Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[B:32]1(B2OC(C)(C)CC(C)O2)[O:37]C(C)(C)CC(C)[O:33]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>C1COCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([B:32]([OH:37])[OH:33])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC1CC(C)(C)OB(B2OC(C)CC(C)(C)O2)O1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1ncc(B(O)O)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (400 mg, 0.754 mmol), bis(hexyleneglycolato)diboron (249 mg, 0.981 mmol), tricyclohexylphosphine (85 mg, 0.302 mmol), potassium acetate (163 mg, 1.659 mmol), 1,1bis(di-tert-butylphosphino)ferrocene palladium dichloride (51.3 mg, 0.075 mmol) and THF (10 mL) were sealed in a microwave vessel and subject to microwave irradiation at 140° C. for 60 min. LCMS indicated complete consumption of starting material and formation of the desired product. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 50 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were evaporated into a brown solid foam as the titled compound. LCMS calc.=495.09. found=495.91 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7](O)=[O:8])=[O:4].C[N:17]1CCOCC1.ClC(OCC(C)C)=O.N.O1CCOCC1>C(Cl)Cl.Cl>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7]([NH2:17])=[O:8])=[O:4]
Reactant: CC#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5R)-1-(chloroacetyl)-5-propynyl-L-proline (1.10 g, 4.8 mmol) in CH2Cl2 (24 mL) at −15° C. under nitrogen was added 4-methylmorpholine (0.64 mL, 5.76 mmol), and then isobutyl chloroformate (0.81 mL, 6.24 mmol) over 10 minutes. A white precipitate formed. The reaction mixture was stirred at −15° C. under nitrogen for 30 minutes, and a solution of NH3 in dioxane (0.5 M, 29 mL, 14.4 mmol) was added. The reaction mixture was stirred at −15° C. for 30 minutes, warmed to room temperature, and stirred at that temperature for 16 hours. The reaction mixture was diluted with 1M HCl to pH 4 and extracted with ethyl acetate (3×). The extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (60-75% ethyl acetate/hexane) provided the titled compound. MS (DCI) m/z 229 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(SC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1ccc(-c2oncc2CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propionate (1.60 g) in tetrahydrofuran (60 ml) was gently added diisobutylaluminum hydride (0.95 M toluene solution, 15.2 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from a fraction eluted with acetone-hexane (1:1, volume ratio) were recrystallized from ethyl acetate-hexane to give 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propan-1-ol as a colorless prism crystal (1.36 g, yield 95%). melting point: 54–55° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[Cl:14])C.[C:18]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27]O)=[CH:20][CH:19]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[OH-].[Na+]>>[C:18]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:15][CH3:16])[C:4]([OH:3])=[O:17])=[C:8]([Cl:14])[CH:9]=2)=[CH:22][CH:23]=1
Reactant: OCCCOc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1Cl)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1Cl)C(=O)O

Procedure:
A mixture solution of 3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester from Step F and 3-(Biphenyl-4-yloxy)-propan-1-ol were allowed to react under the Standard Mitsounobu coupling conditions B (DIAD/toluene) to give the corresponding coupled product which by the Standard hydrolysis procedure C (NaOH) yield the title compound. MS (ES) for C25H25ClO5 [M+NH4]+: 458.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[CH2:8][CH2:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13].N1([CH:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[NH:27][C:28](=[O:30])[O-:29])C=CC=N1>>[C:34]([O:33][C:32]([NH:31][C:26](=[N:27][C:28](=[O:30])[O:29][C:5]([CH3:6])([CH3:20])[CH3:4])[NH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][CH:18]=[C:7]([CH2:8][CH2:9][C:10]([OH:17])([CH2:11][CH2:12][CH3:13])[CH2:14][CH2:15][CH3:16])[CH:6]=1)=[O:38])([CH3:35])([CH3:36])[CH3:37]
Reactant: CCCC(O)(CCC)CCc1cccc(CCCN)c1
Reactant: CC(C)(C)OC(=O)NC(NC(=O)[O-])n1cccn1
Product: CCCC(O)(CCC)CCc1cccc(CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1

