Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]3[N:14]([Si](C(C)C)(C(C)C)C(C)C)[CH:15]=[CH:16][C:11]3=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28][N:29](C=O)C.ClS(N=C=O)(=O)=O.CCOC(C)=O>C(#N)C>[O:27]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[C:12]3[NH:14][CH:15]=[C:16]([C:28]#[N:29])[C:11]3=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(N3CCS(=O)(=O)CC3)nc21
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1c[nH]c2nc(N3CCS(=O)(=O)CC3)ccc12
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
In a 25 mL round-bottomed flask 6-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (322 mg, 790 μmol, Eq: 1.00) was combined with DMF (11.9 ml) to give a colorless solution. The reaction mixture was cooled to −20° C. and stirred for 5 min. Chlorosulfonyl isocyanate (335 mg, 206 μl, 2.37 mmol, Eq: 3) in acetonitrile (11.9 ml) was added dropwise and the resultant cooled reaction was stirred at −20° C. and stirred for 3 hrs The reaction mixture was poured into 25 mL EtOAc and washed with sat NaCl (3×20 mL). After evaporation, crude material was purified by flash chromatography (silica gel, 12 g, 5% to 10% MeOH in DCM) to obtain 6-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (122 mg, 56%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(OC1CCCCO1)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
A mixture of 7 g. 4-(8-cyclohexyloctylamino)benzoic acid, 2 g. 2,3-dihydropyran and 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and condensed. The residue is crystallized from methylcyclohexane to white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([NH2:20])=[CH:18][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:11][C:5]=2[CH:4]=1.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[N:26]2[N:25]=1)=O>>[CH3:1][O:2][C:3]1[C:19]([NH:20][C:24]2[N:29]=[CH:28][C:27]3=[CH:30][CH:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH3:40])[N:26]3[N:25]=2)=[CH:18][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1N)CCCC(N1CCOCC1)C2
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4OC)n3n1)CCCC(N1CCOCC1)C2
Yield: 6.6 %

