Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:33][CH2:32]1>CN(C)C=O.O>[CH3:44][O:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH2:28][N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:11]3[C:19]([F:26])=[C:20]([F:25])[C:21]([F:24])=[C:22]([F:23])[C:10]=3[F:9])[CH2:14][CH2:15]2)[CH2:36][CH2:35]1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCN2CCC(Oc3c(F)c(F)c(F)c(F)c3F)CC2)CC1
Temperature: 75 °C
Reaction time: 7 h
Yield: 51.4 %

Procedure:
A mixture of 10 g of potassium carbonate, 0.18 g of potassium iodide, 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 50 ml of dimethylformamide was treated with a solution of 4.56 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine in 25 ml dimethylformamide and stirred for seven hours at 75° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 7.5% methanol/dichloromethane). Evaporation of the appropriate fractions afforded 3.84 g of 1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-4-(2,3,4,5,6-pentaflurophenoxy)piperidine as an oil. The oil was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate the corresponding dihydrochloride salt. Recrystallization from isopropanol afforded 3.34 g (44.6%) of 1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-4-(2,3,4,5,6-pentaflurophenoxy)piperidine hydrochloride, m.p. 261°-263° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: CCN=C=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Solvent: C1COCCO1
Product: CCNC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Reaction time: 16 h

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) (50 mg 0.13 mmol) in dioxane (3 mL) at room temperature (20° C.) was added ethyl isocyanate (20 uL 0.26 mmol). The reaction mixture was stirred for 16 h. The solvent was removed in vacuo and the solid residue triturated with ether. The solid was collected by filtration and dried in vacuo to afford (32 mg 55%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:29])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1.[F:30]C1C=CC(C2N=C(C3CCNCC3)NC=2)=CC=1C(F)(F)F>>[Br:1][C:2]1[C:3]([NH2:29])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:30])=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1
Reactant: Nc1ncnc(N2CCC(c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)c1Br
Reactant: Fc1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1C(F)(F)F
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)c[nH]3)CC2)c1Br

Procedure:
The title compound was prepared in an analogous manner as 5-bromo-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=485, obsd.=485).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:38]=[C:31]2[C:32](OC(=O)[NH:36][C:30]2=[CH:29][CH:28]=1)=[O:33]>O1CCCC1>[NH2:36][C:30]1[CH:29]=[CH:28][C:27]([Cl:26])=[CH:38][C:31]=1[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:33]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-chloropyridine (787 mg, 6.1 mmol) in tetrahydrofuran (5 ml) was added 0.5M potassium bis(trimethylsilyl)amide in toluene (20 ml, 10.1 mmol) dropwise at −78° C. After stirred for additional 0.5 hr at −78° C., the mixture was added 5-chloroisatoic anhydride (1 g, 5.1 mmol) at −78° C. The mixture was warmed up to r.t gradually and stirred overnight. After concentrated, the crude was washed with saturated ammonium chloride solution and extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide as yellow solid (1.39 g. 99%). MS found for C12H9Cl2N3O M+=282, (M+2)+=284.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].Cl.C([O:16][C:17](=O)[CH2:18][NH:19][CH3:20])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][N:19]1[CH2:18][C:17](=[O:16])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12]
Reactant: CCOC(=O)CNC
Reactant: CC(C)c1ccccc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccccc1N1C(=O)CN(C)C1=S
Yield: 80 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 14.2 g of 2-isopropylphenyl-isothiocyanate, 12.29 g of sarcosine ethyl ester hydrochloride, 16.0 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether afforded the title compound (15.9 g) as a peach solid, m.p. 129°-131° C. Anal. Calcd. for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.89; H, 6.38; N, 11.28. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>C(OCC)(=O)C>[CH2:1]([N:5]1[C:9]([CH:29]=[O:30])=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCn1cc(C(OC)OC)nc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCn1c(-c2ccccc2)nc(C(OC)OC)c1C=O

