Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH2:66])[CH:61]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:61]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)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: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 83% yield: LCMS (ESI) m/z 432 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([OH:9])[CH:3]=1.[Se](=O)=[O:11]>COCCOCCOC>[CH:1]([C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([OH:9])[CH:3]=1)=[O:11]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: O=[Se]=O
Solvent: COCCOCCOC
Product: O=Cc1cc(O)cc(=O)o1

Procedure:
6-Methyl-4-hydroxypyran-2-one may be oxidised with selenium dioxide in boiling diglyme to give 6-formyl-4-hydroxypyran-2-one;
Reaction SMILES: [I:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[O:8][C:9](=O)[C:4]=2[CH:3]=1.O.[NH3:18]>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[N:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:18][C:9]2=[O:8]
Reactant: O=c1oc(C(F)(F)F)nc2ccc(I)cc12
Reactant: N
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)nc2ccc(I)cc12
Temperature: 0 °C

Procedure:
6-iodo-2-trifluoromethyl-benzo[d][1,3] oxazin-4-one (0.6 g, 1.76 mmole) was stirred with 25 mL of concentrated ammonia water at 40° C. for 5 h, cooled to 0° C., the precipitate was filtered and dried under vacuo. The product was recrystallized from ethyl acetate and haxanes to give 0.58 g, mp >255° C. (sub), MS (CI): m/z 341 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:35])[CH:15]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C(C)=O)c1
Solvent: Cc1ccccc1
Product: COC(=O)C=C(C)c1cccc(OC)c1
Temperature: 25 °C

Procedure:
1-(3-Methoxyphenyl)ethanone (15 g, 0.1 mmol) and methyl(triphenylphosphoranylidene)acetate (62 g, 0.186 mmol) in toluene (75 ml) were heated at 100° C. for 2 days. After allowing cooling to ambient temperature the solvent was removed under reduced pressure to give crude product. Precipitation with EtOAc and heptane followed by flash chromatography of the concentrated mother liquor on silica (eluent: 20% EtOAc in heptane) afforded the product as a mixture of geometric isomers (21.8 g, 86%).
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.C(N(CC)CC)C.[F:19][C:20]([F:60])([F:59])[C:21]1[CH:22]=[C:23]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[CH2:24][N:25]1[C:29]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:28]([C:36]([C:38]2[C:39]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])=[N:40][O:41][C:42]=2[CH2:43]O)=[O:37])[N:27]=[N:26]1>ClCCl.C1COCC1>[F:56][C:55]([F:58])([F:57])[C:53]1[CH:52]=[C:23]([CH:22]=[C:21]([C:20]([F:59])([F:60])[F:19])[CH:54]=1)[CH2:24][N:25]1[C:29]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:28]([C:36]([C:38]2[C:39]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])=[N:40][O:41][C:42]=2[CH2:43][Cl:10])=[O:37])[N:27]=[N:26]1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Add N,N-dimethylaminopyridine (119 mg, 0.974 mmol), p-toluenesulfonyl chloride (465 mg, 2.44 mmol) and triethylamine into an ice-cold solution of [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chlorophenyl)-5-hydroxymethyl-isoxazol-4-yl]-methanone (1.0 g, 1.62 mmol) in dichloromethane (5.0 mL) and THF (5.0 mL). Warm the mixture to RT. After 1 h., concentrate in vacuo. Dilute the mixture with dichloromethane (50 mL) and wash with water (3×40 mL). Dry (MgSO4), filter, and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to provide the title compound (59% yield) as a brown oil. MS (ES) 634.1 (M++1); TLC Rf=0.5 (50% EtOAc in hexanes).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl.C([O-])([O-])=O.[Na+].[Na+].[CH3:21][NH:22][CH2:23][CH2:24][NH2:25]>C(O)CCC.O>[CH3:21][N:22]1[C:5]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:14])[NH:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CNCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CN1CCNC(=O)c2cccc([N+](=O)[O-])c21
Temperature: 80 °C
Yield: 22.2 %

