Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].N[C@@H](C(C)(C)C)[C:34](NCCO)=[O:35]>>[OH:35][CH2:34][CH2:7][NH:6][C:4](=[O:5])[C@@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:2]([CH3:31])([CH3:30])[CH3:1]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC(C)(C)[C@H](N)C(=O)NCCO
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NCCO)C(C)(C)C)C1

Procedure:
Compound 40 was prepared according to the procedure described for the synthesis of compound 37 by replacing tert-leucine methyl amide with intermediate 23. 1H NMR (CDCl3) δ 7.87 (d, J=9.2 Hz, 1H), 7.47-7.53 (m, 1H), 6.98-7.05 (m, 1H), 6.81 (br, 1H), 4.21 (d, J=9.2 Hz, 1H), 3.69 (br, 2H), 3.39-3.43 (m, 4H), 3.17 (br, 2H), 2.74 (t, J=5.9 Hz, 2H), 2.46 (s, 3H), 1.08 (s, 9H). LCMS (+ESI) m/z=468 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:27])([C:24]([OH:26])=O)[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:36]1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.N>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:27])([C:24]([NH2:36])=[O:26])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[C@@]1(C(=O)O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(C(N)=O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanecarboxylic acid, 826, (0.050 g, 0.108 mmol), benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium hexafluorophosphate (0.081 g, 0.216 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.075 mL, 0.432 mmol) were combined in 5 mL of THF. To the reaction was then added ammonia hydrochloride (0.002 g, 0.032 mmol) and the reaction was allowed to stir overnight at room temperature. After concentration under reduced pressure, the mixture was purified by reverse phase HPLC chromatography, yielding 3.3 mg of desired product.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Na].Cl[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[CH2:1]([O:5][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCCCO
Agent: [Na]
Solvent: O
Product: CCCCOc1ccc(C#N)cc1

Procedure:
250 ml of butanol and 15.2 g (0.66 mol) of sodium are heated in a sulfonation flask under a protective-gas atmosphere until the metal has fully reacted. The mixture is cooled, p-chlorobenzonitrile is added in portions, and the reaction mixture is subsequently refluxed for about 16 hours. The cooled mixture is poured into water and extracted with ethyl acetate. The organic phase is then dried using MgSO4 and filtered, and the solvent is evaporated, giving 95% of theory of the title product.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:11])[C:4](=[O:10])[CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:11])[C:4](=[O:10])[CH2:5][CH2:6][C:7]1([CH3:8])[O:14][CH2:13][CH2:12][O:9]1
Reactant: CON(C)C(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CON(C)C(=O)CCC1(C)OCCO1

Procedure:
To a solution of 4-1 (38 g, 0.239 mol) in 500 mL benzene was added ethylene glycol (17.3 mL, 0.310 mol) and p-toluenesulfonic acid (1 g). The mixture was heated at reflux for 2 h with azeotropic removal of water. After cooling, the solution was washed with 200 mL sat. NaHCO3, brine, and dried over Na2SO4. Evaporative removal of the solvent gave 4-2 as a yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:11][O:12][CH2:13]Br.O>CN(C=O)C>[CH3:11][O:12][CH2:13][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3]
Reactant: COCBr
Reactant: Oc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1Br
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a stirring suspension of sodium hydride (1.2 g, 52.1 mmol, 60% dispersion in mineral oil) in DMF (75 mL) at 0° C. was added 2-bromophenol (6.0 g, 34.7 mmol) dropwise. After stirring for 20 min, bromomethyl methyl ether (4.3 g, 34.7 mmol) was added. After stirring for 16 h at room temperature, the mixture was poured into water (250 mL) and extracted with hexane. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (4.0 g, 53%). 1HNMR (400 MHz, CDCl3) δ7.55 (d, 1H), 7.28 (t, 1H), 7.16 (d, 1H), 6.91 (t, 1H), 5.25 (s, 2H), 3.54 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]2=[O:32])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([N:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:15][CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][CH:10]=3)=[O:30])=[CH:25][C:24]2=[O:32])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccn(-c2cccc(F)c2)c(=O)c1
Reactant: Cc1cc(-c2ccc(CN)cn2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccn(-c4cccc(F)c4)c(=O)c3)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 (14 mg, 0.07 mmol), 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid 89-3 (16 mg, 0.07 mmol), and HATU (29 mg, 0.076 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.098 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and subjected to reverse phase preparative HPLC separation to yield 1-(3-fluorophenyl)-N-((2′-methyl-[2,4′-bipyridin]-5-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide 89. MS m/z 415.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:18]([F:23])[F:22])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Product: O=Cc1ccc(OC(F)F)c(Br)c1
