Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][O:14][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].O.O.O.[F-].C([NH3+])(C)(C)C.O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][OH:14])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: CCN(CC)C(CO[Si](C)(C)C(C)(C)C)c1cccc2c(C)c(C)oc12
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(CO)c1cccc2c(C)c(C)oc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
2.77 g (7.68 mmol) of 2,3-dimethyl-7-(1-diethylamino-2-[tert-butyldimethylsilyloxy]ethyl)benzofuran and 30 ml of tetrahydrofuran are introduced into a 250 ml round-bottomed flask. The reaction mixture is cooled to 0° C. by an ice bath and a solution of 2.9 g (9.21 mmol) of tert-butylammonium fluoride trihydrate in 10 ml of tetrahydrofuran is added. The reaction mixture is stirred at 0° C. for 1 hour and at room temperature for 16 hours. 150 ml of water are added and extraction is carried out with ethyl ether (3×200 ml). The organic phases are combined, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent: 5% methanol in dichloromethane). 1.6 g (Yield: 80%) of 2,3-dimethyl-7-(1-diethylamino-2-hydroxyethyl)benzofuran are obtained in the form of an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=1.[OH:19][CH:20]([C:33]1[CH:38]=[CH:37][C:36](/[C:39](=[N:41]\O)/[NH2:40])=[CH:35][CH:34]=1)[CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C(OCC)(=O)C>[OH:19][CH:20]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:41]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11]=3[C:12]([F:13])([F:14])[F:15])[O:18][N:40]=2)=[CH:35][CH:34]=1)[CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]1
Reactant: O=C(O)c1onc(-c2ccccn2)c1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(/C(N)=N\O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid, Int-IV (45 mg, 0.174 mmol), (3S)-ethyl 1-(2-hydroxy-2-(4-((E)-N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (70 mg, 0.209 mmol), and BOP-Cl (53 mg, 0.208 mmol) in DMF (5 mL) was added TEA (0.073 mL, 0.523 mmol). The reaction mixture was stirred at room temperature for 2 hr then TBAF (0.174 mL, 0.174 mmol) was added. Next, the reaction mixture was stirred for 3 days. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried with MgSO4, filtered, and concentrated. The crude residue was purified by a silica gel cartridge using an EtOAc/hexanes gradient to yield 37 mg of (3S)-ethyl 1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](F)[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[NH2:27][C@@H:28]([CH3:31])[CH2:29][OH:30]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:27][CH:28]([CH3:31])[CH2:29][OH:30])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)CO
Reactant: O=C(NC(CO)c1cccc(Cl)c1)C1CCN(c2ccnc(F)c2)CC1
Solvent: CS(C)=O
Product: CC(CO)Nc1cc(N2CCC(C(=O)NC(CO)c3cccc(Cl)c3)CC2)ccn1
Temperature: 160 °C

Procedure:
The 2′-fluoro-3,4,5, 6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid [1 -(3-chloro-phenyl)-2-hydroxy-ethyl]-amide compound (10 mg, 0.026 mmol) was combined with (S)-2-amino-propanol (0.2 mL) in DMSO and heated in an oil bath to 160° C. for 18 hours. The crude mixture was pipetted onto a preparative TLC plate (1 mm silica) and the compound eluted with ethyl acetate. Isolation of the most UV active band afforded 2.6 mg of the title product as a colorless oil. Rt=4.40 minutes, LCMS 447.3 (M=1), 1H NMR δ 7.66 (s, 1H) 7.32–7.20 (m, 4H) 6.34 (NH) 5.94 (s, 1H) 5.07–5.06 (m, 1H) 4.17 (m, 1H) 3.90 (m, 1H) 3.62 (m, 2H) 3.36 (m, 2H) 2.85 (m, 1H) 2.63 (m, 2H) 2.33 (m, 1H) 2.08 (s, 3H) 1.94 (m, 4H) 1.19 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.C([NH:24][CH:25]([C:32](O)=[O:33])[CH2:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(OC(C)(C)C)=O.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:32](=[O:33])[CH:25]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[N:24]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1Nc2ccccc2C(c2ccccc2F)=NC1Cc1cccs1
Reaction time: 72 h