Procedure:
To a solution of 1-butyl-4-dimethoxymethyl-2-phenyl-1H-imidazole 209 (2.74 g, 10 mmol) in anhydrous TH-F under nitrogen at −78° C., n-BuLi (1.6 M in hexane, 7.5 ml, 12 mmol) is added dropwise and the mixture is continued stirring at this temperature for 30 ran. After anhydrous DMF (4 mL) is added, the mixture is stirred at room temperature for 16 h. Saturated ammonium chloride and ethyl acetate were added at 0° C. and the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography to yield the desired product as a white solid. Yield: 1.94 g; LC-MS (MH+): 303. 1H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 7.60-7.56 (m, 2H), 7.51-7.46 (m, 3H), 5.63 (s, 1H), 4.32 (t, J=6.3 Hz, 2H), 3.47 (s, 6H), 1.73-1.63 (m, 2H), 1.28-1.16 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH3:25])=[CH:13][CH:12]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH+:8]([O-:35])[C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH3:25])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)[NH+]([O-])c2c(Cl)cncc2Cl)c2c1oc1ccccc12
Yield: 71.8 %

Procedure:
A suspension of N-(3,5-dichloropyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide (200 mg, 0.518 mmol) (example 1) and m-chloroperbenzoic acid (50-55%) (880 mg, 2.5 mmol) in chloroform (10 ml) was refluxed for 2 h. The reaction was cooled and washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 20% acetone-chloroform as the eluent to give 150 mg of N-(3,5-dichloropyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 265-270° C.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=[O:8].[CH3:10][CH2:11]O>S(=O)(=O)(O)O>[O:6]=[C:5]1[NH:1][C@@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:4]1
Reactant: CCO
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H]1CCC(=O)N1

Procedure:
To a solution of D-pyroglutamic acid (compound I-A, 20.4 g, 0.16 mol) in 100 mL of EtOH, 1.2 mL of conc. sulfuric acid was added. The mixture was heated under reflux overnight. Solvent was removed under reduced pressure to give (R)-ethyl 5-oxopyrrolidine-2-carboxylate (compound II-AA).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH:29]1[C:33](B(O)O)=[CH:32][CH:31]=[N:30]1.C(=O)(O)[O-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:31]5[NH:30][N:29]=[CH:33][CH:32]=5)[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)cc(Cl)nn23)ccc1C(=O)NC1CC1
Reactant: OB(O)c1ccn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2cnc3c(NCC(C)C)cc(-c4ccn[nH]4)nn23)ccc1C(=O)NC1CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a mixture of 125 mg (314 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 111 mg (942 μmol) 1H-pyrazol-5-yl boronic acid, 44 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.63 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then the mixture was filtered and concentrated and purified by chromatography to give 41 mg of the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:15][CH:16]([C:21](=[O:24])[CH2:22][Br:23])[CH2:17][C:18]([OH:20])=O>ClCCl>[Br:15][CH:16]1[C:21](=[CH:22][Br:23])[O:24][C:18](=[O:20])[CH2:17]1
Reactant: O=C(O)CC(Br)C(=O)CBr
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: O=C1CC(Br)C(=CBr)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Phosphorus pentoxide (22.5 g) was added with stirring to a solution of 3,5-dibromo-4-oxopentanoic acid (30.4 g, 0.11 mol) in dry dichloromethane (500 ml). The mixture was heated at reflux with stirring for 2 h, and cooled to room temperature. The resulting mixture was filtered through a pad of filter aid, washed with brine, dried over sodium sulfate and evaporated to yield the tetrahydrofuranone (mixture of Z- and E-isomers in 4:1 ratio) as a pale yellow oil (23.4 g, 82%). The oil solidified on standing at room temperature overnight. Crystallisation from dichloromethane/light petroleum (60-80° C.) gave an analytically pure sample of the Z-isomer. m. p. 79° C. νmax 3094, 3027, 2947, 1799, 1634, 1393, 1289, 1114, 949, 838, 747, 718, 660 cm−1. λmax 279 nm (ε 4938). 1H n.m.r. δ (CDCl3) 3.10, dd, J 2.3 Hz, 18.8 Hz, Ha3; 3.45, dd, J 7.9 Hz, 18.8 Hz, Hb3; 5.07, m, H4; 5.90, s, 5-CHBr. 13C n.m.r. δ (CDCl3): 37.2, C3; 40.5, C4; 86.9, 5-CHBr, 152.3, C5; 169.5, C2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:5]([C:6](=[O:12])[NH:7][C:8](=O)[CH:9]=2)[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:8]1[CH:9]=[C:10]2[N:2]([CH3:1])[CH2:3][CH2:4][N:5]2[C:6](=[O:12])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1CCn2c1cc(=O)[nH]c2=O
Product: CN1CCn2c1cc(Cl)nc2=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
A suspension of 1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidine-5,7(1H,6H)-dione (0.41 g, 2.45 mmol) in POCl3 (15 mL, 161 mmol) was stirred at 90° C. for 6 h. The suspension was concentrated in vacuo to remove all of POCl3. Cold water was added to the resultant residue, and then solid NaOH was added dropwise to adjust pH to ˜12. The solution was stirred at rt for 2 h. Aqueous HCl was added to adjust pH to ˜7. Purification via Mass Directed AutoPrep (MDAP) afforded the title compound as a white solid (0.42 g, 93% yield).
Reaction SMILES: [Li+].[OH-].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24].C(O)(=O)C(O)=O>C1COCC1.O>[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCO
Agent: O=C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCCCCCCCCCCCCCCO
Reaction time: 10 h
Yield: 91.3 %

