Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:16]1([C:3]2[C:2]([N:31]3[CH2:32][CH2:33][CH:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccccc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 4-phenylpiperidine (141.68 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (100:1). This resulted in 92.9 mg (49%) of methyl 2-phenyl-3-(4-phenylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C(O[C:4](=[O:26])[C@H:5]([CH3:25])[NH:6][CH2:7][C:8]([NH:10][C:11]1[C:12]2[C:17]([N:18]=[C:19]3[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])C.[NH2:27][C:28](N)=[O:29].O>CN1CCCC1=O>[CH3:25][C@@H:5]1[N:6]([CH2:7][C:8]([NH:10][C:11]2[C:12]3[C:17]([N:18]=[C:19]4[C:24]=2[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[C:28](=[O:29])[NH:27][C:4]1=[O:26]
Reactant: NC(N)=O
Reactant: CCOC(=O)[C@H](C)NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H]1C(=O)NC(=O)N1CC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
In 9 ml of N-methylpyrrolidone, was dissolved 3.9 g of the compound obtained in Example 38, and 2.64 g of urea was further added thereto. The reaction was carried out at 160° C. for one hour. The reaction mixture was cooled to 80° C. and 100 ml of water was added. The precipitated crystals were collected by filtration and dissolved in a mixture of 5 ml of methanol and 150 ml of chloroform. The solution was dried over anhydrous sodium sulfate and evaporated to dryness. The obtained product was recrystallized from ethanol-ethyl acetate to obtain 2.44 g of the titled compound having the melting point of 260° to 263° C.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:7][C:6]1=[O:17])/[CH:2]=[CH:3]/[CH3:4]>C1C=CC=CC=1>[CH2:1]([C@H:5]1[CH2:9][C@H:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[O:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: C/C=C/C[C@H]1C[C@H](c2ccc(F)cc2)OC1=O
Solvent: c1ccccc1
Product: CCCC[C@H]1C[C@H](c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
(3S,5R)-3-((E)-but-2-enyl)-5-(4-fluorophenyl)dihydrofuran-2(3H)-one (100.0 mg, 0.43 mmol) was dissolved into 8 mL benzene and to it added Wilkinson catalysis (39.0 mg, 0.4 mmol). The solution was saturated with H2 (stream of H2 bubbled through solution) and then stirred for 20 h at room temperature under an atmosphere of hydrogen balloon. The solvent was removed under reduced pressure and the product isolated by flash column chromatography eluting with 3% to 30% ethyl acetate/hexane to give 94 mg of the title compound as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[OH:32][CH:31]([C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:30][CH2:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)C1CCCC1
Reactant: O=CCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C1(C(O)CCCCc2ccccc2)CCCC1
Temperature: -40 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Diisopropylamine (17.5 mL, 124 mmol) is dissolved in THF (80 mL), cooled to -40° C. and 2.38 M n-butyl lithium in hexanes (52 mL, 124 mmol) is added over 5 minutes. The reaction is allowed to warm to 0° C. and cyclopentanecarboxylic acid (6.7 mL, 62 mmol) in THF (60 mL) is added over 5 minutes. The reaction is heated at 40° C. for 1 hour. The reaction is cooled to -78° C. and 5-phenylpentanal (10 g, 62 mmol) in THF (20 mL) is added dropwise over 15 minutes. The cooling bath is removed and the reaction is allowed to stir at room temperature overnight. The reaction is acidified with 2 N HCl (120 mL) and the organics are removed in vacuo. The resulting aqueous mixture is extracted with CH2Cl2 (200 mL) and this organic layer is dried over MgSO4. The solution is concentrated in vacuo, and the resulting residue is purified by column chromatography (silica, 50% ether in petroleum ether) to yield 1-(1-hydroxy-5-phenylpentyl)cyclopentanecarboxylic acid (13.1 g, 77%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.19-7.15 (m, 3H), 3.53-3.46 (m, 1H), 2.64-2.58 (m, 2H), 2.20-2.13 (m, 1H), 2.07-1.99 (m, 1H), 1.95-1.73 (m, 1H), 1.67-1.49 (m, 8H), 1.44-1.32 (m, 3H); MS (EI) m/e 276 (M+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23][NH2:24])=[O:22]
Reactant: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(CC(=O)NN)c2cc(O)ccc2n1Cc1ccccc1
