Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:23]([NH2:25])=[O:24])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][O:20][S:21][NH2:22])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.CN1C(=O)CCC1>C1(C(C)C)C=CC=CC=1.[Pd]>[NH2:1][C:2]1[CH:27]=[CH:26][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][O:20][S:21][NH2:22])=[CH:15][CH:14]=4)[N:10]=[C:9]3[C:23]([NH2:25])=[O:24])=[C:4]2[CH:3]=1
Reactant: NSOOc1ccc(-n2nc(C(N)=O)c3c2-c2cc(N)ccc2CC3)cc1
Agent: [Pd]
Solvent: CC(C)c1ccccc1
Solvent: CN1CCCC1=O
Product: NSOOc1ccc(-n2nc(C(N)=O)c3ccc4ccc(N)cc4c32)cc1
Yield: 90.5 %

Procedure:
The product of Example 4b (1 g) and 5% Pd/C (300 mg) suspended in cumene (50 mL) and NMP (5 mL) was heated at reflux for 16 h. The mixture was then filtered and concentrated. The residue was diluted with methanol (10 mL) and added to water, after 1 h the resulting precipitate was collected by filtration and dried to yield the title compound (0.9 g).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[CH:9]([O:11][CH3:12])=O.COS(OC)(=O)=O.[NH4+].[OH-]>C1(C)C=CC=CC=1.CO.CCOCC>[CH3:12][O:11][CH:9]=[C:4]([CH3:3])[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)CC
Reactant: COC=O
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: CO
Product: CCC(=O)C(C)=COC
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a suspension of NaH (4.40 g, 110 mmol, 60% dispersion in mineral oil) in toluene (90 mL) and MeOH (0.1 mL) at 0° C. was added a mixture of 3-pentanone (10.6 mL, 105 mmol) and methyl formate (8.00 mL, 130 mmol) over 1 hr. The reaction mixture was warmed to rt, stirred for another 3 h, and then diluted with Et2O. The suspension was filtered and the precipitate was washed with Et2O. The resulting crude sodium salt of 1-hydroxy-2-methyl-1-penten-3-one was dissolved in DMSO (100 mL) and Me2SO4 (9.16 mL, 97.0 mmol) was added at rt. After stirring for 30 min, the reaction mixture was treated with 2M NH4OH and diluted with Et2O. The organic layer was separated, washed with H2O and saturated aqueous NaCl solution, dried (MgSO4), and concentrated under reduced pressure to afford 1-methoxy-2-methyl-1-penten-3-one (8.27 g, 74%). To a solution of 1-methoxy-2-methyl-1-penten-3-one (2.60 g, 20.3 mmol) in Et2O (12.0 mL) was added Et3N (7.08 mL, 50.8 mmol) and TMSOTf (3.68 mL, 20.3 mL) at 0° C. The reaction mixture was warmed to rt, stirred for another 3 h, and then poured onto a saturated aqueous NaHCO3 solution. The organic layer was separated, washed with saturated aqueous NaCl solution, dried (MgSO4), and concentrated under reduced pressure to afford butadiene 3 (3.66 g, 90%). 1H-NMR (400 MHz, CDCl3) δ 6.35 (s, 1H), 4.75 (q, J=6.9, 1H), 3.63 (s, 3H), 1.66 (s, 3H), 1.62 (d, J=6.9, 3H), 0.22 (s, 9H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]1[CH:6]=[CH:5]2.[SH:16][C:17]1[CH:18]=[C:19]([C:23]2([C:29]#[N:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH3:15][C:13]1[N:14]=[C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([S:16][C:17]4[CH:18]=[C:19]([C:23]5([C:29]#[N:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)[CH:20]=[CH:21][CH:22]=4)[CH:3]=3)[N:8]2[CH:12]=1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Reactant: Cc1cn2c(ccc3cc(I)ccc32)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn2c(ccc3cc(Sc4cccc(C5(C#N)CCOCC5)c4)ccc32)n1
Temperature: 80 °C

Procedure:
1m (30 mg, 0.13 mmol) and 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (1n, 35 mg, 0.11 mmol) were dissolved in 1,4-dioxane (4 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.04 mL, 0.22 mmol), Pd2dba3 (catalytic), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (catalytic) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 80° C. overnight, then cooled to room temperature, concentrated, and purified by preparative HPLC to give the desired product, 1o.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH:4]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=1)[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:7]=1.[OH-].[Li+].C1COCC1.O>CO>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:10][C:6]([CH2:5][CH:4]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=3)[C:3]([OH:43])=[O:2])=[N:7]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C(Cc1cc(-c2ccc(C)cc2)n(-c2ccc(OC)cc2)n1)c1cn(COCC[Si](C)(C)C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CC(C(=O)O)c3cn(COCC[Si](C)(C)C)c4ccccc34)cc2-c2ccc(C)cc2)cc1
Yield: 89.7 %

Procedure:
The title compound was synthesized by Method 2 from 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid methyl ester (Example 69, 0.19 g, 0.32 mmol), lithium hydroxide (40 mg, 0.96 mmol), THF (1.25 mL), water (0.43 mL) and MeOH (0.43 mL), giving 167 mg (89%) of 3-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-3-yl]-propionic acid. HPLC: Rt=3.66 (Method B). MS (ES+): mass calculated for C34H39N3O4Si, 581.27; m/z found 582.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.64 (d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.45 (s, 1H), 7.19-7.04 (m, 6H), 7.01 (d,J=8.2 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.33 (s, 1H), 5.52 (s, 2H), 4.21 (m, 1H), 3.76 (s, 3H), 3.41 (m, 2H), 3.07 (dd, J=6.3, 14.3 Hz, 1H), 2.27 (s, 3H), 0.75 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:32])[C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[O:32])=[CH:17][N:16]=[C:15]([NH:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]2)[N:20]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)cc1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-carbamic acid tert-butyl ester (1.32 g) obtained from Example 113 was dissolved in 50% trifluoroacetic acid/dichloromethane (30 mL) and the solution was stirred at room temperature for 30 minutes. The solvent was removed and the residue was treated with saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate/tetrahydrofuran (3:1, 30 mL). The extracts were combined, dried (Na2SO4) and concentrated under reduced pressure to a solid (980 mg). Yield, 95%. MS(ES) (M+H)+=360.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O>[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH3:19]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CCOCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOCCCNc1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 44 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol) with 3-ethoxypropylamine (Aldrich Chemical Company) (0.225 g, 2.18 mmol) and K2CO3 (0.34 g, 2.50 mmol) in H2O (2.5 mL) to give a biphasic reaction mixture, which was partitioned between CH2Cl2 and H2O. The organic layers were separated, dried over MgSO4 and concentrated. The resulting yellow oil was purified by flash chromatography on silica gel (1:40 MeOH/CH2Cl2 followed by 1:20 MeOH/CH2Cl2 as eluant) to give 0.056 g (44%) of the title compound as a light yellow oil that solidified upon standing. Mp: 208-209.5° C. 1H NMR (CDCl3; 500 MHz): δ 1.16 (t, 3, J=7.0), 1.99 (quin, 2, J=5.8, 6.4), 2.58 (s, 3), 3.52 (q, 2, J=7.1), 3.63 (t, 2, J=5.6), 3.74 (t, 2, J=6.6), 5.95 (br s, 1), 6.67 (s, 1), 7.33 (t, 1, J=7.4), 7.40 (t, 2, J=7.6), 7.66 (d, 2, J=7.6); MS m/z: 311 (M+1).
Reaction SMILES: C(N1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)CC1)(C)C.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.[H-].[Na+]>>[CH2:7]([O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:24](=[O:25])[C:15]3=[CH:14][C:13]=2[CH:12]=1)[C:8]1[CH:9]=[CH:13][CH:12]=[CH:11][CH:19]=1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=C1c2cc3cc(OCc4ccccc4)ccc3n2CCCN1CC1CC1

Procedure:
The title compound was synthesized in analogy to example 17, from 9-benzyloxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 15, intermediate b)), 1-(bromomethyl)cyclopropane and sodium hydride, to give the compound as a white solid (76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[C:31]([CH3:39])[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=6)[N:32]=[C:31]([CH3:39])[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)c2ccccc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)nc5ccccc45)ncn3)CC1)C(=O)N2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
75 mg (0.27 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 70 mg (0.26 mmol) 4-(6-chloro-pyrimidin-4-yloxy)-2-methyl-quinoline and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at 90° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[C:7]([N:30]2[CH2:31][CH2:32][CH2:33][C@@H:29]2[CH2:28][O:27][CH3:26])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: COC[C@H]1CCCN1
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC[C@H]1CCCN1c1c(C(=O)N(C)OC)cc(Cl)c2cccnc12
Temperature: 65 °C
Yield: 96.5 %

Procedure:
A stirred mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.150 g, 0.376 mmol), (2R)-2-(methoxymethyl)pyrrolidine (0.0521 g, 0.452 mmol, Fluka), palladium acetate (2 mg, 0.008 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7 mg, 0.01 mmol), and cesium carbonate (0.343 g, 1.05 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane, and filtered. The filtrate was washed with brine, dried over sodium sulfate, and evaporated to dryness. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (132 mg, 96%). LCMS calculated for C18H23ClN3O3(M+H)+: m/z=364.1; found: 364.1.
Reaction SMILES: C1(O[C:8]([N:10]2[CH2:14][CH2:13][N:12](C)[C:11]2=[C:16]([N+:26]([O-:28])=[O:27])[C:17](=[O:25])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[C:19]1([O:18][C:17](=[O:25])[C:16](=[C:11]2[NH:12][CH2:13][CH2:14][N:10]2[CH3:8])[N+:26]([O-:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCN(C(=O)Oc2ccccc2)C1=C(C(=O)Oc1ccccc1)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCNC1=C(C(=O)Oc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 15.66 g of phenyl chloroformate in 25 ml of methylene chloride was added to a stirred and ice-cooled solution of 8.21 g of 1-methylimidazole in 175 ml of methylene chloride. To the resulting white suspension was added 7.15 g of 1-methyl-2-(nitromethylene)imidazolidine in portions as a solid. After stirring overnight at room temperature, the reaction mixture was washed twice with water. The organic layer was dried (MgSO4) and concentrated. The residual orange syrup was treated with water, and this mixture allowed to stand at room temperature overnight. The resulting solid was isolated by filtration. Trituration with ethyl acetate gave white powder. Recrystallization from a mixture of 60 ml of dimethyl sulfoxide and 45 ml of water gave 3-methyl-2-(1-nitro-2-oxo-2-phenoxyethylidene)-1-imidazolidinecarboxylic acid phenyl ester (1A), as a white solid, m.p.: 214°-215° C. A heterogeneous mixture of 1.92 g of 1A in 10 ml of dimethyl sulfoxide and 0.55 g of sodium carbonate in 3 ml of water was stirred at room temperature for two days. Crude, solid product was obtained by dilution with 30 ml of water and then filtration. Recrystallization from dimethyl sulfoxide: water yielded 1, as white crystals, m.p.: 234°.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([CH:10]3[O:15][CH2:14][C:13](=O)[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]3)[CH:7]=[CH:6][C:5]=12.S(C)C.CO>O1CCCC1>[N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([CH:10]3[O:15][CH2:14][CH2:13][N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11]3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)N1CC(c2ccc3nnnn3c2)OCC1=O
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)N1CCOC(c2ccc3nnnn3c2)C1
Yield: 100.3 %

Procedure:
To a solution of 2-(tetrazolo[1,5-a]pyrid-6-yl)-4-(1,1-dimethylethyl)-5-oxo-morpholine (2.09 g) in 100 ml of dry tetrahydrofuran (THF), a 2.0M solution of BH3.Me2S in tetrahydrofuran (10 ml) was added dropwise under nitrogen. The reaction mixture was then heated at reflux for 5 hours. The mixture was cooled and treated with 25 ml of methanol. The mixture was then heated at reflux for 3 hours. The solution was concentrated under reduced pressure and the residue (2.45 g) purified by column chromatography (95:5 methylene chloride:ethanol) on silica gel to give 1.99 g of product. Mass spectrum (FAB) 262 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: Nc1ccccc1F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccccc3F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 2-fluorophenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=373.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[C:23]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:22][C:19]([CH:20]=O)=[C:18]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:17]=1>>[CH3:14][O:15][C:16]1[C:23]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:22][C:19](/[CH:20]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])=[C:18]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH:17]=1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OCCCN2CCOCC2)c(C=O)cc1-c1cccs1
Product: COc1cc(OCCCN2CCOCC2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 48 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) in a similar manner as described in Ex-22. Yellow solid, 48% yield, mp 193–196° C. 1H-NMR (DMSO-d6) δ 8.24 (m, 3H), 8.06 (s, 1H), 7.96 (d, 2H), 7.89 (d, 1H), 7.63 (d, 1H), 7.51 (m, 1H), 7.10 (dd, J=3, 4 Hz, 1H), 6.81 (s, 1H), 4.23 (t, 2H), 3.98 (s, 3H), 3.55 (t, 4H), 2.47 (m, 2H), 2.35 (t, 4H), 1.98 (q, 2H). MS m/z=542 ([M]+, 38%), 100 (100%). Anal. calculated for C27H30N2O6S2.3/5H2O: C, 58.59; H, 5.68; S, 11.59; found C, 58.59,H: 5.55, S, 11.40.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5](COC)=[CH:4][N:3]=1.ClC1C(Cl)=CC([C:20]([O:22][CH3:23])=[O:21])=CN=1>>[Cl:8][C:7]1[C:2]([C:20]([O:22][CH3:23])=[O:21])=[N:3][C:4]([C:20]([O:22][CH3:23])=[O:21])=[CH:5][CH:6]=1
Reactant: COCc1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(Cl)c(C(=O)OC)n1
Yield: 73 %

Procedure:
Example 2 was repeated, except that the 2,3-dichloro-5-(methoxymethyl)pyridine was replaced by the same molar amount of methyl 2,3-dichloro-5-pyridinecarboxylate. After a reaction time of 6 hours at a bath temperature of 160° C., 1.20 g (73 percent) of a yellow product was obtained. Other data concerning the product was:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-:50][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1.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].O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:50])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(C2CCCN2c2ccnc(Cl)c2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(N2CCCC2c2ccc(F)cc2)ccn1
Temperature: 65 °C
Yield: 67.7 %

Procedure:
2-Chloro-4-[2-(4-fluoro-phenyl)-pyrrolidin-1-yl]-pyridine (97 mg, 0.35 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol) and 2-(dicyclohexylphosphino)biphenyl (25 mg, 0.070 mmol) are mixed in dry THF (2.0 mL). Then Argon is bubbled through the solution for 5 min and 1.0 M LiHMDS (0.53 mL, 0.53 mmol) is added. Then the reaction mixture is heated at 65° C. for 6 hrs before more 1.0 M LiHMDS (0.53 mL, 0.53 mmol) is added. The resulting mixture is heated at 65° C. for another 16 hrs. Then saturated NH4Cl aqueous solution (20 mL) is added along with water (25 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by Gilson preparative HPLC affords 61 mg of desired product.
Reaction SMILES: Cl.C([S:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@@H:8]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[CH2:28][CH2:27]2)=[O:25])[CH2:7]1)(=O)C>>[SH:5][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C@@H:8]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:36])[CH2:30][CH2:31]2)=[O:25])[CH2:7]1
Reactant: CC(=O)S[C@H]1C[C@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Product: O=C(OCCN1CCN(C(=O)[C@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 60.5 %

Procedure:
40 ml of a 10% w/v methanolic solution of hydrogen chloride were added to a solution of 1.0 g of (2R,4S)-4-acetylthio-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (ii) above] in 10 ml of 1,4-dixoane, and the resulting mixture was stirred at 50° C. to 52° C. for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with 100 ml of ethyl acetate. The dilute solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and washed, in turn, with 30 ml of water and with 30 ml of an aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 566 mg of the title compound, as a colorless powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6]>CC(C)CO>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][O:6][CH2:5][CH:4]([CH3:9])[CH3:3])=[C:4]([CH:9]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Solvent: CC(C)CO
Product: CC(C)COCc1ccc(Cl)cc1C(=O)O

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 16 from methyl 2-(bromomethyl)-5-chlorobenzoate and 2-methylpropan-1-ol:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][N:15]=[CH:14][CH:13]=1.[Cl:17]N1C(=O)CCC1=O>ClCCCl>[Cl:17][C:13]1[CH:14]=[N:15][NH:16][C:12]=1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)c(-c2ccn[nH]2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Product: COC(=O)c1ccc(C)c(-c2[nH]ncc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
Methyl 4-methyl-3-(1H-pyrazol-5-yl)benzoate (compound 51.1, 385 mg, 1.78 mmol) was dissolved in 1,2-dichloroethane (60 mL), then N-chlorosuccinimide (250 mg, 1.87 mmol) was added. The mixture was stirred at room temperature for 16 hours then washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-20% EtOAc in hexanes) to yield 152 mg (34%) of the title compound as an oil. m/z (ES+) 251 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 8.07-7.94 (m, 2H), 7.63 (d, J=0.7 Hz, 1H), 7.47-7.34 (m, 1H), 3.93 (s, 3H), 2.36 (s, 3H).