Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Br:23])[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Cl)cc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a mixture of 2-(3-bromo-5-chloro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (7.67 g, 17.5 mmol) and triethylsilane (10 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(3-bromo-5-chloro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.12 g, 42%) as a white solid: LC/MS m/e calcd for C20H21BrClNO2 M+: 422.8, observed: 422.0, 424.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=[N:27][CH:28]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)n[nH]1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(F)cc2)n[nH]1
Yield: 11 %

Procedure:
This compound was synthesized from 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (20 mg, yield 11%). 1H NMR (400 MHz, MeOD) δ 9.38-9.37 (d, J=1.5 Hz, 1H), 9.15 (d, J=1.5 Hz, 1H), 8.82 (m, 1H), 8.06-8.02 (m, 2H), 7.21-7.17 (t, J=8.5 Hz, 2H), 3.76 (s, 2H), 1.53 (s, 6H). MS (ESI) m/z: Calculated for C21H17F4N7O2: 475.14. found: 476.2 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([NH:40][C:41](=[O:43])[CH3:42])[CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:44][C:45]([F:50])([CH3:49])[C:46](O)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[F:44][C:45]([C:49]1[N:32]([CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[C:31]2[CH:30]=[CH:29][C:28]([NH:40][C:41](=[O:43])[CH3:42])=[CH:27][C:26]=2[N:25]=1)([F:50])[CH3:46]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
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: CN(C)C=O
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(F)F)n2CC1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
HATU (1.58 g, 4.17 mmol) and N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (1.00 g, 3.79 mmol) were added to a solution of 2,2-difluoropropanoic acid (0.43 g, 3.98 mmol) and DIPEA (0.80 mL, 4.55 mmol) in DMF (100 mL) at ambient temperature. The reaction mixture was stirred overnight and the solvent was concentrated. The intermediate was heated to 80° C. for 3 h in glacial AcOH (100 mL), and the solvent was concentrated. The crude product was recovered in DCM (300 mL), washed with saturated NaHCO3 solution (3×100 mL), brine and dried over anhydrous MgSO4. The solvent was concentrated and the product was purified by normal-phase MPLC using MeOH 5% and Acetone 10% in DCM to provide the title compound as a white solid. Yield: 1.07 g (83%); MS (ESI) (M+H)+=338.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:30]3[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:24]#[N:25])[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C#N)c3)nn3ccnc23)n1
Yield: 51.6 %

Procedure:
To a solution of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (500 mg, 1.52 mmol) and 3-cyanophenylboronic acid (336 mg, 2.29 mmol) in dioxane/H2O (10 mL/2 mL) was added Na2CO3 (322 mg, 3.04 mmol) followed by Pd(dba)2 (175 mg, 0.30 mmol) and X-Phos (73 mg, 0.15 mmol) under nitrogen with stirring. The mixture was stirred at reflux for 15 h under nitrogen. After cooling, the solvent was concentrated in vacuo. The residue was purified by chromatography (silica, ethyl acetate) to give 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzonitrile (310 mg, 52%) as a yellow oil. LC-MS: 396.2 [M+H]+, tR=1.89 min.
Reaction SMILES: CN1CCCC1=O.[C:8]([OH:12])(=[O:11])[CH2:9]O.C[N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.O>[O:11]=[C:8]([OH:12])[CH2:9][N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]
Reactant: CN(CCO)CCO
Reactant: O=C(O)CO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)CN(CCO)CCO
Temperature: 70 °C

