Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([O:12][C:13](OCC)=[CH2:14])[CH3:11].CCO>[O-]CC.[Na+].CCOC(C)=O>[C:3]([C:2](=[C:10]([O:12][CH2:13][CH3:14])[CH3:11])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: C=C(OCC)OCC
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)=C(C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A 5 L 4-neck flask equipped with a mechanical stirrer, condenser, thermowell, addition funnel and N2 inlet was charged with ethyl acetoacetate (493.1 g, 483 mL, 3.7931 mol, 1.0 equiv) and sodium ethoxide (3.1 g, 0.046 mol, 1.2 mol %). Ketene diethylacetal (880.0 g, 1000 mL, 7.5862 mol, 2.0 equiv) was added over 1 hr maintaining the reaction temperature at <22° C. by external cooling. When addition was complete, the reaction mixture was heated at 85° C.±5° C. for 7.5 hr. The yellow brown reaction mixture was cooled to room temperature and stirred overnight. Much of the lower boiling components [EtOH, EtOAc, Me(OEt)3] were stripped on a roto-evaporator (bath temperature ˜65° C.). The residual yellow-orange oil was distilled, collecting the fraction with by 100-107° C. (1.8-2.1 Torr) to give 675.2 g (89%) of product as a yellow liquid.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:29]([O:33][C:34]([NH:36][C:37]1[S:41][C:40]([C:42]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=2[F:49])=[N:39][C:38]=1[C:50](O)=[O:51])=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:50]([C:38]3[N:39]=[C:40]([C:42]4[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:43]=4[F:49])[S:41][C:37]=3[NH:36][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[O:51])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)sc1NC(=O)OC(C)(C)C)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (20 mg, 0.051 mmol), (5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, step 6, 22 mg, 0.062 mmol), HATU (49 mg, 0.13 mmol), DMF (0.12 mL) and DIPEA (20 mg, 0.15 mmol) were mixed together and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with 0-100% EtOAc in hexanes) to give the sub-title compound as a colorless gum (30 mg, 80%). LCMS calc. for C35H43F2N6O7S (M+H)+: m/z=729.3. Found: 729.1.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]([CH:37]1[NH:42][CH2:41][CH2:40][NH:39][C:38]1=[O:43])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH3:35][CH:34]([CH:37]1[N:42]([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[CH2:41][CH2:40][NH:39][C:38]1=[O:43])[CH3:36]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: CC(C)C1NCCNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (250 mg, 0.473 mmol, Intermediate B), 3-isopropylpiperazin-2-one (67.3 mg, 0.473 mmol, ChemBridge, San Diego, Calif.), and potassium carbonate (196 mg, 1.419 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (3.15 mL) was heated to 120° C. for 30 min After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). After concentration of the filtrate, the crude residue was purified by reverse-phase HPLC, (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient), two peaks were collected and each was partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layers were dried (Na2SO4), filtered and concentrated to give 4 isomeric products
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)[Si](C)(C)OCCN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 52 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.122 mmol) was reacted with (2-bromoethoxy)(tert-butyl)dimethylsilane (60 mg, 0.254 mmol), following the procedure of Example 136. The product was triturated with ether-hexanes to yield 36 mg (52%) of pure product. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1 H), 7.87 (s, 1 H), 7.79 (d 1 H), 7.56 (m, 2 H), 7.33 (m, 4 H) 7.15 (d, 1 H), 6.67 (s, 1 H), 5.63 (s, 2 H) 4.10-3.2 (m, 7 H), 3.00-1.75 (m, 4 H), 0.85 (m, 9 H), 0.05 (s, 6 H); ES-MS m/z 568.3 [M+H]+, HPLC RT (min) 3.11.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([F:12])=[CH:7][C:6]=2[C:5]2[C:13](CC#N)=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:17])[C:4]1=2)[CH3:2].Cl.[C:28]([OH:31])(=[O:30])[CH3:29]>O>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([F:12])=[CH:7][C:6]=2[C:5]2[C:13]([CH2:29][C:28]([OH:31])=[O:30])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:17])[C:4]1=2)[CH3:2]
Reactant: CC(=O)O
Reactant: CCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Agent: Cl
Solvent: O
Product: CCn1c2ccc(F)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21

Procedure:
A solution of 5.8 g (16.8 mmol) of 5-ethyl-8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile in 200 ml of a 1/1 mixture of concentrated hydrochloric acid and of glacial acetic acid is heated at reflux for 2 h. The solution is cooled, 100 ml of water are added and the insoluble material is collected by filtration and washed copiously with water and with ether on sintered glass. After drying in an oven, 5.2 g (15 mmol) of a white solid are obtained, which solid is used as is in the following stage.
