Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[C:17](=[O:25])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17](=[O:25])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)c1cn2c3ccc(Br)cc3c3cc(OC)cc(c1=O)c32
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(=O)c(C(=O)O)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
10-bromo-5-ethoxycarbonyl-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 98 was suspended in ethanol (10 ml), and 1N sodium hydroxide (3 ml) was added. The mixture was stirred at room temperature for 12 hours, and the solvent was evaporated under reduced pressure. To the residue was added 1N hydrochloric acid to pH 1, and the crystals precipitated were recovered by filtration, and washed with ethanol and ether to obtain the title compound (310 mg, 83%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH:13]1[CH2:21][OH:22]>N1C=CC=CC=1.C1CCCCC1>[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH:13]1[CH2:21][O:22][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2ccccc2O1
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79 %

Procedure:
p-Toluenesulphonyl chloride (26.7 g, 140 mmol) was added to a solution of (2,3-dihydro-benzofuran-2-yl)-methanol (preparation 96) (21 g, 140 mmol) in pyridine (400 mL) and the mixture was stirred at room temperature for 4 days. The reaction mixture was then concentrated in vacuo and the residue was azeotroped with toluene, diluted with ethyl acetate (500 mL) and washed with 2M hydrochloric acid (2×300 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to give a brown oil. Trituration of the oil in cyclohexane then afforded the title compound as a white solid in 79% yield, 33.5 g. LRMS APCI m/z 305 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N=[CH:17][N:16](C(N2C=NC=C2)=O)[CH:15]=1.Cl.CNC.CCN(CC)CC>C1COCC1>[CH3:15][N:16]([CH3:17])[C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a stirred solution of 2-(3-nitrophenyl)acetic acid (0.2 g, 1.104 mmol) in THF (6 ml) was added CDI (0.269 g, 1.656 mmol). resulting mixture was heated at 50° C. for 1 hr, cooled to room temperature and then dimethyl amine hydrochloride (0.108 g, 1.325 mmol) and Et3N (0.15 ml, 1.104 mmol) were added sequentially. Resulting reaction mixture was stirred for 24 h at ambient temperature. Solvents were evaporated under vacuum. The residue was purified by flash chromatography to obtain N,N-dimethyl-2-(3-nitrophenyl)acetamide (0.192, 84% yield).
Reaction SMILES: [ClH:1].NN1C(=O)C2[C:6](=[C:7]([CH3:22])[C:8](N3CC4C(C4N)C3)=C(F)C=2)N(C2CC2)C1=O.C(OC(=O)[NH:33][CH:34]1[CH:39]2[CH:35]1C[N:37]([C:40]1[C:49]([CH3:50])=[C:48]3[C:43]([C:44](=[O:56])[N:45]([NH2:55])[C:46](=[O:54])[N:47]3[CH:51]3[CH2:53][CH2:52]3)=[CH:42][C:41]=1[F:57])[CH2:38]2)(C)(C)C>>[ClH:1].[NH2:55][N:45]1[C:44](=[O:56])[C:43]2[C:48](=[C:49]([CH3:50])[C:40]([N:37]3[CH2:38][CH:39]([CH:34]([NH2:33])[CH3:35])[C:7]([CH3:22])([CH3:8])[CH2:6]3)=[C:41]([F:57])[CH:42]=2)[N:47]([CH:51]2[CH2:53][CH2:52]2)[C:46]1=[O:54]
Reactant: Cc1c(N2CC3C(C2)C3NC(=O)OC(C)(C)C)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Reactant: Cc1c(N2CC3C(N)C3C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Agent: Cl
Product: Cc1c(N2CC(C(C)N)C(C)(C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12

