Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[CH2:26][C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:52](I)[CH3:53].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[C@H:26]([CH2:52][CH3:53])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C(C/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a solution of (S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)hex-3-ene-1,6-dione (600 mg, 1.08 mmol) in THF (50 mL) at −78° C., a solution of NaHMDS (1 M in THF, 1.4 mL, 1.4 mmol) in diluted with THF (2.5 mL) was added dropwise. The reaction mixture was stirred for 1 hr at −78° C. and ethyl iodide (1.70 g, 10.9 mmol) was added dropwise. The reaction mixture was warmed to rt and allowed to stir overnight. Saturated aqueous NH4Cl (3 mL) was added to the reaction mixture and the crude product was extracted with EtOAc (4×5 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford the crude product, which was purified using silica gel chromatography to afford (2S,5S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-ethylhex-3-ene-1,6-dione (100 mg, 0.172 mmol, 16% yield). Anal. Calcd. for C35H36N2O6 m/z 580.3. found 579.2 (M−); 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.29 (m, 5H), 7.27-7.24 (m, 5H), 7.19-7.16 (m, 3H), 7.05 (m, 2H), 5.7 (dd, 1H), 5.58 (dd, 1H), 4.71 (q, 1H), 4.66-4.57 (m, 2H), 4.20-4.07 (m, 6H), 3.27-3.19 (m, 2H), 3.08 (m, 1H), 2.82 (m, 1H), 2.71 (m, 1H), 2.58 (m, 1H), 1.8-1.75 (m, 1H), 1.52-1.45 (m, 1H), 0.81 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Br[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=1>>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:16][C:15]=2[CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Fc1ccc(Br)nc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN(CC)C(=O)OC(C)(C)C)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(F)cn3)cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [2′-[(tert-butoxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-3-yl]-acetic acid ethyl ester and 2-bromo-5-fluoropyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[C:10]=2[N+:16]([O-])=O)=[C:5]([CH3:19])[CH:4]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>>[CH3:1][O:2][CH2:3][CH:4]([NH:15][C:11]1[C:10]([NH2:16])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:19])[CH:14]=[CH:13][N:12]=1)[CH3:5]
Reactant: COc1ccc(-c2ccnc(N)c2[N+](=O)[O-])c(C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2C)c1N
Yield: 61 %

Procedure:
2-Methoxy-1-methyl-ethyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine (0.120 g, 0.36 mmol), and Na2SO4 (0.509 g, 2.9 mmol), were treated as in Part D of Example 67a to give a crude yield of 0.066 g (61%) of N2-(2-methoxy-1-methyl-ethyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine; MS(AP) m/z 302.2 [(M+H)+, 100]. The crude product was taken on to Part E.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:16])=[O:5])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:19]1[CH:20]=[CH:21][C:22]([CH:24]([CH3:26])[CH3:25])=[CH:23][C:18]=1[Cl:17])=[O:5])[CH3:2]
Reactant: CC(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1c(N)c2cnccc2n1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc(C(C)C)cc2Cl)c2cnccc2n1C
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A degassed solution of 3-amino-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (300 mg, 1.4 mmol), trifluoro-methanesulfonic acid 2-chloro-4-isopropyl-phenyl ester (700 mg, 2.3 mmol), Pd2dba3 (63 mg, 0.068 mmol), Xantphos (79 mg, 0.14 mmol) and K3PO4 (0.58 g, 2.7 mmol) in toluene (10 ml) was heated at 120° C. for 18 hours. The reaction mixture was cooled to ambient temperature then filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give a brown gum. The gum was purified by flash chromatography (Si-SPE, DCM:EtOAc, 90:10) to provide the title compound as a yellow gum (120 mg, 24%). LCMS (method B): RT=2.82 min, M+H+=372.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:18])=[CH:11][C:12]([Br:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]([CH:23](P(OC)(OC)=O)[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22].CN(C)C(N(C)C)=N.Cl>ClCCl>[CH3:19][O:20][C:21](=[O:22])/[C:23](/[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[CH:14]/[C:13]1[CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([CH3:18])=[CH:11][C:12]=1[Br:17]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: Cc1cc(Br)c(C=O)cc1OCc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C(=C/c1cc(OCc2ccccc2)c(C)cc1Br)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.1 %