Reaction SMILES: [BH3-]C#N.[Na+].C(OC([NH:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:20])=[O:16])=O)(C)(C)C.[OH:35][C:36]1[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O.CO>C(O)(=O)C>[NH2:12][C:13]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[C:36]=2[OH:35])[CH2:27][CH2:28]1)=[O:20])=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: Cc1cccc(C=O)c1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH3CN (0.40 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 2-hydroxy-3-methylbenzaldehyde (0.25 mmol), methanol (1.0 mL) and acetic acid (0.040 mL). The resulting mixture was stirred at 50 overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. The residue was dissolved in ethyl acetate/methanol=5:1 (1 mL), loaded onto a Varian™ SCX column, eluted with ethyl acetate/methanol=5:1 (5 mL) and concentrated. The residue was dissolved in methanol (2 mL), and a 4 M dioxane solution of HCl (0.50 mL) was added to the resulting solution. The obtained mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL), concentrated and purified by preparative TLC to thereby provide 4-[[N-(2-amino-4,5-difluorobenzoyl) glycyl]aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compd. No. 2106). The purity was determined by RPLC/MS (97%). ESI/MS m/e 447.0 (M++H, C23H28F2N4O3).
Reaction SMILES: [CH2:1]([Br:4])[CH2:2][OH:3].[CH2:5]=[C:6]1[O:10][C:8](=[O:9])[CH2:7]1>C(N(CC)CC)C.ClCCl>[C:8]([O:3][CH2:2][CH2:1][Br:4])(=[O:9])[CH2:7][C:6]([CH3:5])=[O:10]
Reactant: C=C1CC(=O)O1
Reactant: OCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCBr
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To 30 g of ethylene bromohydrin in ice bath were added by turns 22 g of diketene and 1.5 g of triethylamine with stirring while the reaction temperature was controlled at 30°-40° C. The reaction was continued at room temperature for 3 hours. To the reaction solution was added dichloromethane, the mixture was washed successively with diluted hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by distillation to obtain 45.3 g of 2-bromoethyl acetoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:17](=[O:19])[CH:16]([N:15]1[CH2:14][C:5]2[CH2:4][C:3]3[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][C:6]=2[C:12]1=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: Nc1ccccn1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)CC(C(=O)Nc1ccccn1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 220.1 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol), commercially available 2-aminopyridine (101 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, to afford S)-2-(8-Chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid pyridin-2-ylamide (970 mg, 26.4%), as a white solid. 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.34 (d, J=3.9 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.3 Hz, 1H), 7.21-7.42 (m, 2H), 7.02-7.17 (m, 2H), 5.07 (d, J=4.9 Hz, 1H), 4.44 (d, J=18.6 Hz, 1H), 4.07 (d, J=18.6 Hz, 1H), 3.75 (s, 2H), 1.75-1.90 (m, 1H), 1.61-1.74 (m, 1H), 1.46 (br. s., 1H), 1.24 (s, 1H), 0.93 (t, J=5.9 Hz, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH:15]=O.[CH3:17][C:18](=[O:22])[O:19][CH2:20][CH3:21]>C1COCC1.O>[CH2:20]([O:19][C:18](=[O:22])/[CH:17]=[CH:15]/[C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[N:6]=2)[N:11]=[CH:10][CH:9]=1)[CH3:21]
Reactant: COc1ccc2nccc(C=O)c2n1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
