Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[C:45]([C:46]([F:49])([F:48])[F:47])=[C:44]([C:50](O)=O)[CH:43]=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:50]([C:44]2[CH:43]=[N:42][N:41]([CH3:40])[C:45]=2[C:46]([F:49])([F:47])[F:48])[O:16][N:15]=1
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cnn(C)c2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.0194 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1 H), 7.88 (d, J=0.9 Hz, 1 H), 7.53 (d, J=8.9 Hz, 1 H), 7.45 (d, J=8.6 Hz, 1 H), 5.40 (s, 2 H), 4.01 (s, 3 H), 2.96 (t, 2 H), 1.87-1.68 (m, 2 H), 1.03 (t, 3 H); MS (ES) m/z 449 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH2:16][CH3:17])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@H:23]1[O:25][CH2:24]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:22]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[O:12][C:13]([CH2:16][CH3:17])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:23]1[O:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CCc1nnc(-c2cc3c(O)cccc3o2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)o1
Yield: 98.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4-hydroxybenzo(b)furan-2-yl)-5-ethyl-1,3,4-oxadiazole (3.1 g) obtained in Starting Material Synthesis Example 75, (S)-glycidyl nosylate (3.5 g) and potassium carbonate (5.6 g), the title compound (3.8 g) was obtained as pale-yellow crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]([CH3:29])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].[F-].[Cs+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]([CH3:29])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)nn2C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc2c(c1)c(-c1cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n1)nn2C
Reaction time: 48 h
Yield: 51.7 %

Procedure:
To a solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (46.3 mg, 88.2 μmol) in acetonitrile (5 mL) was added CsF (134 mg, 882 μmol) and 18-crown-6 (70.0 mg, 265 μmol), the reaction mixture was heated to reflux with stirring for 48 h, reaction diluted with dichloromethane (20 mL), filtered over celite and concentrated. The residue was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane/MeOH and cyclohexane added to allow solid formation, which was separated by decantation and dried to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 45.6 μmol, 51.7%) as a yellow solid. MS (M+H)+=377; 1H NMR (DMSO-d6) δ: 8.96 (s, 1H), 8.34 (s, 1H), 7.98 (br. s., 1H), 7.79 (br. s., 1H), 7.68 (d, J=9.1 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 4.93 (br. s., 1H), 4.13 (s, 3H), 3.86 (s, 3H), 3.60 (d, J=4.9 Hz, 2H), 1.39 (s, 6H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C:38]#[C:39][CH2:40][N:41]1[C:45](=[O:46])[C:44]([CH3:57])([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH:54]([CH3:56])[CH3:55])=[CH:49][CH:48]=2)[NH:43][C:42]1=[O:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>O1CCCC1>[OH:36][CH2:37][C:38]#[C:39][CH2:40][N:41]1[C:45](=[O:46])[C:44]([CH3:57])([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH:54]([CH3:55])[CH3:56])=[CH:49][CH:48]=2)[NH:43][C:42]1=[O:58]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)N(CC#CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C2(C)NC(=O)N(CC#CCO)C2=O)cc1
Yield: 66.5 %

Procedure:
A solution of tetrabutylammonium fluoride in tetrafuran (602 μL) was added to a mixed solution of 3-[4-(t-butyl-diphenylsilyloxy)-2-butynyl]-5-methyl-5-[4-(1-methylethoxy)phenyl]imidazolidine-2,4-dione (300 mg, 547 μmol) in tetrahydrofuran (5 mL) at room temperature. After completion of the reaction, 1 mol/L hydrochloric acid (0.5 mL) was added, followed by extraction with ethyl acetate-water. The organic layer was washed with a saturation sodium chloride solution and then dried over sodium sulfate. The solvent of the filtrate was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 115 mg of the title compound (yield: 90%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>ClCCl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:27][CH2:26][CH2:24][OH:25])=[O:20])=[CH:17][CH:16]=1
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)c1ccc(-c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
Triethylamine (0.14 ml) was added to a suspension of 4-pyridine-2-ylbenzoylchloride hydrochloride (254 mg) in dichloromethane (2 ml). To the mixture a solution of ethanolamine (0.060 ml) in dichloromethane (3 ml) was added. This mixture was stirred for 30 minutes. At the end of this time the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate and concentrated to afford crystals. The crystals were washed with isopropyl ether to afford the title compound (111 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]Cl>>[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[C:20](=[O:28])[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Fc1cc(F)cc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4ccccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 491.5(M+H+).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]2[NH:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[C:11]=3[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.I[CH3:24]>CN(C)C=O.C(OCC)C>[CH:3]1([C:8]2[N:12]([CH3:24])[C:11]3[C:13]([O:21][CH3:22])=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[N:9]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CI