Procedure:
To a solution of 5-benzyloxy-2-bromo-4-methylbenzaldehyde (0.39 g) and N-(benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester (0.38 g) in dichloromethane (2 mL) was added 1,1,3,3-tetramethylguanidine (0.18 g) at room temperature and this mixture was stirred at room temperature for 2 days. To this reaction mixture was added 1 mol/L hydrochloric acid and the precipitated solid was collected by filtration, and washed with water, dried under reduced pressure to give the title compound (0.34 g).
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[CH:9]([N:22]1[CH2:25][C:24]([NH:29][CH3:30])([C:26]([NH2:28])=[O:27])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:9]([N:22]1[CH2:25][C:24]2([C:26](=[O:27])[N:28]=[CH:30][N:29]2[CH3:1])[CH2:23]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COC(OC)N(C)C
Product: CN1C=NC(=O)C12CN(C(c1ccccc1)c1ccccc1)C2
Reaction time: 3 h
Yield: 95.7 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (1.1 ml, 8.3 mmol) was combined with 1-benzhydryl-3-methylaminoazetidine-3-carboxylic acid amide (I-3A-2b; 153 mg, 0.52 mmol) and heated to reflux. After 3 hours, the suspension was cooled and extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined extracts were dried (Na2SO4), and concentrated, in vacuo, to afford I-3A-4a as a solid (152 mg, 96%): +ESI MS (M+1) 306.3; 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 7.47 (d, J=7.5 Hz, 4H), 7.27 (t, J=7.5 Hz, 4H), 7.17 (t, J=7.5 Hz, 2H), 4.57 (s, 1H), 3.58 (s, 3H), 3.55 (d, J=10.0 Hz, 2H), 3.34 (d, J=10.0 Hz, 2H).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:46])[CH:16]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:38][CH:37]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1.CI>O1CCCC1.CCCCCC.O>[C:42]([C:39]1[CH:38]=[CH:37][C:36]([O:35][C:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:21][CH:22]=2)([CH3:1])[C:15]([O:14][CH3:13])=[O:46])=[CH:41][CH:40]=1)([CH3:43])([CH3:45])[CH3:44]
Reactant: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.7 ml of N,N-diisopropylamine in 15 ml of tetrahydrofuran under argon is stirred and cooled to 0° C. To the solution is added dropwise 8.5 ml of 2M n-butyllithium in hexane. The solution is cooled to -70° C. and a solution of 7.24 g of methyl(p-tert.-butylphenoxy){p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate in 15 ml of tetrahydrofuran is added dropwise. After stirring at -70° C. for 30 minutes, 1.87 ml of methyl iodide is added and the mixture is stirred while slowly allowing to warm to room temperature. The mixture is poured into 100 ml of water and is extracted with ether. The ether extract is washed with 10% HCl, water, saturated NaCl and dried (MgSO4). The solvent is removed under reduced pressure to give 7.5 g of a clear gum. Chromatography over silica gel with dichloromethane-hexane as eluent gives 5.6 g of colorless gum.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:30]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:31])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) was added 1-naphthoyl chloride (0.055 g, 0.288 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature. The reaction mixtures were filtered through a 2.0 g Varian Bond Elut SCX (stong cation-exchange) cartridge eluting with 20 mL of methanol, followed by 7N ammonia in methanol (20 mL), and concentrated under vacuum. The crude product was purified over a silica gel column eluting with methanol in dichloromethane (0-10%) over 30 minutes to obtain 0.0247 g (62%) of the compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1
Reactant: CI
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1H-Indole-3-carboxylic acid (960 mg) was dissolved in N,N-dimethylformamide (15 ml) and cooled to 0° C. Sodiumhydride (720 mg) was added in two divided portions thereto, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled again to 0° C., and a solution of methyl iodide (0.67 ml) in N,N-dimethylformamide (5 ml) was added slowly dropwise thereto, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0° C., then ice was added thereto, water (50 ml) was further added thereto, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give the title compound (910 mg, Y.:87%) as yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:5]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:4][NH:3]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:57]([N:59]([CH2:62][CH2:63][NH2:64])[CH2:60][CH3:61])[CH3:58]>O.CN(C)C=O>[CH2:57]([N:59]([CH2:60][CH3:61])[CH2:62][CH2:63][NH:64][C:17]([C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:7]3[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)[CH:6]=3)=[N:9][C:10]=2[CH:16]=1)=[O:19])[CH3:58]
Reactant: CCN(CC)CCN
Reactant: O=C(O)c1ccc2nc(-c3cc(-c4ccncc4)n[nH]c3=O)[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNC(=O)c1ccc2[nH]c(-c3cc(-c4ccncc4)n[nH]c3=O)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture consisting of 50 mg of 2-(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazin-4-yl)-3H-benzoimidazole-5-carboxylic acid, 0.065 ml of triethylamine and 1.5 ml of dimethylformamide (DMF) is stirred at room temperature for 10 minutes, mixed with 68.4 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Hatu) and stirred at room temperature for a further 30 minutes. Then 21 mg of diethylaminoethylamine are added, and the mixture is stirred at 50° C. for 3 hours. After cooling, it is diluted with 5 ml of water, and the precipitate is filtered off with suction and stirred with isopropanol at 60° C., filtered off with suction and dried in vacuo.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4](=[CH:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:19].ClC1C=CC=C(C(OO)=[O:28])C=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[CH2:10][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3([O:28][CH:5]3[CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1C(=O)CC2(c3ccccc3)CCCC=C2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC2(c3ccccc3)CCCC3OC32C1=O
Yield: 65.8 %

