Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-]>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.O.COCCOC>[O:12]([C:19]1[CH:20]=[CH:21][C:22]([C:2]2[C:6]3[C:7]([NH2:11])=[N:8][CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1nccc2scc(Br)c12
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: Nc1nccc2scc(-c3ccc(Oc4ccccc4)cc3)c12
Yield: 74.3 %

Procedure:
A mixture of Example 219A (5.43 g, 23.7 mmol), 4-phenoxyphenylboronic acid (6 g, 28.03 mmol), Na2CO3 (3.7 g, 34.9 mmol), Pd(PPh3)4 (5.4 g, 4.7 mmol), DME (96 mL), and water (24 mL) was stirred for 18 hours at 80° C. under nitrogen, poured into 10% aqueous NaCl (400 mL), and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was dissolved in 300 mL of dichloromethane. Silica gel (90 g) was added to the solution and the mixture was concentrated under vacuum. The residual silica gel with the absorbed crude product was transferred to a silica gel column (600 g) and chromatographed (eluent 40% ethyl acetate/heptane) to provide 5.61 g (75%) of the desired product. 1H NMR (DMSO-d6, 400 MHz) δ 7.85 (d, 1H), 7.49-7.44 (m, 5H), 7.29 (d, 1H), 7.22 (t, 1H), 7.16-7.12 (m, 4H), 5.44 (br s, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 156.9, 156.1, 154.5, 148.3, 141.8, 136.1, 130.9, 130.1, 123.9, 123.0, 119.2, 118.4, 118.1, 107.8.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=1[CH3:13])#[CH:2].[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19](Cl)[CH:20]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[Cl:14][C:15]1[C:16]([C:22]#[N:23])=[N:17][CH:18]=[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][C:4]=2[CH3:13])[CH:20]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(OCOC)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (8) (1.0 equiv.), 3,5-dichloropicolinonitrile (9) (0.90 equiv.), CuI (0.10 equiv.), and Pd(PPh3)2Cl2 (0.10 equiv.), and triethylamine (5.0 equiv.) in DMF (0.25M) was degassed and flushed with nitrogen. The reaction mixture was then heated to 60° C. and stirred overnight. After cooling to room temperature, water was added. The mixture was extracted with EA (2×). The combined organic layers were washed with 10% aq NH4OH (2×), brine, and concentrated. The crude material was filtered through a pad of silica (wetted with hexane). The silica was eluted with 10% EA in Hex. The fractions were combined and concentrated. The resulting solids were washed in hot ether and filtered to give a yellow solid, which was used in the next step without further purification. The filtrate was concentrated and purified by Combiflash using 0-10% EtOAc in Hexanes to give 3-chloro-5-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)picolinonitrile (10) as a yellow solid.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6].[CH3:39][C:40]([CH3:42])=O.[BH3-]C#N.[Na+]>CO.CC([O-])=O.[Na+]>[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH:40]([CH3:42])[CH3:39])[CH2:35][CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6]
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)cc3)nc2)CC1
Temperature: 80 °C
Yield: 31 %

Procedure:
To a stirred solution of N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride (50 mg, 0.091 mmol) from Step 4 of Example 17 (65 mg, 0.12 mmol) in 2 mL of pH˜4 MeOH/NaOAc buffer was added acetone (0.3 mL, excess) and NaCNBH3 (25 mg, excess). The resulting mixture was reflux at 80° C. for 3 h. LC-MS indicated that the reaction was 50% complete. The reaction was cooled to rt and the crude product was purified by reverse phase HPLC to give N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpiperidin-4-yloxy)picolinamide as a white solid (20 mg, 31% yield). LC-MS (ESI) m/z 557 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.83 (br. s., 1H), 9.03 (br. s., 1H), 8.35 (d, J=2.83 Hz, 1H), 8.08 (d, J=8.67 Hz, 1H), 7.81 (d, J=9.04 Hz, 2H), 7.65 (dd, J=2.73, 8.76 Hz, 1H), 7.43 (d, J=9.04 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.57 (s, 3H), 2.73 (d, J=6.40 Hz, 3H), 2.23-2.45 (m, 2H), 1.99 (br. s., 2H), 1.53-1.73 (m, 2H), 1.34 (s, 3H), 0.98 (d, J=6.59 Hz, 6H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[O:30][C:29]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22](OCC)=[O:23])[CH2:18][CH2:17]3)=O)=[CH:10][C:9]=2[O:8]1.C(OCC)(=O)C.[OH-].[Na+]>C1COCC1>[CH2:7]1[O:30][C:29]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]3)=[CH:10][C:9]=2[O:8]1
Reactant: CCOC(=O)C1CCN(C(=O)COc2ccc3c(c2)OCO3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC1CCN(CCOc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Lithium aluminum hydride (1.81 g) is suspended in THF (60 ml) under ice-cooling and thereto is added dropwise a solution of ethyl 1-(3,4-methylenedioxyphenoxyacetyl)-piperidine-4-carboxylate (4.00 g) in THF (20 ml). The mixture is stirred at room temperature for 30 minutes, and further stirred under refuxing for 14 hours. To the reaction mixture are added ethyl acetate and a small amount of 1N aqueous sodium hydroxide solution to decompose the excess reducing agent. The mixture is filtered and the filtrate is concentrated under reduced pressure to give the desired product (3.25 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[Br:20]Br>ClCCl>[Br:20][C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Reactant: BrBr
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Br)cnn23)c1

