33]([O:40][C@@H:41]3[O:49][C@H:48]([CH2:50][OH:51])[C@@H:46]([OH:47])[C@H:44]([OH:45])[C@H:42]3[OH:43])=[N:34][NH:35][C:36]=2[CH:37]([CH3:39])[CH3:38])=[C:27]([CH3:52])[CH:26]=1)[C:17](=[O:19])[NH2:18]
Reactant: Cc1cc(OCCCN[C@@H](CCCCNC(=O)OCc2ccccc2)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(OCCCN[C@@H](CCCCN)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a solution of 4-[(4-{3-[(S)-5-benzyloxycarbonylamino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.17 g) in methanol (4 mL) was added 10% palladium-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.13 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:32])[N:14]([CH3:31])[N:15]=[C:16]([CH2:26][O:27]COC)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].Cl.O.[OH-].[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:32])[N:14]([CH3:31])[N:15]=[C:16]([CH2:26][OH:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(COCOC)nn(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(CO)nn(C)c1=O
Temperature: 65 °C
Reaction time: 1.25 h
Yield: 85.1 %

Procedure:
To a solution of 4-(2,6-diethyl-4-methylphenyl)-6-methoxymethoxymethyl-5-benzyloxy-2-methyl-3(2H)-pyridazinone (2.3 g, 4.91 mmol) in methanol (15 ml) was added concentrated hydrochloric acid (2 ml) and water (1 ml), and stirred at 65° C. for 75 minutes. After cooling to room temperature, the mixture was neutralized with 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate 2 times. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 1.64 g of Compound (I-29) (yield: 85%) as solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([O:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(C#N)c(O)n1
Reactant: ClCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C#N)c(OCc2ccccc2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile (85.0 g, 0.574 mol) and benzyl chloride (87.0 g, 0.688 mol) in toluene (800 mL) was added Ag2O (146 g, 0.631 mol). The reaction mixture was stirred at 110° C. overnight. The reaction mixture was filtered through CELITE® and the solids washed with CH2Cl2. The filtrate was concentrated under vacuum and purified by column chromatography (petroleum ether/EtOAc) to give 2-(benzyloxy)-4,6-dimethylpyridine-3-carbonitrile (Cpd W, 89 g, 65%) as a white solid.
Reaction SMILES: [CH:1]1([NH:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([OH:18])=[C:10]([C:19]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:22]=4[S:21](=[O:31])(=[O:30])[N:20]=3)[C:9]2=[O:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([NH2:43])=[O:42]>CN(C)C=O>[CH:1]1([NH:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([OH:18])=[C:10]([C:19]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([O:29][CH2:40][C:41]([NH2:43])=[O:42])=[CH:28][C:22]=4[S:21](=[O:30])(=[O:31])[N:20]=3)[C:9]2=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NC1CCCCC1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCCCC3)c1=O)N2

Procedure:
The product of Example 306C (13 mg, 0.028 mmol) in N,N-dimethylformamide (5 mL) was reacted with cesium carbonate (0.0137 g, 0.114 mol) and 2-bromoacetamide (0.008 g, 0.058 mmol) according to the procedure as described in Example 304J to give the title compound. The sodium salt was prepared according to the procedure of Example 1D (7 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (m, 10 H) 2.96 (bs, 1 H) 4.49 (s, 2 H) 5.67 (d, J=4.04 Hz, 1 H) 7.04 (t, J=7.54 Hz, 1 H) 7.20 (m, 3 H) 7.40 (s, 1 H) 7.47 (m, 1 H) 7.62 (s, 1 H) 7.74 (d, J=8.46 Hz, 1 H) 8.05 (d, J=6.62 Hz, 1 H) 16.26 (s, 1 H). (ESI−) m/z 510 (M−H)−, m/z 532 (M+Na−H)−1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([OH:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]O)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([O:18][CH2:27][CH2:26][NH:25][C:24](=[O:29])[O:23][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a stirred slurry of 2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-ol (3.80 g, 15.6 mmol), N-(2-hydroxyethyl)carbamic acid tert-butyl ester (3.9 g, 24 mmol), and triphenylphosphine (6.3 g, 24 mmol) in tetrahydrofuran (120 mL) at 0° C. was added diisopropylazodicarboxylate (4.7 mL, 24 mmol). After 1 hour, the solution was allowed to warm to room temperature. More N-(2-hydroxyethyl)carbamic acid tert-butyl ester (3.9 g, 24 mmol) and triphenylphosphine (6.3 g, 24 mmol) were added, then a solution of diisopropylazodicarboxylate (4.7 mL, 24 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred over the weekend, then concentrated under reduced pressure. Dichloromethane (150 mL) was added and the solution was washed with water (2×25 mL). The organic layer was dried over potassium carbonate, filtered, and concentrated under reduced pressure. The solid was washed with diethyl ether/hexanes twice and dried to afford 1.5 g of crude tert-butyl 2-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]oxy}ethylcarbamate, which was used without purification in Part D below.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18](O)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH2:33].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([NH:33][C:32]2[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:31]=2[CH3:30])=[O:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:4])[CH3:3])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: Cc1cccc(C)c1N
Reactant: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound of Example 11 (2.3 g, 0.0068 mole) was dissolved in benzene and the solution cooled to +10° C. in an ice bath. A solution of oxalyl chloride (1.14 g, 0.009 mole) in benzene (10 ml) was added dropwise over a period of 20 minutes. The ice bath was removed and the solution stirred at room temperature for 12 hours. The benzene was removed, fresh benzene (10 ml) added and the procedure repeated. The residue was taken up in benzene and a solution of 2,6-dimethylaniline (0.84 g, 0.007 mole) in benzene (25 ml) added over a period of 20 minutes, followed by the dropwise addition of a solution of triethylamine (1 ml). The solution was stirred for 4 hours and the benzene removed. The residue was taken up in ethyl ether (100 ml), stirred, and the white solid filtered. The filtrate was stripped and the product purified by chromatography on silica. The product was recrystallized from ethyl acetate/hexane, filtered and dried, m.p. ca. 137°-139.5° C. Analysis calc. for C27H39NO2S(441.67): Calc.: C, 73.43; H, 8.90; N, 3.17; S, 7.26. Found: C, 73.75; H, 8.90; N, 3.12; S, 7.41.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:15])=[C:7]([CH3:14])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:15])=[C:7]([CH3:14])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2ccc(O)c(C)c2oc1=O
Product: CC(=O)Oc1ccc2c(C)c(C)c(=O)oc2c1C
Temperature: 0 °C

Procedure:
A solution of 7-hydroxy-3,4,8-trimethylcoumarin (5.19 g, 25.4 mmol) was refluxed in acetic anhydride (10 mL) for 1.5 hours. The solution was slowly poured into ice water (200 mL) and the resulting solid was filtered, then rinsed with water to yield 7-acetoxy-3,4,8-trimethylcoumarin, a beige solid (6.22 g, 99.5%). 1H NMR (CDCl3): δ 7.47 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([N:12]([CH3:31])[C@H:13]([C:15]([NH:17][C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH3:14])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OC(=O)C)C.Cl>[NH2:1][C@H:2]([C:10]([N:12]([CH3:31])[C@H:13]([C:15]([NH:17][C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH3:14])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)N(C)C(=O)[C@@H](N)Cc1ccccc1

Procedure:
Following the procedure of Example 2 using 73.37 grams of BOC-Phe-N-Me-Ala-Tyr-OMe in 500 ml of ethylacetate and hydrogen chloride gas there is obtained 3 crops of "Phe-N-Me-Ala-Tyr-OMe" as follows: