Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([NH:12][C:13]([NH:15][CH3:16])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[C@@H:1]1([NH:12][C:13]([N:15]([CH3:16])[N:17]=[O:18])=[O:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=N[O-]
Reactant: CNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
1-(β-D-mannopyranosyl)-3-methyl-urea (200 mg) was dissolved in a mixture of 1.5 ml of glacial acetic acid and 3.5 ml of water, and the resulting solution was admixed with 99 mg of sodium nitrite. The mixture so obtained was agitated for 3 hours at ambient temperature to effect the nitrosation. The reaction mixture was treated with Amberlite IR-120 (H+ form) to remove sodium cation therefrom. The reaction mixture so treated was then concentrated by distillation under reduced pressure at a temperature of less than 30° C. to remove the solvent, so that a crystalline product was deposited. This crystalline product was collected by filtration and washed with n-propanol, affording 180 mg of the titled compound. Yield 78%. mp. 103° C. (with decomposition). [α]D25 -12.6° (c 0.99, H2O).
Reaction SMILES: C(N1CCC(CO)(CC2C=CC=CC=2F)CC1)C1C=CC=CC=1.[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:40]3[CH:41]=[CH:42][C:43]([F:45])=[CH:44][C:39]=3[C:38](=O)[O:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]2([C:40]3[CH:41]=[CH:42][C:43]([F:45])=[CH:44][C:39]=3[CH2:38][O:37]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccc(F)cc21
Agent: OCC1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)COC21CCN(Cc2ccccc2)CC1
Yield: 77.5 %

Procedure:
This reaction was performed as described for (ii) above using 1′-benzyl-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (200 mg, 0.642 mmol), borane THF complex 1M solution (1.34 mL, 1.34 mmol) and THF (3 mL) to give the sub-titled compound (148 mg).
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.[C:28]1(CCBr)C2C(=CC=CC=2)C=C[CH:29]=1>>[CH3:27][O:26][C:25]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][C:1]3[C:4]4[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:29]=[CH:28][CH:2]=3)[CH2:12][CH2:13]2)=[CH:18][C:19]2[O:23][CH2:22][CH2:21][C:20]=2[CH:24]=1
Reactant: COc1cc2c(cc1N1CCN(CCC3Cc4ccccc43)CC1)OCC2
Reactant: BrCCc1cccc2ccccc12
Product: COc1cc2c(cc1N1CCN(CCc3cccc4ccccc34)CC1)OCC2

Procedure:
Prepared in the same manner as the product of Example 3 but using 2-(naphth-1-yl)-1-bromoethane instead of 2-(benzocyclobutan-1-yl)-1-bromoethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (53 mg, 45%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2]1.S(=O)(=O)(O)O.[CH3:15]O>CCOCC>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9][CH3:15])=[O:8])[CH2:2]1
Reactant: CO
Reactant: O=C(O)CC1CCOC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)CC1CCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A mixture of 2-(tetrahydrofuran-3-yl)acetic acid (2.00 g, 15.4 mmol, 1.00 equiv) and sulfuric acid (2 mL) in methanol (20 mL) was stiffed for 3 h at 80° C. in an oil bath. After cooling to ambient temperature, the mixture was diluted with 50 mL of ether and washed with 2×20 mL of water, 2×20 mL of sodium bicarbonate (aq., sat. Note: gas evolution), and 2×20 mL of brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1.50 g (68%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.C>N1C=CC=CC=1>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])=[CH:10][CH:11]=1)(=[O:17])[CH3:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(=O)(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethylsulfamoyl chloride (14.4 g., 0.10 mole) is added dropwise to p-aminoacetophenone (13.5 g., 0.10 mole) in pyridine (60 ml.) at 10°-15° C. The mixture is stirred at room temperature overnight and then added to excess 6N HC1 to give 14.1 g. (58%) of solid. The solid is dissolved in base, treated with charcoal, reprecipitated with dil. HC1, and recrystallized from water-isopropanol to give 8.9 g. (37%) of the above pure intermediate, m.p. 129°-130° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[C:13]([OH:15])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[CH2:43][NH2:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[CH2:43][NH:44][C:13]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:12])[N:3]1[CH2:1][CH3:2])=[O:15]