Procedure:
(aaaaaa) 3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 134) (mp 180–182° C., MS ES: m/z 346 (MH+)) from [3-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid tert-butyl ester (Example 28n) using General Method A.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1([CH3:18])[CH2:12][CH:11]([NH:13][CH2:14][CH3:15])[CH2:10][C:9]([CH3:17])([CH3:16])[NH:8]1.[OH-].[Na+]>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]([N:13]([CH2:14][CH3:15])[CH:11]1[CH2:12][C:7]([CH3:6])([CH3:18])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCNC1CC(C)(C)NC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)CCl)C1CC(C)(C)NC(C)(C)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 23.16 g (0.205 mol) of chloroacetyl chloride in 30 ml of methylene chloride is slowly added to a solution of 36.85 g (0.2 mol) of N-(2,2,6,6-tetramethyl-piperidin-4-yl)-ethylamine in 160 ml of methylene chloride cooled to -20° C., taking care that the temperature does not rise above -10° C. The mixture is stirred for one hour and then left to stand, allowing the temperature to rise to 0° C.; a solution of 8.4 g (0.21 mol) of sodium hydroxide in 35 ml of water is then added in the course of 1 hour.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:31])=[O:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:37]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([O:31][CH3:37])=[O:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CC(=O)O)(c2ccccc2)OC1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Yield: 68 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (1 g, 2.3 mmol) in MeOH (15 mL) was added thionyl chloride (408 mg, 3.5 mmol) dropwise at 0° C. under N2 atmosphere. After refluxing overnight, the mixture was concentrated to give the crude product, which was purified by chromatography to give methyl 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetate (680 mg, 68%).
Reaction SMILES: I.[C:2]([NH:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:22])SC)[S:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH3:3].[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>C(O)C>[C:2]([NH:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:22])[NH:27][CH2:23][CH2:24][CH2:25][CH3:26])[S:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH3:3]
Reactant: CSC(N)=Nc1nc(-c2cccc(CNC(C)=O)n2)cs1
Reactant: CCCCN
Agent: I
Solvent: CCO
Product: CCCCNC(N)=Nc1nc(-c2cccc(CNC(C)=O)n2)cs1

Procedure:
A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)(methylthio)methyleneamino]thiazole hydriodide (1.5 g) and n-butylamine (1.6 ml) in ethanol (30 ml) was heated under reflux for 40 hours. The solvent was removed by concentration and residue was added to a mixture of ethyl acetate, tetrahydrofuran and water. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and a separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino) (n-butylamino)methyleneamino]thiazole (0.48 g).
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([NH:20][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)c1ccccc1O

Procedure:
N-octyl salicylic acid amide was prepared, using the process described in Example 1, from salicylic acid methyl ester and n-octylamine (quantities used 1 mole:1 mole) and purified and recrystallized in the same way as described in Example 1.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([Cl:16])=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:19]([O:23][C:24](=[O:27])[CH2:25][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:18])[CH3:17])[CH:15]=2)[C:11]([Cl:16])=[CH:12]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(Cl)c2ccc(O[Si](C)(C)C(C)(C)C)cc21

Procedure:
In analogy to the procedure described in example 1 b], 6-(tert-butyl-dimethyl-silanyloxy)-3-chloro-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of cesium carbonate in DMF to obtain [6-(tert-butyl-dimethyl-silanyloxy)-3-chloro-indol-1-yl]-acetic acid tert-butyl ester as yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9](C(OCC)=O)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C[Si](I)(C)C.CO>ClCCCl>[CH:7]12[NH:9][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2](=[O:1])[CH2:8]2
Reactant: CCOC(=O)N1C2CCC1CC(=O)C2
Agent: C[Si](C)(C)I
Solvent: ClCCCl
Solvent: CO
Product: O=C1CC2CCC(C1)N2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a stirred solution of ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.53 mmol) in 1,2-dichloroethane (10 mL) was added 369 μL (2.60 mmol) of trimethylsilyl iodide (TMSI) under a nitrogen atmosphere. The reaction mixture was heated at 60° C. for 4 h and cooled to room temperature. Methanol (10 mL) was added and the mixture was stirred for 30 min at room temperature (rt). The solvent was removed on vacuo and the residue was partitioned between CH2Cl2 and 1M aqueous NaOH solution (5 mL). The mixture was extracted with CH2Cl2 (3×10 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, methylene chloride/EtOH/NEt3 85/10/5) to afford a pale yellow oil (140 mg, 44%).
Reaction SMILES: [C:1]1([C:7]([CH3:18])([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)(C)C.N.[H][H]>[Ru].[Pd].O>[C:1]1([C:7]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC(CCCC#N)(CCCC#N)c1ccccc1
Agent: [Pd]
Agent: [Ru]
Agent: N
Solvent: CC(C)(C)O
Solvent: O
Product: CC(CCCCN)(CCCCN)c1ccccc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A one liter autoclave was charged with 50 g 0.21 mol of a dinitrile consisting essentially of 5-phenyl-5-methylnonanedinitrile. Also charged to the reactor was 300 mL 237 g t-butyl alcohol, 25 mL water, 5 g of 5 percent by weight ruthenium on alumina, and 2 g of 5 percent by weight palladium on alumina. The reactor was flushed with nitrogen and charged with 70 g 4.1 mol of ammonia. The reactor was pressured to 1200 psig with hydrogen and heated with stirring at 170° C. for two hours. Hydrogen uptake indicated only reduction of nitrile groups to amino groups had taken place thus producing the aralkylenediamine, 5-phenyl-5-methyl-1,9-nonanediamine.
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=O>CO.Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:13]=[N+:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O-:6])[CH:15]=1
Reactant: CC(C)(C)NO
Reactant: O=Cc1cc(Cl)ccc1O
Agent: Cl
Solvent: CO
Product: CC(C)(C)[N+]([O-])=Cc1cc(Cl)ccc1O
Yield: 98.5 %