Procedure:
Reaction of 4-(3-(3-aminopropyl)phenethyl)heptan-4-ol with tert-butyl (1H-pyrazol-1-yl)methylenedicarbamate following the method described in Example 168 gives tert-butyl (tert-butoxycarbonylamino)(3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylamino)methylenecarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:14]2[CH:15]=[CH:16][C:11]([CH3:17])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 48.9 %

Procedure:
175 g of 4-chlorobenzoyl chloride are added dropwise at about 70° C. to a mixture of 553 g of toluene and 140 g of AlCl3. After completion of the evolution of HCl, the reaction mixture is added to 1 1 of water, and the solid obtained is separated off and recrystallized from 20 ethanol/toluene (50:1 parts by wt). 112.7 g of 4'-chloro-4-methylbenzophenone (melting point 129° C. to 130° C.; content of 4,4,-isomer>99.5% by GCSA) are obtained. 4-(4-Chlorobenzoyl)benzoic acid (melting point 256° C. to 258° C.) is accessible from this in 95% yield by oxidation. This acid is converted into the acid chloride by phosgenation. 97.7 g of 4-(4-chlorobenzoyl)benzoyl chloride, dissolved in 250.0 g of fluorobenzene, are added dropwise at 60° C. to 85° C. to a mixture of 254.5 g of fluorobenzene and 49.0 g of AlCl3. After the evolution of gas is complete, the reaction mixture is added to 0.5 1 of water and, after distillative removal of excess fluorobenzene, the precipitate is separated off, washed until neutral and recrystallized from chlorobenzene. Yield of 1-(4chlorobenzoyl-4-(4-fluorobenzoyl)benzene: 54.0 g (melting point 211° C. to 212° C.).
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH:8]2[CH2:13][CH2:12][C:11]([C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])([C:14]#[N:15])[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:3][CH2:2]1>N.CO.[Ni]>[NH2:15][CH2:14][C:11]1([C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])[CH2:12][CH2:13][CH:8]([S:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:7])[CH2:9][CH2:10]1
Reactant: N#CC1(C(=O)N2CCCC2)CCC(S(=O)(=O)CC2CC2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC1(C(=O)N2CCCC2)CCC(S(=O)(=O)CC2CC2)CC1
Reaction time: 18 h
Yield: 103 %

Procedure:
To 4-cyclopropylmethanesulfonyl-1-(pyrrolidine-1-carbonyl)-cyclohexanecarbonitrile (231 mg; 0.712 mmol) in 2 M ammonia in methanol solution (15 ml) under a nitrogen atmosphere was added Raney Nickel (approx. 1 ml of 50% aqueous slurry). The resulting mixture was agitated under an atmosphere of hydrogen (50 psi) on a Parr apparatus for 18 hours. The mixture was filtered through a catalyst filter and the catalyst washed extensively with MeOH (200 ml, added in portions). The filtrate was evaporated in vacuo to give the product as a pale green oil (241 mg). m/z=329 (M+H+).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]4[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=4)[C:34](O)=[O:35])=[N:23][CH:22]=[N:21][C:20]=3[S:19][CH:18]=2)=[CH:13][CH:12]=1.Cl.[NH2:41][CH2:42][C:43]([NH2:45])=[O:44].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:45][C:43](=[O:44])[CH2:42][NH:41][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:24]2[C:25]3[C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)=[CH:18][S:19][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:32]=1
Reactant: O=C(O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: NCC(N)=O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CNC(=O)c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
1,3-Diisopropylcarbodiimide (13.0 mg, 0.10 mmol) was added to a stirred mixture of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzoic acid (21 mg, 0.050 mmol), 2-amino-acetamide hydrochloride (11 mg, 0.10 mmol), 1-hydroxybenzotriazole (6.7 mg, 0.05 mmol), diisopropylethylamine (40 mg, 0.30 mmol) and 4-dimethylaminopyridine (13 mg, 0.10 mmol) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at room temperature for 6 hours and then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (30 mL), washed with aqueous sodium bicarbonate solution (2×25 mL) and the organic layer was separated and concentrated. The product was purified by column chromatography over silica gel using 5% methanol in 1:1 of ethyl acetate/hexanes to give 9.6 mg (40%) of N-(2-amino-2-oxoethyl)-3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)benzamide as a white solid. MS [M+H] 481.1, 1H NMR (CDCl3) δ (ppm) 8.68 (s, 1H), 7.60-7.24 (m, 4H), 7.21 (s, 1H), 7.18-6.95 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.31 (b, 1H), 5.62 (b, 1H), 4.59 (t, J=6.0 Hz, 2H), 4.19, (d, J=5.1 Hz, 2H), 3.74 (t, J=6.0 Hz, 2H), 2.10 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:14]1([CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][OH:11])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC(CC1CCCC1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CO)CC1CCCC1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 72.2 %

