Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:34]=[CH:33][C:17]([O:18][C:19]4[CH:20]=[C:21]([C@@:25]5([CH3:32])[O:29][C:28](=[O:30])[NH:27][C:26]5=[O:31])[CH:22]=[CH:23][CH:24]=4)=[C:16]([CH2:35]CC)[CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=[O:39].[Cs+].[Cs+].O>CN(C=O)C>[CH:35]([C:16]1[CH:15]=[C:14]([C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[O:10][C:9](=[O:13])[CH:8]=2)[CH:34]=[CH:33][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([C@@:25]2([CH3:32])[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])[CH:22]=[CH:23][CH:24]=1)=[O:39]
Reactant: CCCc1cc(-c2cc(=O)oc3cc(OC)ccc23)ccc1Oc1cccc([C@@]2(C)OC(=O)NC2=O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccc(Oc4cccc([C@@]5(C)OC(=O)NC5=O)c4)c(C=O)c3)cc(=O)oc2c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step 1 (0.30, 1.0 mmol) and intermediate 13 (0.20, 1.0 mmol) and Cs2CO3 (0.65 g, 2.0 mmol) in DMF (5.0 mL) was stirred at 80° C. for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to to give the title compound as a solid.
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:43]I>CCCCCCC.CCOC(C)=O>[I:43][CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17]
Reactant: II
Reactant: COc1ccc2c(c1)N(C[C@H](C)CO)C(=O)CO2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Yield: 81.7 %

Procedure:
The compound (S)-4-(3-Hydroxy-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF34) (2.70 g, 12.0 mmol), triphenylphosphine (6.92 g, 26.4 mmol), Imidazole (1.96 g, 28.8 mmol) and I2 (8.53 g, 33.6 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (111MF36) (3.54 g, 82%). 1H NMR (CDCl3) d 6.92 (d, J=8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.53 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.54 (q, J=14.8 Hz, J=23.6 Hz, 2H), 3.92 (d, J=7.4 Hz, 2H, 3.80 (s, 3H), 3.18 (dd, J=1.0 Hz, J=6 Hz, 2H), 2.17-2.08 (m, 1H), 1.05 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3) d 165.4, 155.6, 139.6, 129.4, 117.7, 108.0, 102.5, 68.0, 56.1, 46.1, 33.6, 18.9, 12.0.
Reaction SMILES: Cl[CH:2]=[C:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.[Na].C[O-].[Na+].N1C=CN=C1>C(#N)C.CO>[N:18]1([CH:2]=[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)C(=CCl)Oc1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)C(=O)C(=Cn1ccnc1)Oc1ccc(F)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
256.7 g (1 mol) of 1-chloro-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one in 150 ml of acetonitrile were added dropwise to a suspension of 90 g (1 mol) of sodium imidazole, prepared from sodium methylate and imidazole in methanol, in 2,500 ml of acetonitrile, while stirring. Thereafter, the reaction mixture was heated to the boiling point for 6 hours. It was allowed to cool to room temperature and was concentrated by distilling off the solvent in vacuo. The residue was taken up in 1,000 ml of ethyl acetate, the mixture was washed three times with 200 ml of water each time and the organic phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. 272.4 g (94.5% of theory) of crude 1-(imidazol-1-yl)-2-(4-fluorophenoxy)-4,4-dimethyl-1-penten-3-one were obtained as a brown oil, which was purified in the customary manner, via the nitrate, and then had a refractive index of nD20 =1.5590. ##STR52##
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]=1[CH:23]=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][N:7]=[CH:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[OH:12])=[O:5]
Reactant: NNC(=O)c1ccccc1N
Reactant: O=Cc1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)NN=Cc1c(O)ccc2ccccc12

Procedure:
The hydrazone is prepared by refluxing 30.2 g (0.20 mol) o-aminobenzhydrazide, 34.4 g (0.20 mol) 2-hydroxy-1-naphthaldehyde and 250 ml toluene in a 500 ml flask for 1 hour. The solid formed is collected on a filter and washed with hot ethanol yielding 40 g of yellow 2-hydroxy-1-naphthaldehyde-o-aminobenzoyl hydrazone, melting at 188°-191° C.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:3][NH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CN(C=O)C>O.CCOC(C)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[N:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]2)[CH2:1]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ncccn1)C2
Temperature: 102.5 °C

