Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6]/[C:5](=[CH:7]\[C:8](O)=[O:9])/[C:4](=[O:11])[O:3]1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1([CH3:12])[O:6]/[C:5](=[CH:7]\[C:8]([Cl:16])=[O:9])/[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (Z)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetic acid (0.27 g, 1.6 mmol) in CH2Cl2 (3.9 mL) was added oxalyl chloride (0.13 mL, 1.6 mmol). A few drops of DMF were added, and the reaction mixture was stirred at rt for 2 h to produce a 0.4 M stock solution of (Z)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetyl chloride (Solution A). An aliquot of Solution A (0.25 mL, 0.1 mmol) was added to each 16×100 mm Wheaton tubes that had been charged separately with CH2Cl2 (0.25 mL), DIEA (0.050 mL, 0.3 mmol) and an amine (0.1 mmol) corresponding to the R5-amide contained in the final example. The vials were capped and the reaction mixtures were agitated at 400 rpm at rt for 16 h using an INNOVA® platform shaker. After removal from the shaker, each reaction mixture was diluted with MeOH (0.25 mL), treated with polystyrene-isocyanate resin (0.091 g, 1.1 mmol/g, 0.1 mmol) and agitated at 400 rpm for 2 h. Following filtration to remove the polystyrene beads, the filtrates were collected and dried under a stream of N2 for 1 h using a ZYMARK® tabletop dryer set to 45° C. The amides thus formed were carried onto the next step without further purification. To a separate reaction vessel was added paraformaldehyde (87 mg, 2.88 mmol), MeOH (10.6 mL) and CH3NH2 (2.0 M in THF; 1.44 mL, 2.88 mmol). This mixture was heated to 60° C. for 5 min using microwave irradiation to provide Solution B. To each vial containing an amide was added a 0.5 mL aliquot of Solution B. The reaction mixtures were agitated at 400 rpm at 80° C. for 16 h on an INNOVA® platform shaker. The reaction mixtures were removed from the shaker, cooled to rt and diluted with MeOH (0.25 mL). Examples 1-12 were purified from their corresponding solutions by RP preparative HPLC using Method H. HPLC/MS data for each compound was collected using Method E, and the molecular masses were determined by MS (ES) by the formula m/z. Both the retention time and MS data for Examples 6, 7 and 9 are listed in Table 2. Note: 2.0 M CH3NH2 in MeOH may be substituted for 2.0 M CH3NH2 in THF.
Reaction SMILES: O1C2C=CC=CC=2OCC1CN1CCCC(CO)(C)C1.[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH2:23][CH:22]1[CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][C:34]([CH2:40][O:41][CH2:42][CH2:43][OH:44])([CH2:38]C)[CH2:33]1>>[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH2:23][CH:22]1[CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][C:34]([CH2:40][O:41][CH2:42][CH2:43][OH:44])([CH3:38])[CH2:33]1
Reactant: CCC1(COCCO)CCCN(CC2COc3ccccc3O2)C1
Agent: CC1(CO)CCCN(CC2COc3ccccc3O2)C1
Product: CC1(COCCO)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared from [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol using the procedure described above for 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl-methoxy]ethanol.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:22])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(OC)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(OC)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (21.6 mL of 0.31M stock solution, 6.69 mmol) cooled to −78° C. was treated with a solution of (3-fluoro-4-methoxy-phenyl)-acetic acid methyl ester (1.26 g, 6.38 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.47 g, 7.02 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 48 h. The reaction mixture was then quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-fluoro-4-methoxy-phenyl)-propionic acid methyl ester (1.50 g, 83.8%) as a clear oil: EI-HRMS m/e calcd for C16H21FO3(M+) 280.1477 found 280.1474.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:5]([CH:40]([CH3:42])[CH3:41])[N:4]=1.[CH3:43]I.[H-].[Na+]>O1CCCC1.O>[CH3:43][O:1][CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:5]([CH:40]([CH3:41])[CH3:42])[N:4]=1