Procedure:
To a 0.01 mole sample of 7-(α,α,α-trifluoro-m-tolyl)-pyrazolo [1,5-a]pyrimidine in 50 ml. of dichloromethane is added 0.01 mole of bromine. After standing, the mixture is worked up as for Example 15 to give the product as crystals, m.p. 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([C@@:13]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([NH:15][CH:16]([CH3:18])[CH3:17])[CH3:14])[CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.I(O)(=O)(=O)=[O:27].P([O-])([O-])(O)=O.[Na+].[Na+]>C(#N)C.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([C@@:13]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([NH:15][CH:16]([CH3:18])[CH3:17])[CH3:14])[CH2:9][CH2:10][C:11]([OH:27])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CC(C)N[C@](C)(c1ccc(Cl)cc1)[C@H](CCCO)c1cccc(Cl)c1
Agent: [Cr+6]
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)N[C@](C)(c1ccc(Cl)cc1)[C@H](CCC(=O)O)c1cccc(Cl)c1

Procedure:
To a solution of (4R,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexan-1-ol (Example 418, Step F, 185 mg, 0.486 mmol) in wet acetonitrile (0.75% water v/v) (3 mL) at ambient temperature was added over three minutes a solution of periodic acid (0.44M in acetonitrile(0.75% water v/v), 2.76 mL, 1.216 mmol) with chromium trioxide (2.43 mg, 0.024 mmol). The reaction was stirred for fifteen minutes. To the reaction was added a solution of 0.6 g disodium hydrogen phosphate in 10 mL water. The aqueous mixture was extracted with toluene. The organic layer was washed with water/brine then with a solution of 0.2 g sodium hydrogen sulfite in 5 mL water. The organic layer was then dried with anhydrous magnesium sulfate and concentrated to afford a peach-colored foamy solid. The product was isolated by chromatography on silica (24 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) eluting with 50-100% ethyl acetate gradient in hexane to afford the title compound as a colorless foam.
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[K].[C:14]([NH2:25])(=[O:24])[C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](N)=[O:18]>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3](=[O:12])[CH2:2][N:25]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1C(N)=O
Reactant: O=C(CCl)Cc1ccc(F)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of example 30 (85 mg, 0.45 mmol) in DMF (1 mL), under a nitrogen atmosphere, was added potassium salt of phthalamide (96 mg, 0.52 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a mixture of ice-water and filtered. The slightly pink solid was washed with water to give the titled compound as a white product (79 mg, 62% yield).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].Br[C:14]1[C:15](=[O:22])[N:16]([CH3:21])[N:17]=[C:18]([Cl:20])[CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:20][C:18]1[CH:19]=[C:14]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:11][N:10]=2)[C:15](=[O:22])[N:16]([CH3:21])[N:17]=1
Reactant: CCS(=O)(=O)c1ccc(N)nc1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
In a 250 mL round-bottomed flask, 5-(ethylsulfonyl)pyridin-2-amine (183 mg, 983 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (263 mg, 1.18 mmol), xantphos (85.3 mg, 147 μmol) and Cs2CO3 (960 mg, 2.95 mmol) were combined with dioxane (10 mL) to give a light brown suspension. The flask was evacuated and filled with argon. Pd2(dba)3 (45.0 mg, 49.1 mmol) was added and the reaction mixture was stirred at 100° C. for 20 h under argon. Cooled to 25° C. and diluted with DCM. The reaction mixture was filtered through celite and the filter cake was washed with DCM until clear. The filtrate was concentrated and purified by flash chromatography (silica gel, 40 g, 0% to 2% MeOH in DCM) to afford 0.323 g (25%) of the title compound as a tan powder. (M+H)+=329/331 m/e. 1H NMR (300 MHz, DMSO-d6) δ: 10.18 (s, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.12 (dd, J=8.9, 2.5 Hz, 1H), 7.74 (d, J=9.1 Hz, 1H), 3.69 (s, 3H), 3.32 (q, J=7.4 Hz, 2H), 1.11 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][O:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:27])([F:28])[F:17])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Reactant: OCc1cccc(C(F)(F)F)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and (3-trifluoromethyl-phenyl)-methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10](=[CH2:12])[CH3:11]>>[C:10]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:9]
Reactant: C=C(C)C
Reactant: Oc1ccc(Br)cc1
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 80 °C