Procedure:
A 2 L round-bottom flask was charged with tert-butyl 2,6-diazaspiro[3,3]heptane-6-carboxylate (64.3 g, 0.32 mol), cesium carbonate (317.0 g, 0.97 mol), 2-chloropyrimidine (45.5 g, 0.4 mol), and DMF (759.0 mL). The reaction mixture was heated to 100-105° C. for 20 min. The reaction mixture was cooled to ambient temperature, diluted with water (759.0 mL) and EtOAc (759.0 mL). The organic layer was washed with water (2×500.0 mL) and brine (500.0 mL). The organic layer was dried over sodium sulfate and filtered through Celite™. The filtrate was concentrated under reduced pressure. Column chromatography of the resulting crude product on silica gel, eluting with EtOAc and heptane (50-100%) afforded the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][CH2:14]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(Br)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 13.8 %

Procedure:
A solution of 2-bromo-5-methylpyridine (1.00 g, 5.8 mmol), tert-butyl piperidine-4-ylcarbamate (1.28 g, 6.39 mmol) and TEA (1.21 ml, 8.72 mmol) in DMSO (5 ml) was heated at 110° C., After 17 h the reaction mixture was heated at 130° C. for 4 h before more TEA (0.40 ml, 2.91 mmol) was added. After 2.5 h, DBU (1.73 ml, 11.63 mmol) was added and the reaction mixture heated at 110° C. for 17 h. The reaction mixture was then allowed to cool to rt and EtOAc was added. The reaction mixture was washed with brine and evaporated to dryness. The residue was purified using the Biotage SPI eluting with 25% EtOAc in pet. ether 40-60° C. to give the title compound (0.233 g, 14%) as a solid. 1H NMR (500 MHz, CDCl3): 8.02 (d, 1H), 7.31 (dd, 1H), 6.62 (d, 1H), 4.48 (bs, 1H), 4.16-4.10 (m, 2H), 3.68 (bs, 1H), 2.95 (dt, 2H), 2.20 (s, 3H), 2.08-2.00 (m, 2H), 1.48-1.40 (m, 9H). 13C NMR (CDCl3): 158.1, 155.4, 147.9, 138.6, 122.3, 107.5, 79.5, 48.4, 45.1, 32.3, 28.7, 17.5. Mass Spectrum: M+H 292.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[C:16]([C:24]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Br:33][C:31]1[CH:32]=[C:24]2[C:25](=[CH:29][CH:30]=1)[C:26](=[O:27])[N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:15][CH:14]=1)[C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCC(O)CNCc1ccc(SC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 35.4 %

Procedure:
To a solution of 1-(4-methylsulfanylbenzylamino)butan-2-ol (8.5 g) and 2-benzoyl-4-bromobenzoic acid (14.7 g) and 1-hydroxy-1H-benzotriazole (7.4 g) in DMF (100 ml) was added triethylamine (8.4 ml) and then WSC (11.5 g) was added at room temperature. The mixture was stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, and the residue was partitioned between dichloromethane and water, washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1-+13/7). The resulting colorless amorphous form was dissolved in dimethyl sulfoxide (100 ml) and triethylamine (25.3 ml) was added. Under ice-cooling, pyridine sulfur trioxide complex (14.5 g) was added, and the mixture was stirred at room temperature for 8 hrs. Water (300 ml) was added, and the mixture was extracted with ethyl acetate and washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine. Sodium sulfate was added to dry the mixture. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1→2/3). The obtained colorless amorphous form was dissolved in 0.1N potassium hydroxide-ethanol solution (75 ml) and heated under reflux for 12 hrs. 1N Hydrochloric acid (7.5 ml) was added and the mixture was stirred under ice-cooling for 1 hr. The crystals were collected by filtration and washed with 70% ethanol-water to give the title compound (6.58 g, 34%).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([C:26]2[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:33][C:28]4[N:27]=[C:26]([C:23]5[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=5)[C:31]([CH3:32])=[CH:30][N:29]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(N)ncc2C)cn1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ncc2C)cn1
Temperature: 90 °C