Triethylphosphonoacetate (7.3 g, 32.6 mmol) was added to a suspension of a NaH dispersion (1.4 g, 32.5 mmol, 55% in paraffin) in THF (40 mL) at 0° C. The mixture was stirred at 0° C. for 20 min before the dropwise addition of 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (4.0 g, 21.3 mmol; prepared as in WO 2006/032466) in THF. The mixture was stirred at rt for 5 h, diluted with water and EA. The phases were separated and the aq. phase extracted with EA (2 times 50 mL). The combined org. phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (Hex/EA 1:1) to give the desired alkene as a colourless solid (3.0 g, 56% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].S(OC)(O[CH3:21])(=O)=O>O>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C:11](=[O:13])[N:10]([CH3:21])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C1CN(c2cccc(I)c2)C(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN1C(=O)CN(c2cccc(I)c2)C1=O
Reaction time: 4 h

Procedure:
1-(3-Iodophenyl)imidazolidine-2,4-dione (0.588 g) was suspended in water (13 ml) and treated with potassium hydroxide (0.37 g). The reaction was placed in a warming bath (45° C.) and treated with dimethyl sulfate (0.784 ml). After stirring for 4 h the reaction mixture was chilled and filtered. The cake was washed with water and dried to give the title compound (0.381 g). LCMS RT=2.94 min.
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])(O)=O.[Na+].O.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: C1=CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)N1CC=CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 3-pyrroline (3.5 gms) in ethanol (20 mL) was added ~25 mL saturated aq. NaHCO3 and enough water to allow rapid stirring. The mixture was cooled to 10° C. and allyl chloroformate (5.92 mL) was slowly added via pressure equalized addition funnel. The mixture was removed from ice bath and allowed to stir at room temperature for 2 hours. Product was extracted into Et2O (3×150 mL). The organic phase was washed with water (2×50 mL), dried (MgSO4) and solvent was evaporated at reduced pressure. Purification on silica (Et2O) afforded pure title compound.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[O:8][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[O:6][C:5]([C:7]3[O:8][C:9]([C:12]4[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=4)=[CH:10][CH:11]=3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(-c2ccc(-c3ccc(Br)o3)o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(-c3ccc(-c4ccc(C#N)cc4)o3)o2)cc1
Temperature: 80 °C
Yield: 52 %

Procedure:
Method (i): Referring now to Scheme 4, to a stirred solution of 4 (1.256 g, 4 mmol), and tetrakis(triphenylphosphine)palladium (230 mg) in toluene (8 mL) under a nitrogen atmosphere was added 4 mL of a 2 M aqueous solution of Na2CO3 followed by 4-cyanophenyl boronic acid (658 mg, 4.8 mmol) in 4 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 24 h, then cooled, and the precipitate was filtered. The precipitate was partitioned between methylene chloride (250 mL) and 2 M aqueous Na2CO3 (20 mL) containing 2.4 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 15 in 52% yield; mp 298-299° C. (DMF). 1H NMR (DMSO-d6); δ 7.09 (d, J=3.6 Hz, 2H), 7.39 (d, J=3.6 Hz, 2H), 7.89 (d, J=8.1 Hz, 4H), 7.97 (d, J=8.1 Hz, 4H). 13C NMR; δ 151.1, 145.8, 133.3, 132.7, 123.8, 118.6, 111.4, 109.45, 109.40. MS (m/z, rel.int.); 336 (M+, 100), 307 (5), 279 (5), 206 (15), 168 (15). High resolution calcd for C22H12N2O2 ms 336.08988. Observed 336.08978. Calcd for C22H12N2O2-0.75H2O: C, 75.52; H, 3.86; N, 8.00. Found. C, 75.12; H, 3.48; N, 7.74
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH2:23].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