Procedure:
The procedure of Example 1 was carried out using 2-amino-2'-fluorobenzophenone (1.26 gm, 5.86 mmol), N-Boc-β-(2-thienyl)-DL-alanine (1.75 gm, 6.45 mmol), and DCC (6.45 ml of 1.0M solution in CH2Cl2) in CH2Cl2 (25 ml). Filtration, concentration in vacuo and flash chromatography (silica gel, 1% (v/v) Et2O in CH2Cl2) gave a white foam which was deprotected and cyclized by the procedure of Example 2. After stirring 3 days, the mixture was evaporated in vacuo, treated with H2O (50 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4, filtered, and evaporated to dryness in vacuo. The resulting foam was crystallized from Et2O to give the title compound as a white solid. The solid was dried in vacuo at 65° C.: (m.p. 189°-91° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Cl-].[Li+].C(N(CC)CC)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:11]1[C:5]2[C:4](=[O:20])[O:3][C:2]([CH3:21])([CH3:1])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=Cc1cccc2c1C(=O)OC(C)(C)O2
Temperature: 100 °C
Yield: 80.8 %

Procedure:
A mixture of 2,2-dimethyl-5-trifluoromethanesulfonyloxy-4H-1,3-benzodioxin4-one (9.90 g, 30.3 mmol), tributyl(vinyl)tin (10.10 g, 31.9 mmol), lithium chloride (8.70 g, 205 mmol), and triethylamine (5.0 mL, 36.0 mmol) in 1,4-dioxane (300 mL) was deoxygenated by bubbling nitrogen through the mixture for 1 h. To the mixture was added tetrakis(triphenylphosphine)palladium (3.40 g, 2.90 mmol) and the mixture was heated at 100° C. for 3 h. The mixture was allowed to cool to rt and was filtered. The filtrate was concentrated and purified by flash chromatography (1:12, EtOAc/hexanes) to provide 5-ethenyl-2,2-dimethyl-4H-1,3-benzodioxin-4-one (5.00 g, 81%) as a yellow oil: 1H NMR: (CDCl3) δ1.72 (s, 6H), 5.43 (dd, J=11.0, 1.3 Hz, 1), 5.72 (dd, J=17.5, 1.3 Hz, 1 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.73 (dd, J=17.5, 11.0 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:4][CH2:3]1.[N:19]#[C:20]Br.[OH-].[K+].CC(C)=O>O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[C:20]2[NH2:19])[CH2:6][CH2:7]1
Reactant: N#CBr
Reactant: CN1CCN(CCCNc2ccccc2N)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCN(CCCn2c(N)nc3ccccc32)CC1
Yield: 32.5 %

Procedure:
To a stirred solution of N-[3-(4-methyl-1-piperazinyl)propyl]-o-phenylendiamine (334.8 g., 1.35 mole) in water (1400 ml.) under nitrogen, was added cyanogen bromide (200 g., 1.89 mole) at a rate sufficient to maintain the reaction temperature at 50°-65° C. The addition took place over a 2 hour period. The reaction mixture was then cooled and the pH adjusted to 10 by the dropwise addition of 50% KOH. The basic aqueous layer was extracted from chloroform (5 × 500 ml.). The organic layers were combined, dried (MgSO4), and evaporated in vacuo to give a dark brown semi-solid. Slurrying with acetone (300 ml.) gave on filtration and washing with acetone 120.1 g., (32.5% yield) of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-aminobenzimidazole as a pale yellow solid, m.p. 195°-197° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=O)(C)(C)C.[ClH:24].O1CCOCC1>C(Cl)Cl>[ClH:24].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl 6-(tert-butoxycarbonylamino)hexanoate (1 eq) in DCM (0.17 M) was added 4M HCl in dioxane (30 eq). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated en vaccuo. The crude material was dissolved in DCM and precipitated in diethyl ether to give the product as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4](=[O:9])[C:3]=1[OH:10].[CH3:11][O-:12].[Na+].[Na]>CO>[OH:10][C:3]1[C:4](=[O:9])[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[O:12][CH3:11]
Reactant: O=c1ccccc(Br)c1O
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1ccccc(=O)c1O
Temperature: 80 °C