Temperature: 65 °C
Reaction time: 5.5 h

Procedure:
A suspension of 3-bromo-4-hydroxy-benzaldehyde (4.97 mmol; 1.0 eq.), cesium carbonate (7.46 mmol; 1.5 eq.) and sodium chlorodifluoroacetate was stirred at 65° C. for 5.5 h. The mixture was partitioned with ethyl acetate and water, and the aqueous portion extracted with diethyl ether. The combined extracts were washed with successive portions of water and brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound, I-286, as a yellow oil. 1H NMR (400 MHz, DMSO-d6): 7.49 (t, J=72.4 Hz, 3H), 7.54 (d, J=8.4 Hz, 1H), 8.00 (dd, J=8.4, 2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 9.96 (s, 1H) ppm.
Reaction SMILES: CS(O[C@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:10][O:9][C:8]([CH3:23])([CH3:22])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:24]([C@H:6]1[CH2:7][C:8]([CH3:23])([CH3:22])[O:9][CH2:10][C@H:11]1[NH:12][C:13](=[O:14])[O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[N+:25]=[N-:26]
Reactant: CC1(C)C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@H](N=[N+]=[N-])[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
To a solution of (4R,5R)-2,2-dimethyl-5-((2-(trimethylsilyl)ethoxy)carbonylamino)-tetrahydro-2H-pyran-4-yl methanesulfonate (550 mg, 1.25 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (812 mg, 12.5 mmol) and sodium acetate (1.05 mg, 12.5 mmol) at room temperature. The resultant mixture was stirred at 95° C. for 2 days. After that, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL×8) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound (510 mg, crude) as a yellow oil which was directly used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH:28]([C:30]1[O:31][C:32](=[O:47])[C:33]2[C:38]([C:39]=1[CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:29]>CN(C=O)C>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([CH:28]([C:30]3[O:31][C:32](=[O:47])[C:33]4[C:38]([C:39]=3[CH2:40][N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:29])[N:11]=[C:10]([C:4]3[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[CH:3]=3)[C:18]=12
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1CN1CCOCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3CN3CCOCC3)c3ncnc(N)c23)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
3-(3-Fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate G1, 0.135 g, 0.521 mmol) and potassium carbonate (0.206 g, 1.498 mmol) were mixed in DMF (5 ml) and stirred at r.t. for 10 min. Then a solution of 3-(1-bromoethyl)-4-(morpholinomethyl)-1H-isochromen-1-one hydrobromide (intermediate C48, 0.215 g, 0.496 mmol) in DMF (5 ml) was added and the mixture was heated at 70° C. for 3 hrs. The reaction was quenched by the addition of 1M HCl (2 ml) and the solvent was removed under vacuum. The crude was purified by reverse phase flash chromatography on C18 Biotage cartridge (H2O:CH3CN=80:20 to 100% CH3CN, with 0.1% HCOOH) to afford 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(morpholinomethyl)-1H-isochromen-1-one (0.033 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[C:24]([O:33][CH2:34][C:35]#[C:36][CH2:37][OH:38])[N:23]=[C:22]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[N:21]=2)(=[O:18])=[O:17])=[N:14][CH:15]=1)([CH3:9])[CH3:8].[CH3:45][O:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[N:50]=[C:49](S(C)(=O)=O)[N:48]=1>CN(C=O)C>[CH:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[C:24]([O:33][CH2:34][C:35]#[C:36][CH2:37][O:38][C:49]3[N:50]=[C:51]([O:53][CH3:54])[CH:52]=[C:47]([O:46][CH3:45])[N:48]=3)[N:23]=[C:22]([C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)[N:21]=2)(=[O:18])=[O:17])=[N:14][CH:15]=1)([CH3:9])[CH3:8]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)C)cn3)nc(-c3ccncc3)nc2OCC#CCO)cc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OCC#CCOc2nc(-c3ccncc3)nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c2-c2ccc(C)cc2)n1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 243 mg of K2CO3 in 15 ml of DMF 450 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 11) was added. After stirring for 0.5 h at 90° C., 192 mg of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added and stirring was continued for 16 h at 90° C. Eventually, the solvent was evaporated and the remaining residue was partitioned between 50 ml of 10% aqueous acetic acid and 50 ml of DCM. The organic layer was separated and the aqueous layer was extracted two more times with 50 ml of DCM. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with DCM:methanol 20:1 to give 88 mg of 5-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige foam. LC-MS: tR=5.54 min, [M+1]+=668.38, [M−1]+=666.39.