Procedure:
In a 250 ml bottle equipped with a magnetic stirrer, heating mantel, temperature controller, and dry nitrogen purge, was added DESMODUR™ N-3300 (N3300) (13.19 g, 0.020 mole, 0.068 equivalent), FBSEE (1.885 g, 0.00487 mole, 0.00974 equivalent), bicine (HOCH2CH2)2NCH2COOH) (0.815 g, 0.0050 mole, 0.010 equivalent —OH, 0.0050 equivalent —COOH), 4 drops of dibutyltin dilaurate, and 30 g N-methylpyrrolidone. The resulting mixture was stirred and heated at 70° C. for one hour, followed by addition of MeFBSE (9.996 g, 0.028 mole, 0.028 equivalent), and glycolic acid (1.368 g, 0.018 mole, 0.018 equivalent). The resulting reaction mixture was heated for another hour at 70° C., followed by addition of APTMS (0.442 g, 0.0025 mole, 0.0025 equivalent) and heated with stirring at 70° C. for an additional two hours. A 5 g portion of the resulting unneutralized chemical composition was taken for GPC analysis, and the remaining composition was cooled to 60° C. and then neutralized by adding to the composition an amount of methyldiethanolamine equivalent to the number of equivalents of carboxylic acid groups present. After 10 minutes at 60° C. the mixture was cooled and a portion of the resulting neutralized chemical composition was diluted with water to form an aqueous solution containing 3% by weight of the chemical composition. The 3% aqueous solution was evaluated for performance using Test Method I, and the results are shown in Table 3. The GPC analysis, conducted according to Test Method III, showed that the unneutralized chemical composition was comprised of components having a weight average molecular weight (Mw) of 22,183, a number average molecular weight (Mn) of 4,553, and a polydispersity (Mw/Mn) of 4.872. thus indicating the presence of both high and low molecular weight components.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:28](Br)[CH:29]=[CH2:30]>C1COCC1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:6][C:7](=[O:16])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[CH2:30][CH:29]=[CH2:28])[CH3:2]
Reactant: CCOC(=O)CNC(=O)c1ccc(OC)cc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(NC(=O)c1ccc(OC)cc1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of 11.7 g of (4-methoxy-benzoylamino)-acetic acid ethyl ester (49.6 mmol) in 250 ml of abs. THF was cooled down to −78° and treated with 2.1 eq. of lithium hexamethyldisilazide (104 ml 1M[hexane]). After stirring for 30 min., 1.1 eq. of allyl bromide (4.62 ml) was added neat via syringe and the reaction mixture kept for 15 min. at −78° and for 30 min. at 0°. Pouring onto crashed ice, twofold extraction with AcOEt, twice washing with water, drying over natrium sulfate and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15) afforded 10.56 g of the title compound as off-white solid of mp. 76-78°, besides of 2.74 g of dialkylated product as yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH2:13][CH3:14])[C:7](=[O:15])[CH:6]([C:16]([O:18][CH3:19])=[O:17])[C:5]2=[O:20].[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C.O1CCOCC1>[CH2:13]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:21][C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:11][C:10]=2[CH3:12])[C:5](=[O:20])[CH:6]([C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:15])[CH3:14]
Reactant: CCN1C(=O)C(C(=O)OC)C(=O)c2cc(Br)cc(C)c21
Reactant: Cc1cccnc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: CCN1C(=O)C(C(=O)OC)C(=O)c2cc(Nc3ncccc3C)cc(C)c21
Temperature: 80 °C

Procedure:
100 mg of methyl 6-bromo-1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolone-3-carboxylate were transferred together with 40 mg of 2-amino-3-methylpyridine, 20 mg of Pd(OAc)2, 60 mg of XANTPHOS and 250 mg of cesium carbonate into a suitable reaction vessel, a protective gas atmosphere was generated with argon, and 10 ml of dioxane were added. The mixture was then heated at 80° C. for 8 h. The pure product was isolated from the reaction solution by chromatography on an HPLC system. This entailed use of a Merck Purospher RP-18 column and an acetonitrile:water mixture as eluent; the initial acetonitrile content was 15% and rose to 95% over the course of 20 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([Cl:15])=[CH:10][C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:28]1[N:33]=[C:32]([S:34][C:35]#[N:36])[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][N:29]=1.O>O1CCCC1>[Cl:15][C:11]1[C:12]([NH:14][C:28]2[N:33]=[C:32]([S:34][C:35]#[N:36])[C:31]([N+:37]([O-:39])=[O:38])=[CH:30][N:29]=2)=[CH:13][C:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[C:9]([F:16])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N)c(Cl)cc1F
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cc(Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl(5-amino-4-chloro-2-fluorophenyl)carbamate (5.17 g, 19.8 mmol) in tetrahydrofuran (10 mL) were added N-ethyl-N-isopropylpropane-2-amine (6.93 mL, 39.6 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (6.44 g, 29.7 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (300 mL, 50 mL). The combined organic layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {4-chloro-2-fluoro-5-[(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[NH:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:16]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>O.CC(C)=O>[C:16]([NH:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:10]2[CH2:11][CH2:12][N:8]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[C:9]2=[NH:13])(=[O:32])=[O:31])=[CH:28][CH:29]=1)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]
Reactant: C/C=C/C(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: N=C1NCCN1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C/C=C/C(=O)NCCc1ccc(S(=O)(=O)N2CCN(C3CCCCC3)C2=N)cc1