Procedure:
A solution of 3-bromo-2-hydroxy-2,4,6-cycloheptatrien-1-one [27.5 g, described by T. Toda et al., Nippon Hagaku Zasshi, 88, 1234-5 (1967), (CA 68 101342)] and sodium methoxide (prepared from 12.6 g of sodium in methanol followed by evaporation of the methanol) in dimethyl sulfoxide (300 ml) is heated at 80° C for 1 hour. The solution is cooled poured on ice, acidified with 2N sulfuric acid and extracted with ethyl acetate. The organic extract is washed with brine, dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate-hexane to give 2-hydroxy-3-methoxy-2,4,6-cycloheptatrien-1-one. Evaporation of the mother liquors gives 2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:12]=1.[Br:21]Br.O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:21][SH:9]1[CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:12]=[C:8]1[NH:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1
Reactant: N#Cc1cccc(-c2csc(Nc3cnccn3)n2)c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(C2=C[SH](Br)C(Nc3cnccn3)=N2)c1

Procedure:
3-[2-(Pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile (1.5 g, 5.36 mmol) is suspended in hot glacial acetic acid (10 ml) and bromine (0.275 ml) is added dropwise at room temperature with stirring. The resultant suspension is stirred at room temperature for 10 minutes. Water (ca. 100 ml) is added to the mixture, which is basified to pH 9 with solid potassium carbonate. The resulting precipitate is filtered and washed with water to yield 3-[S-bromo-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile, m.p. 215° C. (dec.), m.s. 279 (ES+, M+—Br).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(C=O)n1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cccc(C=C2N=C(c3cccs3)OC2=O)n1
Temperature: 90 °C
Yield: 44.2 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-methoxy-2-pyridinecarboxaldehyde (46 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 38 mg of the above-captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C@H:61]1[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:60][C@H:61]3[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]3)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CC[C@H](O)CC1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (200 mg, 0.54 mmol; example 5.1) in dry DMF (4 mL) was added dry DIPEA (3.2 mmol) followed by HATU (1.6 mmol) at 0° C. Then the reaction mixture was allowed to warm to rt and stirred for 45 min at that temperature. TLC shows total consumption of acid and formation of a new spot. (trans)-4-Amino-cyclohexanol (0.64 mmol) was added to this reaction mixture at 0° C. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. TLC shows total consumption of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid and DMF was removed in vacuo at 60° C. It was then diluted with H2O (5 ml). Aqueous layer was extracted with EtOAc (5×5 mL) and combined organic layers were washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo. Crude product was subjected to column chromatography [SiO2 (230-400 mesh), EtOAc:Hexane 10:90] to give the title compound (40 mg, 24%) as off-white solid. MS: m/e=470.0 [M+H+].
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7](=O)C=CC1C=CC=CC=1)=[O:6])[CH3:3].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]O)=O)[CH:19]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1.C(Cl)CCl>C(Cl)(Cl)Cl>[CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:24]([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[O:26]1)=[O:6])[CH3:3]
Reactant: CC(C)NC(=O)C(=O)C=Cc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)NC(=O)C1OC1c1ccccc1

Procedure:
A mixture of N-(1-methylethyl)cinnamoylcarboxamide (18 g.), m-chloroperbenzoic acid (23.6 g.), 4,4'-thiobis(6-tert-butyl-m-cresol) (0.3 g.) and ethylene dichloride (250 ml.) was heated under gentle reflux for 1 hour, then chilled in ice. A precipitate (m-chlorobenzoic acid) was separated by filtration and washed with ethylene dichloride. The filtrate and washings were combined, and evaporated under reduced pressure on a rotary evaporator to give an amber oil. The oil was dissolved in chloroform (300 ml.) and the chloroform solution was washed with 5% aqueous sodium bicarbonate solution twice, then with saline. The chloroform solution was dried over magnesium sulfate, then evaporated under reduced pressure in a rotary evaporator to give an oil. The oil solidified on standing. The solid mass was recrystallized from ether giving 8.4 g. of product, m.p. 114°-115°.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[NH2:18])=[O:12])=[CH:6][CH:5]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=O)=[CH:23][CH:22]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.ClCCl>[F:20][C:2]([F:19])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[NH:18][CH2:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=[CH:22][CH:23]=2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: Nc1ccsc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1sccc1NCc1ccnc2ccccc12
Temperature: 25 °C