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)[S:3]1.[OH:29]S(O)(=O)=O.O1CCOCC1>O>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:29])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CC2SC(=N)NC2=O)cc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 58.8 %

Procedure:
A mixture of 2-imino-5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-thiazolidinone (11.4 g), 1N.H2SO4 (100 ml) and dioxane (100 ml) was stirred at 80° C. for 5 hours, and poured in water. The aqueous mixture was extracted with chloroform. The chloroform layer was washed with water, dried (MgSO4) and concentrated. The oily residue was chromatographed on a column of silica gel (200 g), and from the fractions eluted with chlorform-methanol (100:1, V/V), there was obtained 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-2,4-thiazolidinedione (6.7 g, 58.8%). Recrystallization from ethyl acetate-hexane afforded colorless plates. m.p. 162°-163° C. Elemental analysis for C21H18N2O4S, Calcd.: C, 63.95; H, 4.60; N, 7.10. Found: C, 63.84; H, 4.63; N, 6.90. This product showed the IR and NMR spectra in accordance with those of the compound obtained in Example 6.
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[CH:1]1(/[CH:6]=[CH:7]/[C:8]([Cl:14])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)/C=C/C1CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)/C=C/C1CCCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2E)-3-cyclopentylacrylic acid (1.3 g, 9.3 mmol) in DCM (65 mL) at 0° C. was added oxalyl chloride (3.1 mL, 37 mmol), dropwise. The resulting solution was stirred at 0° C. for 40 minutes, then at room temperature for 2 hours. The volatiles were evaporated to afford (2E)-3-cyclopentylacryloyl chloride as a colorless liquid. A portion of this (2E)-3-cyclopentylacryloyl chloride (0.75 g, 4.7 mol) was dissolved in methanol (10 mL) and the resulting solution was stirred for 2 hours. The solvent was evaporated to afford the product (700 mg, 96%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5](=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2].[NH3:13]>>[NH2:13][C:5]([CH2:4][CH2:3][C:1]#[N:2])=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: N
Reactant: CCOC(=O)CC(=O)CCC#N
Product: CCOC(=O)C=C(N)CCC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
3.80 g (22.4 mmol) of ethyl 5-cyano-3-oxopentanoate were taken up in 5 ml of a saturated ethanolic ammonia solution and stirred at room temperature for 24 h. The volatile components were distilled off using a rotary evaporator, giving 3.60 g (95%) of ethyl 3-amino-5-cyano-2-pentenoate. 1H-NMR (300 MHz, DMSO) 1.16 (t, 3H), 2.37 (t, 2H), 2.75 (t, 2H), 3.99 (q, 2H), 4.41 (s, 1H), 6.96 (s, broad, 1H), 7.69 (s, broad, 1H). MS (DCI/NH3): 169 (M+H)+, 186 (M+NH4)+, 337 (2M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]2[CH:24]=1.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:27][CH2:26][NH:25][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:22])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NCCN1CCOCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCCN3CCOCC3)cc2n1
Yield: 48 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) was converted, using N-(2-aminoethyl)morpholine instead of aminomethylcyclopropane, to the title compound (41 mg, 48%) which was obtained as a light yellow foam. MS: m/e=432.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][Sn](C)(C)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[N:14][S:13][C:9]2=[C:10]([CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3F)c2c1O
Reactant: C[Sn](C)(C)C
