Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6].[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:11][CH2:12][CH2:13][O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=CCCOCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
0.27 g (55%, 6.2 mmol) of sodium hydride was added to a solution of glycerol 0.57 g (6.2 mmol) in dry N,N-dimethylformamide (6 mL) with cooling on ice. After the mixture was stirred for 30 min at 50° C., the above (4,8,12-trimethyltridec-3-enyl)tosylate was added dropwise, with additional stirring for 10 hours at the same temperature. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 79 mg of the title compound (6% yield in 2 steps). The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+].C(OCC)C>CN(C)C=O>[CH3:18][S:15]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][S:21][C:19](=[O:22])[CH3:20])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)SCc1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Yield: 98.6 %

Procedure:
A solution of 4′-bromomethyl-3-methylsulfonylbiphenyl (190 mg, 0.57 mmol) (WO 01/70753) and potassium thioacetate (78 mg, 0.68 mmol) in N,N-dimethylformamide (4 mL) was heated at 150° C. in a microwave for 3 min. The reaction mixture was poured into diethyl ether (30 mL) and washed with water (3×15 mL), brine (15 mL), dried with magnesium sulfate, filtered, and concentrated to give a crude yellow oil. The crude oil was purified by flash column chromatography to yield 1.35-A (180 mg, 89%) as a thick light yellow oil. LCMS found for C16H17O3S2 (M+H)+: m/z=321.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[C:7]([C:14]([F:17])([F:16])[F:15])=[N:6]2.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:8]1[C:7]([C:14]([F:17])([F:16])[F:15])=[N:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2[nH]c(=O)c(C(F)(F)F)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 6-methoxy-3-(trifluoromethyl)quinoxalin-2(1H)-one (500 mg, 2.05 mmol) and POCl3 (4 mL) was stirred under microwave at 140° C. for 2 hours. The reaction was quenched with aqueous saturated NaHCO3 (50 mL) and extracted with EtOAc (50 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to give Intermediate 11 (460 mg, yield 86%). 1H NMR (DMSO-d6 400 MHz): δ 8.10 (d, J=9.6 Hz, 1H), 7.76 (dd, J=9.2, 2.8 Hz, 1H), 7.68 (d, J=2.8 Hz, 1H), 4.01 (s, 3H).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=[C:35]([NH:48][CH3:49])[N:34]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:38]4[C:33]([O:32][CH3:31])=[N:34][C:35]([NH:48][CH3:49])=[N:36][CH:37]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: CNc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate AE) and [4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-methyl-amine (Intermediate V) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively to afford the title compound as a white solid. ESI-MS: tR=0.83 min, [M+H]+ 544/546 (LC-MS 1); TLC: Rf=0.38 (9:1 CH2Cl2/MeOH).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.BrCCC=C>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:21][O:20][C:18]([C:13]1([CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: COC(=O)C1CCCC1
Reactant: [Li]CCCC
Agent: C=CCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCCC1(C(=O)OC)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (10.5 mL, 75 mmol) in tetrahydrofuran (100 mL) pre-cooled to −75° C. was added a 2.5 M solution of n-butyllithium in hexanes (30 mL, 75 mmol) dropwise. Following addition, the reaction mixture was warmed to 0° C. for 30 min and then re-cooled to −75° C. To the mixture was added a solution of methyl cyclopentane carboxylate (8 g, 62 mmol) in tetrahydrofuran (40 mL) dropwise. After stirring for 30 min, a solution of 4-bromo-1-butene (8.2 mL, 81 mmol) in HMPA (6 mL) was added dropwise. The cooling bath was removed to allow the mixture to warm to 20° C. After 1.5 h, the reaction mixture was poured into ice/H2O (200 mL). The two layers were separated and the aqueous layer was extracted with Et2O (100 mL). The organic solutions were combined and dried over K2CO3, filtered and concentrated to afford the 12.1 g of the title compound as an oil. LC/MS: RT=3.57 min. MS (ESI) m/z=183 (M+H+)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH2:8])=[O:7])=[CH:2]1.C(Cl)(=O)[C:10](Cl)=[O:11]>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]=[C:10]=[O:11])=[O:7])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccoc1
Solvent: ClCCl
Product: O=C=NC(=O)c1ccoc1
Temperature: 25 °C

Procedure:
3-Furancarboxamide (167 mg) was suspended in dichloromethane (10 ml), followed by addition of oxalyl chloride (0.20 ml) under ice-cooling, and the temperature of the reaction mixture was raised to room temperature. The reaction mixture was refluxed for 10 hours and the solvent was distilled off to give crude 3-furoyl isocyanate. In the same manner as in Example 8, the above product was reacted with fumagillol (213 mg) with stirring at room temperature for 30 minutes. Purification by silica gel column chromatography (eluent: n-hexane-ethyl acetate=2:1) gave colorless, powdery O-[N-(3-furoyl)carbamoyl]fumagillol (120 mg) (38% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[CH3:26][N:27]([CH3:37])[C:28](=[O:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:26][N:27]([CH3:37])[C:28](=[O:36])[CH2:29][N:30]1[CH2:31][CH2:32][N:33]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[NH:17][S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH:4]=2)[CH2:34][CH2:35]1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: O=S(=O)(Nc1cccc2cc(-c3ncc(CCl)s3)[nH]c12)c1cccs1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.2 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.250 g) in N,N-dimethylformamide (6 ml) were added N,N-dimethyl-2-piperazin-1-ylacetamide (0.208 g) and triethylamine (0.17 ml), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and recrystallized from ethyl acetate-hexane to give the title compound (0.230 g, yield 69%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[Cl:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[Cl:13]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-3-[2-chloro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:13].[N:21]1([CH2:27][CH2:28][CH2:29][OH:30])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>O1CCOCC1>[NH2:3][C:4]1[CH:9]=[C:8]([O:30][CH2:29][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:7]([F:11])=[CH:6][C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:13]
Reactant: OCCCN1CCOCC1
Reactant: Nc1cc(F)c(F)cc1C(=O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1cc(OCCCN2CCOCC2)c(F)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
A mixture of 1.4 g (0.035 mole) of 60% sodium hydride, 25 mL of dioxane, 2.68 g (0.01 mole) of (2-amino-4,5-difluorophenyl)-(2-chlorophenyl)-methanone (Xmm) and 2.23 g (0.016 mole) of 4-morpholinepropanol was stirred at room temperature for 4 hours. The mixture was quenched by the addition of 50 mL of water. The mixture was extracted with ethyl acetate, and the extract washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane and then recrystallized from hexane-ethyl acetate to give 2.55 g of (2-amino-5-fluoro-4-(3-(4-morpholinyl)propoxy)phenyl)-(2-chlorophenyl)-methanone (Xi). MH+/Z=393.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([F:29])[C:10]3[N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]4[C:17]([S:18][C:19]=3[CH:20]=2)=[CH:16][C:15](Br)=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:82]1[CH2:86][CH2:85][CH2:84][CH2:83]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([F:29])[C:10]3[N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]4[C:17]([S:18][C:19]=3[CH:20]=2)=[CH:16][C:15]([N:82]2[CH2:86][CH2:85][CH2:84][CH2:83]2)=[CH:14][CH:13]=4)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(N3CCOCC3)cc(F)c21
Reactant: C1CCNC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)N1c2ccc(N3CCCC3)cc2Sc2cc(N3CCOCC3)cc(F)c21

Procedure:
To a stirred solution of 3-morpholino-1-fluoro-7-bromo-10-Boc-phenothiazine (150 mg, 0.3 mmol) in touene (10 mL) Pd(dba)2 (5.8 mg, 0.01 mmol), BINAP (6.3 mg, 0.01 mmol), Cs2CO3 (326 mg, 1.0 mmol) and pyrrolidine (42.6 mg, 0.6 mmol) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: N(C1C=CC(C[CH:9]2[CH2:20][N:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][N:16]([CH2:25][C:26]([OH:28])=[O:27])[CH2:15][CH2:14][N:13]([CH2:29][C:30]([OH:32])=[O:31])[CH2:12][CH2:11][N:10]2[CH2:33][C:34]([OH:36])=[O:35])=CC=1)=C=S.[N-]=C=S>>[CH2:9]1[N:10]([CH2:33][C:34]([OH:36])=[O:35])[CH2:11][CH2:12][N:13]([CH2:29][C:30]([OH:32])=[O:31])[CH2:14][CH2:15][N:16]([CH2:25][C:26]([OH:28])=[O:27])[CH2:17][CH2:18][N:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:20]1
Reactant: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)C(Cc2ccc(N=C=S)cc2)CN(CC(=O)O)CC1
Agent: [N-]=C=S
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1

Procedure:
QFP-phage and control insertless phage were amplified to a high titer for labeling with 64Cu radionuclide via the macrocyclic bifunctional chelator 2-(4-isothiocyanato benzyl)-1,4,7,10 tetraazacyclo dodecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA) (Macrocyclics, Dallas, Tex.). The isothiocyanate functionality of the p-SCN-Bn-DOTA reacts with primary amino groups on the phage coat protein pVIII to produce a covalent attachment of DOTA to the phage surface (Jakubowski et al. (2008) J Anal At Spectrom 23(5):1497-1507). To carry out this functionalization procedure, phage (1×1011 pfu) were re-suspended in 400 μl conjugation buffer (carbonate-bicarbonate buffer, pH=9) and 4 μl p-SCN-Bn-DOTA (100 mM stock) were added. The conjugation reaction was conducted overnight at 35° C. DOTA-phage intermediate was separated from the unreacted DOTA through a 50K microcone filter by centrifugation at 14000 g for 10 minutes. DOTA-phage conjugates were re-suspended in 400 μl 10.1M sodium acetate buffer (pH=5.5) and incubated with 64CuCl2 (2 mCi per reaction, decay corrected) for 50 minutes at 50° C. Unbound 64Cu2+ was removed by ultracentrifugation as described above. 64Cu labeled phage were reconstituted in sterile PBS. Activity was determined using a γ-counter (Packard) immediately before injecting into mice. Complexes of DOTA-phage with cold CuCl2 were prepared to test phage infectivity and target binding upon labeling.
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10](Cl)=[O:11])[CH:5]=1.CC(OC)(C)C>CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:1])=[O:11])[CH:5]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aqueous NH4OH (40%, 250 mL) was added dropwise at 0° C. to a suspension of 4-chloro-pyridine-2-carbonyl chloride (75 g, 533 mmol) in EtOAc. Upon addition, the temperature rose to 30° C. The mixture was stirred for 2 h at RT then kept at RT for 12 h without stirring. MTBE (250 mL) was added to the mixture and the resulting emulsion was filtered. The solid was washed with EtOAc. The MTBE/EtOAc layer was washed twice with water and once with 5% Na2CO3, then dried over MgSO4 and concentrated under vacuum. The resulting solid was suspended in EtOAc several times and filtered out to give the desired compound.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9](O)=[O:10])=[O:6].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9]([Cl:17])=[O:10])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CNC(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CNC(=O)OCC(Cl)(Cl)Cl

Procedure:
N-(2,2,2-Trichloroethyloxycarbonyl)-glycine (0.75 g, 3 mMol) is suspended in CH2Cl2 (30 ml) and the mixture is stirred under N2 with ice-bath cooling. Oxalyl chloride (0.28 ml, 3.3 mMol) and DMF (0.023 ml, 0.3 mMol) are added thereto, and the mixture is stirred for 1 hour in the cold. The resulting solution is washed with ice-cold water and ice-cold brine, dried briefly over Na2SO4, and filtered. This solution of N-(2,2,2-trichloroethyloxycarbonyl)glycyl chloride is used immediately in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:35]([C:34]1[CH:37]=[CH:38][C:31]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:32][CH:33]=1)=[O:36]
Reactant: N#Cc1cccc(CO)c1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(COc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 3-(Hydroxymethyl)benzonitrile (1.1 equiv), triphenylphosphine (1.1 equiv), and 4-Hydroxybenzaldehyde (1 equiv) in dry THF was added dropwise Diethyl azodicarboxilate (DEAD) (1.4 equiv). The reaction mixture stirred at room temperature overnight. The reaction was monitored by TLC. The solvent was removed under vacuum. It was purified by silica gel chromatography using Hexane:Ethyl acetate (3:1) to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:21][C:15]=1[C:16](OCC)=[O:17].C(=O)(O)[O-].[Na+]>>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:14]3[N:13]=[C:2]4[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][N:7]4[C:16](=[O:17])[C:15]=3[CH:21]=2)=[O:34])=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1cc(NC(=O)c2ccc(C)cc2)ccc1N
Reactant: CCOC(=O)c1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc2nc3ccc(NC(=O)c4ccc(C)cc4)cc3c(=O)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 6-chloro-3-pyridazinecarboxylate (0.12 g, 0.64 mmol, Example 1, Step A) and ethyl 2-amino-5-[(4-methylbenzoyl)amino]benzoate (0.22 g, 0.74 mmol, Example 2, Step C) was heated as a melt at 165°-170° C. for 15 min. The resulting orange solid was suspended into saturated sodium bicarbonate solution, stirred at room temperature for 1 h then filtered. The solid was washed with water and diethyl ether to give ethyl 8-[(4-methyl-benzoyl)-amino]-10-oxo-10H-pyridazino[6,1-b]-quinazoline -2-carboxylate as an orange solid, mp 225°-230° C. dec.