Reactant: COC(=O)c1ccc(OC)c2nc(C3CCCC3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1nc(C1CCCC1)n2C
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A suspension of sodium hydride (0.55 g, 60% dispersion in mineral oil) in dimethylformamide (1 ml), cooled to 0° C., was treated with a solution of methyl 2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [3.61 g, Reference Example 3(t)]) in dimethylformamide (34 ml). The resulting mixture was stirred for 40 minutes then treated with iodomethane (0.82 ml). The reaction mixture was allowed to stand at 4° C. for 2 days then diluted with diethyl ether, then washed with brine, then dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica to give methyl 2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate (3.18 g), [NMR (CDCl3): δ 1.70 (m, 2H), 1.90(m, 2H), 2,16(m, 4H), 3.25(m, 1H), 3.95(s, 6H), 4.00(s, 3H), 6.64(d, J=8 Hz, 1H), 7.89(d, J=8 Hz, 1H)]; and methyl 2-(cyclopentyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate (0.37 g), [M+288, NMR (CDCl3): δ 1.70(m, 2H), 1.90(m, 2H), 2.14(m, 4H), 3.25(m, 1H), 3.92(s, 6H), 4.02(s, 3H), 6.64(d, J=8 Hz, 1H), 7.75(d, J=8 Hz, 1H)].
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:21][CH3:22].[C:23]([C:27]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[N:29]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[N:39][CH:40]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:16]4[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:21][CH3:22])=[O:34])[N:29]([C:35]2[CH:40]=[N:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cn1
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1N
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(C)nc34)cc2SC)cn1
Yield: 35 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 5-(3-tert-butyl-5-isocyanato-1H-pyrazol-1-yl)-2-methoxypyridine to afford the title compound (33 mg, 35%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1)=[CH2:19]
Reactant: CCn1ncc(Br)c1-c1csc(C(=O)OC)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1cnn(CC)c1-c1csc(C(=O)OC)c1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A mixture of methyl 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (200 mg, 0.64 mmol), Pd(Ph3P)4 (73.3 mg, 0.06 mmol), and tributyl(ethenyl)stannane (302 mg, 0.95 mmol) was heated at 90° C. for 1 h under N2 in a sealed tube. The mixture was purified on Silica (10%-20% EtOAc in Hex) to give the title compound (151 mg, 76%): LC-MS (ES) m/z 263 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:5][CH:4]=1
Reactant: OCc1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of the product of Step A (4.44 g, 22.1 mmol) in CH2Cl2 were added N,N-diisopropylethylamine (1.2 eq.), 4-dimethylaminopyridine (0.1 eq), and tert-butyldimethylsilyl chloride (1.2 eq). The reaction mixture was stirred for 1.5 hours at room temperature, then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluted with 2.5% ethyl acetate/hexane to afford 5.0 g (71%) of the titled product.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[CH:15]1([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:23])[C:3]([OH:24])=[O:2])=[CH:10][CH:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C(=O)c1ccc(OCCOC2CCCCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOC2CCCCCCC2)cc1
Yield: 76.5 %

Procedure:
A mixture of 4-[[2-(cyclooctyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.3 g) in methanol (10 mL) and 0.5N sodium hydroxide (4 mL) was treated as in Example 19. Extraction with dichloromethane provided material which was crystallized from diethyl ether-hexane to give 0.22 g of colorless 4-[[2-(cyclooctyloxy)ethyl]oxy]-alphaoxobenzeneacetic acid, mp 64°-65° C.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:12](=[O:32])[CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[N:27][C:26]([CH3:29])=[N:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[CH:8]=[CH:9][C:10]=1[Cl:11].[Cl-].[NH4+]>C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]([OH:32])([CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[N:27][C:26]([CH3:29])=[N:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[CH3:1])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: COc1cc(C#CCCCC(=O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C#CCCCC(C)(O)c2ccc(Cl)c(Cl)c2)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (12% THF solution, 550 μL) was added to a mixture of 1-(3,4-dichlorophenyl)-6-[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]hex-5-yn-1-one (198 mg) in THF (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Methylmagnesium bromide (12% THF solution, 550 μL) was added to the reaction mixture under ice-cooling, and the mixture was stirred for 15 min under ice-cooling. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (177 mg).
