Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([CH3:20])[C:10]=2[CH3:21])[CH:7]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([CH3:20])[C:10]([CH3:21])=[C:9]2[NH:8][C:6]1[CH:7]=[C:2]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:3]=[CH:4][C:5]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: Cc1nc2c(Cl)cccc2c(Nc2cc(Br)ccc2N2CCOCC2)c1C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2c(Cl)cccc2c(Nc2cc(N3CCOCC3)ccc2N2CCOCC2)c1C
Temperature: 120 °C

Procedure:
In a teflon-capped vial, a mixture of N-(5-bromo-2-morpholinophenyl)-8-chloro-2,3-dimethylquinolin-4-amine (75 mg, 168 μmol), morpholine (0.02 mL, 252 μmol), Pd2dba3 (15 mg, 17 μmol), X-Phos (8 mg, 17 μmol) and cesium carbonate (82 mg, 252 μmol) in 1,4-dioxane (4.00 mL) was purged with nitrogen, capped and heated in a 120° C. oil bath for 72 h. The reaction mixture was partitioned between 25 mL EtOAc and 25 mL water. The organic separation was stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford and orange oil. The product was purified by preparative reversed-phase HPLC to afford a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.83 (2H, dd, J=11.7, 7.8 Hz), 7.34-7.44 (1H, m), 7.09-7.18 (2H, m), 6.90 (1H, dd, J=8.8, 2.5 Hz), 6.60 (1H, d, J=2.7 Hz), 3.76 (8H, ddd, J=17.8, 4.7, 4.5 Hz), 2.97-3.16 (8H, m), 2.92 (3H, s), 2.24 (3H, s). Mass Spectrum (ESI) m/e=453.1 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:12]([CH2:15][C:16]4[CH:17]=[C:18]5[C:23](=[CH:24][CH:25]=4)[N:22]=[CH:21][CH:20]=[CH:19]5)=[N:13][N:14]=3)[N:11]=2)[CH:3]=[N:2]1)(=[O:38])=[O:37]
Reactant: c1cnc2ccc(Cc3nnc4ccc(-c5cn[nH]c5)nn34)cc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)n1cc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of 6-[6-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl]-quinoline as prepared in Example 3 (10 mg, 0.03 mmol) and DIEA (9 μL, 0.05 mmol) in DCM (2 mL) was added methane sulfonylchloride (4 μL, 0.05 mmol). The reaction was stirred at rt overnight. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (3.1 mg, 31%) as a white solid. 1H-NMR (CD3OD): δ 9.06-9.00 (2H, q, J=5.3, 7.0 Hz), 8.89 (1H, s), 8.44 (1H, s), 8.29-8.10 (4H, m), 7.96-7.92 (1H, q, J=5.3, 3.0), 7.75-7.73 (1H, d, J=9.8 Hz), 4.87 (2H, s), 3.42 (3H, s). ESI-MS (m/z): Calcd. For C19H15N7O2S: 405.10; found: 406.1 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[C:15]=2[CH3:30])=[O:13])=[CH:7][CH:6]=1)C.O.[OH-].[Li+].O.C1COCC1>CO>[CH3:30][C:15]1[N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:28])([F:29])[F:27])[C:17]([CH3:19])=[CH:18][C:14]=1[C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:31])=[O:3])=[CH:10][CH:9]=1)=[O:13]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(C)n(-c3ccccc3C(F)(F)F)c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)Nc2ccc(C(=O)O)cc2)c(C)n1-c1ccccc1C(F)(F)F
Reaction time: 17 h
Yield: 14.7 %