Procedure:
A solution of N-(4-trifluoromethoxyphenyl) 3-aminothiophene-2-carboxamide (1 g, 3.31 mmol) and quinoline-4-carboxaldehyde (347 mg, 2.21 mmol) in trifluoroacetic acid:dichloromethane (1:1, 30 mL) was heated at reflux for 2 h under nitrogen. The reaction was cooled to RT and triethylsilane (0.71 mL, 4.42 mmol) was added. The resulting solution was then stirred at reflux for 16 h under nitrogen. After cooling to RT, the reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (3×100 mL) and saturated sodium bicarbonate solution (50 mL). The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20–30% ethyl acetate in hexane) to give EXAMPLE 1 as a light yellow solid, mp: 168–170° C. 1H-NMR (400 MHz/CDCl3): δ=5.01 (d, J=6.2 Hz, 2 H), 6.56 (d, J=5.4 Hz, 1 H), 7.12 (s, 1 H), 7.22 (d, J=8.7 Hz, 2 H), 7.25 (s, 1 H), 7.44 (d, J=4.3 Hz, 1 H), 7.58 (d, J=9.0 Hz, 2 H), 7.62 (t, J=8.2 Hz, 1 H), 7.76 (t, J=8.3 Hz, 1 H), 8.02 (d, J=7.5 Hz, 2 H), 8.17 (d, J=8.3 Hz, 1 H), 8.86 (d, J=4.5 Hz, 1 H). MS (ES+): 444 [MH+]. 13C-NMR (400 MHz/CDCl3): δ=45.9, 101.4, 117.9, 118.9, 119.5, 121.9, 122.0, 122.6, 126.5, 127.2, 129.1, 129.7, 130.6, 136.8, 144.5, 145.4, 148.3, 150.7, 155.9, 163.8. Anal. Calcd for C22H16F3N3O2S: C, 59.59; H, 3.64; N, 9.48; F, 12.85; S, 7.23. Found: C, 59.59; H, 3.67; N, 9.46; F, 13.01; S, 7.23.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)C(C)C
Yield: 25.8 %

Procedure:
1-(2-Aminoethyl)-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.01 mL, 7.26 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372-376. The crude product was recrystallized from isopropanol (4 mL/g) and then triturated with acetonitrile (12.5 mL/g), isolated by filtration, and dried overnight in a drying oven to provide 0.61 g of N-{2-[4-amino-2-butyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 228-230° C.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[N:12]([CH3:26])[C:11]2=[O:27])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[C:31]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][CH:13]2[CH2:14][N:10]([CH2:9][C:8]3[CH:28]=[CH:29][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)[C:11](=[O:27])[N:12]2[CH3:26])=[CH:19][C:20]=1[CH3:25])([CH3:38])[CH3:37])[CH3:36]
Reactant: Cc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1C
Temperature: 50 °C
Yield: 87.9 %

Procedure:
1-(4-tert-Butyl-benzyl)-4-[3-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.060 g, 0.152 mmol) is dissolved in DMF (1.5 mL), to it is added ethyl 2-bromoisobutyrate (0.141 g, 0.760 mmol) followed by potassium carbonate (0.105 g, 0.760 mmol). After heating at 50° C. overnight, the reaction mixture is diluted with ethyl acetate (2 mL), washed with water (2 mL), the separated organic layer is passed through a chem elut tube, and the tube is washed with more DCM (50 mL). Evaporation of solvent followed by chromatography on silica gel, (gradient elution 0-40% ethyl acetate in hexane) to provide an oil (0.068 g, 88%). Mass [EI+] 510 (M+H)+.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)=[CH:26][CH:27]=1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Product: CCCCCCCCc1noc(-c2ccc(CNCCc3ccc(-c4ccccc4)cc3)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(1,1′-biphenyl-4-yl)ethylamine gave the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH3:16].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][CH3:16])=[CH:12][CH:11]=1)[CH3:10]
Reactant: CCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C(=O)OCC)cc1
Yield: 90.8 %

Procedure:
(Scheme 1, Compound A) To a solution of ethyl 4-hydroxybenzoate (2.0 g, 12 mmol) and bromopropane (4.0 g, 32.8 mmol) in DMF (50 mL) was added NaH (60% in mineral oil, 0.80 g, 20.8 mmol). The resultant suspension was stirred at room temperature for 1.0 hour. The mixture was diluted with ethyl acetate (EtOAc) (300 mL), washed with H2O, and then was dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a yellow oil (2.26 g, 10.9 mmol, 91% yield). 1H NMR (DMSO-d6) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.24 (q, 2H, J=6.9 Hz), 3.98 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (t, 3H, J=6.6 Hz), 0.97 (t, 3H, J=7.2 Hz); Anal. Calcd for C12H16O3.0.47C6H14: C, 71.54; H, 9.14; N, 0.00. Found: C, 71.57; H, 8.78; N, 0.00; Mass Spec.: 209.04 (MH+).