Procedure:
2-Chloro-3-nitro-benzoic acid methyl ester (500 mg, 2.32 mmol) was dissolved in n-butanol (2.5 ml). Na2CO3 (246 mg, 2.32 mmol) was added followed by N, methylethylenediamine (204 μL, 2.32 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled and diluted with water (50 ml). The resulting mixture was extracted with EtOAc (3×50 mL), dried over MgSO4, and concentrated. Silica gel chromatography (0-100% EtOAc in hexanes) afforded 1-Methyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a bright orange solid (114 mg, 24%). Cmp 183-184° C.; LCMS: m/z=222.25 (M+H+) 1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 1H), 8.32 (dd, J=8.4 Hz, 1.8 Hz, 1H), 8.15 (dd, J=7.8 Hz, 1.5 Hz, 1H), 6.78 (t, J=8.3 Hz, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.20 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1.[C:17](O)(=[O:19])[CH3:18]>C(OC(=O)C)(=O)C>[C:17]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:15][CH:16]=1)(=[O:19])[CH3:18]
Reactant: NCc1ccc(OCCn2ccnc2)cc1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCc1ccc(OCCn2ccnc2)cc1

Procedure:
1-[2-(4-Aminomethylphenoxy)ethyl]imidazole (1.1 g) was heated on a steam bath for 2 hours in a mixture of acetic acid (10 ml) and acetic anhydride (1 ml). The solution was then evaporated and the residue was dissolved in a small volume of water. The solution was made basic with sodium bicarbonate and the resulting solid was filtered off, washed with water and crystallised from water to give 1-[2-(4-acetylaminomethylphenoxy)ethyl]imidazole (0.70 g), m.p. 115°-166° C. Found: C, 60.45; H, 6.72; N, 15.35. C14H17N3O2.H2O requires: C, 60.63; H, 6.91; N, 15.15%.
Reaction SMILES: B.[C:2]1([CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])C(O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:22]1CCC[CH2:23]1>O>[C:2]1([CH2:8][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][OH:22])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCC(C(=O)O)c1ccccc1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Solvent: O
Product: OCCCCCCCCCCCc1ccccc1
Reaction time: 5.5 h

Procedure:
To 200 ml. of 1M borane in tetrahydrofuran, cooled in an ice bath under nitrogen, is added dropwise over 35 minutes, a solution of 52.5 g. of phenylundecanoic acid in 150 ml. of tetrahydrofuran. The solution is allowed to stand at room temperature for 5.5 hours and poured onto ice. To the mixture is added 8 ml. of concentrated hydrochloric acid and the mixture is diluted with water to 2.2 liters. The mixture is extracted with ether (ca 500 ml.) and the extracts dried over magnesium sulfate. Concentration in vacuo gives a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1[CH:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]([CH2:20][C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: Cc1cc(CCl)on1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN(C(=O)CCl)c2c(C)cccc2C)on1
Yield: 30 %

Procedure:
A mixture of 4.54 g N-chloroacetyl-2,6-dimethylaniline and 3 g 3-methyl-5-chloromethylisoxazole (prepared as in Example 8 above) in 100 ml dry dimethylformamide was treated with 1.33 g sodium hydride as in Example 3 above. After workup, the solid product was purified by column and high-pressure liquid chromatography to yield 2.0 g pure product, m.p. 78°-82° C. This product is shown as Compound 1 in Table I. C15H17ClN2O2 : calc., %C 61.54, %H 5.81, %N 9.57; found, %C, 63.37, %H 6.16, %N 9.65.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10]O)=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14]CCl.C(N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C.O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][Cl:14])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(CO)cc(OC)c1Br
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(CCl)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of (4-bromo-3,5-dimethoxyphenyl)methanol (10.0 g, 40.6 mmol) and dichloromethane (100 mL) were added triethylamine (12.4 mL, 89.3 mmol) and methanesulfonyl chloride (3.46 mL, 44.7 mmol) in that order while cooling on ice, and the mixture was stirred at room temperature for 14 hours. Water was added to the mixture, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=4/1) to obtain the title compound (2.47 g, 9.30 mmol).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([NH2:12])=[CH:7][N:6]=1>CO.CCOC(C)=O>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([NH2:12])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: Nc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nc(Cl)ncc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
Sodium methoxide (0.5M in methanol, 3.7 mL, 1.829 mmol) was added to a solution of 2,4-dichloropyrimidin-5-amine (0.2 g, 1.220 mmol) in MeOH (2.5 mL). The reaction was stirred at room temperature for 1.5 hours. The reaction was then diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title product as a brown solid (177 mg, 91%). 1H NMR (500 MHz, CDCl3): δ 3.93 (s, 3H), 5.31 (br s, 2H), 7.73 (s, 1H). LC (Method B)-MS (ESI, m/z) tR 1.6 min, 160 [M+H]+
Reaction SMILES: FC(S(O[C:9]1[C:17]2[CH:16]=[CH:15][O:14][C:13]=2[C:12]([C:18]2[C:19](=[O:35])[N:20]([CH3:34])[C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:11][CH:10]=1)(=O)=O)(F)F.[C:36](=[NH:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)C>[C:36](=[N:49][C:9]1[C:17]2[CH:16]=[CH:15][O:14][C:13]=2[C:12]([C:18]2[C:19](=[O:35])[N:20]([CH3:34])[C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:11][CH:10]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2ccc(OS(=O)(=O)C(F)(F)F)c3ccoc23)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2ccc(N=C(c3ccccc3)c3ccccc3)c3ccoc23)C1=O
Temperature: 25 °C