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (369 mg, 1.42 mmol) and 4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-amine (153 mg, 0.71 mmol), pyridine (4 mL) was added. The reaction was heated at 90° C. for three and a half hours. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in ethyl acetate and filtered. The filtrate was washed with saturated aqueous NaHCO3 (×3). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 440.13, found 441.5 (M+1)+. Retention time 1.72 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:7][N+:8]1[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][C:12]=2[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=O)[N:9]=1)[CH2:18][CH2:17][CH2:16]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[N:1]1([CH2:23][CH2:22][CH2:21][C:10]2[N:9]=[N+:8]([O-:7])[C:13]3[CH:14]=[C:15]4[C:19]([CH2:18][CH2:17][CH2:16]4)=[CH:20][C:12]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: [O-][n+]1nc(CCCN2CCCCC2)nc2cc3c(cc21)CCC3
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Piperidine (3.0 g, 35 mmol) was added to a stirred solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 86 (1.33 g, 69%) as a yellow oil: 1H NMR δ 8.24 (s, 1H, H-9), 7.74 (s, 1H, H-5), 3.09-3.15 (m, 4H, H-6, H-8), 3.02-3.07 (m, 2H, CH2), 2.82-2.95 (m, 6H, 3×CH2), 2.27-2.38 (m, 2H, CH2), 2.17-2.26 (m, 2H, H-7), 1.76-1.87 (m, 4H, 2×CH2), 1.50-1.60 (m, 2H, CH2); 13C NMR δ 164.3, 155.0, 149.2, 147.4, 132.3, 122.7, 114.2, 57.1, 53.5 (2), 34.3, 33.2, 32.8, 25.7 (2), 23.7, 22.9, 22.6; HRMS (FAB+) calcd for C18H25N4O (MH+) m/z 313.2025, found 313.2025.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]([C:19]([O:21]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O)=[N:2]1.[C:27]1([C:33]2[N:34]=[C:35]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[S:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:19]([N:41]2[CH2:40][CH2:39][CH:38]([C:35]3[S:36][CH:37]=[C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:34]=3)[CH2:43][CH2:42]2)=[O:21])=[N:2]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Reactant: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1noc2ccccc12)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Yield: 47.5 %

Procedure:
A solution of bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (277 mg, 0.573 mmol), 4-(4-phenyl-1,3-thiazol-2-yl)piperidine (280 mg, 1.15 mmol) and diisopropylethylamine (0.0998 ml, 0.573 mmol) in dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (110 mg, 47.4%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][CH2:19][O-:20].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH2:19][CH3:18])[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: CC[O-]
Reactant: CSc1nc(N)nc(-c2ccccc2)c1C#N
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)nc(-c2ccccc2)c1C#N
Yield: 29 %

Procedure:
To a stirred solution of 0.2 g (0.86 mmol) 2-amino-4-(methylthio)-6-phenyl-5-pyrimidinecarbonitrile in 10 ml ethanol was added 0.33 ml (0.89 mmol) sodium ethylate solution (2.7M in ethanol) and the mixture heated at reflux for 2 h. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and dichloromethane and the organic phase dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/1) afforded 60 mg (29%) 2-amino-4-ethoxy-6-phenyl-pyrimidine-5-carbonitrile as a white crystalline solid. MS m/e (%):240 (M+, 100), 239 ([M—H]+, 50), 170 (56).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.CN1CCOCC1>CO>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:24][CH:25]=1
Reactant: NCc1ccc(N)cc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccc(N)cc3)cc2s1
Yield: 12.1 %

Procedure:
the title compound (15 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 4-aminomethylphenylamine (69 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 415.4 (M+1, 100%). Yield=12%.
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(OC(C)C)OC(C)C>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:23]3[O:22][CH:26]=[CH:25][CH:24]=3)=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: Fc1ccc(Nc2ncnc3cc(Br)ccc23)cc1Cl
Reactant: CC(C)OB(OC(C)C)c1ccco1
Agent: Cl
Product: Fc1ccc(Nc2ncnc3cc(-c4ccco4)ccc23)cc1Cl
Yield: 36 %

Procedure:
Using an analogous procedure to that described in Example 1, 7-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 2-furylboronate to give 4-(3-chloro-4-fluoroanilino)-7-(2-furyl)quinazoline in 36% yield, m.p.>250° C.;
Reaction SMILES: C(C1ON=C(N)C=1)(C)C.[CH:10]1([C:15]2([CH2:20][C:21](=[N:23][OH:24])[NH2:22])OCCO2)[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl>C(O)C>[CH:10]1([C:15]2[O:24][N:23]=[C:21]([NH2:22])[CH:20]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: NC(CC1(C2CCCC2)OCCO1)=NO
Agent: CC(C)c1cc(N)no1
Agent: Cl
Solvent: CCO
Product: Nc1cc(C2CCCC2)on1
Yield: 6.2 %

Procedure:
According to the procedure described for 5-isopropylisoxazol-3-amine in Example 133A Step 4, 2-(2-cyclopentyl-1,3-dioxolan-2-yl)-N′-hydroxyacetimidamide (1.99 g, 93 mmol) was dissolved in ethanol (2 mL) and acidified with 37% aq. hydrochloric acid to give 5-cyclopentylisoxazol-3-amine (875 mg, 62%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 5.52 (s, 1H), 3.86 (bs, 2H), 3.09-3.04 (m, 1H), 2.04 (d, 2H), 1.75-1.62 (m, 6H); LC-MS (ESI) m/z 153 (M+H)′
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH:14]1([CH2:19][C:20](=O)[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.[Cl-].[Na+].O>[CH:14]1([CH2:19]/[C:20](/[CH3:21])=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(=O)CC1CCCC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)CC1CCCC1
Temperature: 0 °C
Yield: 99 %

