Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[N:9]=2)[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:3]=1[C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C([Li])CCC.[C:49](=[O:51])=[O:50]>O1CCCC1>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:8]2[N:9]=[C:10]3[C:2]([C:49]([OH:51])=[O:50])=[C:3]([C:31]4[CH:36]=[CH:35][C:34]([N:37]5[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]5)=[CH:33][CH:32]=4)[N:4]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:5]3=[N:6][CH:7]=2)[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: O=C=O
Reactant: COc1cc(CCc2cnc3c(n2)c(Br)c(-c2ccc(N4CCN(C)CC4)cc2)n3COCC[Si](C)(C)C)cc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3c(n2)c(C(=O)O)c(-c2ccc(N4CCN(C)CC4)cc2)n3COCC[Si](C)(C)C)cc(OC)c1
Reaction time: 0.17 h

Procedure:
The a stirred solution of 7-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]-pyrazine (55 mg, 82.7 μmol) in tetrahydrofuran (2 mL), n-butyllithium (2.5 M in hexanes, 50 μL, 0.125 mmol) was added at 78° C. After 10 minutes, dry CO2 (prepared by passing the CO2 through drying tube) was bubbled into the reaction. After 20 minutes, the reaction was quenched with saturated aqueous NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated to give the crude product (50 mg), which was used directly in the next step. LCMS calculated for C34H46BN5O5Si (M+H)+: m/z=632.3. Found: 632.3.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[F:13].[NH2:15][C:16]1[S:17][C:18](Br)=[CH:19][N:20]=1>O1CCCC1>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([O:12][CH:18]2[S:17][CH:16]([NH2:15])[N:20]=[CH:19]2)[CH:9]=[CH:8][C:7]=1[F:13]
Reactant: COC(=O)c1cc(O)ccc1F
Reactant: Nc1ncc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC2C=NC(N)S2)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium hydride (1.7 g, 44.11 mmol) in tetrahydrofuran (50 mL) was added solution of 2-fluoro-5-hydroxy benzoic acid methyl ester (5 g, 29.41 mmol) in tetrahydrofuran (50 mL) under argon atmosphere and stirred for 15 minutes. A solution of 2-amino-5-bromothiazole (5.2 g, 29.41 mmol) in tetrahydrofuran (47 mL) was added dropwise over a period of 30 min and stirred at room temperature for 4 hrs. Reaction mixture was poured into ice cold water (300 mL) extracted with ethyl acetate (3×200 mL), combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude compound was purified by silica gel column chromatography using 40% ethyl acetate in hexane as eluent to afford pure 5-[(2-amino-5H-thiazol-5-yl)oxy]-2-fluoro-benzoic acid methyl ester. (2.5 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[C:26]([O:36][CH3:37])=[C:27]([C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:28](=[O:29])[C:27]3[C:31]([O:34][CH3:35])=[CH:32][CH:33]=[C:25]([Br:24])[C:26]=3[O:36][CH3:37])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Br)c(OC)c1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg), 3-bromo-2,6-dimethoxybenzoic acid (23 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (68 mg) and N,N-diisopropylethylamine (32 l) in dichloromethane (4 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])#[N:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[C:10]([C:8]#[N:9])=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of cyclohexanone (84.1 g, 1 mol) in dry benzene (100 mL) was added methyl cyanoacetate (99.1 g, 1 mol), ammonium acetate (10 g) and glacial acetic acid (20 mL). The reaction mixture was heated to reflux using Dean-Stark apparatus for 12 hours and allowed to cool to room temperature. Excess of solvents was removed in vacuo and the residue was dissolved in EtOAc (400 mL). The organic layer was washed with water, dried over sodium sulfate and evaporated to give cyano-cyclohexylidene-acetic acid methyl ester as pale yellow oil. Further purification of the pale yellow oil by distillation (10 mm Hg, 150–155° C.) gave product the title compound (110 g, 61%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.70–1.85 (m, 6H), 2.70 (t, 2H), 3.00 (t, 2H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 25.9, 28.6, 28.9, 31.9, 37.2, 52.8, 101.9, 115.8, 162.7, 180.8.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=O)[NH2:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O>C1COCC1>[C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=[S:40])[NH2:2]
Reactant: Cc1nc2nc(C(N)=O)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2nc(C(N)=S)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 220.3 %

Procedure:
To a stirred solution of tert-butyl (2-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (intermediate for Example 62, 150 mg, 0.33 mmol) in THF (10 mL) was added Lawesson's reagent (202 mg, 0.50 mmol). After heating to 65° C. for 20 h, the reaction mixture was poured into H2O (5 mL). The resulting mixture was extracted with EtOAc and the organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure afforded crude tert-butyl (2-carbamothioyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (339 mg, 100% crude yield) as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[CH2:25][CH2:26][N:27]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]2=[O:37])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1.CC[OH:40].CC(O)=O>[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([OH:37])=[O:40])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: CCO
Reactant: O=C1CN(c2ccc(/C=C/CCN3C(=O)c4ccccc4C3=O)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CN(c2ccc(CCCCNC(=O)c3ccccc3C(=O)O)cc2O)S(=O)(=O)N1

Procedure:
A solution of 2-{(E)-4-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-but-3-enyl}-isoindole-1,3-dione (70 mg, 0.135 mmol) in 6 mL of EtOH/HOAc (4:2) is hydrogenated at 50 psi over 10% Pd/C (70 mg) for 18 h. The catalyst is filtered, the solvent is removed under reduced pressure and the residual yellow foam triturated with EtOAc to give the title compound as a solid: (M−1)−=446.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl.N1C=CC=CC=1>[Br:8][C:7]1[C:2]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][C:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:5][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc(N)c(Br)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(=O)OC(C)(C)C)ncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl 4-amino-5-bromopicolinate (546 mg, 2 mmol) in CH2Cl2 (5 mL) and pyridine (1 mL) at 0° C., was added ethyl chloroformate (271 mg, 2.5 mmol). The mixture was stirred at rt for 2 h, diluted with dichloromethane, washed with 5% citric acid, and sat. K2HPO4 aq. solution. The organic layer was dried over MgSO4 and the product was purified by flash column chromatography (SiO2, eluting with 20% EtOAc/CH2Cl2) to give a white solid (570 mg, 83%). LC-MS: m/z 345 (M+).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:1]1([S:7][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C=CC(=O)OCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCSc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of 12.12 g (0.11 mol) of thiophenol, 10.01 g (0.10 mol) ethyl acrylate, 20 mL of HCCl3 at 0° C. in a 100-mL, round-bottom flask, 0.50 mL of triethylamine was added under N2. The ice bath was removed after the addition of triethylamine and the solution was allowed to stir at room temperature for 3 hours. The resulting solution was idluted with 150 mL of ether and washed with 10% NaOH, H2O, and saturated NaCl solution. The mixture was dried (Na2SO4, overnight) and the solvents were removed. Vacuum distillation gave 19.36 g (92.1%) of ethyl 3-(phenylthio)propionate as a clear, colorless liquid: bp 112°-115° C./0.2 mm [literature reports 117° C./2.5 mm; see K. Iwai, H. Kosugi, A. Miyazaki, and Huda, Synthetic Communications, 6, 357 (1976)]; IR (neat) 1740 cm-1 (C=O); 1H NMR (DCCl3) δ1.14 [t, 3H, CO2CH2CH3 ], 2.54 [t, 2H, CH2CO2CH2CH3 ], 3.10 [t, 2H, ArSCH2 ], 4.06 [q, 2H, CO2CH2CH3 ], 7.13-7.32 [m, 5H, ArH]; 13C NMR (DCCl3) ppm 13.6 [CO2CH2CH3 ], 28.3 [ArSCH2 ], 33.8 [CH2CO2CH2CH3 ], 60.0 [CO2CH2CH3 ], 125.8, 128.4, 129.3, 134.8, 170.9 [C=O]. Both hydrogen and carbon-13 NMR spectra shifts were measured from tetramethylsilane (TMS) standard on a Varian XL-300 spectrometer confirming the correct hydrogen distribution and carbon atom assignments. ##STR11##
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.Br[CH:42]1[CH2:44][CH2:43]1.CCN(C(C)C)C(C)C>CC#N>[CH:42]1([N:32]2[CH2:31][CH2:30][CH:29]([N:22]3[CH2:21][C:20]4[CH:19]=[C:18]5[C:26]([NH:27][C:16]([C:10]6[C:11](=[O:15])[NH:12][CH:13]=[CH:14][C:9]=6[NH:8][CH2:7][CH:6]([OH:35])[CH2:5][O:4][C:3]6[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:2]=6[CH3:1])=[N:17]5)=[CH:25][C:24]=4[C:23]3=[O:28])[CH2:34][CH2:33]2)[CH2:44][CH2:43]1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: BrC1CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C3CC3)CC2)C4)c(C)c1