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of 165 mg (0.51 mmol) of 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide (Example 17, Part B) in 30 mL of CH2Cl2 was added 1.0 mL of 1M BBr3 in CH2Cl2 and the mixture stirred for 1.5 hours, then an addition 0.5 mL of the BBr3 solution was added. After 1.5 hours, the reaction mixture was washed with Na2CO3 solution, dried (Na2SO4), and concentrated at reduce pressure. The residue was chromatographed on silica eluting with 2% MeOH/CH2Cl2 →5% MeOH/CH2Cl2 to give 60 mg (39% yield) of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide, mp, 216°-219° C.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[SH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][S:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH:5]=1
Reactant: BrCc1cccnc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: Br
Product: COC(=O)c1ccc(SCc2cccnc2)cc1

Procedure:
1 g of 3-(bromomethyl)pyridine hydrobromide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(pyridin-3-ylmethylthio)benzoate. 980 mg of methyl 4-(pyridin-3-ylmethylthio)benzoate was reacted via Procedure R to give methyl 4-(pyridin-3-ylmethylsulfonyl)benzoate. 760 mg of methyl 4-(pyridin-3-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-3-ylmethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-3-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-3-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[N:20]1[S:21][N:22]=[C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][C:24]=12.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]3[C:24]([CH:25]=2)=[N:20][S:21][N:22]=3)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: BrCc1ccc2nsnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2ccc3nsnc3c2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), (benzo-[c][1,2,5]-thiadiazol-6-yl)methylbromide (252 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.115 g (28.8%); MS m/z: 400.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.55 (q, 2H, 3J=7.6 Hz); 4.73 (s, 2H); 4.87 (s, 2H); 6.77-6.81 (m, 2H); 7.15 (d, 2H, 3J=7.9 Hz); 7.22 (d, 2H, 3J=7.9 Hz), 7.34 (d, 1H, 3J=8.5 Hz); 7.69 (dd, 1H, 4J=1.5 Hz, 3J=9.2 Hz); 7.85 (s, 1H); 7.90 (s, 1H); 8.05 (d, 1H, 3J=8.9 Hz), 11.93 (br s, 1H); HPLC (METHOD [A]): rt 17.72 min (96.4%)
Reaction SMILES: [N:1](=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:4]=[N:5][OH:6])[NH2:2].[C:13](OC)(OC)(OC)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:13][C:14]1[N:2]=[N:1][C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][N+:5]=1[O-:6]
Reactant: NN=C(C=NO)c1ccccc1
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Cc1nnc(-c2ccccc2)c[n+]1[O-]
Temperature: 130 °C
Reaction time: 18 h
Yield: 36.6 %

Procedure:
To a solution of hydrazono-phenyl-acetaldehyde oxime (28 g, 168 mmol) at room temperature under nitrogen in dichloromethane (300 ml) was added trimethyl orthoacetate (19 ml, 168 mmol) and p-toluenesulfonic acid (1.6 g, 8.4 mmol). The reaction mixture was stirred for 18 h and then concentrated in vacuo. Xylene (300 ml) was added followed by trimethyl orthoacetate (19 ml, 168 mmol) and the mixture heated to 130° C. for 2 h. The reaction mixture was evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 50% EtOAc in hexanes) and the product was recrystallised from a mixture of dichloromethane and ethyl acetate to afford the title compound as a white solid (11.5 g). δH (400 MHz; CDCl3) 2.86 (3H, s), 7.57 (3H, m), 7.99 (2H, m), 8.52 (1H, s). m/z (ES+) 188 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>N1C=CC=CC=1>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:13][C:10]2[N:9]=[CH:8][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:12][CH:11]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc(N2CCCCC2)cn1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(N2CCCCC2)cn1
Temperature: 50 °C
Yield: 25.6 %

Procedure:
3,4,5,6-Tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.19 g) and 3-chloro-2-methylbenzenesulfonyl chloride (0.24 g) were dissolved in pyridine (4 mL) and heated at 50° C. over night. The mixture was concentrated in vacuo, taken up in ethyl acetate and extracted with 1M Cu(II)SO4 solution. The organic layer was washed once again with Cu(II)SO4 solution, dried over Na2SO4 and evaporated in vacuo. The product was purified by flash chromatography on silica gel (gradient of ethyl acetate in heptane) to give 3-chloro-2-methyl-N-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-benzenesulfonamide (0.1 g) as a light brown foam. MS (ESI−): 364.0 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:21][CH:22](OC)[CH:23]=[CH2:24].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:24]=[CH:23][CH:22]=[O:21])[CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(OC)OC