Procedure:
To a solution of 2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (730 mg, 2.84 mmol) in THF (7.5 mL) cooled to −10° C. was added N-methylmorpholine (0.312 mL, 2.84 mmol) followed by isobutyl chloroformate (0.373 mL, 2.84 mmol). The reaction mixture was then stirred for 5 min. The solid obtained was removed by filtration and washed with THF (5 mL). The filtrate was cooled to −10° C. and treated with NaBH4 (161 mg, 4.26 mmol) in water (5 mL) dropwise. The reaction mixture was stirred at −10° C. for 10 min and allowed to warm to room temperature and stirred for another 30 min. The reaction mixture was then quenched with cold water (5 mL). The aqueous layer extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford a residue which was purified by column chromatography (pet ether: ethyl acetate) to afford tert-butyl 1-cyclopentyl-3-hydroxypropan-2-ylcarbamate (500 mg, 2.05 mmol, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ 6.38 (m, 1 H), 4.51 (m, 1 H), 3.85-3.65 (m, 1 H), 3.42 (m, 1 H), 3.25 (m, 1 H), 3.8 (m, 1 H), 2.75 (m, 1 H), 1.85-1.65 (m, 4H), 1.6-1.25 (m, 12 H), 1.15 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:30])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH3:24])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Yield: 98 %

Procedure:
Compound B (1.20 g, 3.02 mmol) was dissolved in 20 ml of dimethylformamide. To the solution were added 1.04 g (7.55 mmol) of potassium carbonate and subsequently 0.38 ml (6.04 mmol) of methyl iodide, and the resultant mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 400 ml of water was added to the filtrate. The mixture was extracted three times with 100 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 1% methanol/chloroform), followed by recrystallization from propanol/water to give 1.22. g (yield 98%) of Compound 1 as white needles.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:27]([CH3:30])(=[O:29])=[O:28])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:27]([CH3:30])(=[O:29])=[O:28])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](CCCc1cccnc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](CCCc1cccnc1)C(=O)NO
Yield: 94.3 %

Procedure:
A solution of 0.33 g of 2(R)-[1(S)-[(benzyloxy)carbamoyl]-4-(3-pyridyl)butyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in 10 ml of methanol was hydrogenated in the presence of 80 mg of 10% palladium-on-carbon for 1.5 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.26 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-(3-pyridyl)butyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:9]=2[C:23]([F:26])([F:25])[F:24])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:34]1[CH:39]=[CH:38][N:37]([CH2:40][CH:41]2[CH2:43][CH2:42]2)[C:36](=[O:44])[C:35]=1[C:45]#[N:46]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:41]1([CH2:40][N:37]2[CH:38]=[CH:39][C:34]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[C:9]([C:23]([F:24])([F:25])[F:26])[CH:10]=3)=[C:35]([C:45]#[N:46])[C:36]2=[O:44])[CH2:42][CH2:43]1
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)c(C(F)(F)F)c2)OC1(C)C
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(C(F)(F)F)c2)ccn(CC2CC2)c1=O
Yield: 83.6 %

Procedure:
To a solution of intermediate 17 (0.63 g, 1.69 mmol) in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml) was added intermediate 8 (0.42 g, 1.69 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 3 (0.59 g, 9%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)=[O:5])C.[Li+].[OH-].Cl>O1CCCC1.C(O)C>[C:16]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15]2)#[N:17]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc2ncc(C(=O)O)cc2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 107 %

