Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[CH2:13]([OH:16])[C:14]#[CH:15]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([C:15]#[C:14][CH2:13][OH:16])[O:6][N:5]=1
Reactant: Ic1cc(-c2ccccn2)no1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cc(-c2ccccn2)no1
Temperature: 65 °C
Yield: 22 %

Procedure:
A solution of 2-(5-iodo-3-isoxazolyl)pyridine (prepared as described in WO0232919, 1.38 g, 5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmol) in 8 mL triethylamine was degassed with nitrogen. Propargyl alcohol (560 mg, 10 mmol) was added and the mixture was heated at 65° C. for 16 h. The reaction mixture was cooled to room temperature, concentrated to remove the solvent. The residue was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3, water and brine. The organic layer was dried and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded 220 mg (22%) of the title compound. MS 201 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:7]=1.[NH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=1)[O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:8]([N:6]1[C:5](=[O:15])[N:4]([CH3:16])[C:3](=[O:17])[C:2]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=2)[O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:7]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Reactant: CCCCCCCn1nc(Br)c(=O)n(C)c1=O
Product: CCCCCCCn1nc(NCCc2cccc(OC(C)(C)C(=O)OCC)c2)c(=O)n(C)c1=O

Procedure:
Compound 57 (oil) is prepared from triazine 4b and from intermediate 13b according to synthesis method 1.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])C.[OH-].[Na+]>C(O)C>[C:21]1([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4]([OH:27])=[O:3])=[CH:20][CH:19]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: CCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCC(Oc1ccc(C2=CCCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 22.7 g of α-[p-(1cyclohexenyl)-phenoxy]-decanoic acid ethyl ester in 120 ml of ethanol are added 100 ml of 2N sodium hydroxide solution and the mixture stirred for 3 hours at room temperature. The ethanol is stripped off in vacuo and the residue partitioned between 2N hydrochloric acid and ether. The organic phase is washed until neutral, dried over sodium sulphate and evaporated to dryness. Distillation of the residue at 0.03 mm yields in the fraction boiling at 175°-180° C the α-[p-(1-cyclohexenyl)-phenoxy]-decanoic acid of the formula ##STR22## (m.p. 75°-78° C).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:48][C:49]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50]1.CCN(C(C)C)C(C)C>ClCCl.CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:51]3[CH2:52][CH2:53][C:49]([F:54])([F:48])[CH2:50]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: FC1(F)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC(F)(F)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
In a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (1 g, 1.0 eq.) was charged in dichloromethane (20 mL, 20 V). The reaction mixture was cooled to 0° C. HOBT (0.461 g, 1.2 eq.), EDC.HCl (0.819 g, 1.5 eq.), 3,3-Difluoropyrrolidine hydrochloride (0.490 g, 1.2) and DIPEA (0.731 mL, 1.5 eq.) was added to the reaction mixture. The clear reaction mixture was stirred at 0° C. for 1.5 h. The progress of the reaction was followed by TLC using 5% methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was quenched in water (50 mL). Organic layer was separated and aqueous layer was extracted with dichloromethane (20×2). The combined organic layer was washed with brine solution, dried over Na2SO4 and concentrated by rotary evaporation (25° C., 20 mm Hg) to afford 0.67 g of crude compound. The crude compound was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collection (25 mL fractions). The compound started eluting from 0.9% to 1.0% methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.115 g Yield (9.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(-c2cccc(OC)c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc(OC)ccc2Br)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
