Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([NH:19][CH:20]1[C:23](=[O:24])[NH:22][CH:21]1[CH2:25][OH:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C(C)O.C(OCC)(=O)C>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([O:26][CH2:25][C@H:21]1[C@@H:20]([NH:19][C:17]([O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:18])[C:23](=[O:24])[NH:22]1)(=[O:9])=[O:8]
Reactant: CC(C)(C)OC(=O)NC1C(=O)NC1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of 0.9 g (4.3 mmole) of 98% p-toluenesulfonyl chloride in 10 ml of dry pyridine at 0° is added 0.9 g (4.15 mmole) of 3-t-butoxycarbonylamino-2-hydroxymethyl-4-oxoazetidine. The mixture is stirred for 2 hr at 0° and then stored at 5° overnight. After addition of 0.5 ml of 85% lactic acid, the mixture is stirred for 1 hr, poured into ethyl acetate and washed with dilute HCl, 5% NaHCO3, and brine. The extract is dried over magnesium sulfate and evaporated to dryness to give 1.1 g (70%) of crystalline title product. Recrystallization from hexane-ethyl acetate gives an analytical sample, mp 160°-162° (d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH:12]([F:14])[F:13].C(N(CC)C(C)C)(C)C.Cl.Cl.[O:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH:12]([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:38][CH:35]2[CH2:34][CH2:33][N:32]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH2:37][CH2:36]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)F)c(Cl)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 70 °C
Yield: 95.1 %

Procedure:
A stirred solution of 1-chloro-2-(difluoromethyl)-5-fluoro-4-nitrobenzene (D96, 200 mg, 0.89 mmol) in dimethylformamide (4 ml) at room temperature under argon was treated with N,N-diisopropylethylamine (0.47 ml, 2.7 mmol), followed by 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (D40, 240 mg, 0.94 mmol) and then heated at 70° C. for 1.5 hrs. The reaction mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum to leave an orange solid. This was purified by chromatography on silica gel eluting with 0-20% methanol/ethyl acetate to afford the title compound as a yellow solid (330 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:24])[N:4]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>CN(C)C=O.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[C:3](=[O:24])[N:4]([C:10]2[CH:19]=[C:18]([C:20]([NH:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:34][C:33]1[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=1[F:31]
Reactant: CNC(=O)c1ccc(C(=O)OC)c(-n2c(C)cc(O)c(Br)c2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C(=O)OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reaction time: 6.5 h

Procedure:
To a solution of methyl 2-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-[(methylamino)carbonyl]benzoate (from Step 3) (241 mg, 0.610 mmol) in dimethylformamide (0.5 mL) was added sequentially K2CO3 (240 my, 1.73 mmol) and 2,4 difluorobenzyl bromide (0.085 mL, 0.66 mmol). The resulting suspension was stirred for 6.5 hours until complete consumption of starting material by LCMS analysis. The reaction was then diluted with ethyl acetate (200 mL) and brine washed (3×200 mL). The resulting organic extract was Na2SO4 dried, filtered, and concentrated in vacuo to approximately 5 mL volume. The resulting mother liquor rapidly precipitated and furnished an amorphous solid that was collected. 1H NMR (400 MHz, d4-MeOH) δ 8.22 (d, J=8.2 Hz, 1H), 8.03 (dd, J=8.2, 1.7 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.67 (app q, J=8.3 Hz, 1H), 7.05 (app t, J=8.6 Hz, 2H), 6.64 (s, 1H), 5.37 (s, 2H), 3.74 (s, 3H), 2.90 (s, 3H), 2.01 (s, 3H) LC/MS C-18 column, tr=2.87 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 521 (M+H). ES-HRMS m/z 521.0491 (M+H calcd for C23H20BrF2N2O5 requires 521.0518).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([CH2:18][CH2:19][C:20](=[O:36])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8]CC)=[O:7].[OH-].[Na+]>>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([CH2:18][CH2:19][C:20](=[O:36])[C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)=[CH:24][CH:25]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:11])([CH3:12])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3cccc(C(F)(F)F)c3)s2)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3cccc(C(F)(F)F)c3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from ethyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure F using 10 equivalents of 2N sodium hydroxide solution.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:33])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([OH:31])=[C:17]([Br:32])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1.[OH-].[Na+].Cl[S:42]([C:45]1[CH:53]=[CH:52][C:48]([C:49]([OH:51])=[O:50])=[C:47]([OH:54])[CH:46]=1)(=[O:44])=[O:43]>C(O)C(N)(CO)CO>[Br:32][C:17]1[C:18]([O:31][S:42]([C:45]2[CH:53]=[CH:52][C:48]([C:49]([OH:51])=[O:50])=[C:47]([OH:54])[CH:46]=2)(=[O:44])=[O:43])=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH:20]=[C:15]([C:14](=[O:33])[NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:16]=1