0.753 ml of 4-tert-butylbenzaldehyde (4.5 mmol) and 0.436 ml of 2-(2,4-dichloro-phenyl)-ethylamine (3 mmol) were dissolved in 8 ml methanol at rt and after 30 min at rt refluxed for 3.5 h. After cooling down to rt, 170 mg (4.5 mmol) of sodium borohydride were added in portions and the reaction mixture was then refluxed overnight. After cooling down to rt, the reaction mixture was treated with 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 691 mg colorless oil (68%). MS(ISP) 336.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([O:8]/[N:9]=[C:10](\[NH2:26])/[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=O)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]2[O:8][N:9]=[C:10]([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]4)[N:26]=2)=[CH:4][CH:3]=1
Reactant: N/C(CCCOc1ccc2c(c1)CCC(=O)N2)=N\OC(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCCCc3noc(-c4ccc(Cl)cc4)n3)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a stirred solution of (Z)—N′-((4-chlorobenzoyl)oxy)-4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)butanimidamide (0.030 g, 0.074 mmol) in dry DMF/THF (4 mL, 1:1) at 0° C., TBAF (1 M in THF; 0.02 mL, 0.02 mmol) was added and allowed to stir at room temperature overnight. Solvent was removed under vacuum. Ice cold water (2 mL) was added to the residue. The solid which formed was filtered and dried to yield 6-(3-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (0.020 g, 71%) as an off-white solid. 1H NMR: 400 MHZ, DMSO-d6: δ 2.16 (t, J=6.80 Hz, 2H), 2.39 (t, J=7.20 Hz, 2H), 2.82 (t, J=8.00 Hz, 2H), 2.95 (t, J=7.60 Hz, 2H), 4.02 (t, J=6.00 Hz, 2H), 6.71-6.78 (m, 3H), 7.72 (d, J=8.40 Hz, 2H), 8.11 (d, J=8.80 Hz, 2H), 9.89 (s, 1H). LCMS: RT 2.06 min. LCMS (ES-API), m/z 384.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH2:25]([NH:27][CH2:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:26]>C(#N)C>[CH2:25]([NH:27][CH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:3][C:2]=2[F:1])[CH2:30]1)[CH3:26]
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1
Yield: 87.6 %

Procedure:
To 0.62 g (1.8 mmol) of 6,7,8-trifluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.23 g (1.0 equivalent) of N-ethyl-3-pyrrolidinemethanamine and 0.28 g (1.0 equivalent) of 1,8-diazobicyclo [5.4.0]undec-7-ene in 5 ml of acetonitrile. The reaction was refluxed for one hour and then checked by thin layer chromatography. Excess (10%) N-ethyl-3-pyrrolidine methanamine was added as necessary and the mixture heated to reflux for an additional two hours. The solids were then filtered and washed with ether to give 0.70 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, mp 249°-251° C.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].CCN(C(C)C)C(C)C.[CH:44]1([N:50]=[C:51]=[O:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[C:51]([NH:50][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:52])=[CH:33][CH:34]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C=NC1CCCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)NC3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
To a suspension of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate hydrochloride (500 mg, 1.05 mol) in anhydrous DCM (10 ml) was added DIEA (0.2 mL, 1.18 mmol) and cyclohexyl isocyanate (Aldrich, 0.28 mL, 2.20 mmol). The reaction mixture was stirred at rt for 15 hrs. Then PS-trisamine resin (670 mg, Novabiochem, 3.5 mmol/g) was added and the resulting mixture was stirred at rt for 5 additional hrs. The resin was removed by filtration, washed with DCM and the solvent was evaporated off under reduced pressure. Purification by flash chromatography on silicagel (c-Hex/EtOAc (2/1)) gave 500 mg (84%) of the title compound as a pale yellow oil. HPLC, Rt: 5.9 min (purity: 100%). LC/MS, M+(ESI): 567.4. 1H NMR (DMSO-d6) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.18 (d, J=7.6 Hz, 1H), 4.76 (s, 2H), 4.37 (s, 2H), 4.31 (s, 2H), 3.68 (s, 3H), 3.48 (m, 1H), 2.60 (t, J=7.5 Hz, 2H), 1.75-1.01 (m, 14H), 0.89 (t, J=7.4 Hz, 3H).