Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH:7]=O.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].N1CCCC1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[Na]>C1(C)C=CC=CC=1>[C:9]([C:11](=[CH:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: Cc1nnsc1C=O
Reactant: CCOC(=O)CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)C(C#N)=Cc1snnc1C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To 50 ml of toluene were added 1.5 g (12 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbaldehyde, 1.5 g (13 mmol) of ethyl cyanoacetate, 0.40 g (6.0 mmol) of pyrrolidine and 0.20 g (1.2 mmol) of tosylic acid. In a reactor equipped with a Dean-Stark dehydrating apparatus, the mixture obtained above was stirred for 2 hours with heating under reflux. After the reaction was completed, a saturated aqueous solution of sodium Achloride was added to the reaction mixture, the objective product was extracted with ethyl acetate, the organic layer was washed successively with dilute hydrochloric acid, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.73 g of the objective compound was obtained.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][NH2:18]>CCO>[C:2]1([C:1]2[C:9]3[CH:13]=[CH:12][S:11][C:10]=3[C:14](=[O:16])[NH:17][N:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1ccsc1C(=O)O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c2ccsc12
Temperature: 25 °C

Procedure:
To 3-benzoylthiophene-2-carboxylic acid (1.00 g, 4.31 mmol) and EtOH (15 mL) was added hydrazine (1.35 ml, 43.1 mmol). A water condenser was attached to the reaction flask and the mixture was heated to reflux under nitrogen for 3.5 hours. The reaction was cooled to RT, the resulting solids filtered and washed with water, and dried to yield 4-phenylthieno[2,3-d]pyridazin-7(6H)-one as a white solid. MS m/z=229 [M+1]+. Calc'd for C12H8N2OS: 228.27.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:5]=1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].S(OC)(O[CH3:26])(=O)=O.O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:5]=1[N:6]([CH3:26])[S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:8])=[O:9]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.07 g (1.75 mmol)) in DMF (2.0 ml), 2′,4′-dichloro-p-toluenesulfonanilide (0.50 g (1.58 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.17 ml (1.80 mmol)) was added dropwise. After 15 hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The crystals separated were filtered and washed with diisopropyl ether to give 0.38 g (73%) of the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:20]=[CH2:21])[C@H:12]([CH3:22])[N:11]1[C:23](=[O:33])[CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:34].[Na+].OO>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][OH:34])[C@H:12]([CH3:22])[N:11]1[C:23](=[O:33])[CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(F)cccc1Cl)[C@H]2C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(CCO)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dissolve 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethan-1-one (1.54 g, 3.15 mmol) in THF (31 mL). Cool to 0° C. Add BH3 (6.3 mL, 6.3 mmol, 1M in THF). Stir 4 h at room temperature. Cool to 0° C. Add NaOH (12.6 mL, 3 M in water) and H2O2 (1.92 mL, 30% wt/wt % in water). Stir overnight at room temperature. Add ethyl acetate, wash with saturated NaHCO3 solution and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-60%) to give 1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethan-1-one as a white foam (1.08 g, 2.13 mmol). MS (m/z): 506.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([CH3:13])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1cc(Br)c2c(c1)CC(CO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(Br)c3O2)cc1
Yield: 83.3 %

Procedure:
Treatment of 2-bromo-4-methylphenol (19.09 g, 102 mmol) with potassium carbonate (56.0 g, 400 mmol) and allyl bromide (15.96 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-methylphenol. Treatment of 2-allyl-6-bromo-4-methylphenol (5.21 g, 23.0 mmol) with 3-chloroperoxybenzoic acid (9.13 g, 34.50 mmol, 77%) followed by potassium carbonate (7.9 g, 57.5 mmol) generally according to the procedure described for Intermediate 9 afforded 2.14 g (43%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (2.41 g, 10.0 mmol) with p-toluenesulfonyl chloride (2.1 g, 11.0 mol) generally according to the procedure described for Intermediate 10 gave 3.31 g (84%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.25 g, 0.63 mmol) and phenylboronic acid (0.23 g, 1.89 mmol) generally according to the procedure described for Intermediate 154 afforded 0.23 g, (93%) of (±)-(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.15 g (97%) of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.297 g, 1.13 mmol) according to the procedure described in Example 21 afforded 0.106 g (61%) of (±)-[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 227-228° C.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[C:5](=[CH:10][C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[CH3:29][NH2:30]>C(O)CO>[NH:21]([C:11]1[CH:10]=[C:5]2[C:6](=[O:7])[N:30]([CH3:29])[C:3](=[O:28])[C:4]2=[CH:13][C:12]=1[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)OC
Reactant: CN
Solvent: OCCO
Product: CN1C(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc2C1=O