Procedure:
A mixture of 4-({2,5-dimethyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbonyl}-amino)-benzoic acid ethyl ester (0.46 g, 1.1 mmol), lithium hydroxide monohydrate (0.15 g, 3.5 mmol, 3.3 eq), 2 mL of water, 2 mL of THF, and 3 mL of MeOH was stirred 17 h and then was concentrated under reduced pressure. The resulting suspension was treated with 200 μL of TFA and was washed into a separatory funnel with DCM and water. The water was separated and extracted with DCM. The combined extracts were dried (Na2SO4) and concentrated in vacuo. The crude acid was purified by reverse-phase HPLC to afford the title compound (65 mg, 15%) as a colorless solid; 1H NMR (DMSO-d6): δ 12.7-12.8 (br s, 1H), 9.84 (s, 1H), 8.12 (d, J=8 Hz, 1H), 8.03 (t, J=8 Hz, 1H), 8.00 (s, 4H), 7.93 (t, J=8 Hz, 1H), 7.61 (d, J=2H), 6.77 (s, 1H), 2.26 (s, 3H), 2.00 (s, 3H); MS (ESI) m/z 403 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11](=[O:27])[N:12]([C@@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](O)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:41])[CH2:34][CH:35]([NH2:40])[CH:36]([OH:39])[CH2:37][F:38])([CH3:31])([CH3:30])[CH3:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:28]([O:32][C:33](=[O:41])[CH2:34][CH:35]([NH:40][C:17](=[O:18])[C@@H:16]([N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11]1=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:36]([OH:39])[CH2:37][F:38])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(Nc1cccn([C@@H](Cc2ccccc2)C(=O)O)c1=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(O)CF
Temperature: 0 °C
Yield: 36.7 %

Procedure:
A stirred mixture of (S)-2-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid (2.20 g, 6.07 mmol), 3(R,S)-Amino-5-fluoro-4(R,S)-hydroxy-pentanoic acid tert-butyl ester (1.39 g, 6.68 mmol), HOBt (902 mg, 6.68 mmol), DMAP (853 mg, 6.98 mmol) and THF (20 mL) was cooled to 0° C. then EDC (1.28 mg, 6.68 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (30-70 to 55-45% ethyl acetate/hexane) to afford the title compound as a white foam (1.23 g, 32%); 1H NMR (400 MHz, CDCl3) δ 0.88-0.93 (3H, m), 1.35-1.42 (9H, 2s), 2.50-2.65 (2H, m), 3.20-3.35 (2H, m), 3.60 (1H, m), 3.98 (1H, m), 4.10-4.32 (3H, m), 5.62-5.70 (1H, m), 6.44 (1H, m), 6.80-6.98 (1H, m), 7.21-7.41 (5H, m), 7.55-7.62 (3H, m), 7.95 (2H, m), 8.58 (1H, t), 9.18 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH3:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:34]2[CH2:35][CH2:36][CH:31]([CH3:30])[CH2:32][CH2:33]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: CC1CCN(Cc2ccc3c(c2)cc(-c2ccc(Cl)c4c2C(=O)NC4)n3C(=O)OC(C)(C)C)CC1
Yield: 50.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (41.0 mg, 0.0998 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-methylpiperidine (0.048 mL, 0.41 mmol), acetic acid (0.345 mL, 6.03 mmol) and sodium triacetoxyborohydride (169 mg, 0.797 mmol). The reaction mixture was added with water and sodium hydrogen carbonate to adjust the pH of to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-methylpiperidinomethyl)indol-2-yl]isoindolinone (25.0 mg, yield 51%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH:38]=[C:39](OS(C(F)(F)F)(=O)=O)[N:40]=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1.O>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:39]4[N:40]=[CH:41][C:42]5[C:37]([CH:38]=4)=[C:36]([Cl:35])[CH:45]=[CH:44][C:43]=5[F:46])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Oc1cc2c(Cl)ccc(F)c2cn1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn2)CC1
Temperature: 100 °C