Procedure:
Following a procedure analogous to 251c, 3-Methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (0.164 g, 0.59 mmol) and 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (85 mg, 0.30 mol) were converted to the title compound (19.6 mgs). 1H-NMR (DMSO-d6) δ 8.70 (s, 1H), 8.16 (s, 1H), 8.02 (d, J=7.4 Hz, 1H), 7.45-7.41 (m, 2H), 7.50-7.45 (m, 2H), 7.14-7.07 (m, 2H), 7.03 (d, J=4.9 Hz, 1H), 6.71 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.79-3.74 (m, 4H), 2.91-2.50 (complex series of m, 7H), 2.40 (t, J=10.6 Hz, 1H), 2.16-2.00 (m, 2H), 1.80-1.70 (m, 1H), 1.43-1.33 (m, 1H); LC/MS (ESI+): 500.17 (M+H).
Reaction SMILES: CSC1C=[C:10]2C(C[CH:8]([N:12]([CH2:16][CH2:17]C)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=CC=1.Cl[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23](OO)=O.C([O-])([O-])=O.[Na+].[Na+].F[C:37](F)(F)[S:38](O)(=[O:40])=[O:39]>>[CH3:37][S:38]([C:29]1[CH:28]=[C:27]2[C:22]([CH2:23][CH:16]([N:12]([CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][CH3:15])[CH2:17]2)=[CH:21][CH:20]=1)(=[O:40])=[O:39]
Reactant: CCCN(CCC)C1Cc2ccc(SC)cc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN(CCC)C1Cc2ccc(S(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of (6-methylsulfanyl-indan-2-yl)-dipropyl-amine (Example 12, 85 mg, 0.32 mmol) in trifluoromethanesulfonic acid (5 ml) was added 3-chloroperoxy-benzoic acid (90 mg, 75%, 0.39 mmol). The solution was then stirred for 2 h at room temperature. Another portion of 3-chloroperoxy-benzoic acid (20 mg 75%, 0.09 mmol) was added and the reaction mixture was stirred for an additional 1 h. The pH was adjusted to 11 with aqueous Na2CO3 and the layers were separated. The organic layer was dried and evaporated to dryness. The crude product was chromatographed (SiO2) using dichloromethane-methanol as eluant (19:1). Pooling of the pure fractions yielded 65 mg (69%) of (6-methylsulfonyl-indan-2-yl)-dipropyl-amine. The amine was converted to the hydrochloride and recrystallized from a mixture of 2-propanol and isopropyl ether. m.p. 190-192 (HCl); 1H NMR (300 MHz, CDCl3) δ 0.90 (t, 6H), 1.50 (m, 4H), 2.50 (t, 4H), 2.90-3.20 (m, 7H), 3.70-3.80 (m, 1H), 7.40 (d, J=8 Hz, 1H), 7.70-7.80 (d, 2H); 13C NMR (75.4 MHz, CDCl3) δ 11.97, 20.25, 36.43, 36.82, 44.68, 53.29, 63.08, 123.33, 125.18, 125.81, 138.65, 143.72, 148.89; MS m/e 295 (5, M+), 266 (100), 116 (18), 267 (18), 115 (15).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([O:37]CC2C=CC(OC)=CC=2)[CH:22]([CH2:30][CH2:31]OS(C)(=O)=O)[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([OH:37])[CH:22]([CH2:30][CH2:31][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[C:23]([OH:25])=[O:24])=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Potassium phthalimide (8.8 mg, 60 μmol) was added in one portion to a stirred solution of 1,1-dimethylethyl 5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl) oxy]ethyl}pentanoate (28.4 mg, 50 μmol) in dimethylformamide (0.5 mL) under nitrogen at room temperature. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue taken up in dichloromethane (0.5 mL). Trifloroacetic acid (0.5 mL) was added in one portion and the resulting solution stirred for 1 h at room temperature. The volatiles were evaporated and the residue purified by mass directed auto-preparative HPLC to give the title compound as a white solid (6.0 mg, 27%). LC/MS: 3.43 min; z/e 444, calcd (M+1) 444. 1H NMR (400 MHz: CDCl3): 7.85 (2H), 7.70 (2H), 7.55 (1H), 7.50 (1H), 7.45 (2H), 7.30 (1H), 7.25 (4H), 3.85(3H), 2.95 (1H), 2.75 (1H), 2.60(1H), 2.20 (1H), 2.05 (1H), 1.90 (2H).
Reaction SMILES: C(OC([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][N:57](C(OC(C)(C)C)=O)[CH3:58])[CH:39]=1)=O)(C)(C)C.O.[ClH:67].O1CCOCC1>>[ClH:67].[CH3:37][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][S:19]([N:16]1[CH2:15][CH2:14][C:11]2([N:10]=[C:9]([C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=[C:40]([O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][NH:57][CH3:58])[CH:39]=3)[NH:8][C:12]2=[O:13])[CH2:18][CH2:17]1)(=[O:20])=[O:21])[C:30]([OH:32])=[O:31]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCCOCCOCCN(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CNCCOCCOCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)O)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
2-[3-(2-{2-[2-(tert-Butoxycarbonyl-methyl-amino)-ethoxy]-ethoxy}-ethoxy)-5-trifluoromethyl-phenyl]-8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (37.4 mg, 39.7 μmol) was dissolved in 4 N hydrochloric acid-dioxane (0.79 mL). Water (14.3 μL, 795 μmol) was added and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure to give 3-methyl-4-{2-[2-(3-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethoxy}-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-benzoic acid hydrochloride (28.0 mg, 98%).
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(N[C@H]2CC[C@H](C)CC2)CCC1.NC1SC=NC=1.C([O:49][C:50](=[O:54])C(S)C)C>>[CH:24]1([N:16]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:50]([OH:54])=[O:49])=[CH:9][N:10]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C(C)S
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: C[C@H]1CC[C@H](NC2CCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCC2)CC1

Procedure:
{2-[3-Cyclobutyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cyclobutyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.[Na].P(=O)(O)(O)O.[CH:12]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][CH3:19])([CH3:14])[CH3:13]>C(O)(C)C>[CH:12]([O:15][CH2:16][CH:17]([O:20][CH2:2][CH:3]([OH:1])[CH2:4][CH3:5])[CH2:18][CH3:19])([CH3:14])[CH3:13]
Reactant: CCC(O)COC(C)C
Reactant: CCC1CO1
Agent: O=P(O)(O)O
Agent: [Na]
Solvent: CC(C)O
Product: CCC(O)COC(CC)COC(C)C