3,3′-dimethoxybiphenyl (5.0 g, 23.34 mmol) was dissolved in a dimethylformamide solvent and cooled to 0° C. N-bromosuccinimide (4.15 g, 23.34 mmol) was dissolved in a dimethylformamide solvent (63 ml) and added slowly to a solution of 3,3′-dimethoxybiphenyl for about 1.5 hours. The mixture was stirred at room temperature for about 12 hours and distilled water was added thereto, followed by stirring for about 10 minutes. The resultant was filtered three times with hexane and the filtrate was washed three times with distilled water and dried over sodium sulfate. Hexane was removed under reduced pressure to obtain a desired product (Yield: 6.70 g, 98%). The obtained product was identified as 2-bromo-5,3′-dimethoxybiphenyl through the nuclear magnetic resonance (NMR) spectrum, corresponding to the compound I of the reaction scheme 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9]>CO>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(F)cncc1F
Solvent: CO
Product: OCc1c(F)cncc1F
Yield: 73 %

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 7, replacing 3,4-difluoro-2-pyridinecarbaldehyde with 3,5-difluoro-4-pyridinecarbaldehyde (FRONTIER) and using MeOH as solvent. (200 mg, 1.398 mmol, 73% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.51 (s, 2H), 5.55 (t, 1H), 4.55-4.57 (m, 2H). [ES+MS] m/z 146 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[O:15]1[CH2:16][CH2:17][CH:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC(C2CCOCC2)C1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C1CC(C2CNC2)CCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a solution of 3-(tetrahydropyran-4-yl)azetidine-1-carboxylic acid tert-butyl ester (730 mg, 3.0 mmol) in DCM (10 mL) were added water (0.15 mL) and TFA (10 mL). The reaction mixture was stirred at room temperature for 4 hours and the concentrated under reduced pressure to give a residue that was taken up in MeOH. The resulting solution was loaded onto a SCX-2 cartridge (10 g) which was washed with MeOH. The desired product was eluted with a 2M solution of ammonia in MeOH. The appropriate fractions were combined and concentrated to give 3-(Tetrahydropyran-4-yl)azetidine as a yellow oil (393 mg, 92%). 1H NMR (300 MHz, CDCl3): δ 3.96 (dd, J=11.0, 4.0, 2 H); 3.65 (dd, J=8.0, 8.0 Hz, 2 H); 3.44 (dd, J=7.6, 7.6 Hz, 2 H); 3.37 (ddd, J=11.9, 11.9, 2.1, 2 H); 2.50 (m, 1 H); 1.75 (m, 1 H); 1.53 (m, 2 H); 1.18 (ddd, J=25.0, 11.9, 4.3, 2 H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]2[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([CH3:28])[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]=12>CN1CCCC1=O>[CH2:1]([O:8][C:16]1[N:17]=[N:18][CH:19]=[C:20]2[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([CH3:28])[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c([N+](=O)[O-])c2cnnc(Cl)c2n1CC(C)C
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1c([N+](=O)[O-])c2cnnc(OCc3ccccc3)c2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.3 ml (177 mmol) of benzyl alcohol are added dropwise at room temperature to a solution of 33.0 g (295 mmol) of potassium tert-butoxide and 1.5 g (5.9 mmol) of [18]crown-6 in 180 ml of anhydrous N-methylpyrrolidone. The mixture is subsequently stirred at room temperature for a further 1 h. A solution of 15.9 g (59 mmol) of 7-chloro-1-isobutyl-2-methyl-3-nitropyrrolo[2,3-d]pyridazine in 50 ml of anhydrous N-methylpyrrolidone is then added dropwise in the course of 15 min. The suspension is then stirred at 80° C. for 2 h. After cooling to room temperature, it is treated with 400 ml of ice-water, and extracted with 3×300 ml of ethyl acetate. The organic extracts are washed with 3×200 ml of water and subsequently dried over magnesium sulfate. The residue which remains after concentration is chromatographed on silica gel (eluent: toluene/ethyl acetate=4:1). After concentration of the fractions of Rf=0.25 and crystallization from diisopropyl ether/ethyl acetate, 5.1 g (25%) of the title compound are isolated. M.p.: 162°-164° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+].C>O.C(O)CO>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: COc1ccc(Nc2ccccc2C(=O)O)cc1
Temperature: 125 °C
Yield: 49.3 %

Procedure:
4-Methoxyaniline (1.86 gm; 20 mmol), 2-chlorobenzoic acid (1.56 gm; 10 mmol), ethylene glycol (5 ml) and anhydrous sodium carbonate (1.1 gm; 10 mmol) were placed in a reaction vessel and stirred until effervescence ceased. Cupric chloride (100 mg; 0.75 mmol) dissolved in 2 ml of water was added to the reaction mixture which was then heated to 125° C. for 6 hours. The reaction was allowed to cool then water (30 ml) and charcoal were added. The mixture was filtered and acidified to pH 2 with conc. hydrochloric acid. The precipitate was collected by filtration, washed with water and then re-dissolved in 1M sodium hydroxide solution. Material was re-precipitated by the addition of acetic acid, filtered off, washed with aqueous acetic acid, then water and finally dried under vacuum over phosphorous pentoxide to give 1200 mg (49%) of N-(4-methoxyphenyl)anthranilic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[C:31]1=[O:38].Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:35]([CH:32]2[CH2:33][CH2:34][N:30]([CH3:29])[C:31]2=[O:38])=[O:36])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[N:9]=[C:10]([I:26])[C:11]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CN1CCC(C(=O)O)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (300.0 mg, 0.6119 mmol), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (87.59 mg, 0.6119 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (351.9 mg, 1.836 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (248.0 mg, 1.836 mmol), N-ethyl-N-isopropylpropan-2-amine (395.4 mg, 3.060 mmol) and THF (50 mL). The reaction mixture was stirred at ambient temperature overnight, and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (0.360 g, 95.6%). LRMS (APCI pos): m/e 616 (M+1). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.31 (d, 1H), 7.79 (dd, 1H), 7.36 (d, 2H), 7.29 (m, 1H), 7.20 (t, 1H), 6.83 (m, 2H), 6.20 (d, 1H), 5.61 (s, 2H), 3.78 (s, 3H), 3.42-3.50 (m, 3H), 2.94 (s, 3H), 2.50-2.61 (m, 1H), 2.35-2.48 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][O:9][CH3:10].[OH:11][C:12]1[C:20]2[O:19][C:18]([CH3:22])([CH3:21])[C:17](=[O:23])[C:16]=2[C:15]([CH3:24])=[CH:14][C:13]=1[CH3:25].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C=O)C>[CH3:10][O:9][CH2:8][O:11][C:12]1[C:20]2[O:19][C:18]([CH3:21])([CH3:22])[C:17](=[O:23])[C:16]=2[C:15]([CH3:24])=[CH:14][C:13]=1[CH3:25]
Reactant: COCCl
Reactant: Cc1cc(C)c2c(c1O)OC(C)(C)C2=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(C)c2c1OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.4 %

Procedure:
Potassium carbonate (1.23 g, 8.92 mmol) and chloromethylmethylether (539 mg, 6.69 mmol) were sequentially added to a suspension of DMF (20 mL) containing 7-hydroxy-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (920 mg, 4.46 mmol) synthesized in Reference Example 69 at 0° C. The reaction solution was warmed to room temperature and stirred for 15 hours. The resulting mixture was poured into saturated sodium bicarbonate water, and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 85/15) to give 920 mg of the title compound (yield: 82%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=[N:3]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=[N:3]1
Reactant: COC(=O)c1cccc(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nccc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-(1-methyl-1H-pyrazol-5-yl)benzoate (200 mg, 0.93 mmol) in MeOH (3 mL) was added aqueous NaOH (1 mL, 0.4M). The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated and the residue was dissolved in water and adjusted pH to 5˜6 with 2N of HCl. The solution was extracted with EtOAc (2×20 mL). The combined organic layers were dried and concentrated to give the target crude product which was used directly in the next step. LCMS (m/z): 203.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][C:30]1=[O:35].N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I.O>[F:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C:30]2=[O:35])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=C1COCCN1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cn(-c2ccc(N3CCOCC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 58.9 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 3-morpholinone (60.7 mg, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol), and K3PO4 (212 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was refluxed for 6 h under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (136 mg, 59% yield) as a white solid: mp 193-195° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.75-3.79 (2H, m), 3.90 (3H, s), 4.04-4.07 (2H, m), 4.35 (2H, s), 6.41 (1H, t, J=9.0 Hz), 7.00 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.31 (1H, d, J=2.3 Hz), 7.33-7.46 (6H, m), 7.78-7.80 (2H, m). LC-MS (ESI) m/z 462 [M+H]+. Anal. Calcd for C24H20FN5O4: C, 62.47; H, 4.37; N, 15.18. Found: C, 62.31; H, 4.33; N, 15.25.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:12]([F:20])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:22]N(Cl)C(OCC)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)(=O)C>[C:1]([C:5]1[O:6][C:7]2[C:13]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:12]([F:20])[CH:11]=[C:10]([Cl:22])[C:8]=2[N:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)N(Cl)Cl