Procedure:
20.4 g of 1-cyclohexyl-2-imino-imidazolidine hydrochloride are added to 8.5 g of sodium hydroxide in 85 ml of water. There is added to the resulting solution 28.8 g of 4-(2-crotonylaminoethyl)-benzenesulphonyl chloride dissolved in 100 ml of acetone, the reaction mixture becoming warm. It is heated at 90° for half an hour and then concentrated by evaporation under reduced pressure. The residue is recrystallised from ethyl acetate, and 1-{4-[2-(crotonylamino)-ethyl]-phenylsulphonyl}-3-cyclohexyl-2-imino-imidazolidine (trans) which melts at 157° to 158° is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[CH:26]([O:29][C:30]1[C:31](=O)[C:32](=[O:38])[C:33]=1[O:34]C(C)C)([CH3:28])[CH3:27].C(N(CC)CC)C>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:31]4[C:32](=[O:38])[C:33](=[O:34])[C:30]=4[O:29][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]3)=[O:17])=[CH:24][CH:25]=2)=[N:2]1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Oc1c(N2CCN(C(=O)c3ccc(/C=C/c4n[nH]c5ccccc45)cc3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 79.9 %

Procedure:
(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine (1.0 g, 2.5 mmol) obtained in Example 18 was dissolved in methanol (9.9 mL), and the solution was added with 3,4-diisopropoxy-3-cyclobutene-1,2-dione (0.69 g, 3.5 mmol) and triethylamine (0.69 mL, 4.9 mmol), followed by stirring at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was added with ethanol, followed by stirring. The deposited crystal was collected by filtration to obtain (E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione (0.94 g, 81%).
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C@H:7]([CH2:13][P:14]([C:18]#[C:19][C:20]1[C:21]([CH:37]([CH3:39])[CH3:38])=[N:22][C:23]2[C:28]([C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)([O:16][CH3:17])=[O:15])[CH2:8][C:9]([O:11][CH3:12])=[O:10])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)=O.[N+](=C)=[N-]>C1COCC1.CCOCC.CO>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH:37]([CH3:39])[CH3:38])[C:20]=2[C:19]#[C:18][P:14]([O:16][CH3:17])([CH2:13][C@@H:7]([OH:6])[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:15])=[CH:35][CH:34]=1
Reactant: COC(=O)C[C@@H](CP(=O)(C#Cc1c(C(C)C)nc2ccccc2c1-c1ccc(F)cc1)OC)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(C(C)C)nc2ccccc2c1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
A mixture of (S)-3-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[[4-(4-fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]methoxyphosphinyl]butanoic acid, methyl ester (1.041 gm, 1.44 mmol), tetra-n-butylammonium fluoride (1.0M in THF, 5.7 ml, 5.7 mmol), and HOAc (525 mg, 8.73 mmol) in THF (14 ml) was stirred at room temperature for 18 hours. The solution was partitioned between 5% KHSO4 and EtOAc. The layers were shaken and separated and the EtOAc layer was washed again with 5% KHSO4. The pooled aqueous washings were back-extracted twice with EtOAc. The combined EtOAc layers were washed with brine and dried (Na2SO4). Filtration and removal the solvent afforded an oil. The oil was dissolved in cold (0° C.) 1:1 Et2O:MeOH and treated with excess diazomethane for 30 minutes. The excess diazomethane was destroyed by the addition of HOAc and the solvent was removed in vacuo. The residue was chromatographed (flash, Merck SiO2, 40% acetone in hexane followed by 1:1 actone:hexane) to afford (S)-4-[[[4-(4-Fluorophenyl)-2-(1-methylethyl)-3-quinolinyl]ethynyl]-methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester (612 mg, 91%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[CH2:20](Br)[CH:21]=[CH2:22]>>[CH2:22]([N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:18]([Cl:19])=[CH:17][C:5]=2[N:6]=[C:7]1[C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=1)[CH:21]=[CH2:20]
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Reactant: C=CCBr
Product: C=CCn1c(-c2ccc(C=O)cc2)nc2cc(Cl)c(Cl)cc21

Procedure:
1-Allyl-5,6-dichloro2-(4-formylphenyl)benzimidazole was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and allylbromide by following General Procedure 3.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][C:6](=[O:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[CH3:13][CH:14]([CH2:16][CH2:17][CH:18](O)[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:15].C(OCC)=O.C([Mg]Br)CC(C)C.Cl.[NH2:38][OH:39].[OH-].[K+].Cl>C(O)C.O>[CH3:3][CH:2]([CH2:4][CH2:5][CH:6]([OH:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:1].[CH3:13][CH:14]([CH2:16][CH2:17][C:18](=[N:38][OH:39])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:15]
Reactant: NO
Reactant: CC(C)CCC(=O)CCC(C)C
Agent: CC(C)CCC(O)CCC(C)C
Agent: CC(C)CC[Mg]Br
Agent: Cl
Solvent: O
Solvent: CCOC=O
Solvent: CCO
Product: CC(C)CCC(CCC(C)C)=NO
Temperature: 0 °C