Reaction SMILES: [O:1]([CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24]C2CCCCO2)=[CH:17][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:24][CH2:23][CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCO)cc1)Oc1ccccc1
Yield: 90.8 %

Procedure:
In a similar manner to that described in Reference example 3(f), a reaction was carried out using ethyl 2-phenoxy-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (4.53 g), which is the product of Reference example 4(d), and p-toluenesulfonic acid monohydrate (2.70 g) and the reaction mixture was treated to afford the desired compound (3.28 g) as a syrup.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:9])[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]([NH:29][C:30]([C:32]2[CH:33]=[C:34]([C:45](Cl)=[N:46][OH:47])[CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][N:39]=3)[CH:37]=2)=[O:31])[CH3:28])=[N:25][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]([NH:29][C:30](=[O:31])[C:32]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][N:39]=3)[CH:35]=[C:34]([C:45]3[CH2:8][C:7]([OH:9])([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[O:47][N:46]=3)[CH:33]=2)[CH3:28])=[N:25][CH:26]=1
Reactant: CC(=O)c1ccccn1
Reactant: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(F)cn3)cc(C(Cl)=NO)c2)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(F)cn3)cc(C3=NOC(O)(c4ccccn4)C3)c2)nc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 1-(2-pyridinyl)ethanone (1.04 mL, 9.26 mmol) in tetrahydrofuran (15 mL) at −20° C. was added dropwise lithium bis(trimethylsilyl)amide (1M in hexanes, 9.26 mL, 9.26 mmol). The reaction mixture was stirred at −20° C. for 30 min. The reaction mixture was cooled to −78° C. The reaction mixture was sequentially added (1 equivalent, ˜5 mL, per portion) to a solution of 3-({[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]amino}carbonyl)-N-hydroxy-5-(5-methyl-2-pyridinyl)benzenecarboximidoyl chloride (0.765 g, 1.85 mmol) in tetrahydrofuran (4 mL) at −78° C. After addition of 5 equivalents (˜25 mL), the reaction mixture was warmed to 0° C. Saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Two purifications by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol, then 50% hexane/ethyl acetate→95% ethyl acetate/methanol) gave the title compound (0.221 g) HRMS 498.1956 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.59 (d, J=4.9 Hz, 1H); 8.52 (s, 1H); 8.49 (t, J=1.6 Hz, 1H); 8.46-8.42 (m, 2H); 8.18 (s, 1H); 7.83 (tdd, J=7.7, 3.6, 1.6 Hz, 1H); 7.73 (dd, J=8.2, 2.3 Hz, 1H); 7.71-7.67 (m, 1H); 7.63 (dd, J=7.9, 4.9 Hz, 1H); 7.60 (d, J=8.2 Hz, 1H); 7.43-7.33 (m, 3H); 5.44-5.36 (m, 1H); 3.92 (dd, J=17.7, 4.8 Hz, 1H); 3.77 (dd, J=17.7, 2.7 Hz, 1H); 2.39 (s, 3H); 1.72 (s, 1H); 1.60 (d, J=6.8 Hz, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][C:6]=1[O:16][CH3:17])(=O)C.[OH-].[Na+].Cl>O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][C:6]=1[O:16][CH3:17]
Reactant: COc1cc(CCC(=O)O)ccc1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CCC(=O)O)ccc1O
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution was prepared from 8.0 g (0.034 mol) of acetyldihydroferulic acid and 4.7 g (0.118 mol) of sodium hydroxide in 100 mL of water and refluxed for 5 h. After cooling to room temperature, the aqueous solution was acidified with hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The evaporation of the solvent left a yellow crude product that was dissolved in dichloromethane and precipitated in hexanes to yield 5.5 g of an off-white powder in 83% yield.