Procedure:
80.00 g (426.0 mmol) of 4-bromophenol and 8.00 g of Dowex 50WX8 sulphonic acid resin are mixed in a 250 ml three-necked flask. The mixture is heated to 80° C. and a stream of isobutylene is passed through for 30 hours. The reaction mixture is cooled and the residue is purified by passing through a silica column eluted with a mixture composed of 95% dichloromethane and of 5% heptane. 88.00 g (90%) of the expected compound are collected in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:11]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:12](=[O:14])[NH:13][C:9]=2[C:8]2[O:7][CH:6]=[CH:5][C:4]=2[C:3]=1[F:23].[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1.C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCCCCC>[CH:24]1([S:27]([IH:21][C:18]2[CH:19]=[CH:20][C:15]([N:11]3[C:10]4[C:2]([F:1])=[C:3]([F:23])[C:4]5[CH:5]=[CH:6][O:7][C:8]=5[C:9]=4[NH:13][C:12]3=[O:14])=[C:16]([F:22])[CH:17]=2)(=[O:29])=[O:28])[CH2:26][CH2:25]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc([IH]S(=O)(=O)C2CC2)cc1F
Temperature: 30 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
TEA (0.062 mL, 0.4465 mmol) was added to a solution of 4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-benzofuro[6,7-d]imidazol-2(3H)-one (I-32a: 0.064 g, 0.1488 mmol) in dry DCM (5 mL) at 0° C. This was followed by the addition of cyclopropanesulfonyl chloride (0.0331 g, 0.222 mmol) and catalytic amount of DMAP. The reaction mass was stirred for 3 hours at 20-40° C. The reaction was monitored by TLC (25% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 40 mg of the product (50% yield). 1H NMR (CDCl3, 300 MHz): δ 7.77 (t, 2H), 7.65 (d, 1H), 7.29 (d, 1H), 6.99 (d, 1H), 3.31-3.38 (m, 1H), 1.62-1.74 (dd, 2H), 1.23-1.30 (m, 2H). LCMS: 93.99%, m/z=534.6 (M+1). HPLC: 96.34%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]=1[OH:19].[CH2:20]=O>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]2[O:19][CH2:20][N:10]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1cccc(CNCCc2ccccc2)c1O
Solvent: C1COCCO1
Product: COc1cccc2c1OCN(CCc1ccccc1)C2

Procedure:
To 5 ml. of dioxane are added 0.6 g. of 2-methoxy-6-phenethylaminomethylphenol prepared as above and 1 ml. of 37 % formalin. The mixture is heated on reflux for 3 hours and distilled to remove the solvent. The residue is purified by column chromatography on silica gel with a mixture of acetone and benzene (1:4). The resultant oil is left standing at cool place for 2-3 days to be solidified. Recrystallization from normal hexane yields 8-methoxy-3-phenethyl-3,4-dihydro-2H-1,3-benzoxazine as colorless needles melting at 63°-66° C. Yield: 0.4 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[OH:21])[CH:16]=O>>[OH:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9](=[O:11])[CH3:10])[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[OH:21]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)Cc1ccc(C)cc1
Product: CC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccc(C)cc1