Procedure:
4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (0.065 g, 0.14 mmol) (BB3), trifluoromethanesulfonic acid 5-chloro-8-fluoroisoquinolin-3-yl ester (0.040 g, 0.12 mmol), Cs2CO3 (75 mg, 0.23 mmol), and Pd(PPh3)4 (7 mg, 0.006 mmol) were placed in a sealable microwave tube, taken up in 1,4-dioxane (2 mL, 30 mmol) and H2O (0.54 mL, 30 mmol), flushed with nitrogen, sealed and heated in the microwave reactor at 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc washed with water, brine, dried over Na2SO4, filtered and concentrated. The compound was purified by prep-TLC with 5% 7M NH3 in MeOH and DCM mixture yielding the title compound as pale yellow solid. MS (ES+): m/z=523.15/525.12 (100/40) [MH+]. HPLC: tR=3.03 min (ZQ2, polar—5 min).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=1>CN(C=O)C.O>[O:18]=[C:8]1[N:7]([CH:4]2[CH2:3][CH2:2][N:1]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:30]=3)[CH2:6][CH2:5]2)[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9]1
Reactant: CCOC(=O)c1cc(Cl)ncn1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
700 mg (2.85 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 470 μL (2.73 mmol) DIPEA were added to 500 mg (2.68 mmol) ethyl 6-chloropyrimidine-4-carboxylate in 10 mL DMF and the reaction mixture was stirred for 1 h at RT. The reaction mixture was diluted with water and stirred for 30 min. The precipitate was suction filtered, washed with water and dried at 50° C. in the CAD.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH:11]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][S:27]([O:16][CH:13]1[CH2:14][CH2:15][C:10]([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11][CH2:12]1)(=[O:29])=[O:28]
Reactant: O=[N+]([O-])c1cnccc1C1=CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC1CC=C(c2ccncc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 4-(3-nitropyridin-4-yl)cyclohex-3-enol (1.0 equiv.) and DIPEA (2.5 equiv.) in CH2Cl2 (0.15 M) was added methanesulfonyl chloride (1.8 equiv.) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with sat NaCl (30 mL). The organic was dried MgSO4, filtered and concentrated to give 4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate (93%). The residue was used in the next step without further purification. LC/MS (m/z): MH+=299.0, Rt=0.70
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[N:23]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[N:22]=[C:21]([C:32]([NH:34][CH3:35])=O)[CH:20]=2)[CH:15]=[CH:16][CH:17]=1.[OH-].[Na+]>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[N:23]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[N:22]=[C:21]([CH2:32][NH:34][CH3:35])[CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CNC(=O)c1cc(Sc2cccc(Br)c2)n(-c2cc(F)ccc2F)n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CNCc1cc(Sc2cccc(Br)c2)n(-c2cc(F)ccc2F)n1
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a suspension of aluminum chloride (1.28 g) in tetrahydrofuran (15 mL) was slowly added lithium aluminum hydride (364 mg) at 0° C., and the mixture was stirred at the same temperature for 15 min. To the obtained suspension was added dropwise a solution of 5-[(3-bromophenyl)thio]-1-(2,5-difluorophenyl)-N-methyl-1H-pyrazole-3-carboxamide (1.35 g) in tetrahydrofuran (7 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. A 8 mol/L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 1.18 g, 90%).
Reaction SMILES: C(C(C(C)C)C(NC(N)=O)=O)#N.C(CC(OC)=O)#N.[C:20]([CH:22]([CH:27]([CH3:29])[CH3:28])[C:23]([O:25]C)=[O:24])#[N:21].[OH-].[Na+].S(=O)(=O)(O)O>CC(C)=O>[C:20]([CH:22]([CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])#[N:21]
Reactant: COC(=O)C(C#N)C(C)C
Agent: CC(C)C(C#N)C(=O)NC(N)=O
Agent: COC(=O)CC#N
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)C(C#N)C(=O)O

Procedure:
The starting compound, N-(2-cyano-3-methylbutanoyl)urea, is a known compound and can be obtained by, for example, reacting methyl cyanoacetate and acetone, hydrolyzing the resulting methyl 2-cyano-3-methylbutyrate with an aqueous sodium hydroxide solution, treating said reaction mixture with sulfuric acid to give 2-cyano-3-methylbutyric acid and heating this compound in the presence of urea and acetic anhydride.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[C:4]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.Cl[CH2:22][CH2:23][N:24]1[C:28]2=[N:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:27]2[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O>[N:24]1([CH2:23][CH2:22][O:1][C:2]2[C:3](=[O:20])[C:4]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=3)=[N:5][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=2)[C:28]2=[N:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:27]2[CH2:26][CH2:25]1
Reactant: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Reactant: ClCCN1CCn2c1nc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(OCCN2CCn3c2nc2ccccc23)c1=O
Temperature: 70 °C
Reaction time: 15 h
Yield: 11 %