Reactant: CCN1C(=O)c2ccccc2C1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)c2ccccc2C1C(=O)NCc1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 51.4 %

Procedure:
2-Ethyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid (0.061 g, 0.3 mmol, prepared as described below) was dissolved in anhydrous dimethylformamide (5 ml) and to this was added 1-hydroxybenzotriazole (0.045 g, 0.3 mmol), diisopropylethylamine (0.105 ml, 0.6 mmol), [(2,4-dichlorophenyl)methyl]amine (0.054 g, 0.3 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.114 g, 0.3 mmol). The mixture was stirred for 3 hrs and then left to stand overnight. The mixture was diluted with water (50 ml) and a little saturated aqueous sodium chloride solution and extracted with ethyl acetate (3×20 ml). The organic fractions were combined and washed with 10% aqueous sodium carbonate (50 ml) and then with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulphate and evaporated to give a gum. The gum was purified by mass-directed automated HPLC to give N-[(2,4-dichlorophenyl)methyl]-2-ethyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxamide (0.056 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH2:21](O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: OCCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride dispersion in mineral oil (0. 175 g) and stirred for 15 minutes. The mesylate of phenethyl alcohol (1.28 g) was added and the mixture was stirred and heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (3 drops) and the volatiles were removed under vacuum. The residue was mixed with water, the product was extracted with diethyl ether (3×50 mL) and the organic layers were washed in turn with water. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 3: 1) to provide 0.4 g of 4-[(2-phenylethyl)oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.[H-].[Na+].[S:21]([NH2:25])([NH2:24])(=[O:23])=[O:22]>CN(C=O)C>[F:8][C:7]1[C:2]([NH:24][S:21]([NH2:25])(=[O:23])=[O:22])=[N:3][C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][CH:6]=1
Reactant: COc1cccc(COc2ncc(F)c(Cl)n2)c1
Reactant: NS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(COc2ncc(F)c(NS(N)(=O)=O)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.2 %

Procedure:
To a magnetically stirred solution of 4-chloro-5-fluoro-2-(3-methoxybenzyloxy)pyrimidine* (1.3 g, 4.84 mmol) in dry DMF (5 mL) was added a pre-mixed suspension of 60% NaH (0.45 g, 10.65 mmol) and sulfamide (0.93 g, 9.68 mmol) in dry DMF (5 mL). The resulting off-white suspension was stirred at room temperature for 72 hrs. The orange suspension was then heated to 50° C. for 48 hours and cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and brine solution. The organic extract was dried over Na2SO4, filtered, and evaporated. The crude material was purified by column chromatography on normal phase silica using a gradient of EtOAc/Hex and reverse phase using a gradient of H2O/ACN to yield [5-Fluoro-2-(3-methoxybenzyloxy)pyrimidin-4-yl]sulfamide (115 mg, 7.2% yield) as a white solid: mp 126-130° C.; 1H NMR (300 MHz, CD3OD) δ 8.01 (d, J=3.63 Hz, 1H), 7.25 (m, 1H), 7.01 (m, 2H), 6.88 (m, 1H), 5.37 (s, 2H), 3.78 (s, 3H); MS (ESI) m/z 326.9 (M−H)−. * The 4-chloro-5-fluoro-2-(3-methoxybenzyloxy)pyrimidine intermediate was prepared as described in the synthesis of 31.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].CC([O-])(C)C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1>CN(C=O)C>[I:18][C:15]1[CH:16]=[CH:17][C:12]([O:4][CH2:1][CH2:2][CH3:3])=[CH:13][C:14]=1[CH3:19]
Reactant: CCCO