Procedure:
Into a 1 L separable flask equipped with a stirrer and a condenser, 180 g of isopropanol and 216 g of epoxybutane were introduced. After filling with nitrogen, 1.6 g of sodium was added and refluxed for 16 hours. After addition of 5 g of phosphoric acid to the mixture, 1-isopropoxy-2-butanol (boiling point: 100° C./120 mmHg) and 1-(1-isopropoxy-2-butoxy)-2-butanol (boiling point: 105° C./50 mmHg) were obtained by fractional distillation under reduced pressure. 1-isopropoxy-2-butanol thus obtained is a model compound in the case where one molecule of 1,2-epoxybutane reacted with a hydroxyl group of EVOH and 1-(1-isopropoxy-2-butoxy)-2-butanol is a model compound in the case where two or more molecules of 1,2-epoxybutane reacted with a hydroxyl group of EVOH.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.Br[CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])=[O:20]>O1CCCC1>[C:1]([CH:3]([CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27])=[O:20])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: CC(Br)C(=O)c1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C#N)C(C)C(=O)c1ccccc1F
Temperature: 70 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of methyl cyanoacetate (15.5 mL) and diisopropylethylamine (64 mL) in tetrahydrofuran (110 mL) was added a solution of 2-bromo-1-(2-fluorophenyl)propan-1-one (36.8 g) in tetrahydrofuran (160 mL), and the mixture was stirred at 70° C. for 20 hr. The reaction mixture was allowed to cool to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=5:1) to give the title compound as a brown oil (yield 31.9 g, 80%).
Reaction SMILES: C1C[O:4]CC1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].C([Si](CC)(CC)O[CH:18]=[C:19]([O:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])[O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])C>>[CH2:6]([Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[O:4][C:19]([O:28][Si:29]([CH2:30][CH3:31])([CH2:32][CH3:33])[CH2:34][CH3:35])([O:20][Si:21]([CH2:22][CH3:23])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:18])[CH3:7]
Reactant: CC[Si](CC)(CC)OC=C(O[Si](CC)(CC)CC)O[Si](CC)(CC)CC
Reactant: CC[Si](Cl)(CC)CC
Reactant: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(O[Si](CC)(CC)CC)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The ester was added to a 0.5 M THF (200 mL, 0.1 mol) solution over 15 minutes and the mixture was stirred at this temperature for an additional 15 minutes to generate the lithium enolate. Triethylsilyl chloride (16.7 mL 0.1 mol) was added over 15 minutes to trap the enolate as the tris(triethylsiloxy)ethene product. The mixture was warmed to ambient temperature and the THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate out the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 minutes while the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give a clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product.
Reaction SMILES: [NH2:1][C:2]([CH2:21][OH:22])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)[CH2:3][OH:4].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>CCOC(C)=O.O>[CH2:27]([O:26][C:24]([NH:1][C:2]([CH2:3][OH:4])([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)[CH2:21][OH:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCc1ccc(CCC(CO)(CO)NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.8 %

Procedure:
A mixture of 3.07 g (10.0 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol and 3.00 g (30.0 mmol) of KHCO3 in 200 mL of EtOAc and 150 mL of H2O was treated with 1.50 mL (10.0 mmol) of benzyl chloroformate, then stirred at rt for 2 h. The organic layer of the reaction mixture was separated, dried over MgSO4 and concentrated to afford 5.29 g of the title compound: 1H NMR (500 Mhz) δ0.88 (t, J=6.5, 3H), 1.22-1.34 (12H), 1.55-1.60 (m, 2H), 1.87-1.91 (m, 2H), 2.53-2.59 (4H), 3.23 (br s, 2H), 3.67 (dd, J=6.5, 11.5, 1H), 3.90 (dd, J=6.5, 11.5, 1H), 5.08 (s, 2H), 5.30 (s, 1H), 7.05-7.09 (4H), 7.32-7.36 (5H); HPLC A 5.34 min.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[CH3:17][NH:18][C:19]([C:21]1[C:25]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([NH2:30])=[CH:29][C:24]=2[O:23][C:22]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:20]>ClC(Cl)Cl>[CH3:17][NH:18][C:19]([C:21]1[C:25]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([NH:30][C:10](=[O:12])[CH3:11])=[CH:29][C:24]=2[O:23][C:22]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(C)=O)c(OC)cc12
Reaction time: 1 h
Yield: 87 %

Procedure:
Diisopropylethylamine (83.2 μL, 477 μmol), followed by acetic anhydride (239 μmol) were added to a solution of 6-amino-2-(4-fluoro-phenyl)-5-methoxy-benzofuran-3-carboxylic acid methylamide, prepared according to Example 17 (75 mg, 239 μmol) in dry trichloromethane (3 mL). After one hour, the reaction was quenched with water (3 mL). After concentration to dryness, the crude oil was purified by HPLC (reverse phase, C18, acetonitrile/water with 0.1% acetic acid) to provide 73 mg (87%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:26])[C:16]=2[N:15]=[C:14]1[CH2:27][CH3:28].[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[NH2:26][C:17]1[C:16]2[N:15]=[C:14]([CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.08 h
Yield: 78.8 %