Temperature: 25 °C
Reaction time: 112 h
Yield: 5.6 %

Procedure:
To a solution of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (54.3 mg, 0.1 mmol) and bromocyclopropane (121 mg, 1.0 mmol) in CH3CN (8 mL) was added DIEA (129.3 mg, 1.0 mmol) and the resulting reaction mixture was stirred at the room temperature for 112 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (490:10:1) afforded the title compound (3.27 mg, 5.6%). 1H NMR (DMSO-d6) δ 1.70 (m, 2H), 1.80 (m, 2H), 2.04 (m, 2H), 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.90-3.00 (4H), 3.45 (m, 1H), 3.70 (m, 1H), 3.95-4.06 (3H), 4.11 (m, 1H), 4.42 (s, 1H), 4.47 (s, 1H), 5.10-5.22 (2H), 5.47 (d, J=3 Hz, 0.5H, NH), 5.52 (d, J=3 Hz, 0.5H, NH), 5.81 (m, 1H), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (d, J=6 Hz, 1H, NH), 11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 583.7 (MH+).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@H:36]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[C:48]([NH:56][C:57](=[O:76])[C@@H:58]2[CH2:62][C@@H:61]([NH:63][C:64](=[O:75])[C@H:65]([OH:74])[CH2:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:60][NH:59]2)[CH:47]=1>ClCCl.C(N(CC)CC)C>[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[C:48]([NH:56][C:57](=[O:76])[C@@H:58]2[CH2:62][C@@H:61]([NH:63][C:64](=[O:75])[C@H:65]([OH:74])[CH2:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:60][N:59]2[C:32](=[O:34])[C@@H:31]2[CH2:35][C@@H:36]([NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:29])[CH:47]=1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
Triethylamine (30 μL), 1-hydroxybenzotriazole (28 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg) were added to a cold (0° C.) stirred solution of N-tert-butoxycarbonyl-trans-4-(N-tert-butoxycarbonylamino)-L-proline (O, 76 mg) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide(H, 76 mg) in dichloromethane (10 mL). The mixture was stirred at room temperature for 16.5 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (Whatman, PLK5F Silica Gel 50, 20 cm×20 cm×2 mm, methanol:chloroform=1:20, v/v) to give the title compound (90 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 1.45 (s, 9H), 1.69-1.84 (m, 5H), 1.90-2.03 (m, 1H), 2.09-2.28 (m, 3H), 2.68-2.83 (m, 3H). 3.39-3.46 (m, 1H), 3.50-3.56 (m, 1H), 3.74-3.81 (m, 1H), 3.93-3.99 (m, 1H), 4.01-4.08 (m, 1H), 4.29-4.37 (m, 1H), 4.45-4.53 (m, 2H), 4.57-4.76 (m, 2H), 4.91-4.98 (m, 1H), 7.15-7.30 (m, 5H), 7.38-7.53 (m, 2H), 7.63-7.70 (m, 1H), 7.81-7.87 (m, 1H), 8.57-8.60 (m, 1H), 8.66-8.70 (br s, 1H), and 9.93 (br s, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:11]=[C:12]([CH2:16][PH:17](=[O:23])[O:18]CC(C)C)[CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.C1COCC1>[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:11]=[C:12]([CH2:16][PH:17](=[O:18])[OH:23])[CH:13]=[CH:14][CH:15]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CO[PH](=O)Cc1cccc(P(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[PH](O)Cc1cccc(P(c2ccccc2)c2ccccc2)c1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
0.50 g (12.6 mmol) of NaOH in 7 ml of water are added dropwise at 23° C. to a solution of 2.50 g (6.3 mmol) of isobutyl (3-diphenylphosphinophenyl)methylphosphinate in 7 ml of THF. After refluxing for 6 hours, 1.04 ml (12.6 mmol) of concentrated hydrochloric acid are added dropwise at 23° C., the mixture is stirred for 10 min at 23° C. and evaporated to dryness under reduced pressure. The residue is substantially dissolved in boiling methanol, filtered hot and crystallized for 22 h at -20° C. 1.02 g of (3-diphenylphosphinophenyl)methylphosphinic acid (60% of theory) are obtained in the form of a colorless solid having an m.p. of 173° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH2:16][OH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C)C=O>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(CO)ccc2[nH]1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(=O)c2cc(C=O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of 0.3 g of 2-butyl-6-(hydroxymethyl)-4(1H)-quinazolinone in 3.5 ml of dry N,N-dimethylformamide is added 1.7 g of pyridinium dichromate. The reaction mixture is stirred at room temperature for 16 hours and then poured into 125 ml of water. The resulting precipitate is removed by filtration and the filtrate extracted with 9:1 chloroform-methanol. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated in vacuo and combined with the precipitate above. The combined solids are purified by flash chromatography on silica gel by eluting with 1:1 ethyl acetate-hexanes to give 0.27 g of the desired product. CI MASS SPEC 231(M+H).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH:8]=O)[CH2:3]1.Cl.[CH3:11][O:12][NH2:13]>O>[ClH:1].[CH3:11][O:12][N:13]=[CH:8][C:4]1[CH2:3][NH:2][CH2:7][CH2:6][CH:5]=1