Reaction SMILES: C(C[C:4]1[CH:5]=[CH:6][C:7]2[O:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](=[O:17])[C:8]=2[CH:18]=1)#N.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl>[O:17]=[C:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[O:16][C:7]2[CH:6]=[CH:5][C:4]([CH2:20][C:19]([OH:22])=[O:21])=[CH:18][C:8]1=2
Reactant: CC(=O)O
Reactant: N#CCc1ccc2oc3ncccc3c(=O)c2c1
Agent: Cl
Product: O=C(O)Cc1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A solution of 12 g of 7-cyanomethyl-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine in a mixture of 60 ml of acetic acid and 25 ml of concentrated hydrochloric acid is heated under reflux on an oil bath for 24 hours. After concentration, water is added to the residue, and further a 10% sodium hydroxide solution is added to dissolve the residue. An insoluble material is removed by extraction with chloroform. The aqueous layer is made acid with acetic acid, and the resulting crystalline precipitate is filtered off and recrystallized from aqueous dimethylformamide to give 8.6 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-7-yl-acetic acid as white needles melting at 244°- 245°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([F:23])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[I-].[NH2:25][N+:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([F:23])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:15]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cc(C#Cc2ccnc(Cl)n2)ccc1F)C(F)(F)F
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of N-{5-[(2-chloro-4-pyrimidinyl)ethynyl]-2-fluorophenyl}-2,2,2-trifluoroacetamide (4.6 g, 13 mmol) in DMF (100 mL) was added aminopyridinium iodide (5.9 g, 27 mmol) and K2CO3 (5.5 g, 40 mmol). After stirring 2 h at rt, the reaction mixture was diluted with diethyl ether (250 mL) and EtOAc (250 mL), and washed with water. The organic layer was adsorbed to silica gel and purified by column chromatography to afford the desired product (3.2 g, 55%) as a tan solid. 1H NMR (400 MHz, CDCl3): δ 8.57 (m, 2H), 8.31 (d, J=5.5 Hz, 1H), 8.14 (s, 1H), 7.47 (m, 2H), 7.31 (t, J=9.4 Hz, 1H), 7.04 (t, J=6.8 Hz), 6.99 (d, J=5.3 Hz, 1H). ES-LC/MS m/z=436 [M+H]+.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](O)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].N1C=CC=CC=1.S(Cl)(Cl)=O>ClC1C=CC=CC=1>[C:1]([NH:10][NH:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NNC(=O)c1ccccc1O
Reactant: CCCCCCCCCCCC(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: CCCCCCCCCCCC(=O)NNC(=O)c1ccccc1O
Reaction time: 1 h
Yield: 53 %

Procedure:
15.2 g (0.1 mol) of salicylic acid hydrazide and 20.0 g (0.1 mol) of lauric acid are suspended in 200 ml of chlorobenzene, 2.0 g (0.025 mol) of pyridine are added and the mixture is heated to the boil. 13.1 g (0.11 mol) of thionyl chloride are added dropwise at this temperature. The product separates out initially as a turbidity and then as a flocculent precipitate. After boiling for 1 hour the mixture is cooled and the product is filtered off and washed with a little benzene and then with petroleum ether. N-Salicyloyl-N'-lauroyl-hydrazine of melting point 158° C is thus obtained in a yield of 53%. The product can be recrystallised from ethylene glycol monomethyl ether.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[C:16]([CH2:18][NH:19]C(OC(C)(C)C)=O)[O:15][N:14]=1)=[O:12])[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[C:16]([CH2:18][NH2:19])[O:15][N:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(CN)on1