Reactant: Cc1cc(F)ccc1I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3.44 mL (45.8 mmol) 1-propanol are added to 3.42 g (30.5 mmol) KOtBu in 18 mL DMF at 0° C. After stirring the solution for 10 min at rt, 1.80 g (7.63 mmol) 4-fluoro-1-iodo-2-methylbenzene are added and the mixture is stirred at 80° C. for 3 h. The reaction is quenched by the addition of sat. aq. NH4Cl solution and extracted with EtOAc (2×). The combined organic layers are washed with sat. aq. NH4Cl solution and brine, dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 9/1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I:17][CH2:18][CH3:19].C(OCC)(=O)C>CN(C)C=O>[I-:17].[C:9]([NH:8][C:7]1[CH:6]=[CH:5][N+:4]([CH2:18][CH3:19])=[CH:3][C:2]=1[F:1])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccncc1F)c1ccccc1
Reactant: CCI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[n+]1ccc(NC(=O)c2ccccc2)c(F)c1
Product: [I-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of N-(3-fluoro-pyridin-4-yl)-benzamide (1.95 kg, 9.0 mol) in anhydrous dimethylformamide (10 L) was placed under nitrogen atmosphere and heated at 70° C. The heated solution was charged with iodoethane via dropwise addition (1.55 kg/0.795 L, 9.9 mol) with temperature monitoring. The addition caused an exoterm that raised the internal reactor temperature to 110° C. for the duration of the addition. A temperature of 100° C. was maintained for a further two hours before the reaction was cooled to room temperature. The reaction mixture was poured into ethyl acetate (50 L, pre-cooled to 5° C.) and stirred for one hour. The precipitated solid was collected by filtration and washed with ethyl acetate (3×10 L). The yellowish solid 4-benzamido-1-ethyl-3-fluoro-pyridinium iodide was dried in a tray vacuum oven at 50° C., yielding 3.25 kg. (97%). 1H NMR (400 MHz, DMSO): δ 11.37 (1H, s), 9.41 (1H, dd, J=5.86, 1.56 Hz), 8.88 (1H, dd, J=7.03, 1.56 Hz), 8.73 (1H, t, J=7.42 Hz), 7.99 (2H, d, J=8.20 Hz), 7.72 (1H, t, J=7.42 Hz), 7.61 (2H, t, J=8.20 Hz), 4.52 (2H, q, J=7.42 Hz), 1.54 (3H, t, J=7.42 Hz).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][CH:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH2:1][O:8][C:17](=[O:18])[CH:16]([CH3:15])[CH2:20][CH:21]=[CH2:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC(C)C(=O)Cl
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCC(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To a 0° C. solution of 23.8 g of benzyl alcohol, 0.05 g of 4-(dimethylamino)pyridine, 18.3 g of pyridine and 250 ml of methylene chloride is added, dropwise, a solution of 29.5 g of racemic 2-methyl-4-pentenoyl chloride in 50 ml of methylene chloride. The mixture is stirred at room temperature for 4 hours, followed by successive washing with 2N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation to give 35.2 g of the desired product as a colorless oil; bp 70°-75° C. at 0.10 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:34]2[S:35][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccc(Cl)s2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13a, and 5-chlorothiophene-2-sulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 574 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:21](=[O:22])[CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(OC)cc2)c(C)[nH]1
Yield: 72 %

Procedure:
4-[2-(4-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (123) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-Methoxyphenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/ −40° C. Purification: prep/HPLC. Yield: 72%. 1H (CDCl3, 400 MHz): δ 10.45 (NH, broad s), 7.31 (1H, s), 7.18 (2H, d), 6.84 (2H, d), 4.37 (2H, q), 4.01 (2H, s), 3.74 (3H, s), 2.57 (3H, s), 1.38 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 194.7, 161.5, 158.4, 140.8, 130.5, 127.1, 121.6, 120.4, 117.1, 114.0, 60.8, 55.2, 46.0, 14.4, 14.0 ppm. LC/MS: 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:27][C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)N1CCNCC1
Reactant: O=Cc1ccc2ccccc2c1
Product: O=C(Nc1ccc(F)cc1)N1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid (4-fluoro-phenyl)-amide and 2-naphthalenecarbaldehyde. 1H NMR (400 MHz, CDCl3): 7.85-7.80 (m, 3H), 7.74 (s, 1H), 7.52-7.45 (m, 3H), 7.30-7.25 (m, 2H), 6.98-6.92 (m, 2H), 6.36 (s, 1H), 3.69 (s, 2H), 3.49 (t, J=5.1 Hz, 4H), 2.51 (t, J=5.1 Hz, 4H).