Reactant: CON
Reactant: O=CC1=CCCNC1
Agent: Cl
Solvent: O
Product: CON=CC1=CCCNC1
Yield: 79.9 %

Procedure:
To a solution of 5 g (0.034 mol) of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde hydrochloride, (CHEM. BER. 40, 4685, 1907)-- in 30 cm3 of water, 2.85 g (0.034 mol) of O-methyl-hydroxylamine hydrochloride is added with agitation for 1 hour at ambient temperature. The reactional mixture is evaporated to dryness and the residue is recrystallized from absolute ethanol. 4.8 g (80%) of product is obtained with m.p.. 208° C.(decomposes) White crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:3]4[CH:4]=[C:5]([NH:8][C:9]([CH:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)=[O:10])[CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:18][CH:19]=3)=[O:25])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)C5CCCCC5)ccc4Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
A mixture of 2′-Chloro-5′-(cyclohexanecarbonyl-amino)-biphenyl-4-carboxylic acid (103 mg), 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (59 mg) and HBTU (148 mg) in dry DMF (10 ml) containing triethylamine (362 μl) was stirred at room temp for 18 h. Most of the DMF was evaporated and the residue diluted with water. The resulting solid was collected by filtration. This material was then purified by reverse phase Prep HPLC giving the title compound as a yellow solid (51 mg)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=1.[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][CH:27]=1>O1CCOCC1>[N:26]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=3[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])[CH:6]=[CH:7][CH:8]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Solvent: C1COCCO1
Product: CC(C)Cc1cc(-c2cccc(Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 93 %

Procedure:
To a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (71.8 mg, 0.162 mmol; see Example 1(e)) in dioxane (2.0 mL) was added benzimidazole (57.3 mg, 0.485 mmol) and the reaction mixture was stirred for 5.5 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (3:97) as eluent to give the sub-title compound in 93% yield as a colourless syrup (72.3 mg, 0.151 mmol).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
to a vigorously stirred solution of N-hydroxyphthalimide (10.0 g, 61.4 mmol) in CH2Cl2 (70 mL) and dioxane (80 mL) was added dihydropyran (6.16 mL, 67.6 mmol) and p-toluenesulfonic acid (200 mg). The resulting solution was stirred overnight at room temperature. The reaction was quenched by slow addition of saturated NaHCO3 (100 mL). After separation, the organic layer was washed with brine and dried over Na2SO4. Solvent removal under vacuum yielded 13.4 g (88%) of 2-(tetrahydro-2H-pyran-2-yloxy)isoindoline-1,3-dione as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:7]=[C:8]([O:12][CH3:13])[NH:9][C:10]=1[CH3:11])=[O:4].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][C:23]([N:7]2[CH:6]([C:14]3[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=3)[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH3:11])[N:9]=[C:8]2[O:12][CH3:13])=[O:24])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1=C(C)NC(OC)=NC1c1ccc(C#N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Intermediate 4 (1.56 g, 5.46 mmol) was dissolved in a mixture of DCM (25 mL) and pyridine (10 mL) and cooled using an ice bath. A solution of 4-nitrophenyl chloroformate (705 mg, 3.50 mmol) in DCM (25 mL) was added over 30 minutes. The reaction mixture was stirred for 1 hour at 0° C. and then the solvent was removed in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in cyclohexane to gave the title compound as a yellow solid. The product thus obtained was used in the subsequent step without further analysis (2.0 g).