Reactant: CI
Reactant: CCCCCc1c(CO)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1c(COC)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 40 °C
Yield: 40 %

Procedure:
A mixture of the intermediate obtained in Example 200, Step B (0.1 g, 0.17 mmol), methyl iodide (0.013 mL, 1.2 equiv), and sodium hydride (8 mg of a 60% dispersion in mineral oil, 1.2 equiv) in tetrahydrofuran (1 mL) was heated at 40° C. for 3 h. The mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (3×10 mL). Silica gel chromatography provided a colorless solid (40 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 7.41 (m, 6H), 7.32 (m, 4H), 7.06 (m, 4H), 4.62 (s, 2H), 4.27 (s, 2H), 3.48 (s, 3H), 3.15 (sept, 6.6 Hz, 1H), 2.36 (m, 2H), 1.27 (m, 2H), 1.18 (d, 6.6 Hz, 6H), 1.12 (m, 2H), 1.00 (s, 9H), 0.87 (m, 2H), 0.78 (t, 6.6 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCO)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCOS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Compound 9a (36 mg, 0.087 mmol) was dissolved in dichloromethane (5 ml) followed by triethylamine (44 mg, 0.44 mmol). Methanesulfonyl chloride (30 mg, 0.26 mmol) was then added via a syringe. The solution was stirred at room temperature for 4 hours. After standard workup with dichloromethane, the residue was purified by silica gel preparative TLC (2.0% methanol in dichloromethane) to afford 10a (39 mg, 91%): 1H NMR δ 7.43 (d, 4H, J=8.6 Hz), 7.20 (d, 2H, J=8.4 Hz), 6.98 (q, 2H), 6.89 (d, 2H, J=8.6 Hz), 4.41 (m, 2H), 4.16 (m, 2H), 3.87 (m, 4H), 3.27 (s, 3H), 3.05 (s, 3H), 1.46 (s, 9H). Anal. (C25H33NO7S) C. H. N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:20])[CH2:18][NH2:19])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH2:21]([O:24][C:25]1[CH:41]=[CH:40][C:28]([C:29]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1)[C:22]#[CH:23].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:20])[CH2:18][NH:19][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([C:29](=[O:30])[C:28]4[CH:40]=[CH:41][C:25]([O:24][CH2:21][C:22]#[CH:23])=[CH:26][CH:27]=4)=[CH:39][CH:38]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: C#CCOc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: NCC(F)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1ccc(C(=O)c2ccc(C(=O)NCC(F)Cn3c4ccc(Br)cc4c4cc(Br)ccc43)cc2)cc1
Yield: 90 %

Procedure:
3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropan-1-amine (Naidoo et al., 2014) (40.2 mg, 0.10 mmol) was added to a solution of 4-(4-(prop-2-yn-1-yloxy)benzoyl)benzoic acid (Bandyopadhyay et al., 2011) (28.5 mg, 0.10 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (21.2 mg, 0.11 mmol) and 1-hydroxybenzotriazole hydrate (15.0 mg, 0.11 mmol) in dimethylformamide (0.4 ml). The reaction went to completion within an hour. The mixture was diluted with EtOAc and washed several times with water and then brine. The organic layer was dried over Na2SO4, filtered and condensed to give a light brown solid in 90% yield. 1H NMR (Acetone-d6, 400 MHz) δ 8.41 (dd, J=2.0, 0.6 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.82 (dd, J=10.3, 8.6 Hz, 4H), 7.71-7.56 (m, 4H), 7.16 (d, J=8.9 Hz, 2H), 5.39-5.10 (dm, 1H), 4.94 (d, J=2.4 Hz, 2H), 4.91-4.85 (m, 1H), 4.82 (d, J=5.4 Hz, 1H), 4.05-3.89 (m, 1H), 3.87-3.70 (m, 1H), 3.17 (t, J=2.4 Hz, 1H). 13C NMR (CD2Cl2, 100 MHz): 194.6, 167.3, 161.7, 141.4, 140.1, 136.9, 132.8, 130.7, 130.2, 129.7, 127.3, 124.1, 123.6, 114.9, 113.0, 111.2 (JC-F=1.9 Hz), 92.1 (JC-F=176.2 Hz), 78.2, 76.3, 56.4, 45.8 (JC-F=22.5 Hz), 42.3 (JC-F=21.2 Hz). MS (ESI), m/z: calculated 660.01. found 660.7 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[H-].[Na+].