Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:58])([F:57])[O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54](O)=[O:55])=[CH:49][CH:48]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:54](=[O:55])[CH2:53][C:50]3[CH:51]=[CH:52][C:47]([O:46][C:45]([F:57])([F:44])[F:58])=[CH:48][CH:49]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 4-trifluoromethoxyphenylacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), and the solution was washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2=4:6) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(4-trifluoromethoxy-phenyl)-acetamide (0.7 g, 64%) as a white solid: mp 134-136° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.41 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.59 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.29-7.32 (d, J=8.6 Hz, 2H), 7.40-7.43 (d, J=8.7 Hz, 2H), 7.63-7.82 (m, 2H), 8.72 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.85, 41.23, 48.83, 120.81, 118.37 (121.76, 125.15), 121.91, 127.14, 130.91, 131.52, 133.22, 134.65, 135.64, 139.02, 147.02, 166.88, 167.41, 169.78, 170.21, 172.72; Anal. Calcd. for C23H18N3O6F3: C, 56.45; H, 3.71; N, 8.59; F, 11.65. Found: C, 56.20; H, 3.39; N, 8.44; F, 11.87.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33].[O:37]=[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[N-:39]1.[K+]>CN(C)C=O.C(OCC)(=O)C>[O:37]=[C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[N:39]1[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: CCOC(=O)c1c(/C=C/CCCCCl)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 160A (531 mg) and potassium 1,3-dioxoisoindolin-2-ide (213 mg) in N,N-dimethylformamide (10 ml) was heated at 80° C. for 8 hours. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and was concentrated. The residue was purified by flash chromatography, eluting with 0-100% ethyl acetate in dichloromethane to give (E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 5 hours. The reaction mixture was concentrated and the residue was dissolved in dimethyl sulfoxide and trifluoroacetic acid-methanol (3:1), and purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 13.06 (s, 2H), 8.25 (t, J=5.52 Hz, 1H), 8.19 (dd, J=7.83, 1.38 Hz, 1H), 7.86 (dd, J=7.21, 1.99 Hz, 1H), 7.74 (dd, J=7.52, 1.38 Hz, 1H), 7.60-7.69 (m, 2H), 7.43-7.58 (m, 5H), 7.34-7.41 (m, 2H), 6.99-7.16 (m, 2H), 6.85 (d, J=7.36 Hz, 1H), 6.15-6.32 (m, 1H), 4.65-4.96 (m, 2H), 4.13 (t, J=5.68 Hz, 2H), 3.20-3.29 (m, 2H), 2.20-2.36 (m, 4H), 1.49-1.67 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>CN(C=O)C>[CH:21]([NH:25][C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1)([CH2:23][CH3:24])[CH3:22]
Reactant: Fc1cccc(Cl)c1-c1c(Cl)nc2ccncc2c1Cl
Reactant: CCC(C)N
Solvent: CN(C)C=O
Product: CCC(C)Nc1nc2ccncc2c(Cl)c1-c1c(F)cccc1Cl
Temperature: 70 °C

Procedure:
The product from Step 3 (0.10 g) was dissolved in DMF (2 ml). Sec-butylamine (0.2 ml) was added and the mixture was refluxed in a sealed tube at 70° C. for 14 hours. The dark coloured reaction mixture was evaporated to give an oil, which was purified by flash column chromatography on silica gel (40-60) in ethyl acetate:hexane 1:1 to give N-sec-butyl-4-chloro-3-(2-chloro-6-fluorophenyl)-1,6-naphthyridin-2-amine as a light yellow gum (0.08 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][C@H:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:12]=[CH:11]/[CH2:10][C@@H:9]([OH:13])[CH3:8])[CH:3]=1
Reactant: C=CC[C@H](C)O
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](O)C/C=C/c1cccnc1
Temperature: 135 °C
Yield: 63.3 %

Procedure:
A mixture of 3-bromopyridine (11.22 g, 70.58 mmol), (2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (527 mg, 2.35 mmol), tri-o-tolylphosphine (1.79 g, 5.88 mmol), triethylamine (30 mL, 216 mmol) and acetonitrile (30 mL) was heated in a sealed glass tube at 130-140° C. for 8 h. The reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure on a rotary evaporator. Water (20 mL) was added and the mixture was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation, producing a pale-yellow oil (6.00 g). The crude product was purified by column chromatography over silica gel, eluting with chloroform-acetone (95:5, v/v). Selected fractions were combined and concentrated by rotary evaporation, affording 3.95 g (41.7%) of a pale-yellow oil.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24]1[CH:39]=[CH:38][C:27]([CH2:28][NH:29][C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:28][C:27]3[CH:38]=[CH:39][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:30](=[O:37])[C@H:31]([C@H:33]([CH2:35][CH3:36])[CH3:34])[NH2:32])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccc(OC)cc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccc(OC)cc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 82.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (140 mg, 0.48 mmol, 1.0 eq), L-isoleucine 4-methoxybenzylamide (238 mg, 0.95 mmol) and dichloromethane (2 mL), was treated with triethylamine (400 uL, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (610 uL, 2.0 eq), to provide 207 mg (82%) of L-isoleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] 4-methoxybenzylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[I:18]N1C(=O)CCC1=O>C(#N)C.ClCCl>[I:18][C:17]1[CH:16]=[N:15][N:5]2[CH:6]=[C:7]([C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=12
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(-c2cnn(C)c2)cn2nccc12
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Reaction time: 1 h

