Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:23]4[O:22][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 2-benzofuranboronic acid (278 mg, 1.71 mmol) the subtitle compound was obtained (342 mg, 61%). The product was used directly in the next step without purification
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][C:2]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A mixture of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Intermediate B, 2 g, 6.43 mmol), 1-(bromomethyl)-3-nitrobenzene (1.39 g, 6.43 mmol) and Cs2CO3 (4.2 g, 12.9 mmol) in DMF (40 mL) was stirred at RT for 16 h. The mixture was then diluted with H2O and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (20 mL) and brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the title compound as a yellow solid (1.8 g, 56.4%). LC-MS (ES+) C19H13F3N6O4 requires: 446. found: 447 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1.[CH3:28][O:29][C:30](=[O:45])[C@@H:31]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH2:33][C:34](O)=[O:35].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.C(#N)C>[CH3:28][O:29][C:30](=[O:45])[C@@H:31]([NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:32][CH2:33][C:34](=[O:35])[NH:25][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:26]=[CH:27][C:9]([CH2:8][O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)NC(=O)OC(C)(C)C
Yield: 14.6 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-methyl ester (370 mg, 0.70 mmol; 66% purity) described in Manufacturing Example 2-1 and methanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred for 5 hours at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated from the filtrate under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-methyl ester (300 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 0.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-methyl ester (crude, 220 mg), N-methylmorpholine (46 μL, 0.42 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (180 mg, 0.46 mmol) in this order at 0° C., which was stirrer overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1), so as to obtain the titled compound (37 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[N:12][C:3]=12.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH:28]([C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]([CH2:27][CH2:26][O:25][CH3:24])[CH3:23])=[CH:17][CH:18]=3)=[N:12][C:3]=12)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: Nc1ccccc1
Product: COCCN(C)CCOc1ccc(-c2nc3c(Nc4ccccc4)c(C#N)cnc3[nH]2)cc1
Temperature: 180 °C
Yield: 2 %

Procedure:
7-Chloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine-6-carbonitrile (Example 243) (0.050 g, 0.13 mmol) was dissolved in aniline (2 ml) and heated at 180° C. for 3 h in a sealed vial. The excess aniline was evaporated and the crude product was purified by HPLC-C18, giving the title product (0.001 g, 2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[C:10]([C:17]#N)[C:9]2=[O:19])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21].[OH-:25].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[C:10]([C:17]([OH:21])=[O:25])[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(C)c1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 65 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-6-(1-methylethyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (604 mg, 2.35 mmol) and water (5 mL) was added conc. sulfuric acid (5 mL) at 0° C., and the mixture was stirred at 100° C. for 14 hr. After cooling to 0° C., the mixture was basified (pH 11) with 8N aqueous sodium hydroxide solution and washed with ethyl acetate. The aqueous layer was acidified (pH 4) with 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to give the title compound (425 mg, 65%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][S-:11].[Na+].CCOC(C)=O>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (1.0 g, 6.1 mmol) in EtOH (15 ml) was added sodium thiomethoxide (0.43 g, 6.10 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The mixture was poured onto water and EtOAc. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the crude title compound (910 mg) as a yellow solid. LC-MS (ES) m/z=176 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[N+:35]([O-:37])=[O:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:38]([OH:44])([C:40](F)(F)F)=[O:39].BrCC(OC(C)(C)C)=O>C(Cl)Cl.C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:40][C:38]([OH:44])=[O:39])[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[N+:35]([O-:37])=[O:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c([N+](=O)[O-])c2)CC1
Agent: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Solvent: CC#N
Product: O=C(O)CN1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c([N+](=O)[O-])c2)CC1