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a suspension of N-dodecyl-3-bromo-4-hydroxy-5-(m-trifluoromethylphenyl)-benzamide (1.799 g, 1.51 mmol, 1 eq) in 0.05 N tris(hydroxymethyl)aminomethane pH 9 buffer/THF (10:3) (7.5 mL) was added 2.5 N NaOH (0.665 mL, 1.66 mmol, 1.1 eq) and THF (10 mL). The reaction was stirred at rt for 30 minutes and then cooled to 5° C. 4-Chlorosulfonyl-2-hydroxy-benzoic acid (0.715 g, 3.02 mmol, 2 eq) was added portionwise while keeping the pH at 9 by the addition of 2.5 N NaOH. This mixture was allowed to warm to rt and to stir for 2 days. The reaction was quenched by the addition of 2 M HCl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane+1% Formic Acid ) to afford the title compound (0.895 g, 79%) as a yellow foam. 1H NMR (DMSO-d6) δ 11.40 (bs, 1H); 10.35 (bs, 1H); 8.70 (t, 1H); 8.22 (d, 1H); 7.85 (d, 1H); 7.72-7.45 (m, 5H); 6.98 (dd, 1H); 6.86 (d, 1H); 3.25 (dd, 2H); 1.50 (dd, 2H); 1.25 (m, 18H); 0.85 (t, 3H); IR (KBr) 3410, 2800, 2700, 1690, 1640, 1605, 1390, 1330, 1180, 1120, 620, 600 cm−1; mass spectrum [(+)APCI], m/z 728/730 (M+H)+; Anal. Calcd. for C33H37BrF3NO7S+0.25 C4H8O2: C, 54.40; H, 5.24; N, 1.87, Found: C, 53.23; H, 4.77; N, 1.79.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]1/[CH:18]=[CH:19]/[C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1.Cl>C(Cl)Cl.CO>[CH3:3][O:4][C:5](=[O:30])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]1/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1
Reactant: COC(=O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)COCCCCN1C(=O)CC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
Sodium borohydride (4.3 mg, 0.11 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester (42 mg, 0.10 mmol) in CH2Cl2 (1 mL) at 0° C. Methanol (3 drops) was added and the reaction was stirred at rt for 3 h. Aqueous HCl (0.5 M, 5 mL) was added and the mixture was extracted with CH2Cl2 (3×5 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (0%→5% MeOH/CH2Cl2) to afford 31 mg (73%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-5-oxo-pyrrolidin-1-yl}-butoxy)-acetic acid methyl ester.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([OH:23])(=O)/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[CH:34][CH:35]=2)[CH2:30]1.ON1C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:40][O:39][C:33]1[CH:32]=[C:31]2[C:36]([CH2:37][CH2:38][N:29]([CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:13](=[O:23])/[CH:14]=[CH:15]/[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:30]2)=[CH:35][CH:34]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: COc1ccc2c(c1)CN(CCCCN)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(CCCCNC(=O)/C=C/c1ccccc1)CC2
Reaction time: 18 h
Yield: 67.9 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.41 g, 2.14 mmol) was added to a solution of trans-cinnamic acid (0.317 g, 2.14 mmol), 2-(4-aminobutyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (0.5 g, 2.14 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) in dichloromethane (8 ml). The mixture was shaken for 18 h, saturated aqueous potassium carbonate (5 ml) added and shaking continued for a further 1 h. The organic layer was chromatographed on silica gel using 10-100% ethyl acetate-hexane gradient elution to afford the title compound as a yellow gum (0.53 g, 68%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][CH3:11])[C:3]([OH:23])=[O:2]
Reactant: CNc1ccc(C(=O)OC)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylamino-benzoic acid methyl ester in 3 ml of MeOH:water/3:1, 14 mg of lithium hydroxide monohydrate were added and the reaction was stirred at RT for 16 h. The solution was acidified with half-concentrated hydrochloric acid and the solvent was evaporated. The crude acid was subjected to the subsequent amide coupling without further purification.