Reaction SMILES: C(OC(=O)[N:7]([C:14]1[C:15]2[N:16]([C:20](Br)=[CH:21][N:22]=2)[CH:17]=[CH:18][N:19]=1)[CH2:8][CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])(C)(C)C.CS[C:27]1[N:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][N:28]=1.[CH3:46][NH2:47]>>[CH3:13][S:10]([CH2:9][CH2:8][NH:7][C:14]1[C:15]2[N:16]([C:20]([C:29]3[CH:30]=[CH:31][N:32]=[C:27]([NH:47][CH3:46])[N:28]=3)=[CH:21][N:22]=2)[CH:17]=[CH:18][N:19]=1)(=[O:11])=[O:12]
Reactant: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1nccn2c(Br)cnc12
Reactant: CN
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Product: CNc1nccc(-c2cnc3c(NCCS(C)(=O)=O)nccn23)n1

Procedure:
(2-Methanesulfonyl-ethyl)-[3-(2-methylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-(2-methanesulfonyl-ethyl)-carbamic acid tert-butyl ester (from Example 5 supra), 2-methylsulfanyl-4-tributylstannanyl-pyrimidine, and methylamine. LC-MS: [M+H]+ 348.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C:24](OCC)(=O)[CH:25]=[O:26].CC(C)=O>C(O)C.C1(C)C=CC=CC=1>[O:26]=[C:25]1[CH:24]=[N:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[C:7]=2[NH:8]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1
Reactant: CCOC(=O)C=O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
tert-butyl 4-(2,3-diaminopyridin-4-yloxy)phenylcarbamate (0.86 g, 2.71 mmol) was dissolved in 15 ml of dry ethanol; 0.8 ml (4 mmol) of a 50% ethyl glyoxalate solution in toluene were added and the solution was stirred overnight at room temperature under Argon atmosphere. The solvent was partially evaporated, and tert-butyl 4-(2-oxo-1,2-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate (0.430 g, 45% yield) is precipitated by addition of acetone (10 ml) and filtered off.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10](=[O:13])(=O)[O-:11])=[CH:5][CH:4]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([Cl:16])(=[O:13])=[O:11])=[CH:5][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1ccc(NS(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(NS(=O)(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To sodium 4-methoxyphenylsulfamate (10.0 g 44 mmol) suspended in benzene (100 mL) was added PCl5 (9.2 g, 44 mmol) cautiously. The mixture was slowly warmed up and refluxed for 15 hrs. After cooling to rt., the mixture was filtered through a pad of Celite and solvent was removed from filtrate to leave a brown oil as 4-methoxyphenylsulfamoyl chloride, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl.[Cl:50][C:51]1[CH:52]=[C:53]([CH:64]=[CH:65][C:66]=1[Cl:67])[C:54]([N:56]1[CH2:61][CH2:60][O:59][C@@H:58]([CH2:62][NH2:63])[CH2:57]1)=[O:55]>CN(C)C=O>[Cl:50][C:51]1[CH:52]=[C:53]([CH:64]=[CH:65][C:66]=1[Cl:67])[C:54]([N:56]1[CH2:61][CH2:60][O:59][C@@H:58]([CH2:62][NH:63][C:14](=[O:16])[CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:17])[CH2:57]1)=[O:55]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)O
Reactant: NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
A mixture of Intermediate 12 (0.015 g), 1-hydroxybenzotriazole (0.0097 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.012 g) and N,N-diisopropylethylamine (0.027 ml) in N,N-dimethylformamide (2 ml) was stirred at 20° C. for 10 min. The mixture was treated with Intermediate 31 (0.023 g) and stirred at 20° C. for 96 h. The mixture was applied sequentially to a sulphonic acid ion exchange cartridge (1 g SCX, prewashed with methanol) and IsoluteR aminopropyl solid phase extraction cartridge (1 g), eluting both cartridges with methanol (5 ml). The solvent was removed in vacuo to give the title compound as a yellow gum (0.032 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[CH:21](O)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C:21](=[N:25][OH:26])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: CC(=NO)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a solution of 9B (3.86 g, 11.3 mmol) in methanol:water (2:1, 50 mL) was added hydroxylamine hydrochloride salt (3.0 g) followed by pyridine (5.0 mL). The reaction was stirred at rt for 18 hr. Extract product into EtOAc, washing once with sat. aqueous NaHCO3 and once with water. Back extract the aqueous washings with EtOAc and combine this with the initial extract. Dry organic extract over MgSO4, filter and concentrate. Dilute residue in toluene and remove solvent under vacuum to provide the title compound as a white solid (2.9 g). MS (ES) m/z 359.30 [M+H]+