Procedure:
To a solution of 6-cyano-quinoline-3-carboxylic acid ethyl ester (1.28 g) in tetrahydrofuran (6 ml) and ethanol (6 ml) was added a 1M aqueous LiOH solution (6.79 ml) at 0° C. The mixture was stirred at 0° C. for 1.5 h, then the mixture was acidified with 1M aqueous HCl. The precipitate was filtered off, washed with water and a small amount of ether and dried to give the crude title compound (1.2 g) as an off-white solid that was used in the next step without further purification. MS (m/e, ISP neg. ion)=197.2 [M−H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[K].[CH:13](=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>O>[N+:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[O:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[CH:13]=[O:21])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: O=Cc1ccccc1O
Agent: [K]
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
Briefly, 200 parts of 2,5-dichloro-nitrobenzene were heated to 160° C. and stirred, and 160 parts of the potassium salt of salicylaldehyde was added over a period of 30 minutes. After the addition was complete, an exothermic reaction took place, and the temperature rose to about 195° C. Heating was discontinued until the reaction subsided, and the mixture was heated for 1 hour at 150° C. The mixture was cooled, ice and water were added, and it was extracted with ether (Et2O). The ether layer was filtered to remove insoluble material, and the resultant solution was dried over sodium sulfate (Na2SO4). The ether solvent was evaporated, and the residual oil was recrystallized from a mixture of hexane and benzene to give 2-(2-nitro-4-chlorophenoxy)benzaldehyde melting at about 100°-101° C.
Reaction SMILES: [CH2:1]([N:8]1[N:17]=[C:16](Cl)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[OH:37].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[N:17]=[C:16]([C:26]2[CH:25]=[CH:24][C:23]([OH:37])=[C:22]([O:21][CH3:20])[CH:27]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccccc2c(Cl)nn1Cc1ccccc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(-c2nn(Cc3ccccc3)c(=O)c3ccccc23)ccc1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 7.5 %

Procedure:
A mixture of 2-benzyl-4-chloro-2H-phthalazin-1-one (1.35 g, 5 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenol (1.50 g, 6 mmol), Pd(PPh3)4 (0.87 g, 0.75 mmol) and Na2CO3 (2.12 g, 20 mmol) in toluene (25 mL), ethanol (12.5 mL) and water (12.5 mL) was degassed and then heated to reflux with stirring for 19 h. After that time, the reaction was cooled to rt and diluted with ethyl acetate (150 mL) and water (100 mL). The organic phase was separated, washed with water (2×30 mL) then brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with hexanes (100 mL) to give a yellow solid. The product was purified by flash column chromatography (silica gel, 70:30 hexanes/ethyl acetate) followed by recrystallization from CHCl3/hexanes to give 2-benzyl-4-(4-hydroxy-3-methoxyphenyl)phthalazin-1(2H)-one (0.135 g, 7.5%) as a white solid: mp 197-200° C.; 1H NMR (400 MHz, CDCl3) δ 8.54-8.52 (m, 1H), 7.79-7.71 (m, 3H), 7.52 (d, J=7.2 Hz, 2H), 7.34-7.25 (m, 4H), 7.11-7.04 (m, 2H), 5.82 (s, 1H), 5.47 (s, 2H), 3.93 (s, 3H); ESI MS m/z 359 [M+1]+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:5]([C:6]([OH:8])=O)=[C:4]([O:13][CH3:14])[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:27][NH:28][O:29][CH3:30].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[C:5]([C:6]([N:28]([O:29][CH3:30])[CH3:27])=[O:8])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CNOC
Reactant: COc1cc(I)cc(OC)c1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(I)cc(OC)c1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 4-iodo-2,6-dimethoxybezoic acid (308.0 mg, 1.00 mmol) in methylene chloride (5.0 mL) were added dimethylformamide (0.020 mL, 0.26 mmol) and oxalyl chloride (0.13 mL, 1.5 mmol), and the resulting mixture was stirred for 30 minutes. The reaction mixture was poured into an ice-cold solution of N,O-dimethylhydroxyamine hydrochloride (488.0 mg, 5.00 mmol) and N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) in methylene chloride (5.0 mL). The ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. 0.1 M Hydrochloric acid was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The organic layer was washed with 0.1 M aqueous sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Hexane was added to the residue and the resulting precipitate was collected by filtration to yield crude 4-iodo-N,2,6-trimethoxy-N-methylbenzamide as a pale yellow crystalline powder (305.0 mg, yield: approx. 87%).