Procedure:
4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (486 mg, 2.13 mmol) was suspended in acetonitrile (30 ml). N-iodosuccinimide (958 mg, 4.26 mmol) was added and the mixture was allowed to stir for 1 h. The reaction mixture was diluted in dichloromethane, washed with water, 1N aqueous sodium hydroxide and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H); 8.28 (s, 1H); 8.01 (s, 1H); 7.92 (1, 1H); 6.89 (s, 1H); 3.96 (s, 3H); 3.85 (s, 3H). LRMS (ESI) calculated for C12H12IN4O [M+H]+, 355.0; found 354.9.
Reaction SMILES: [C:1]([O:4][CH:5](P(OCC)(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Li+].[Cl-].CN(C)C(N(C)C)=N.[CH3:29][Si:30]([CH3:61])([CH3:60])[CH2:31][CH2:32][O:33][CH2:34][N:35]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[C:36]1[N:41]2[N:42]=[CH:43][CH:44]=[C:40]2[N:39]=[C:38]([CH:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)[CH:37]=1>C1COCC1.C(Cl)Cl>[C:1]([O:4][C:5](=[C:48]1[CH2:49][CH2:50][CH:45]([C:38]2[CH:37]=[C:36]([N:35]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH2:34][O:33][CH2:32][CH2:31][Si:30]([CH3:61])([CH3:29])[CH3:60])[N:41]3[N:42]=[CH:43][CH:44]=[C:40]3[N:39]=2)[CH2:46][CH2:47]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Reactant: CCOC(=O)C(OC(C)=O)P(=O)(OCC)OCC
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)=O)=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL roundbottom flask was charged ethyl 2-acetoxy-2-(diethoxyphosphoryl)acetate (1121 mmol, 3.16 g), LiCl (11.21 mmol, 475 mg), and THF (25 mL). The flask was then flushed with argon, sealed, and cooled to −78° C. in a dry ice/IPA bath. Added dropwise to this solution was a solution of 1,1,3,3-tetramethylguanidine (11.21 mmol. 1.41 g) in THF (5 mL). The resulting solution was allowed to stir at −78° C. for 30 minutes. At 30 minutes, 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (5.09 mmol, 2.50 g) was added in THF (3 mL). The reaction was then allowed to slowly warm to room temperature and then stirred for 48 hours. After 48 hours, the reaction was diluted with DCM (100 mL) and washed with H2O (50 mL). The organic layer was collected, dried over Na2SO4, and reduced in vacuo. The resulting residue was purified via flash chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[O:28][CH2:29][CH2:30][OH:31].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Cl:1][C:2]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:3]=1[O:4][C:5]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)(=[O:16])=[O:17])=[CH:12][C:8]([C:9]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:11])=[CH:7][C:6]=1[O:28][CH2:29][CH2:30][OH:31]
Reactant: Nc1ccccc1
Reactant: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc(C(=O)O)cc2OCCO)c1
Product: COc1ccc(Cl)c(Oc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)cc(C(=O)Nc3ccccc3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-trifluoromethyl-benzenesulphonylamino)-benzoic acid with aniline there was obtained 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-N-phenyl-5-(4-trifluoromethyl-benzenesulphonylamino)-benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[C-:17].Cl(O)(=O)(=O)=O>C(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[CH2:18][NH:16][C:17]1[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:2]2=[N:1][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: Nc1ncccc1OCc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)CNc1c(C2CCCCC2)nc2c(OCc3ccccc3)cccn12

Procedure:
Compound (30) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3-benzyloxypyridine solution (0.1 M, DCM), 0.575 ml of methyl isocyanoacetate solution (0.2 M, DCM), 0.500 ml of cyclohexylcarbaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[S:30][C:29]([NH2:31])=[N:28][N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:31][C:29]2[S:30][C:26]([CH3:25])=[N:27][N:28]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Reactant: Cc1nnc(N)s1
Product: Cc1nnc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3)cc2=O)s1
Yield: 31.4 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 19) and 5-methyl-[1,3,4]thiadiazol-2-ylamine afforded 3-cyclopentyl-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionamide as a white solid (60.1 mg, 31.4%); ES+-HRMS m/e calcd for C21H23N5O3S [M+Na+] 448.1414, found 448.1413. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.77 (m, 9H), 1.96 (m, 1H), 2.26 (m, 1H), 2.58 (s, 3H), 5.52 (dd, J=4.2, J=10.6 Hz, 1H), 5.73 (d, J=2.7 Hz, 1H), 7.28 (d, J=7.5 Hz, 2H), 7.35 (t, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 2H), 8.14 (d, J=2.7 Hz, 1H), 12.82 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1ccccc1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 47 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), benzoyl chloride (0.44 g, 3.1 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 20 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.13 g, 38%).
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]=1.[OH-].[Na+].Cl>C(O)C>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]=1
Reactant: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4CCC3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(Nc2cc3c4c(c2)CCCC4CCC3)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A suspension of ethyl 2-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]pyrimidine-5-carboxylate (0.055 g) in ethanol (5 ml) was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol-chloroform to obtain the title compound (0.045 g, yield: 90%) as colorless needles (melting point: 296-298° C.).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][N:7]=1)=[O:4].C1C(=O)N([Cl:21])C(=O)C1>CC#N>[Cl:21][C:10]1[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:12])[F:13])=[N:7][NH:8][C:9]=1[CH3:11]
Reactant: Cc1cc(NC(=O)C(F)(F)F)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1[nH]nc(NC(=O)C(F)(F)F)c1Cl