Procedure:
Triethylamine (0.59.mL, 4.3 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) in chloroform (100 mL). The solution was stirred in an ice bath for 5 min. Phenyl isocyanate (0.38 mL, 3.5 mmol) was slowly added. The resulting precipitate was isolated by filtration, washed with chloroform (4×30 mL), and then dried in an Abderhalden drying apparatus overnight to provide 1.11 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as a white solid, m.p. 179.7-181.4° C. Analysis: Calculated for C23H26N6O.. 0.6 H2O: %C, 66.84; %H, 6.63; %N, 20.33; Found: %C, 67.20; %H, 6.61; %N, 20.46.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]([F:9])([F:8])[F:7].[CH3:10][CH2:11][C:12](=[O:15])[CH2:13][CH3:14]>O1CCCC1>[F:7][C:6]([F:9])([F:8])[CH2:5][CH2:4][CH2:3][C:12]([CH2:13][CH3:14])([OH:15])[CH2:11][CH3:10]
Reactant: FC(F)(F)CCCBr
Reactant: CCC(=O)CC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCC(F)(F)F
Reaction time: 1 h
Yield: 76.1 %

Procedure:
1.3 g of magnesium, 10.0 g of 1-bromo-4,4,4-trifluorobutane and 20 g of tetrahydrofuran were added to a four-necked flask equipped with a nitrogen feeding pipe, a reflux condenser, a dropping funnel and a thermometer, and a Grignard reagent was prepared by a conventional method. Then, a mixed solution containing 5.0 g of 3-pentanone and 4 g of tetrahydrofuran was dropwise added to the obtained Grignard reagent at a temperature of 25 to 35° C. over 30 minutes, followed by stirring at the same temperature for 1 hour. The reaction mixture was treated by a conventional method, and the resulting organic phase was washed with water, followed by drying with anhydrous magnesium sulfate. Thereafter, the resultant was concentrated under reduced pressure, thereby obtaining 7.9 g of 7,7,7-trifluoro-3-ethyl-3-heptanol in the form of a pale yellow oily matter.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH:25]([C:32](=O)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=O)=[CH:17][CH:16]=1.C([O-])(=O)C.[NH4+:44].C(O)(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[O:24][C:25]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:44]=2)=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: COC(=O)CCC(OC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1oc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Yield: 82.8 %

Procedure:
A mixture of methyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]acetoxy-5-oxo-5-phenylpentanoate (1.34 g), ammonium acetate (685 mg) and acetic acid (5 ml) was refluxed for 3 hrs. After cooling, ethyl acetate was added to the reaction mixture. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-5-oxazolyl]propionate (1.07 g, yield 83%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:5, volume ratio).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:26][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[O:9])[CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCCC1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Product: Cc1cc(O)ccc1NC(=O)c1cc(NC2CCCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and cycloheptylamine (Aldrich), the title compound was obtained as a beige solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:8][C:7]([CH3:15])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:16]
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 1D and 3B. MS m/z 477 (M+1).
Reaction SMILES: Cl.[C:2]([CH:10]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:27]C1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[ClH:27].[C:2]([CH:10]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[S:11]1=[O:35])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)CCCN1C(=O)C(C(=O)c2ccccc2)Sc2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCCN1C(=O)C(C(=O)c2ccccc2)S(=O)c2ccccc21
Reaction time: 2 h

Procedure:
By treating the product from Example 2 (B) with a chloroform solution containing 1 equivalent of m-chloroperbenzoic acid and allowing the mixture to stand for about two hours at room temperature, the title product is obtained.
Reaction SMILES: O([C:8]([N:10]([CH2:12][C:13]#[C:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[N:16]=1)[OH:11])=[O:9])C1C=CC=CC=1.[NH3:35]>CO>[OH:11][N:10]([CH2:12][C:13]#[C:14][C:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[N:17]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:16]=1)[C:8]([NH2:35])=[O:9]
Reactant: COc1ccc(-n2nc(C#CCN(O)C(=O)Oc3ccccc3)cc2-c2ccc(C)cc2)cc1
Reactant: N
Solvent: CO
Product: COc1ccc(-n2nc(C#CCN(O)C(N)=O)cc2-c2ccc(C)cc2)cc1
Reaction time: 8 h

Procedure:
Alternatively, N-phenoxycarbonyl-N-(1(1-(4-methoxyphenyl)-5-(4-methylphenyl)-3-pyrazolyl)-1-propyn-3-yl)hydroxylamine (4.67 mmol, 2.12 g) was dissolved in 20 mL of 14% w/w solution of ammonia in MeOH and stirred overnight in a stoppered round-bottomed flask. The solution was concentrated to give 2.2 g of orange oil which was purified by MPLC to give 0.89 g (51%) of Cpd. 1 as an off white solid. Tables I & J list the analytical data for Cpd. 1 as well as other compounds which were prepared in this manner.