Procedure:
The title compound was prepared by deprotection of the compound of Example 205 with TFA in CH2Cl2. The resultant free amine was treated with tert-butyl bromoacetate and TEA in acetonitrile at room temperature, and followed by deprotection with TFA in CH2Cl2, giving a light solid, mp 120° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 3.20-3.45 (m, 4H), 4.20 (s, 2H), 3.50-3.80 (m, 4H), 4.28-4.46 (m, 4H), 6.86 (d, J=8.5 Hz, 1H), 7.04 (m, J=8.0 Hz, 1H), 7.09 (dd, J=2.0 8.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.40 (d, J=15.5 Hz, 1H), 7.56 (d, J=15.0 Hz, 1H), 7.90 (dd, J=2.0, 8.5 Hz, 1H), 8.63 (m, 1H). MS (ESI) m/z 484 (M−H)+, 486 (M+H)+. Calcd. Anal for C23H21N3O7S.1.19CF3COOH.1.34H2O: 47.63; H, 4.11; N, 6.89. Found: C, 47.93; H, 4.51; N, 6.49.
Reaction SMILES: [OH-].[Li+].[CH:3]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([CH3:16])[CH:7]=2)[CH2:5][CH2:4]1>O.C1COCC1.CO>[CH:3]1([C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:16])[CH:7]=2)[CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C2CC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of lithium hydroxide (90 mg, 1.97 mmol) in H2O (1 mL) was added in one portion to a stirred solution of methyl 4-cyclopropyl-2-methylbenzoate (125 mg, 0.66 mmol) in THF (2 mL) and MeOH (2 mL). The mixture was stirred at room temperature for 30 min then at 50° C. for 2 hours. A further aliquot of lithium hydroxide (90 mg) in H2O (1 mL) and MeOH (1 mL) was added, and the mixture was stirred at 50° C. overnight. The organics were removed under vacuum and H2O (20 mL) was added. The mixture was adjusted to pH 4-5 by the use of 1N HCl (a precipitate emerges) and then extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and the filtrate concentrated under vacuum to give the product (110 mg, 95%) as a solid. 1H NMR (CDCl3; 400 MHz) δ 7.98 (1H, d), 6.96-6.92 (2H, m), 2.63 (3H, s), 1.94-1.87 (1H, m), 1.07-1.01 (2H, m), 0.80-0.76 (2H, m).
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1[CH2:7]Br.O>CS(C)=O>[Br:13][C:11]1[CH:10]=[CH:9][C:6]([CH2:7][C:1]#[N:2])=[C:5]([F:4])[CH:12]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Sodium cyanide (1.37 g, 28.00 mmol) was added to a stirred solution of 2-fluoro-4-bromo benzyl bromide (5.0 g, 18.66 mmol) in dry DMSO (60 mL) at ambient temperature under nitrogen. The reaction was stirred for 4 h at ambient temperature then poured into H2O (150 mL) and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the intermediate title compound as a brown oil (3.85 g, 96%). Electrospray mass spectrum: M=213, M+2=215
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[Cl:12][C:13]1[C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([NH:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=2)=[N:15][N:16]([CH3:22])[C:17]=1[O:18][CH:19]([F:21])[F:20].O>ClCCl>[Cl:12][C:13]1[C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([N:30]=[N:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=2)=[N:15][N:16]([CH3:22])[C:17]=1[O:18][CH:19]([F:21])[F:20]
Reactant: CCOC(=O)NNc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N=Nc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.1 g (6.6 mmol) of m-chloroperbenzoic acid in 10 ml of dichloromethane was added dropwise to a solution of 2.1 g (5.3 mmol) of 4chloro-3-[4-chloro-3-(2-ethoxycarbonylhydrazino)-phenyl]-5-difluoromethoxy-1-methyl-1H-pyrazole in 15 ml of dichloromethane. The mixture was stirred at 35° C. for 30 minutes and poured into 50 ml of water. The organic phase was separated off and washed with 10% strength by weight sodium hydrogen carbonate solution, then dried over magnesium sulfate and finally concentrated. The crude product was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 0.5 g.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:19][C:17]1[CH:18]=[C:2]2[C:3]([C:4](=[O:5])[N:6]([CH:7]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3=[O:14])[CH:20]=[N:1]2)=[CH:15][CH:16]=1
Reactant: COC(OC)OC
Reactant: Nc1cc(F)ccc1C(=O)NC1CCC(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C1CCC(n2cnc3cc(F)ccc3c2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-fluoro-benzamide (0.9 g, 3.4 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (110 mg) was heated to 160° C. in a microwave oven for 15 minutes. To the mixture, was added methanol (10 mL), and the mixture was stirred for 10 minutes. The suspension was filtered and washed with methanol to give 3-(7-fluoro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (650 mg, 70% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.45 min (96.1%); mp: 296-298° C.; 1H NMR (DMSO-d6) δ 2.13-2.19 (m, 1H, CHH), 2.63-2.73 (m, 2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.50 (br, 1H, NCH), 7.46 (dt, J=3, 9 Hz, 1H, Ar), 7.53 (dd, J=3.10 Hz, 1H, Ar), 8.22 (dd, J=6, 9 Hz, 1H, Ar), 8.42 (s, 1H, CH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.45, 30.88, 56.43, 112.3 (d, JC-F=22 Hz), 115.91 (d, JC-F=23 Hz), 118.38, 129.32 (d, JC-F=11 Hz), 148.71, 149.65 (d. JC-F=14 Hz), 159.00, 165.70 (d, JC-F=252 Hz), 169.76, 172.41; LCMS: MH=276; Anal Calcd for C13H10N3O3F: C, 56.73; H, 3.66; N, 15.27. Found: C, 56.39; H, 3.60; N, 15.16.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:31]#[C:30][CH2:29][CH2:28][OH:32])=[CH:22][CH:23]=1
Reactant: C#CCCO
Reactant: Fc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(F)cc1
Reaction time: 5 h
Yield: 86 %