Procedure:
To a solution of 5.11 g of 2,8-dimethylnonan-5-one (b.p.: 103°-105° C./19 mmHg, prepared by oxidizing 2,8-dimethylnonan-5-ol with a bleaching powder; 2,8-dimethylnonan-5-ol was prepared by reaction of ethyl formate and isoamylmagnesium bromide) in 20 ml of ethanol were successively added an aqueous solution of 3.47 of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water. The mixture was heated under reflux. The reaction mixture was then poured into 150 ml of ice-containing water. The aqueous mixture was made acidic by addition of 2N hydrochloric acid and extracted with benzene. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. There was obtained 5.21 g of 2,8-dimethylnonan-5-one oxime as a pale brown oil, yield: 93.7%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:26]2[C:17](=[C:18]3[C:23](=[CH:24][C:25]=2[N+:29]([O-])=O)[CH:22]=[CH:21][C:20]([CH2:32][N:33]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:19]3)[N:16]=1)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].C([O-])=O.[NH4+]>O1CCCC1.C(O)C.O.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]2[C:18]([N:19]=[C:20]([CH2:32][N:33]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:21]=[CH:22]2)=[C:17]2[C:26]=1[CH:27]=[CH:28][C:15]([CH2:14][N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:16]2
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1ccc2cc([N+](=O)[O-])c3ccc(CN(CC(=O)OCC)CC(=O)OCC)nc3c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CN(CC(=O)OCC)Cc1ccc2cc(N)c3ccc(CN(CC(=O)OCC)CC(=O)OCC)nc3c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,9-Bis[N,N-di(ethoxycarbonylmethyl)aminomethyl]-5-nitro-1,10-phenanthroline (3.37 g, 5.4 mmol) was dissolved in a solution of 100 mL tetrahydrofuran and 200 mL absolute ethanol. A solution of 6.8 g (108 mmol) of ammonium formate in 22 mL of distilled H2O was added, followed by 5.72 g of palladium on carbon (10%) (50% wet with water for safety). The reaction was stoppered with a gas bubbler, stirred at room temperature for 30 minutes, and then filtered through a diatomaceous earth filter pad. The solvents were then removed on a rotary evaporator. The residue was dissolved in 300 mL of dichloromethane which was then extracted with 300 mL of distilled water. The organic phase was extracted with 300 mL of saturated sodium chloride, dried with a mixture of Celite diatomaceous earth and sodium sulfate, filtered, and then concentrated under high vacuum to a dark amber oil which weighed 2.90 g. The oil was treated with 9.0 mL of propionitrile to induce the crystallization of a yellow solid. The solid was filtered, washed with 13 mL of propionitrile, 15 mL of hexanes, and then air dried to a constant weight of 1.04 g (32%); mp 137°-139° C. FDMS (m/e) 598 MH+, 597 M. Anal. calcd. for C30H39N5O9.H2O: C, 58.52; H, 6.71; N, 11.38. Found: C, 58.28; H, 6.55; N, 11.53. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[CH:9][CH:8]=[C:7]([S:20]([N:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:22])=[O:21])[CH:6]=2.[C:38]([Zn]C#N)#[N:39]>[Zn].C([Pt](CCCC)CCCC)CCC.[Pd]>[C:38]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[CH:9][CH:8]=[C:7]([S:20]([N:23]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:21])=[O:22])[CH:6]=2)#[N:39]
Reactant: N#C[Zn]C#N
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)c(Br)cnc3c2)cc1
Agent: CCCC[Pt](CCCC)CCCC
Agent: [Pd]
Agent: [Zn]
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)c(C#N)cnc3c2)cc1
Temperature: 25 °C

Procedure:
A vial was charged with 3-bromo-N-(4-methoxybenzyl)-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (64.6 mg, 0.108 mmol), dicyanozinc (63.6 mg, 0.541 mmol), a spatula tip of zinc dust, and palladium compound with tributylplatinum (1:2) (18.18 mg, 0.022 mmol). The vial was flushed with Ar (g), then DMAC (1 mL) was added. The vial was sealed and placed in a 100° C. heating bath for 4 h. The mixture was cooled to room temperature, and then diluted with water and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 20-70% EtOAc/Heptane) to give 3-cyano-N-(4-methoxybenzyl)-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide an off-white solid. m/z (ESI) 543.0 (M+H)+.