[C:16]([O:22][CH2:23]Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([O:22][CH2:23][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH3:13])([CH3:12])[C:6]1=[O:11])=[O:21]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN1C(=O)C(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g of 5-bromo-3,3-dimethyl-1,3-dihydroindol-2-one was dissolved in 100 ml of dimethylformamide, and 217 mg of sodium hydride (60% dispersion in mineral oil) were added. The mixture was then stirred at room temperature for 30 minutes. Then the reaction mixture was cooled to 0° C. in an ice bath, and 941 mg of chloromethyl pivalate were added. The ice bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was diluted by adding 250 ml of ethyl acetate, and 50 ml of water were added. The organic phase was removed and washed once with 100 ml of saturated sodium chloride solution, dried over MgSO4 and then concentrated under reduced pressure. This gave 1.5 g of 5-bromo-3,3-dimethyl-2-oxo-2,3-dihydroindol-1-ylmethyl 2,2-dimethylpropionate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.[OH-:16].[Na+:17].[OH2:18]>[Pd]>[Na+:17].[Na+:17].[Na+:17].[Na+:17].[N+:1]([C:4]1[CH:5]=[C:6]([C:13]([NH:1][C:4]2[CH:12]=[C:8]([C:9]([O-:11])=[O:10])[CH:7]=[C:6]([CH:5]=2)[C:13]([O-:15])=[O:14])=[O:14])[CH:7]=[C:8]([C:9]([NH:1][C:4]2[CH:5]=[C:6]([C:13]([O-:15])=[O:14])[CH:7]=[C:8]([CH:12]=2)[C:9]([O-:11])=[O:10])=[O:10])[CH:12]=1)([O-:18])=[O:16]
Reactant: [OH-]
Reactant: O
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Na+]
Product: O=C([O-])c1cc(NC(=O)c2cc(C(=O)Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)cc([N+](=O)[O-])c2)cc(C(=O)[O-])c1
Reaction time: 1 h

Procedure:
A mixture of 21.1 g of 5-nitroisophthalic acid, 40.5 ml of 5N sodium hydroxide and 2.0 g of 10% palladium on carbon catalyst in 110 ml of water is hydrogenated at room temperature for 1 hour and then filtered through diatomaceous earth. To the solution of 5-aminoisophthalic acid disodium salt is added 9.2 g of sodium bicarbonate followed by 13.65 g of powdered 5-nitroisophthaloyl chloride (prepared as described in Example 1). The solution is cooled in a water bath and stirred vigorously in a baffle flask for 1 hour and 15 minutes. The mixture is filtered, the filtrate is concentrated to approximately 125 ml and 200 ml of ethanol is added to give a yellow precipitate. The mixture is filtered and the product is washed with 66% aqueous ethanol, ethanol and ether. The material is dried, then dissolved in 200 ml of water. The solution is filtered through diatomaceous earth and diluted slowly with stirring and warming with 300 ml of ethanol. The precipitate formed is collected and washed with 100 ml of 60% aqueous ethanol, 400 ml of ethanol and ether. The product is dried by conventional means to give 27.8 g of 5,5'-[5-nitro-1,3-phenylenebis(carbonylimino)]diisophthalic acid tetrasodium salt.
Reaction SMILES: ClC1C2C(=C(N[C:13](=[O:22])C3C(Cl)=CC=CC=3Cl)C=CC=2)N=CC=1.C(NCCN)C1C=CC=CC=1.[CH2:34]([NH:41][CH2:42][CH2:43][NH:44][C:45]1[C:54]2[C:49](=[C:50]([NH:55][C:56](=[O:65])[C:57]3[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=3[Cl:64])[CH:51]=[CH:52][CH:53]=2)[N:48]=[CH:47][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:34]([N:41]1[CH2:42][CH2:43][N:44]([C:45]2[C:54]3[C:49](=[C:50]([NH:55][C:56](=[O:65])[C:57]4[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=4[Cl:64])[CH:51]=[CH:52][CH:53]=3)[N:48]=[CH:47][CH:46]=2)[C:13]1=[O:22])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Nc1cccc2c(NCCNCc3ccccc3)ccnc12)c1c(Cl)cccc1Cl
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Agent: NCCNCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1cccc2c(N3CCN(Cc4ccccc4)C3=O)ccnc12)c1c(Cl)cccc1Cl
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (400 mg) and N-benzylethylenediamine (854 mg) was stirred for 6 hours at 130° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (methanol-dichloromethane) to give a residue containing 4-(2-benzylaminoethylamino)-8-(2,6-dichlorobenzoylamino)quinoline. A mixture of the obtained residue, 1,1'-carbonyldiimidazole (221 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (191 mg) in dimethylformamide was stirred for 4 hours at ambient temperature and for 2 hours at 130° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (methanol-dichloromethane) to give 4-(3-benzyl-2-oxoimidazolidin-1-yl)-8-(2,6-dichlorobenzoylamino)quinoline (150 mg).