Product: CCOC(=O)c1nc(C)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy Example 28 from 7-bromo-3-(2-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and tetramethyltin: MS (m/z) 333.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-2-furoic acid (247 mg, 1.29 mmol) was coupled to aniline (124) (250 mg, 1.29 mmol) using Method C to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][O:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:24][CH2:25][OH:26]>C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][N:10]([CH2:24][CH2:25][OH:26])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CON(CCO)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.2 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557) was dissolved in acetonitrile (20 ml), then potassium carbonate (0.69 g), potassium iodide (0.175 g) and 2-bromoethanol (0.137 g) were added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and then dried over sodium sulphate. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford ((R)-2-(2-hydroxyethyl)-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester as a yellow solid. LCMS (method A) 1.05 min, MH+ 259; 1H-NMR (CDCl3, 400 MHz): 5.55 (br s, 1H), 4.65 (m, 2H), 4.10 (t, 1H), 3.80 (m, 1H), 3.20 (br s, 1H), 1.50 (s, 9H), 1.20 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[CH:15][C:6]1=2
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OCC(=O)Nc2ccc(-c3ccc(F)cc3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-fluoro benzeneboronic acid generally according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 9.92 (s, 1H), 7.64-7.67 (m, 2H), 7.41-7.46 (m, 2H), 7.17-7.25 (m, 2H), 7.12 (s, J=2.26 Hz, 1H), 4.21 (s, 2H), 1.57 (s, 6H); MS (ESI) m/z 286 ([M+H]+); MS (ESI) m/z 284 ([M−H]−).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][O:20][C:19]3[CH:23]=[C:24]([S:27]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:18]2=3)[CH2:3][CH2:2]1.O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:37][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][O:20][C:19]3[CH:23]=[C:24]([S:27]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)(=[O:28])=[O:29])[CH:25]=[CH:26][C:18]2=3)[CH2:5][CH2:6]1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4nccs4)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
EXAMPLE 44 was prepared by charging a 10-mL round bottomed flask with 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide, (EXAMPLE 38, 0.040 g, 0.077 mmol). The reaction vessel was then flushed with N2 gas and the solid starting materials were dissolved in methanol (0.4 mL). To the resulting solution, formaldehyde 37% wt in water (0.085 mL, 1.148 mmol) was added and the mixture was stirred for 5 min at room temperature. Sodium triacetoxyborohydride (0.243 g, 1.148 mmol) was added portion wise and the resulting solution was stirred for 10 min. The reaction mixture was poured into a sep. funnel containing sat. NaHCO3 and EtOAc. The aqueous layer was washed with EtOAc (3×25 mL), the organic layers were combined and dried over Na2SO4. The organic layer was filtered and concentrated to give pure 4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.030 g, 0.056 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (d, J=5.58 Hz, 3 H) 2.41 (br. s., 2 H) 2.91 (br. s., 2 H) 3.57 (br. s., 3 H) 4.25 (br. s., 2 H) 5.22 (s, 1 H) 5.80 (br. s., 1 H) 6.40 (t, J=8.61 Hz, 1 H) 6.60 (d, J=3.62 Hz, 1 H) 6.85 (d, J=4.70 Hz, 1 H) 7.03-7.12 (m, 1 H) 7.13-7.22 (m, 1 H) 7.35 (d, J=4.50 Hz, 1 H) 7.46-7.63 (m, 2 H) 7.64-7.78 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][N:18]1[C:26]2[C:25]([CH3:27])=[C:24]([CH3:28])[N:23]=[C:22]([NH2:29])[C:21]=2[N:20]=[C:19]1[CH3:30]>>[NH2:29][C:22]1[C:21]2[N:20]=[C:19]([CH3:30])[N:18]([CH2:17][CH2:16][O:15][CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:26]=2[C:25]([CH3:27])=[C:24]([CH3:28])[N:23]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: CN(C(=O)Cl)c1ccccc1
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N(C)c3ccccc3)c2c1C

Procedure:
Using the method of Examples 54–68, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 397.2343.