Procedure:
The procedure described in Example 1 was repeated by using 0.81 g of 3-(4-methylphenyl)-2-propanone and 0.92 g of 3,4-dihydroxy-5-nitrobenzaldehyde. Yield 0.82 g, mp 189°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.C(=O)(O)O.[NH2:15][C:16]([NH2:18])=[NH:17].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:17]=[C:16]([NH2:18])[N:15]=[CH:7]2
Reactant: N=C(N)N
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ncc2cc(Cl)ccc2n1
Yield: 50 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzaldehyde (109) (5 g, 31.6 mmol) and guanidine carbonate (7.5 g, 41.1 mmol) was heated at 140° C. in DMA (50 mL) for 3 h. 100 ml water was added and after refrigeration, a solid was isolated by filtration, and dried under vacuum to give the product (110) (2.8 g, 15.8 mmol, 50% yield). ESI-MS (M+1): 180 calc. for C8H6ClN3 179.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].C(O)C.[H][H]>O.[Ni]>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
2,3-Dichloro-6-nitroaniline (20.11 g, 97.14 mmol), Raney-nickel (4.78 g of a 50% slurry in water), and ethanol (250 mL) were combined in an autoclave which was pressurized to 150 psig with hydrogen. The resulting reaction mixture was allowed to stir at RT overnight. The mixture was then filtered through a pad of celite, which was subsequently washed with several portions of methanol, and the solvents were removed by rotary evaporation to leave a dark brown solid. The solid was slurried and in hexanes and was collected on a Büchner funnel to afford 16.31 g (95%) of a brown solid. MS (EI): m/z 177.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[C:8](=[O:14])[N:9]2[CH3:13])=[CH:4][N:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH2:34])([O-:27])=[O:26].C([O-])(C)(C)C.[K+]>CN(C)C=O.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:7]2[C:8](=[O:14])[N:9]([CH3:13])[C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N+:25]([O-:27])=[O:26])[C:11]=3[CH3:12])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COc1cc(OC)cc(-c2cc3cnc(Cl)c(C)c3n(C)c2=O)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc3cnc(Nc4ccccc4[N+](=O)[O-])c(C)c3n(C)c2=O)c1
Temperature: 100 °C
Yield: 14.5 %

Procedure:
A mixture of 7-chloro-3-(3,5-dimethoxyphenyl)-1,8-dimethyl-1,6-naphthyridin-2(1H)-one (800 mg, 2.32 mmol), 2-nitrobenzenamine (320 mg, 2.32 mmol), Pd2(dba)3 (100 mg), John-Phos (100 mg) and potassium tert-butanolate (480 mg, 4.64 mmol) in N,N-dimethylformamide (10 mL) was heated in sealed tube at 100° C. under microwave for 1 h. LCMS monitored the reaction was completed. The mixture was concentrated and purified by Prep-HPLC to get the title compound (150 mg, 15%) as a brown solid. MS (ES+) C24H22N4O5 requires: 446. Found: 447 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].[O:4]([CH:11]1[CH2:20][CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([C:21]([O:23]C)=[O:22])[CH:14]=[CH:13][C:12]1=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCCC1.CO>O>[O:4]([CH:11]1[CH2:20][CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([C:21]([OH:23])=[O:22])[CH:14]=[CH:13][C:12]1=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)CCCC2Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CCCC2Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Lithium hydroxide hydrate (0.04 g, 1.0 mmol) was added to a solution of methyl 5-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.04 g, 0.14 mmol) in a mixed solution of tetrahydrofuran (6.0 mL), methanol (2 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was removed in vacuo. Hydrochloric acid aqueous (3 mol/L) was added to make pH 3-5, and the mixture was extracted with dichloromethane. The combined organic phase was washed with water (20 mL×3), dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to dryness to give pure product 5-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid as a white solid (0.032 g, 86%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[OH:12].C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>CCCCCC.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:12][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1
Reactant: C1=COCCC1
Reactant: Oc1ncnc2ccc(I)cc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Ic1ccc2ncnc(OC3CCCCO3)c2c1
Temperature: 112.5 °C

Procedure:
In a 4-neck glass flask provided with a mechanical stirrer, condenser and thermometer 30 g of 6-iodoquinazoline-4-ol (110 mmoles), 300 mL of toluene dried on molecular sieves, 1.26 g (0.84 mL) of trifluoroacetic acid (0.1 mol. equiv.) and 79.4 g (80 mL) of 3,4-dihydro-2H-pyran (DHP) (944 mmoles; 8.6 mol. equiv.) were introduced, under nitrogen. Stirring was carried out to reflux (T=110-115° C.) for 2-3 hours and the reaction was controlled under TLC with Hexane/Ethyl Acetate (2:8) eluent. Upon completing the reaction a homogeneous solution was obtained which was cooled to ambient temperature and washed using 2×120 mL of saturated solution of sodium chloride. The organic phase was concentrated under vacuum to 40-45° C. ext T up to residue.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O.O>[Si:22]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([OH:12])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C(=O)O)ccc1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.8 %

Procedure:
To a solution of vanillic acid (2.0 g, 11.89 mmol) in N,N-dimethylformamide (50 ml), imidazole (4.04 g, 59.45 mmol) and tert-butyldimethylchlorosilane (4.48 g, 29.72 mmol) were added. The reaction was stirred at room temperature for 24 hours. The mixture was poured in water (70 ml) solution and extracted with diethyl ether (3×70 ml) The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, column FLASH 40+M™ KP-C18 HS, eluent: gradient acetonitrile/water 65/35 (600 ml), to acetonitrile/water 80/20 during 1200 ml). The product (0.70 g) was obtained.