Procedure:
Heat a mixture of 7-[1-methyl-4-(1-methylindol-3-yl)-2,5-dioxo-3-pyrrolin-3-yl]benzo[b]fur-4-yl (trifluoromethyl)sulfonate (100 mg, 0.2 mmol), benzophenone imine (0.037 ml, 0.22 mmol), tris-(benzylideneacetone)-dipalladium(0)(9 mg, 0.01 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.03 mmol), and cesium carbonate (91 mg, 0.28 mmol) in anhydrous toluene (1 ml) to 80° C. for 19 hours under a nitrogen atmosphere. Allow the reaction to cool to room temperature, dilute with diethyl ether, and filter through Celite. Wash the filtrate with water, brine, dry over magnesium sulfate, filter and concentrate. Flash chromatography over silica gel (ethyl acetate: hexanes) affords the title compound as a red oil. MS(ES+): 536.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:17][CH2:16][N:15]([CH3:21])[C:14]3=[O:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1NCCN1c1nc(-c2ccc(Br)cc2)cs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3ccc(Br)cc3)cs2)C1=O
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
1-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]imidazolidin-2-one (0.155 g, 0.480 mmol), prepared in step 2 of Example 4, was dissolved in 2.4 mL of anhydrous tetrahydrofuran and sodium hydride (60% suspension in mineral oil, 20 mg, 0.53 mmol) was added. The mixture was stirred for 20 min and then methyl iodide (0.03 mL, 0.48 mmol) was added and stirring was continued for 4 h. The reaction was quenched with saturated aqueous NH4Cl and diluted with ethyl acetate. The mixture was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (20% acetone/hexane) afforded the title compound (146 mg, 90%) as a white solid. HRMS: calcd for C13H12BrN3OS+H+, 337.99572; found (ESI, [M+H]+), 337.9954. Analytical HPLC: retention time 10.1 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40 C 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([CH:8]=[O:9])=[N:5][C:4]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].Cl([O-])=[O:15].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[CH2:1]([C:3]1[NH:7][C:6]([C:8]([OH:15])=[O:9])=[N:5][C:4]=1[C:10]([F:12])([F:13])[F:11])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCc1[nH]c(C=O)nc1C(F)(F)F
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Yield: 99 %