Reaction SMILES: S(=O)(=O)=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C.[Cl-].[Na+]>CS(C)=O.ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH2:13][CH2:14][CH:15]=[O:16]
Reactant: OCCCc1c(F)cccc1Cl
Agent: O=S(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCc1c(F)cccc1Cl
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of pyridine complex with sulfur trioxide (40.35 g, 0.225 mol) in dimethylsulfoxide (50 mL) was slowly added to a solution of 3-(2-chloro-6-fluoro-phenyl)-propan-1-ol (20.6 g, 0.109 mol) and triethylamine (25.8 g, 0.225 mol) in dichloromethane (250 mL) at 0° C. The reaction was allowed to stir for 30 minutes, and then it was poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The combined organic layers were washed twice with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to afford 3-(2-Chloro-6-fluoro-phenyl)-propionaldehyde (15 g, 80 mmol, 74%), 1H NMR (CDCl3): δ 9.83 (s, 1H), 7.24-7.00 (m, 2H), 6.99-6.94 (m, 1H), 3.13-3.09 (m, 2H), 2.75-2.71 (m, 2H).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:13])C>O1CCCC1>[O:13]=[C:8]1[NH:9][CH2:10][CH2:11][CH2:12][N:7]1[CH2:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(CCN1CCCNC1=O)OCC
Solvent: C1CCOC1
Product: O=CCCN1CCCNC1=O
Yield: 67.7 %

Procedure:
A mixture of 1-(3,3-diethoxypropyl)tetrahydropyrimidin-2-one (1 g, 4.35 mmole), and 1.0 g Dowex 50W2-200 ion exchange resin in 3% aqueous tetrahydrofuran (30 mL) was heated under reflux for 24 hours. The mixture was filtered, the filtrate was concentrated and the residue dissolved in dichloromethane (30 mL), dried with magnesium sulfate, and concentrated to give 3-(2-oxo-tetrahydropyrimidin-1-yl)-propionaldehyde (0.46 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](OC)[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]2[C:18]([N:19]=1)=[N:17][CH:16]=[CH:15][N:14]=2.C([O-])(=O)/C=C/[C:23]([O-])=[O:24]>>[CH3:1][O:2][C:3]1[C:8]([O:24][CH3:23])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13]([N:12]=1)=[N:14][CH:15]=[CH:16][N:17]=2
Reactant: COc1ccc(-c2nc3nccnc3[nH]2)c(OC)c1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cccc(-c2nc3nccnc3[nH]2)c1OC

Procedure:
2-(2,4-dimethoxyphenyl)-1,3,4,7-tetraazaindene, m.p. 210°-215°; fumarate, m.p. 265° (decomposition)
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:5][CH2:4][C:3]1=O.[CH3:16][CH2:17][Mg+].[Br-]>C1COCC1>[CH3:1][N:2]1[C@H:6]([CH2:7][O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:5][CH2:4][C:3]21[CH2:17][CH2:16]2
Reactant: CN1C(=O)CC[C@H]1COC1CCCCO1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CN1[C@H](COC2CCCCO2)CCC12CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To a mixture of (S)-1-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-pyrrolidin-2-one (0.6 g, 2.82 mmol) in 20 mL of THF was added Ti(Oi-Pr)4 (2.56 mL, 8.45 mmol, d=0.937 g/L, Aldrich) via a syringe under nitrogen at rt. After stirring at rt for 30 min, EtMgBr (5.63 mL, 16.9 mmol, 3M ether solution, Aldrich) was added via a syringe pump over 3 hrs. The reaction was continued to stir at rt overnight, and then quenched with a mixture of 20 mL of water and 30 mL of ethyl acetate. After stirring for 20 min, the mixture was filtered through a celite pad. The filtrate was extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (50:1(v/v) CH2Cl2/CH3OH) to afford (5S)-4-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-4-azaspiro[2.4]heptane as pale yellow oil (64 mg, 10%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][OH:33])[C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:54])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@H:22]([C@@:23]([OH:34])([CH2:31][C:32]([OH:33])=[O:54])[C:24]([OH:26])=[O:25])/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:21])[C:14](=[O:18])[N:15]([CH3:16])[CH3:17])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)O)C(=O)O)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-dimethylcarbamoyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (96.8 mg, 0.133 mmol) was dissolved in acetonitrile (2.0 mL) and water (0.6 mL), and 4-acetamide-2,2,6,6-tetramethylpiperidine-1-oxyl (4.3 mg, 19.9 μmol) and diacetoxyiodobenzene (85.7 mg, 0.266 mmol) were added. The mixture was stirred at room temperature for 4 hours. An aqueous solution of citric acid was added to the reaction mixture, which was followed by extraction with ethyl acetate. The organic extract was washed with sodium thiosulfate and a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in formic acid (4.0 mL) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified with preparative HPLC to obtain the title compound (43.2 mg).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[N:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7].[CH3:16]I>>[I:1][C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[N:13]=[CH:12][N:11]([CH3:16])[C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7]
Reactant: CI
Reactant: Cc1nc(I)c(C)n1-c1cc(=O)[nH]cn1
Product: Cc1nc(I)c(C)n1-c1cc(=O)n(C)cn1

Procedure:
The title compound, light yellow cristalline solid, MS: m/e=331.0 (M+H+), was prepared in accordance with the general method of example 3 from 6-(4-iodo-2,5-dimethyl-imidazol-1-yl)-3H-pyrimidin-4-one and methyl iodide.