Procedure:
Analogously to Example 1, 376 mg (1 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester in 33 ml of ethylene glycol are heated at 120° and, with stirring, methylamine is passed through the mixture for 18 hours. Thereaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of slightly yellow crystals, FAB-MS: 344 [M+ +H], m.p. 195°-196° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][C:42]1([CH3:50])[CH2:48][CH2:47][C:46](=[O:49])[O:45][C:43]1=[O:44]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:46](=[O:49])[CH2:47][CH2:48][C:42]([CH3:50])([CH3:41])[C:43]([OH:45])=[O:44])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC1(C)CCC(=O)OC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)CCC(C)(C)C(=O)O)CCC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 150 mg of the crude product of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate and 0.094 mL of triethylamine in 3 mL of THF was added 62.3 mg of 2,2-dimethylglutaric anhydride at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and then washed with 1 M hydrochloric acid, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 5-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-2,2-dimethyl-5-oxopentanoic acid (colorless foamy substance, 225 mg) as a crude product. ESI+: 587
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2=[CH:8][C:9](=[O:14])[CH:10]=[CH:11][CH2:12][CH2:13]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>C(#N)C>[N:22]([CH:11]1[CH2:10][C:9](=[O:14])[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:13][CH2:12]1)=[N+:23]=[N-:24]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1=CC(=O)C=CCC1
Solvent: CC#N
Product: Cn1ncc([N+](=O)[O-])c1C1=CC(=O)CC(N=[N+]=[N-])CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a solution of (2E,6Z)-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohepta-2,6-dienone (690 mg, 2.95 mmol) in acetonitrile (10 mL) was added trimethylsilyl azide (1 mL, 7.57 mmol) and Amberlite™ IRA900F resin (590 mg, 1.47 mmol). The reaction mixture was stirred at 40° C. for 5 hr, cooled to room temperature, filtered and concentrated under reduced pressure to give (E)-6-azido-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-2-enone as a yellow oil. To a solution of this oil (810 mg, 2.93 mmol) in THF (20 mL) and water (6 mL) was added sodium borohydride (166 mg, 4.40 mmol). The mixture was stirred at room temperature for 18 hr before being diluted with water (50 mL). The mixture was extracted with EtOAc (100 mL) and the organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (E)-6-azido-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-2-enol as a yellow oil. This oil (810 mg, 2.91 mmol) was dissolved in THF (15 mL) and added to a suspension of polymer-supported triphenylphosphine (3.1 g, 5.76 mmol) in THF (45 mL) and water (1.5 mL). The mixture was gently stirred at 60° C. for 18 hr, cooled to room temperature and concentrated under reduced pressure. The residue was diluted in DCM (30 mL) and di-tert-butyl dicarbonate (754 mg, 3.46 mmol) and DIPEA (1.51 mL, 8.64 mmol) were added. The mixture was stirred at room temperature for 5 hr, diluted with DCM (50 mL) and quenched with a saturated solution of sodium hydrogencarbonate (50 mL). The organic layer was washed with water (50 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (E)-tert-butyl 5-(1-methyl-4-nitro-1H-pyrazol-5-yl)-3-oxocyclohept-4-enylcarbamate as a white foam (620 mg, 59% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 6.03-5.99 (m, 1H), 4.82-4.60 (m, 2H), 3.86-3.82 (m, 4H), 2.82-2.34 (m, 1H), 2.29-2.35 (m, 1H), 2.34-2.20 (m, 2H), 2.15-2.04 (m, 1H), 1.85-1.51 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: C([O:3][C:4]([CH:6]([C:18](OCC)=[O:19])[CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C)C)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:7]([CH:6]([CH2:4][OH:3])[CH2:18][OH:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCC(C)C(C(=O)OCC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCC(CO)CO

Procedure:
Quantities: compound from Example 5 (76.5 g, 0.28 mol) and lithium aluminum hydride (23 g, 0.6 mol). The experimental procedure was as described in Example 6.
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][CH:7]([C:9]1[N:10]=[C:11]([CH2:31][CH2:32][CH3:33])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:13](=[O:15])[CH:14]=1)[CH3:8].[Br:34]Br>C(O)(=O)C>[Br:34][C:14]1[C:13](=[O:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:11]([CH2:31][CH2:32][CH3:33])=[N:10][C:9]=1[CH:7]([F:6])[CH3:8]
Reactant: BrBr
Reactant: CCCc1nc(C(C)F)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(C(C)F)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of sodium acetate (1.2 g) and 4′-{[4-(1-fluoroethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (5 g) in acetic acid (50 mL) was added bromine (0.72 mL), and the mixture was stirred for 4 hr. Acetic acid was removed in vacuo, and the mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (5 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(CC)C(C)C)(C)C.[C:32]1([C:38]2[O:42][N:41]=[C:40]([NH:43][C:44](=O)[O:45]C3C=CC=CC=3)[CH:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:44]([NH:43][C:40]2[CH:39]=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:42][N:41]=2)=[O:45])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(-c2ccccc2)on1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)on4)c3)c2cc1OC
Temperature: 50 °C
Yield: 32 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol), in tetrahydrofuran (1.5 mL) was treated with N,N-diisopropylethylamine (78 μl, 0.45 mmol), 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate from the previous step (126 mg, 0.45 mmol). The reaction mixture was heated to 50° C. for 2.5 h. After cooling to room temperature, the mixture was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The water phase was back extracted three times with dichloromethane and the organics combined and dried (MgSO4). Concentration under reduced pressure gave a residue which was purified by preparative HPLC (phenylhexyl reverse phase column). The obtained solid was triturated with anhydrous diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea as a white solid (47.16 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.08 (s, 1H), 8.58 (s, 1H), 7.86 (d, 2H), 7.87-7.51 (m, 4H), 7.51-7.40 (m, 2H), 7.31-7.21 (m, 3H), 7.00 (d, 1H), 4.00 (s, 6H); LC-MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[CH:18][CH:17]=1.C([O-])(=O)C.[NH4+]>O>[CH2:1]([O:8][C:9]1[C:10]2=[N:15][C:22]([C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)=[CH:23][C:24](=[O:25])[N:11]2[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: Nc1ncccc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=c1cc(-c2ccncc2)nc2c(OCc3ccccc3)cccn12
Temperature: 150 °C
Yield: 19 %