Procedure:
A solution of 1.0 g (3.92 mmoles) of N-methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline in 10 ml of chloroform was treated with a solution of 746 mg of 85% m-chloroperbenzoic acid in 12 ml of chloroform. The reaction mixture was refluxed for 36 hours, after which it was poured into 5 N sodium hydroxide. The aqueous phase was extracted twice with chloroform and the combined organic layers were washed well with water, then brine. Drying with sodium sulfate and evaporation of the solvent gave 0.7 g of white solid N-methyl-4a-phenyl-1,3-diketo-8,8a-epoxy-decahydroisoquinoline, mp 135°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]([OH:16])=O.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]([N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1)=[O:16]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2Cl)s1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccccc2Cl)s1

Procedure:
prepared by reaction of 5-(2-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28]([C:24]4[O:23][CH:27]=[CH:26][CH:25]=4)=[O:29])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccco4)cc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and furan-2-carbonyl chloride (0.39 g, 3.00 mmol) in CH2Cl2 (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 18 h, the product was isolated by filtration, washed with CH2Cl2 (10 mL) and dried in vacuo to give furan-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.86 g, 75% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.11 min (96.16%); mp: 180-182° C.; 1H NMR (DMSO-d6) δ 1.94-2.17 (m, 1H, CHH), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.59 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.7 Hz, 1H, CH), 6.65 (dd, J=1.8, 3.5 Hz, 1H, Ar), 7.15 (d, J=3.6 Hz, 1H, Ar), 7.74-7.85 (m, 2H, Ar), 7.85-7.97 (m, 2H, Ar), 9.12 (t, J=6.1 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 41.87, 48.99, 111.93, 113.86, 121.97, 123.54, 129.81, 131.59, 133.44, 145.28, 147.39, 147.52, 157.93, 166.97, 167.10, 169.80, 172.72; LCMS: MH=382; Anal Calcd for C19H15N3O6+0.1H2O: C, 59.56; H, 4.00; N, 10.97. Found: C, 59.26; H, 3.45; N, 10.80.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=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].O.C(O)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:18][CH:19]=2)=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Brc1cnc(Br)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 97.9 %

Procedure:
10.43 g (0.044 mol) of 2,5-dibromopyrimidine, 10 g (0.044 mol) of 4-(phenylmethoxy)benzeneboronic acid, 253 mg (0.00044 mol) of Pd(dba)2, (0.001752 mol) of TPPTS and 9.3 g (0.0876 mol) of sodium carbonate are heated at 80° C. in 100 ml of toluene, 50 ml of ethanol and 30 ml of water for 48 hours. The palladium catalyst is subsequently separated at 80° C. from the reaction mixture by filtration. The lower aqueous phase of the reaction mixture is separated off at 80° C. before the organic phase is freed of the solvents on a rotary evaporator and is dried in a high vacuum. The crude product thus obtained is crystallized from acetonitrile (300 ml), giving 14.7 g (93% yield, based on 2,5-dibromopyrimidine) of 5-bromo-2-[4-(phenylmethoxy) phenyl]pyrimidine (content according to HPLC: 98%). ##STR23##
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH2:34]([O:41][C:42]1[CH:49]=[C:48]([N:50]([CH2:55][CH2:56][CH2:57][CH3:58])[CH2:51][CH2:52][CH2:53][CH3:54])[CH:47]=[CH:46][C:43]=1[CH:44]=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>O1CCCC1.C(OCC)(=O)C>[CH2:34]([O:41][C:42]1[CH:49]=[C:48]([N:50]([CH2:55][CH2:56][CH2:57][CH3:58])[CH2:51][CH2:52][CH2:53][CH3:54])[CH:47]=[CH:46][C:43]=1[CH:44]=[CH:14][C:9]1[S:13][CH:12]=[CH:11][CH:10]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OCc2ccccc2)c1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
In a stream of argon, to 25 ml of tetrahydrofuran was added 3.3 g of phenyllithium (19% solution in dibutylether) (7.46 mmol), and 2.68 g (6.79 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under ice cooling. Next, 2.3 g (6.78 mmol) of 2-benzyloxy-4-dibutylaminobenzaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred under ice cooling for 2 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. To the residue, 40 ml of ethyl acetate/hexane (4/1) was added and the precipitate was filtered off. The filtrate was concentrated and then purified by silica gel column chromatography to give 2.64 g of a yellow oily matter (yield: 92.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:11][CH2:12][CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(C(CCCc2c[nH]cn2)c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCO
Product: Nc1ccc(C(CCCc2c[nH]cn2)c2ccc(N)cc2)cc1

Procedure:
4-[4,4-bis(4-nitrophenyl)butyl]-1H-imidazole is hydrogenated in ethanol using 10% palladium on carbon (Pd/C) as a catalyst.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=O)[CH2:29][C:30](OCC)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[CH2:28][CH2:29][CH2:30][OH:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCCO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of intermediate (S)-ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (117 mg, 0.25 mmol) in THF (2 mL) was treated with a 1 N THF solution of lithium aluminum hydride (500 μL, 0.5 mmol) and stirred for 1 h. After this time the reaction mixture was quenched with ice water (250 μL) followed by a 5% NaOH solution (500 uL) and solid MgSO4. The material was dissolved in EtOAc, filtered and evaporated to afford the title compound as a burgundy colored oil (103 mg, 97%). LC/MS (Method A) 5.15 min, [M+1]+ 425.