Reaction SMILES: [Si]([O:8][C@H:9]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[CH2:10][NH:11][C@H:12]([CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]4)[CH2:21]2)[CH2:27]3)[C:15]=1[O:30][CH2:31][CH3:32])(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH:9]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[CH2:10][NH:11][CH:12]([CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]23[CH2:27][CH:26]4[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]4)[CH2:21]2)[CH2:29]3)[C:15]=1[O:30][CH2:31][CH3:32]
Reactant: CCOc1c(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc3c(c2)COC(C)(C)O3)cccc1C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(CC(C)NCC(O)c2ccc3c(c2)COC(C)(C)O3)cccc1C12CC3CC(CC(C3)C1)C2
Yield: 90.1 %

Procedure:
928 mg (1.26 mmol) of the Intermediate 83 and 794 mg (2.52 mmol) of tetrabutylammonium fluoride trihydrate in 30 ml of anhydrous THF are stirred at room temperature overnight. The solution is concentrated and the residue is partitioned in ethyl acetate/water. The organic layer is washed with water, dried and concentrated. The residue is chromatographied on silicagel using dichloromethane/methanol 90:3 as eluent to give 590 mg (990% yield) of the desired compound as a yellowish oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)=[CH:54][CH:53]=[N:52]1>CN(C=O)C>[CH3:50][N:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)=[CH:54][CH:53]=[N:52]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Cn1nccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccnn4C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 77% yield: LCMS (ESI) m/z 376 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCC(F)(F)F)cc1
Product: CC(C)C(=O)Nc1nccc(C(=O)NC(C)c2ccc(OCC(F)(F)F)cc2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)pyrimidine-4-carboxamide (15 mg, 0.04 mmol, Step-1, single enantiomer) and isobutyryl chloride (14 mg, 0.13 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH2:2][C:3]1[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=1)(=[O:22])[CH3:21]
Reactant: CCOC(=O)c1noc(-c2cccc(I)c2)c1CO
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(-c2cccc(I)c2)c1COC(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of ethyl 4-(hydroxymethyl)-5-(3-iodophenyl)isoxazole-3-carboxylate (1.50 g, 4.03 mmol) in pyridine (5 mL) was stirred for 10 min. followed by cooling to 0° C. and slowly adding acetyl chloride (379 mg, 4.83 mmol). The mixture was allowed to come to ambient temperature and stirred for 2 hours. The solvent was removed under vacuo and the mixture purified by column chromatography (0–30% ethyl acetate in hexanes) to provide the titled compound (1.65 g, 99%).
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([NH2:5])=[O:4].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.CCCCCCCCCCCCCCCC>CCCCCC>[CH3:26][Si:27]([CH3:30])([CH3:29])[N:5]([Si:27]([CH3:30])([CH3:29])[CH3:26])[C:3](=[O:4])[C:2]([F:25])([F:1])[C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[F:12]
Reactant: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Solvent: CCCCCC
Solvent: CCCCCCCCCCCCCCCC
Product: C[Si](C)(C)N(C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[Si](C)(C)C

Procedure:
First, perfluorooctaneamide (CF3(CF2)7CONH2) (46 g) was dissolved in n-hexane (300 ml). Thereafter, trimethylchlorosilane (15 ml) was dropped gradually into the solution obtained above, in a dry nitrogen atmosphere. Then this was allowed to react for two hours while being stirred. After the reaction was completed, hexadecane contained in the reaction solution was removed with the evaporator. Thus, N,N-bis(trimethylsilyl)perfluorooctaneamide was obtained.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:12]([NH:19][C:20]1[C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[S:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>O.C1C=CC=CC=1>[CH2:1]([N:19]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:20]1[C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[S:23][C:24]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: c1ccc(CNc2c(-c3ccccc3)sc3ccccc23)cc1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)c2c(-c3ccccc3)sc3ccccc23)cc1
Yield: 62.9 %

Procedure:
40.2 g (0.33 mol) of benzoic acid are added to 100 milliliters of absolute benzene and, by cooling and stirring, 3.78 g (0.1 mol) of NaBH4 are added in portions sufficiently slowly for the temperature not to exceed 20° C. After the addition of 6.3 g (20 mmol) of 3-benzylamino-2-phenyl-benzo(b)thiophene the mixture is refluxed for 60 minutes. The still hot reaction mixture has added to it by stirring half a liter of water and is neutralised by ammonia. By evaporating the organic phase dried over K2CO3 and recrystallising the residue in ethanol, 5.1 g (41% of theory) of 3-dibenzylamino-2-phenyl-benzo(b)thiophene are obtained, colourless crystals, mp 98°-100° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[F:14][C:2]([F:1])([F:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:18]=2)(=[O:25])=[O:24])=[N:10][CH:11]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(COCC(F)(F)F)cn1
Product: O=S(=O)(Nc1ccc(COCC(F)(F)F)cn1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 5-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.06 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.078 g) as an off-white solid (0.056 g). MS (ESI−): 413.1 ([M−H]−).