Reactant: CCOC(=O)Nc1c(F)ccc2nc(C(C)(C)C)oc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c(F)cc(Cl)c2nc(C(C)(C)C)oc12
Reaction time: 4 h
Yield: 69.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 3.1 grams (11.0 mmole) of ethyl N-(2-t-butyl-6-fluorobenzoxazol-7-yl)carbamate, 35 mL of acetic acid, and 0.2 mL (2.4 mmole) of concentrated hydrochloric acid was stirred and cooled in an ice bath. During five minutes 2.2 grams (14 mmole) of N,N-dichlorourethane was added via syringe. Upon completion of the addition the reaction mixture was stirred for 4 hours, then analyzed by TLC, which indicated the reaction was complete. The reaction mixture was poured into 100 mL of water, and 15 mL of aqueous saturated sodium bicarbonate solution was carefully added. The reaction mixture was then extracted with two 75 mL portions of diethyl ether, and the combined extracts were concentrated under reduced pressure, yielding a residual oil. The oil was subjected to column chromatography on silica gel with 8:1 hexane:ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.4 grams of ethyl N-(2-t-butyl-4-chloro-6-fluorobenzoxazol-7-yl)carbamate, m.p. 127°-129° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH2:31]([NH2:34])[CH2:32][CH3:33].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:34][CH2:31][CH2:32][CH3:33])=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCCN
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(I)cc3F)c2C#N)CC1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCCNc1ccc(Nc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C#N)c(F)c1
Temperature: 80 °C
Yield: 36.5 %

Procedure:
4-[5-Cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (250 mg, 0.48 mmol), n-propylamine (408 μL, 4.8 mmol), proline (99 mg, 0.86 mmol), copper iodide (92 mg, 0.48 mmol) and potassium carbonate (152 mg, 1.1 mmol) were mixed together in DMSO (4 mL). The reaction vessel was heated in a microwave at 80° C. for 30 minutes. Progress of the reaction was monitored by TLC and LCMS. Purification by HPLC afforded compound A64 as a white solid (80 mg, 37%). 1H NMR (CDCl3, 400 MHz) δ 9.37 (s, 1H), 8.22 (s, 1H), 6.91 (t, 1H), 6.91 (m, 2H), 5.27 (h, 1H), 4.71 (h, 1H), 3.53 (m, 2H), 3.23 (m, 2H), 2.91 (m, 2H), 1.85 (m, 2H), 1.54 (m, 4H), 1.13 (d, 6H), 0.88 (t, 3H). Exact mass calculated for C23H29FN6O3 456.51, found 457.4 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:8]([O:15][C:16]1[C:17]2[N:18]3[C:22](=[CH:23][CH:24]=1)[C:21]([CH2:25][CH3:26])=[C:20]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:29][CH:28]=1)[C:19]3=[C:41]([CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH:42]=2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>CN(C)C=O.O.C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[C:17]2[N:18]3[C:22](=[CH:23][CH:24]=1)[C:21]([CH2:25][CH3:26])=[C:20]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:29][CH:28]=1)[C:19]3=[C:41]([CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:42]=2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCl)cc3c(OCc4ccccc4)ccc1n32
Reactant: C1CCNC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCN3CCCC3)cc3c(OCc4ccccc4)ccc1n32
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
Pyrrolidine (66 mg, 0.93 mmol) was dissolved in 50 ml of dry dimethylformamide under a nitrogen atmosphere and sodium hydride (60% in oil) (36 mg, 0.89 mmol) was added. The mixture was stirred for 1/2 hour. 5Benzyloxy-2-(4-benzyloxyphenyl)-3-((4-chlorobutoxy)methyl)-1-ethylpyrrolo[2,1,5-cd]indolizine (0.256 g, 0.443 mmol) was added and the mixture was stirred at 55-65° for 6 days. Ethanol (10 ml) was added dropwise, and the reaction mixture was diluted with 250 ml of water. The organic material was extacted into ethyl acetate (4×100 ml), and the combined oranic layers were washed with brine and dried over sodium solfate. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using 6% of methanol in dichloromethane as the eluent. Fractions containing the product were collected to afford 34 mg (12%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((4-pyrrolidinobutoxy)methyl)pyrrolo[2,1,5-cd ]indolizine as an oil. MS(FAB): m/z613 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ: 1.27-1.49 (m, 11H); 2.50-2.56 (m, 6H); 3.05 (q, 2H); 3.40 (t, 2H); 4.71 (s, 2H); 5.20 (s, 2H); 5.58 (s, 2H); 7.20 (d, 2H); 7.31-7.64 (m, 14H); 7.95 (d, 1H).