Procedure:
LiOH (45 μL of a 1 M aqueous soln) was added to a stirring, room temperature solution of the above ester (5.2 mg, 0.015 mmol) in THF/H2O (5:1, 1.5 mL). After 10 hours, the pH was adjusted to 4 using 1 M oxalic acid and the reaction mixture was extracted with EtOAc (3×4 mL). The combined organic extracts were evaporated in vacuo to give 20-hydroxyeicosanoic acid (55) (4.5 mg, 92%) as a solid, mp 86° C. 1H NMR (250 MHz, CD3OD): δ 1.20-1.45 (m, 30H), 1.45-1.63 (m, 4H), 2.28 (t, J˜7.4 Hz, 2H), 3.55 (t, J˜6.5 Hz, 2H); TLC: EtOAc/hexanes (3:7), Rf˜0.08. 19-Hydroxynonadecanoic Acid (56) was prepared in an analogous manner from ester 8a.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:25])([F:24])[C:11]([C:17]1[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:23][C:19]1[CH:18]=[C:17]([C:11]([OH:16])([C:12]([F:14])([F:13])[F:15])[C:10]([F:24])([F:25])[F:9])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: OC(c1cccc(CBr)c1)(C(F)(F)F)C(F)(F)F
Yield: 21.4 %

Procedure:
N-Bromosuccinimide (207 mg, 1.162 mmol) was added to a solution of 1,1,1,3,3,3-hexafluoro-2-m-tolylpropan-2-ol (300 mg, 1.162 mmol) and 2,2′-azobis(isobutyronitrile) (0.191 mg, 1.162 μmol) in carbon tetrachloride (6 mL). The mixture was refluxed for 18 hours and then concentrated under reduced pressure. The crude material was dissolved in diethyl ether and heptane, filtered through dicalite, and purified by silica chromatography (eluting with a solvent gradient from 2% ethyl acetate/98% heptane to 10% ethyl acetate/90% heptane) to afford the title compound (84 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:16])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:15])=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=1[O:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[C:20]([O:28][CH2:29][CH2:30][C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)[CH:21]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:15])=[O:5])[CH3:2]
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1=O
Product: CCOC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1=O

Procedure:
2-Amino-1-oxo-indane-2-carboxylic acid ethyl ester (L. Benati et al., J. Org. Chem. 64 (1999), 7836-7841) (460 mg, 2.10 mmol) was reacted with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 2 of example 13 to yield 0.331 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Reactant: COc1ccc(B(O)O)c(F)c1
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3F)c(F)ccc2c1N
Yield: 66.3 %