Procedure:
To a mixture of 5.02 mmol) of 3-(benzyloxy)pyridin-2-amine and 1.16 g (6.02 mmol) of ethyl 3-(4-pyridinyl)-3-oxopropionate were added 0.774 (10.04 mmol) of ammonium acetate. The reaction mixture was heated at 150° C. for 12 hours. After cooling, water was added and the mixture was extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and evaporated. The residue obtained was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol n the proportions 99/1 to 90/10 to give 0.32 g (19%) of the desired compound which was transformed into the hydrochloride salt in the usual manner to give the pure product as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:15](=[O:16])[C@@H:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: C[C@H](NC(=O)C1COCCN1c1nc(Cl)ncc1Br)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CC(c1ccccc1)N1C(=O)[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 120 °C
Yield: 21.6 %

Procedure:
To a 5 mL microwave vial were added 4-(5-bromo-2-chloropyrimidin-4-yl)-N—((S)-1-phenylethyl)morpholine-3-carboxamide (PREPARATION x46, 0.394 g, 0.926 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.024 g, 0.042 mmol), and palladium (II) acetate (6.23 mg, 0.028 mmol). The vessel was evacuated, refilled with nitrogen, and sealed. Dioxane (3.9 mL) was added and the mixture was heated in a microwave to 120° C. for 3 hours. Additional catalyst was added and the reaction mixture was heated in the microwave to 120° C. for another 6 hours. The reaction mixture was then partitioned between aqueous saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated. The dark brown crude product was purified by normal phase column chromatography (SiO2, 60 gram) eluting with a gradient of 50-100% EtOAc in hexanes over a 20 minute period. The product-containing fractions were combined and concentrated to give the title compound as a white foam (69 mg, 22%). ESI-MS m/z [M+H]+ calc'd for C17H17ClN4O2, 345.10. found 345.3.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][OH:34])[CH:31]=1>>[OH:34][CH2:33][CH2:32][N:30]1[CH:31]=[C:27]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH:28]=[N:29]1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: Nc1cnn(CCO)c1
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)Nc3cnn(CCO)c3)ccc1OCC2

Procedure:
Following the procedure for 126, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 4-amino-1-(2-hydroxyethyl)pyrazole to give 125 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.50 (d, J=2.2 Hz, 1H); 8.38 (s, 1H); 8.10 (s, 1H); 7.96 (s, 1H); 7.78-7.73 (m, 1H); 7.56 (s, 1H); 7.22 (d, J=8.4 Hz, 1H); 6.81 (s, 1H); 5.60-5.47 (m, 1H); 4.57 (t, J=5.7 Hz, 2H); 4.23 (t, J=4.8 Hz, 2H); 4.01 (t, J=4.8 Hz, 2H); 3.20 (t, J=5.7 Hz, 2H); 1.57 (d, J=6.6 Hz, 6H). 1 Exchangeable proton not observed. LCMS: RT=9.27 min, M+H+=449
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH:26][CH:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]2)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1

Procedure:
A mixture of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (3.98 g, 19.19 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 24.94 mmol, 1.3 equiv) in anhydrous DMF (100 mL) was heated to 60° C. for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture extracted from a 1 M NaOH (100 mL) solution with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4 and the product purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.46 g (49%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.42-1.51 (m, 2H), 1.47 (s, 9H), 2.00-2.05 (m, 2H), 2.90-3.01 (m, 2H), 3.92 (s, 3H), 4.05-4.10 (m, 2H), 4.19 (br s, 1H), 7.10 (s, 1H), 7.17 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ28.30, 31.23, 42.41, 48.00, 52.88, 79.61, 106.38, 153.58, 154.61, 161.21, 163.75, 164.23. MS (ISP): 371.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([I:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:15])[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:4]2[C:13]([I:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:15])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(I)c(C2CC2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2CC2)c(I)cc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound 86.2, 15.0 g, 47.5 mmol) in methanol (150 mL). A solution of sodium hydroxide (5.70 g, 143 mmol) in water (75 mL) was added and the resulting solution was stirred for 4 h at 60° C., then cooled to room temperature. The volatiles were removed under reduced pressure and the remaining solution was adjusted to pH 3 with aqueous hydrogen chloride (12 M). The mixture was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with NH4Cl (aq.) (2×400 mL) and brine (400 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 13.0 g (91%) of the title compound as a light yellow solid.