Procedure:
1 g of bis(triphenylphosphine)-palladium(II)-chloride, 3.8 g of copper(II)iodide and 8.7 g of triphenylphosphine were added in succession to a solution of 100 g of 4-bromofluorobenzene in 350 ml of triethylamine. This mixture was heated to the reflux temperature, after which 43.4 g of 3-butynol were added dropwise in the course of 20 minutes at this temperature (about 100° C.). Stirring was continued for a further 5 hours at this temperature. After cooling, the triethylamine was distilled off. The residue was taken up in methyl tertbutyl ether and water. The aqueous phase was extracted twice more with methyl tert-butyl ether and the combined organic extracts were washed in succession with 1N hydrochloric acid and with 10% strength sodium bicarbonate solution and was dried over sodium sulfate. After removal of the solvent, the crude product was distilled under greatly reduced pressure. Yield: 86%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]([O:20][CH3:21])=[CH:8][N:7]=1)(=[O:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1.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.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:22])[C:9]([O:20][CH3:21])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COc1cnc(COC(C)=O)cc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cnc(COC(C)=O)cc1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of 0.50 g of (5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)methyl acetate in 5 mL of dioxane, 0.63 g of potassium carbonate, 0.21 mL of trimethylboroxin and 0.18 g of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was stirred at 70 to 90° C. for 3 hours under a nitrogen atmosphere. The mixture was heated under reflux while further stirring for 3 hours, after cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=80:20 to 50:50 to obtain 0.22 g of (5-methoxy-4-methylpyridin-2-yl)methyl acetate as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9]O)[N:6]=[N:7][CH:8]=1.[CH2:11]([C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH3:12]>>[CH2:11]([C:13]1[N:14]([CH2:9][C:5]2[N:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:15]=[CH:16][N:17]=1)[CH3:12]
Reactant: CCc1ncc[nH]1
Reactant: COc1cnnc(CO)c1
Product: CCc1nccn1Cc1cc(OC)cnn1

Procedure:
The title compound, MS: m/e=219.3 (M+H+), was prepared from (5-methoxy-pyridazin-3-yl)-methanol and 2-ethylimidazole.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([NH:11][N:12]=[CH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:9][C:8](=[O:24])[N:7]([CH3:25])[C:6]1=[O:26])[CH:2]([CH3:4])[CH3:3].[C:27]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O)#[N:28].C(N(CC)CC)C>CN(C=O)C.CCOCC>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[C:32]([C:31]3[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=3)[C:27]#[N:28])=[C:9]2[C:8](=[O:24])[N:7]([CH3:25])[C:6]1=[O:26])[CH:2]([CH3:4])[CH3:3]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(C)Cn1c(NN=Cc2cccc3ccccc23)cc(=O)n(C)c1=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C#N)c3)n(Cc3cccc4ccccc34)nc21
Yield: 69.7 %

Procedure:
A solution of 100 mg (0.26 mmol) of l-naphthaldehyde (3-isobutyl-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone, 36 mg (0.27 mmol) of 3-cyano benzaldehyde and 20 uL of triethylamine in 20 mL DMF was heated at 85° C. for 20 h. The mixture was diluted with ether and washed 4 times with water. The ether was dried (MgSO4) and concentrated to give a yellow solid which was recrystallized from ethanol to give 84 mg of the subtitle product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]#[CH:19])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[ClH:1].[C:18]([C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:16][CH:15]=1)#[CH:19]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C#Cc1cccc(N)c1
Solvent: c1ccncc1
Product: C#Cc1cccc(Nc2ncnc3[nH]ccc23)c1
Product: Cl
Temperature: 85 °C
Yield: 10.8 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 0.065 mol) in dry pyridine (90 ml) was added m-aminophenylacetylene (9.2 g, 0.078 mol), and the mixture was heated in an 85° C. oil bath for 2 days. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (375 g, 40 μm mesh) using 5% methanol/CH2Cl2 to afford the title compound as a pink-orange solid (1.9 g, 12%). HRMS: Calcd. 235.0984, Found 235.1000; anal. RP18-HPLC RT: 3.48 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:11][C:12]#N.[OH-:14].[Na+].[OH2:16]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:11][C:12]([OH:16])=[O:14]
Reactant: N#CCc1cc(C2CC2)ccc1Br
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1cc(C2CC2)ccc1Br
Temperature: 25 °C

Procedure:
To a solution of the above nitrile (12 g) in EtOH (400 mL), is added NaOH (36.6 g) and water (200 mL). The reaction is refluxed for 2 hours and cooled to room temperature. After the ethanol is removed under reduced pressure, the residue is cooled to 0° C. and acidified to pH 1–2 with 3 N HCl. The phenylacetic acid is extracted into ethyl acetate and the aqueous layer discarded. The organic phase is washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 2-bromo-5-cyclopropylphenylacetic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:1]([N:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (100 mg) in 1,4-dioxane (3 ml) were sequentially added N,N-diisopropylethylamine (0.34 ml) and benzoyl chloride (0.05 ml), and the solution was stirred for 1 hour at 100° C. The solution was let to cool down, then a saturated aqueous solution of sodium bicarbonate was added thereto, the soution was extracted with ethyl acetate, then sequentially washed with an aqueous solution of 10% citric acid and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate-tetrahydrofuran system) to provide the title compound (133 mg).