Procedure:
Using method A, 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3-carboxamide (250.0 mg, 0.67 mmol) and (2-fluoro-4-methoxyphenyl)boronic acid (227.1 mg, 1.336 mmol) were reacted to afford the title compound (165.4 mg, 67% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.51 (bs, 1H), 7.90 (d×d, J=5.5 Hz, J=9.2 Hz, 1H), 7.53 (apparent triplet, J=8.9 Hz, 1H), 7.41 (t, J=8.5 Hz, 1H), 6.86 (d×d, J=2.4 Hz, J=8.5 Hz, 1H), 6.80 (d×d, J=2.4 Hz, J=11.6 Hz, 1H), 3.87 (s, 3H), 3.44 (q, J=6.7 Hz, J=12.8 Hz, 2H), 1.65 (apparent sextet, J=7.3 Hz, 2H), 1.00 (t, J=7.3 Hz, 3H). MS APCI, m/z=373 (M+H) HPLC 2.78 min.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:11][CH:10]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]#[C:15][C:12]1[CH:11]=[CH:10][C:9]([NH:7][CH3:6])=[CH:14][CH:13]=1
Reactant: CN(C)CCCC#Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(C#CCCCN(C)C)cc1
Temperature: 25 °C
Yield: 106 %

Procedure:
A solution of 1.45 g (4.58 mmol) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester in 25 ml CH2Cl2 was treated at 0° C. with 11.5 ml TFA (during 20 min) and warmed up to room temperature during 1 h. The solution was concentrated and the residual oil was extracted with aqueous sat. NaHCO3 (+Na2CO3)/EtOAc (3×). The organic phase was dried (Na2SO4) and evaporated to yield 1.05 g (quantitative) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-amine MS: 217 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:30][CH2:29][CH2:28][CH:27]=[CH2:26])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(Cl)c1
Reactant: C=CCCCBr
Agent: N
Product: C=CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (23 mg, 67%) from (7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 5-bromo-1-pentene (25 mg, 0.16 mmol). MS (CI, NH3): 427.1 (base, M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(#N)C.O>[O:28]1[CH2:29][CH2:30][N:25]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:18])[CH2:26][CH2:27]1
Reactant: C1COCCN1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCOCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a stirred suspension of 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.861 mmol) and potassium carbonate (1286 mg, 9.30 mmol) in acetonitrile (10 ml) was added morpholine (0.814 ml, 9.30 mmol) via a syringe. The resulting suspension was then stirred overnight at 75° C. in a sealed tube. The reaction mixture was then cooled to room temperature, diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in ethyl acetate, followed by 5% (2M NH3 in methanol) in dichloromethane, giving the desired 1-(3-morpholinopropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (560 mg, 1.754 mmol, 94% yield). 1H NMR (DMSO-d6) δ 8.14-8.10 (m, 2H), 7.40 (d, J=9 Hz, 1H), 3.95 (t, J=7.4 Hz, 2H), 3.58-3.54 (m, 4H), 3.03-2.97 (m, 2H), 2.64-2.59 (m, 2H), 2.33-2.28 (m, 6H), 1.74-1.64 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([OH:24])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)O)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.3 %

Procedure:
tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.1 g) was dissolved in DCM (2 ml), and trifluoroacetic acid (2 ml) was added. The mixture was stirred at room temperature for 1.5 h and then partitioned between water and DCM. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.09 g) as an colourless gum.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:56]=[CH:55][C:43]2[S:44][CH:45]=[C:46]([CH2:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:42]=2[CH:41]=1)C1C=CC=CC=1.C(S)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:49]1([CH2:48][CH2:47][C:46]2[C:42]3[CH:41]=[C:40]([C@@H:10]4[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]4[OH:8])[CH:56]=[CH:55][C:43]=3[S:44][CH:45]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: c1ccc(CCc2csc3ccc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCS
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2ccc3scc(CCc4ccccc4)c3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a mixture of 5-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(2-phenylethyl)benzo[b]thiophene (0.1 g) and ethanethiol (0.16 g) in dichloromethane (6 mL) was added boron trifluoride diethyl ether complex (0.28 g) at room temperature, and the mixture was stirred at room temperature for 3 hours. A saturated potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (0.034 g).