Procedure:
Following protocol L, 2,2,2-Trifluoro-N-(5-methyl-1H-pyrazol-3-yl)-acetamide was treated with NCS in CH3CN to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:31])[N:14]([C:15]4[C:16]([CH3:30])=[N:17][N:18]([CH2:20][C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:32]([O:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[CH3:33]>>[CH2:32]([O:34][C:35]1[N:40]=[CH:39][C:38]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[NH:12][C:13](=[O:31])[N:14]([C:15]5[C:16]([CH3:30])=[N:17][N:18]([CH2:20][C:21]([N:23]6[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]6)=[O:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:37][CH:36]=1)[CH3:33]
Reactant: Cc1nn(CC(=O)N2CCN(C)CC2)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Reactant: CCOc1ccc(B(O)O)cn1
Product: CCOc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(CC(=O)N6CCN(C)CC6)nc5C)c4c3c2)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-{3-methyl-1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 133.1.1) and 6-ethoxypyridine-3-boronic acid (ABCR, Karlsruhe, Germany) to give the title compound as a white solid. (HPLC: tR 2.27 min (Method A); M+H=527 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.69 (s, br, 1H), 8.71 (s, 1H), 8.45-8.42 (m, 1H), 8.08-8.03 (m, 2H), 7.96-7.88 (m, 2H), 7.74-7.71 (m, 1H), 6.81-6.67 (m, 1H), 5.27-5.11 (m, 2H), 4.32 (q, 2H), 3.58-3.38 (m, 4H), 2.38-2.26 (m, 4H), 2.19 (s, 3H), 1.92 (s, 3H), 1.31 (t, 2H))
Reaction SMILES: [NH2:1][C:2](=[O:35])[C@H:3]([NH:17][C:18]1[C:26]([F:27])=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([NH:28][C:29]2[S:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8](C2C=CN=CC=2)=[CH:7][CH:6]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[NH2:1][C:2](=[O:35])[C@H:3]([NH:17][C:18]1[C:26]([F:27])=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([NH:28][C:29]2[S:33][N:32]=[C:31]([CH3:34])[CH:30]=2)[CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4cccnc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1

Procedure:
The titled compound (13 mg) was synthesized analogously by procedures described in the Example for (R)-4-(1-amino-1-oxo-3-(4-(pyridin-4-yl)phenyl)propan-2-ylamino)-5-fluoro-2-(3-methylisothiazol-5-ylamino)benzamide, using pyridine-3-boronic acid in place of pyridine-4-boronic acid. MS 491.5 (M+H); UV 205.2, 244.2, 299.4 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:10](=[O:12])[O-:11].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:7]([O:12][C:10]([NH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:15]=[CH:14][CH:13]=1)[O:4][C:3]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=1[NH:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:11])([CH3:13])([CH3:8])[CH3:6]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Cl)cc1Oc1cccc(CNC(=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 131.8 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzylcarbamate (5.2 g, 15 mmols), ethyl bromoacetate (3.3 ml, 30 mmols), potassium carbonate (2.1 g, 15 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 12 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 2-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminoacetate (4.3 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7](Br)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:18]/[C:19](/[CH3:28])=[C:20](/[O:26][CH3:27])\[O:21][Si](C)(C)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:27][O:26][C:20](=[O:21])[C:19]([CH3:28])([CH3:18])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(C)(C)OC(=O)NC(Br)C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 12.9 %

Procedure:
Bromo-tert-butoxycarbonylamino-acetic acid tert-butyl ester (1.5 g, 4.8 mmol) was dissolved in 40 mL of dichloromethane and then cooled in a dry ice/acetone bath. A solution of methyl trimethylsilyl dimethylketene acetal (1.9 mL, 9.6 mmol) in dichloromethane (5 mL) was added, followed by slow addition of a solution of titanium (IV) chloride (0.57 mL, 5.28 mmol) in dichloromethane (5 mL), and then a solution of triethylamine (0.73 mL, 5.28 mmol) in dichloromethane (10 mL). The reaction mixture was warned to room temperature with stirring over 16 h. An aqueous solution of citric acid (˜11 g/100 mL) was added and the reaction mixture briefly stirred. The layers were separated and the aqueous layer was extracted once more with dichloromethane. The combined dichloromethane layers were washed with sodium bicarbonate solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 206 mg (13%) of 3-tert-butoxycarbonylamino-2,2-dimethyl-succinic acid 4-tert-butyl ester 1-methyl ester.