Procedure:
A suspension of 5-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (54 mg), 1-(2-chloroethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (49 mg), cesium carbonate (98 mg), and sodium iodide (33 mg) in dimethylformamide (4 mL) was stirred at 70° C. for 15 hr. The reaction mixture was filtered, and the obtained insoluble material was washed with ethyl acetate. The filtrate and washing were combined, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). A fraction containing the title compound was again purified by NH silica gel column chromatography (ethyl acetate/methanol) to give the title compound (10 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B2OCCCO2)=[C:19]([F:29])[C:18]=1[O:30][CH3:31].[F-].[Cs+].N#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([O:30][CH3:31])[C:19]=2[F:29])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: CC(C)OC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(Cl)c2Cl)c1F
Temperature: 25 °C

Procedure:
A 100 mL Schlenk flask was charged with propan-2-yl 4,5,6-trichloropicolinate (10.46 g, 39.0 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (13.27 g, 54.3 mmol) and CsF (11.76 g, 77.0 mmol). Acetonitrile (75 mL) and water (25 mL) were added. The reaction mixture was evacuated/backfilled with N2 (5×). Solid Pd(PPh3)2Cl2 (1.331 g, 1.896 mmol) was added. The solution was evacuated/backfilled with N2 (5×) and then stirred at reflux for 2 h. A white solid precipitated upon cooling to room temperature. The solid was filtered, washed with water and dried in air (10.56 g, 69%): mp 123.8-127.7° C.; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H, pyridine), 7.28 (dd, JH-H=8.5 Hz, JF-H=1.6 Hz, 1H), 7.13 (dd, JH-H=8.5 Hz, JF-H=6.8 Hz, 1H), 5.32 (septet, J=6.3 Hz, 1H, CHMe2), 3.99 (d, J=1.2 Hz, 3H, OMe), 1.41 (d, J=6.3 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, CDCl3) δ 162.7 (CO2R), 153.8, 153.6 (d, JF-C=253 Hz, C2′), 146.7, 144.5 (d, JF-C=13 Hz), 144.0, 134.0, 130.0 (d, JF-C=3.4 Hz), 125.9, 125.3 (d, JF-C=3 Hz), 125.1 (d, JF-C=3 Hz), 70.4 (CHMe2), 61.6 (d, JF-C=4 Hz, OMe), 21.7 (CHMe2). Anal. Calcd for C16H13Cl3NO3: C, 48.94; H, 3.34; N, 3.57. Found: C, 48.91; H, 3.50; N, 3.51.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:30][CH2:31][CH2:32][CH3:33])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[CH2:31]([NH:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:40][N:39]=[N:38][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH2:32][CH3:33]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCNc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCNc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 758.9 %

Procedure:
A solution of ethyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-propylaminobenzimidazole-7-carboxylate (1.20 g) and trimethyltin azide (2.7 g) in toluene (15 ml) was heated for 50 Hours under reflux. Precipitates were collected by filtration and suspended in methanol (20 ml). After addition of 1N-HCl (15 ml), the reaction mixture was stirred at room temperature for 10 minutes. The mixture was adjusted to about pH 5 with 1N-NaOH, followed by extraction with chloroform. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to give crystals. Recrystallization from methanol-ethyl acetate gave colorless crystals (10 g, 77%), m.p. 170-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3,3-bis(4-chlorophenyl)propionate (Step B, 0.78 g, 3.9 mmol), lithium hydroxide monohydrate (0.33 g, 7.8 mmol) in 1:1:1 MeOH/THF/water (15 mL) was stirred at room temperature overnight. The resulting mixture was partitioned between 2 M aqueous hydrochloric acid (50 mL) and ether (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.29-7.23 (m, 4H), 4.49 (t, 1H), 3.02 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[OH:25][C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[N:3]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Reactant: Cc1ncccc1O
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2cccnc2C)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 3-hydroxy-2-methylpyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 34% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](Br)[CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:32])=[O:20])([CH3:17])([CH3:16])[CH3:15].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:32])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCc2ccc(Br)cc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)N(C(=O)OC(C)(C)C)C(=O)CC3)C1=O
Yield: 40.9 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.15 g, 0.00084 mol) was reacted with 7-bromo-2-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.276 g, 0.00084 mol), 1,4-dioxane (20 mL), copper iodide (0.0158 g, 0.000084 mol), trans-1,2-diamino cyclohexane (0.28 g, 0.00025 mol) and potassium phosphate (0.356 g, 0.00168 mol) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in CHCl3) afforded 0.145 g of 7-[3-(4-Methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-2-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (67.48% yield).