Procedure:
The same operation as in Example (33c) was performed using 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carbaldehyde obtained in Example (39d) (110 mg, 0.57 mmol), sodium chlorite (108 mg, 1.19 mmol), sodium dihydrogenphosphate (178 mg, 1.14 mmol) and 2-methyl-2-butene (0.3 mL, 2.84 mmol), to obtain 117.5 mg of the title compound as a white solid (99%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[N:32]1([CH2:31][CH2:30][CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCN2CCOCC2)C3)nc1
Temperature: 90 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 4-(3-chloropropyl)morpholine (0.191 g, 1.16 mmol) in DMF (5.3 mL). Heat at 90° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 10% (2.0 M NH) in methanol) in acetone to give the title compound: MS ES+ 411.2 (M+H)+, HRMS calcd for C23H31N4O3 411.2396 (M+H)+, found 411.2389 time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=5.7 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[F:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[NH:32][C:31]=2[CH:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([CH:35]3[CH2:36][CH2:37][N:38]([CH2:20][C:19]4[CH:22]=[CH:23][C:16]([C:7]5[C:8]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)=[CH:9][N:4]6[N:3]=[C:2]([CH3:1])[N:24]=[C:5]6[N:6]=5)=[CH:17][CH:18]=4)[CH2:39][CH2:40]3)[NH:32][C:31]=2[CH:41]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: Fc1ccc2nc(C3CCNCC3)[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5nc6ccc(F)cc6[nH]5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
200 mg (0.64 mmol)-4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 184 mg (0.76 mmol) 6-fluoro-2-piperidine-4-yl-1H-benzimidazole hydrochloride salt were treated as described in example 2.0. Additional NaBH(OAc)3 has been added after 24 and 26 hours (two equivalents each). After stirring at room temperature for five days and the usual workup und purification 142 mg of the desired compound have been obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:30][CH2:31][CH3:32])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:30][CH2:31][CH3:32])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCOCCCCCCC)[C@@](O)(CCC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCOCCCCCCC)[C@@](O)(CCC)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptyloxy-2-hydroxy-2-propyl-undec-4-enoate (No. 6804256; 65.6 mg, 0.0956 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at room temperature for 5.0 hours. The solvent was distilled off under reduced pressure. To the residue was added dichloromethane, and the solvent was again distilled off under reduced pressure. This operation was repeated twice. The residue was then purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptyloxy-2-hydroxy-2-propyl-undec-4-enoic acid (No. 5500523; 19.3 mg, 32% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][C:29]([NH2:32])=[N:30][OH:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](O)=O.ClC(Cl)(Cl)C(Cl)=O.[OH-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][C:29]3[N:32]=[C:36]([C:35]([Cl:40])([Cl:39])[Cl:34])[O:31][N:30]=3)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CC(N)=NO)c1Cl
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(Cc2noc(C(Cl)(Cl)Cl)n2)c1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
N-(5-Chloropyridin-2-yl)-2-[((4-(2-amino-2-(hydroxyimino)ethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (3.06 g, 5.8 mmol) was dissolved in trichloroacetic acid (3.8 g, 23 mmol) and the mixture heated to 85° C. Trichloroacetyl chloride (1.3 mL, 11.6 mmol) was added, and the temperature was increased to 94° C. After one hour the reaction mixture was allowed to cool to room temperature, diluted with water (150 mL) and a small amount of ethyl acetate, and adjusted to basic pH with 1 N NaOH. The aqueous layer was extracted with ethyl acetate (300 mL). The organic phase was washed with 1 M sodium bicarbonate (150 mL), dried over magnesium sulfate, concentrated in vacuo, and dried under vacuum. The crude product was purified by flash chromatography on silica gel eluting with 25% ethyl acetate/hexanes to afford N-(5-chloropyridin-2-yl)-2-[((4-((5-trichloromethyl-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30]Cl.[Cl-].C([NH+](C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.[OH-].[Na+]>O.C(Cl)Cl>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][N:11]([C:6]1[C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=[CH:8][N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CN(C)CCCCl
Reactant: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Agent: CCCCCCCC(=O)[NH+](C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
A mixture of 3.6 g (0.01 mole) of [2-[(3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone hydrochloride, 4.7 g (0.03 mole) of 3-dimethylaminopropyl chloride, 0.1 g of tricaprylyl ammonium chloride, 16 g (0.20 moles) of 50% aqueous sodium hydroxide, 25 ml methylene chloride, and 5 ml water was refluxed for 27 hrs. Chemical ionization mass spectroscopy analysis indicated the product was mainly the title compound. The mixture was cooled and diluted with methylenechloride-water mixture. The aqueous layer was extracted twice with methylene chloride. The combined methylene chloride layers were washed with aqueous sodium chloride solution, dried, treated with charcoal, filtered and evaporated to give 3.3 g black material (81.5%) which was predominantly the title compound as indicated by thin-layer chromatography and chemical ionization mass spectroscopy analysis of the chromatographed material, i.e. m/e=405.