Temperature: 25 °C
Reaction time: 4 h
Yield: 154615.8 %

Procedure:
Trifluoroacetic acid (2.1 ml, 29 mmol) was added to a solution of 3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 790 mg, 2.9 mmol) in DCM (15 ml). The mixture was stirred at ambient temperature for 4 hours then the volatiles removed by evaporation. The residue was triturated with diethyl ether to give the title compound (763 g, 93%). NMR (DMSO): 1.31 (t, 3H), 4.37 (m, 2H), 6.97 (s, 1H), 8.64 (s, 3H); m/z 171 (MH)+.
Reaction SMILES: C([Mg]Br)C.[Cl:5][C:6]1[N:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16](I)[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1.CN(C)[CH:23]=[O:24]>O1CCCC1>[Cl:5][C:6]1[N:20]=[CH:19][C:9]2[C:10]3[N:11]([CH:15]=[C:16]([CH:23]=[O:24])[N:17]=3)[CH2:12][CH2:13][O:14][C:8]=2[CH:7]=1
Reactant: CN(C)C=O
Reactant: Clc1cc2c(cn1)-c1nc(I)cn1CCO2
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: O=Cc1cn2c(n1)-c1cnc(Cl)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
Ethylmagnesium bromide (3.0 M in Et2O, 100 mmol, 33.3 mL) was added dropwise to a solution of 9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine (10.0 g, 28.8 mmol) in tetrahydrofuran (173 mL) at −20° C. The mixture was maintained at this temperature 20 min and then allowed to warm to ambient temperature for a 1 hr period. At this point, the reaction was re-cooled to −20° C. and N,N-dimethylformamide (8.9 mL, 115 mmol) was added to the mixture. Stirring was continued for 16 h before quenching with saturated aqueous ammonium chloride solution (220 mL) and further dilution with EtOAc (250 mL). The phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic portions were washed once with brine, dried over MgSO4, filtered and concentrated in vacuo. This provided 7.08 g (98% yield) of 9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine-2-carbaldehyde as a yellow solid in >95% purity as determined by analytical HPLC. MS (ESI+): m/z 249.8 (M+H+), calc. 249.65
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25](=[O:26])[NH:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:13][CH:12]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1cncnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cncnc2n1-c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of N4-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyrimidine-4,5-diamine (55 mg) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (53 mg) in DMF (5 mL) was stirred overnight at 80° C. then at 95° C. for 3 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL), 5% aqueous lithium chloride (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 methanol/methylene chloride), solvent exchanged with acetonitrile and freeze dried from acetonitrile/water to afford 9-[4-(1,3-benzoxazol-2-ylamino)phenyl]-7,9-dihydro-8H-purin-8-one (19 mg) as off-white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:15][Mg]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)([OH:9])[CH3:15])=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(F)cc1)c1nccs1
Solvent: CCOCC
Product: CC(O)(c1ccc(F)cc1)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4-fluorophenyl)(thiazol-2-yl)methanone (1.05 g, 5.07 mmol) in diethyl ether (50 mL) and was cooled to 0° C., treated with methylmagnesium bromide (1.85 mL, 3.0 M in Et2O, 5.57 mmol) and stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, extracted with diethyl ether (2×30 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as an oily brown residue (1.052 g, 93% yield). MS (M+H)+ 224.