Procedure:
To a solution of tert-butylhydroxylamine (14.98 g, 168.4 mmol) in MeOH (160 mL) was added 5-chloro-2-hydroxybenzaldehyde (15.8 g, 129.5 mmol) and 3 drops of 37% hydrochloric acid. The resulting solution was refluxed through a Soxhlet apparatus containing molecular sieves (40 g) until no more aldehyde was detected by TLC. The solvent was removed in vacuo and the residue was recrystallized from EtOAc. The title compound was isolated in 98.5% yield as a crystalline solid, m.p. 143.4° C. (Rf=0.45 on a silica gel plate using 7:10 hexanes:EtOAc as an eluant).
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:6][O:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].Cl>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:6][O:7][CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC(COCCO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(COCCOS(C)(=O)=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 19.0 g of 1-acetoxy-1-(3-chlorophenyl)-2-(2-hydroxyethoxy)ethane and 95.0 ml of methylene chloride containing 9.1 ml of methanesulfonyl chloride was dropwise added 16.4 ml of triethylamine with ice cooling over 1 hour. The resulting mixture was stirred for 10 minutes at the same temperature and further for 1 hour at room temperature. The reaction mixture was added to a mixture of 50.0 ml of methylene chloride and 50.0 ml of ice water. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 24.5 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-methanesulfonyloxyethoxy)ethane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@H:12]2[C@@H:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].CO.O>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([N:15]=[N+:16]=[N-:17])[C@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2O[C@H]2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Yield: 31.2 %

Procedure:
Heat a mixture of racemic trans-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (0.56 mol, 112 g), sodium azide (1.12 mol, 73.08 g), ammonium chloride (0.56 mol, 30.07 g) and methanol/water (3:1) (1 L) at 65° C. for 16 h. Dilute the reaction mixture with water, extract with dichloromethane, and wash the organic layer with saturated sodium bicarbonate and brine solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify the residue on a silica gel column using 6% ethyl acetate in hexanes as eluent to obtain the title compound (42.3 g, 42%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 1.84 (br s 1H), 1.97-2.01 (m, 1H), 2.74-2.82 (m, 1H), 2.88 (br s, 1H), 3.37-3.40 (m, 1H), 3.50 (br s, 1H), 3.91 (br s, 1H), 4.09 (dd, 1H). ES-MS m/z 143 [M−Boc]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:20])[CH2:12][C:13]([CH:15]=[CH:16]OCC)=[O:14])[CH3:9]>>[CH2:8]([O:10][C:11](=[O:20])[CH2:12][C:13]([CH:15]=[CH:16][NH:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:14])[CH3:9]
Reactant: Cc1cc(N)on1
Reactant: CCOC=CC(=O)CC(=O)OCC
Product: CCOC(=O)CC(=O)C=CNc1cc(C)no1
Reaction time: 0.75 h