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:16][CH2:17][CH2:18][C:19]#[CH:20]>C(Cl)Cl>[OH:16][CH2:17][CH2:18][C:19]#[C:20][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: C#CCCO
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC)c(C#CCCO)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
461 mg of dimethyl 5-bromopyridine-2,4-dicarboxylate (from Example 3) and 142 mg of 4-hydroxy-1-butyne are dissolved in methylene chloride in a flask flushed with argon, and 680 μl of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 13 mg of ((C6H5)3P)2PdCl2 and 2 mg of CuI are added and the mixture is boiled under reflux for 2 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After the solvent has been evaporated off, 347 mg of a white solid remain.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.O.[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH3:27][N:28]([CH3:38])[C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][CH:34]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Solvent: O
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N(C)C)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 50 mg, 0.125 mmol) and 2-(dimethylamino)pyridine-5-boronic acid hydrate (Fluorochem Ltd., Derbyshire, United Kingdom, 31 mg, 0.163 mmol) to give the title compound as a yellow solid. (HPLC: tR 2.31 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.27-8.18 (m, 2H), 8.07-7.99 (m, 1H), 7.90-7.82 (m, 1H), 7.62-7.55 (m, 1H), 7.41 (s, 1H), 6.70-6.61 (m, 1H), 4.62-4.49 (m, 1H), 3.56 (s, 3H), 3.04 (s, 6H), 1.96 (s, 3H), 1.49 (s, 6H))
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:18])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][C:13]1[N:12]([C:4]2[CH:3]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)[C:16]([CH3:17])=[CH:15][CH:14]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1cc(N2CCN(C)CC2)cc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
A mixture of 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (510 mg, 1.6 mmol), 1-methylpiperazine (210 μL, 1.9 mmol), Pd2(dba)3 (70 mg, 0.08 mmol), 2′-BINAP (100 mg, 0.2 mmol) and cesium carbonate (730 mg, 2.2 mmol) in toluene (5.1 mL) was subjected to MWI at 150° C. for 10 min. The reaction mixture was diluted with DCM and washed with brine. The residue was purified by column chromatography to give 1-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)phenyl]-4methylpiperazine (172 mg, 32%) as a yellow solid. LCMS: (FA) ES+ 338.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[C:11]([OH:13])=O.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O.O>[C:15]1(=[O:24])[N:14]([CH:10]2[CH2:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:11]2=[O:13])[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]12
Reactant: Nc1ccccc1CCC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1Nc2ccccc2CCC1N1C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
In 80 ml of N,N-dimethylformamide is dissolved 10 g of 4-(2-aminophenyl)-2-phthalimidobutyric acid, and 6.7 g of diethyl phosphorocyanidate is added dropwise to the solution under ice-cooling with stirring. After the addition is complete, stirring is continued for 15 minutes, and 3.1 of triethylamine is added dropwise to the mixture under ice cooling, followed by stirring under ice-cooling for 45 minutes and then at room temperature for 30 minutes. The reaction solution is diluted with 200 ml of water, followed by stirring for 1 hour, and the crystals, which separate out, are collected by filtration, dried and added to 100 ml of ethanol, followed by heating. After the solution is concentrated to about half of the original volume, the colorless prisms which separate out are collected by filtration to give 8.3 g of 3-phthalimido-1,3,4,5-tetrahydro-1-benzazepin-2-one. m.p. 261°-263° C.