Procedure:
To a suspension of sodium hydride (956 mg, 60% in oil, 23.9 mmol) in THF (60 mL) cooled at 0° C. was added dropwise trimethyl phosphonoacetate (3.87 mL, 4.35 g, 23.9 mmol). The mixture was stirred for 20 mn at 0° C. and cyclopentylacetone (2.22 mL, 2.00 g, 15.9 mmol) was added dropwise. The solution was warmed to 25° C., then refluxed for 2 h, and poured in a solution of brine (100 mL). The reaction mixture was extracted with ethyl acetate (2×50 mL) and the combined organic phase was dried over sodium sulfate and concentrated to give the ester (2.87 g, 99%) as a mixture of E and Z isomers 3:1. MS (m/z) 182 (M).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][N:28]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: -5 °C
Yield: 60.7 %

Procedure:
Sodium hydride (60%, 0.16 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro 4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.20 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C. with stirring. To the reaction solution is added dropwise a solution of 2,3-dichloro-5-trifluoromethyl pyridine (0.80 g) in 1,2-dimethoxyethane (20 ml) at -5° C. for 10 minutes, which is further stirred for 15 minutes. On completion of the reaction, the reaction solution is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.10 g of desired compound (melting point: 47.0°-49.0° C.).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[O:8]=[CH:9][C@H:10]([C@@H:12]([C@@H:14]([C@H:16]([CH3:18])[OH:17])[OH:15])[OH:13])[OH:11].[CH:19](N)([CH3:21])[CH3:20].C(CN)O.C[N:28]([CH:30]=[O:31])C>>[O:8]=[CH:9][C@H:10]([C@@H:12]([C@@H:14]([C@H:16]([CH3:18])[OH:17])[OH:15])[OH:13])[OH:11].[CH:19]([C:6](=[CH2:7])[C:30]([NH2:28])=[O:31])([CH3:21])[CH3:20]
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Reactant: CC(C)N
Agent: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Solvent: NCCO
Product: C=C(C(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of pNAS (1.0 g, 5.91 mmol) in 50 mL DMF was added triethylamine (1.0 mL), followed by the dropwise addition of the L-fucose derivative 22 (356 mg, 1.18 mmol, 20 mol % with respect to pNAS). The solution was stirred at room temperature for 16 h, and subsequently heated to 40° C. for 18 h. The solution was cooled and isopropylamine (233 mg, 25 mol % with respect to pNAS) was added as a solution in DMF (1 mL). The solution was stirred at 40° C. for a further 24 h, followed by the addition of ethanolamine (2 mL, excess as a solution in 5 mL of DMF). The clear solution was stirred at room temperature for 12 h, followed by dialysis against water using dialysis tubing with a cut-off of 12,000-14,000 kD. The product was recovered by lyophilization. Yield 82%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22](=[O:24])[NH2:23].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:22](=[O:24])[NH2:23]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccn1
Yield: 77.4 %

Procedure:
A mixture of the 9-[(2-pyridyl)methyl]-4-hydroxy-5-carbamoyl carbazole (216 mg, 0.68 mmol) and Cs2CO3 (550 mg; 1.69 mmol) in 5 mL DMF was treated with methyl bromoacetate (0.08 mL; 0.85 mmol). The reaction was stirred until tlc analysis indicated complete consumption of starting material (2 hours). The mixture was concentrated and the residue taken up in H2O (50 mL). The aqueous layer was saturated with solid NaCl and was extracted five times with THF. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The solid was triturated with EtOAc to afford 205 mg (77%) of the {9-[(2-pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as an off white solid. 1H NMR (DMSO-d6) δ 8.47 (d, 1H, J=4.9 Hz), 7.66-7.57 (m, 2H), 7.48 (br s, 1H), 7.38-7.27 (m, 2H), 7.24-7.19 (m, 2H), 7.19 (br s, 1H), 7.04 (d, 1H, J=7.3 Hz), 6.87 (d, 1H, J=7.8 Hz), 6.56 (d, 1H, J=7.8 Hz), 5.71 (s, 2H), 4.89 (s, 2H), and 3.69 (s, 3H). IR (CHCl3, cm−1) 3380, 3140, 1737, 1675, 1500, 1457, 1354, 1340, 1242, 1158, 772, and 715. MS (ES) m/e 390 (M+1).