Procedure:
98 g. of 3-methyl-5-aminoisoxazole (1 mol.) and 186 g. of ethoxymethyleneacetoacetic acid ethyl ester (1 mol.) are heated with stirring for 45 minutes at 130°. After this period, ethanol is removed under reduced pressure. The residue solidifies on cooling and is recrystallized from ethanol, m.p. 93°-95°, yield 208 g. (87%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>CN(C=O)C>[CH2:12]([N:15]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
A 500 mL round-bottom flask was charged with phthalic anhydride (22.2 g, 150 mmol) and anhydrous DMF (150 mL) and stirred at room temperature for 5 min to dissolve the phthalic anhydride. To the solution was slowly added allylamine (11.26 mL, 150 mmol) followed by 20 g of 3A molecular sieves. The resulting mixture was stirred at room temperature 10 minutes and then heated under nitrogen at 80° C. for 16 hrs. The reaction mixture was cooled to room temperature and filtered. To the mother liquor was added 300 mL of EtOAc and 300 mL of brine solution. The organic layer was separated, washed twice with 300 mL of water, and dried over MgSO4. The drying agent was removed by filtration and the mother liquor concentrated. The resulting solid was recrystalized from CH2Cl2/hexane to yield 27.75 g (98% yield) of N-allylphthalimide (1-1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH:19]([CH2:23][OH:24])[CH2:18]2)=[C:13]([CH3:25])[N:12]([CH2:26][C:27]2[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:28]=2[F:37])[C:11]1=[O:38])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:56][C:57]1[O:58][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:60][CH:61]=1>ClCCl>[C:1]([O:5][C:6](=[O:45])[NH:7][C@H:8]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:56][C:57]3[O:58][C:59]([C:62]([F:65])([F:64])[F:63])=[CH:60][CH:61]=3)[CH:19]([CH2:23][OH:24])[CH2:18]2)=[C:13]([CH3:25])[N:12]([CH2:26][C:27]2[C:32]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:30]=[CH:29][C:28]=2[F:37])[C:11]1=[O:38])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N2CCNC(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: FC(F)(F)c1ccc(CBr)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)C(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.5 %

Procedure:
To a solution of {(R)-2-[3-(2-fluoro-6-trifluoromethyl-benzyl)-5-(3-hydroxymethyl-piperazin-1-yl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (0.028 mmol) in dichloromethane (2 mL) were added N,N-diisopropylethylamine (10 μl, 0.056 mol) and 2-bromomethyl-5-trifluoromethyl-furan (7.6 mg, 0.034 mmol) in the order, followed by stirring at room temperature for 6 hrs. After concentration of the solution, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/2/1) and dried in a vacuum to afford 17 mg of a white oil (yield 77%).
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[O:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28]3)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([O:6][CH2:7][C:8]2[C:12]([CH2:13][O:14][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30]([C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28]5)=[CH:23][CH:24]=3)=[C:11]([CH:15]([CH3:17])[CH3:16])[O:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)c1onc(COC2CCCC2)c1CO
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(COC5CCCC5)noc4C(C)C)cc3)ccc2n1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
A solution of [3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (50 mg, 0.21 mmol) in dichloromethane (2.1 mL) was added to a mixture of methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (57 mg, 0.21 mmol) and triphenyl phosphine (82 mg, 0.31 mmol) in a microwave reaction tube. Diisopropyl azodicarboxylate (60 μL, 0.31 mmol) was added before the tube was sealed and heated for 20 minutes at 100° C. The mixture was concentrated and the residue was purified by chromatography (silica gel, hexane to 2:3 ethyl acetate:hexanes). Fractions containing the product were combined and concentrated. The residue was purified by chromatography (silica gel, 10:9:1 hexanes:dichloromethane:ethyl acetate) to provide methyl 6-[4-({[3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (11 mg, 11% as 0.10 ethyl acetate). 1H NMR (400 MHz, CDCl3): δ 8.37-8.32 (m, 2H), 8.22 (d, J=9 Hz, 1H), 8.05-8.00 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 4.99 (s, 2H), 4.58 (s, 2H), 4.09 (s, 3H), 3.99-3.97 (m, 1H), 3.27 (septet, J=7 Hz, 1H), 1.70-1.59 (m, 6H), 1.49-1.46 (m, 2H), 1.33 (d, J=7 Hz, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 145, 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26 mmol) was reacted with phenyl isocyanate to provide 1.59 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]-N′-phenylurea as an off white powder, m.p. 153–155° C. Analysis: Calculated for C29H38N6O. 0.20 H2O: % C, 71.05; % H, 7.89; % N, 17.14; Found: % C, 70.86; % H, 7.97; % N, 16.87. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.61 (dd, J=8.3, 1.0 Hz, 1H), 7.43–7.36 (m, 3H), 7.26–7.17 (m, 3H), 6.87 (t, J=7.3 Hz, 1H), 6.49 (s, 2H), 6.08 (m, 1H), 4.49 (m, 2H), 3.05 (m, 2H), 2.91 (m, 2H), 1.80 (m, 4H), 1.43–1.29 (m, 12H), 0.95 (t, J=7.3 Hz, 3H);