Reactant: O=c1c2ccc(Br)cc2ccn1Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=CC=Cc1ccc2c(=O)n(Cc3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-benzyl-6-bromo-1,2-dihydro-1-oxoisoquinoline (1 g, 3.2 mmol), acrolein dimethyl acetal (2.6 mL, 22.4 mmol), Pd(OAc)2 (15 mg, 0.064 mmol), P(o-tolyl)3 (78 mg, 0.26 mmol) and Et3N (0.5 mL, 3.84 mmol) in DMF (2 mL) is heated in a sealed tube apparatus at 120° for 48 hours. After cooling to room temperature, the reaction mixture is diluted with EtOAc, filtered, washed with saturated NaCl solution, dried over MgSO4 concentrated in vacuo, and the residue is chromatographed (silica gel 1:4 EtOAc/hexane) to yield 3-[2-benzyl-1-oxo-1,2-dihydroisoquinolin-6-yl]-acrolein.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[O:11][CH3:12].N([O-])=[O:15].[Na+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:15])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc(O)cc1OC
Yield: 64.4 %

Procedure:
4-Amino-2-methoxy benzoic acid methyl ester (15 g, 82.7 mmol) was dissolved in sulfuric acid (80 ml of a 25% solution). The solution was cooled in an ice bath and diazotized with saturated sodium nitrite solution (8.57 g, 124 mmol) maintaining the temperature below 5° C. The diazonium solution was poured slowly into boiling sulphuric acid (1L of a 3% solution) and the mixture was heated for an additional 5 mins. The mixture was then allowed to cool before being extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo to afford a brown solid (9.7 g).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:8]=2[CH2:9][NH:10][C:11](=[O:17])[C@@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[CH:6]=[N:5][N:4]=[N:3]1.[C:26]([O:30][C:31]([NH:33][C@@H:34]([C:40](O)=[O:41])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:26]([O:30][C:31]([NH:33][C@@H:34]([C:40]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:11]([NH:10][CH2:9][C:8]1[CH:18]=[C:19]([C:22]([F:25])([F:23])[F:24])[CH:20]=[CH:21][C:7]=1[N:2]1[CH:6]=[N:5][N:4]=[N:3]1)=[O:17])=[O:41])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(NCc1cc(C(F)(F)F)ccc1-n1cnnn1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-[2-(1H-tetraazol-1-yl)-5-(trifluoromethyl)benzyl]-L-prolinamide hydrochloride (35 mg, 0.09 mmol), N-(tert-butoxycarbonyl)-4-methyl-D-leucine (24 mg, 0.10 mmol), EDC (27 mg, 0.14 mmol), HOAt (6.3 mg, 0.05 mmol) and Hünig's base (34 mL, 0.20 mmol) in DMF (1.2 mL) was stirred at room temperature for 16 h. The title compound was isolated by extractive workup (EtOAc) and silica gel chromatography (60%-80% EtOAc-hexanes) as an oily foam which was carried on directly to the deprotection step. 1H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 7.88 (s, 1H), 7.78 (br m, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 4.97 (d, J=6.0 Hz, 1H), 4.59 (d, J=6.4 Hz, 1H), 4.32–4.20 (m, 2H), 3.99–3.95 (m, 1H), 3.51–3.45 (m, 1H), 2.31–2.29 (m, 1H), 2.05–1.92 (m, 3H), 1.62–1.52 (m, 2H), 1.28 (s, 9H), 1.01 (s, 9H). LCMS (M+H): 568.3.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.[O:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.O>[O:36]1[CH2:37][CH:38]=[C:39]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:40][CH2:41]1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cn(-c2ccc(C3=CCOCC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (459 mg, 0.9 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (210 mg, 1.0 mmol), Pd(PPh3)4 (52 mg, 0.045 mmol), Na2CO3 (212 mg, 2.0 mmol), DME (4 mL), and H2O (1 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from THF/MeOH to give the title compound (364 mg, 91% yield) as a white solid: mp 229-231° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 2.40-2.50 (2H, m), 3.77 (3H, s), 3.82 (2H, t, J=5.5 Hz), 4.22-4.27 (2H, m), 6.43-6.48 (1H, m), 6.97 (1H, d, J=1.9 Hz), 7.02 (1H, t, J=8.7 Hz), 7.29-7.46 (6H, m), 7.52 (1H, dd, J=1.9, 12.8 Hz), 7.79 (1H, d, J=1.9 Hz), 8.48 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 445 [M+H]+. Anal. Calcd for C25H21FN4O3: C, 67.56; H, 4.76; N, 12.61. Found: C, 67.31; H, 4.58; N, 12.52.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:13]1[CH2:14][CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: [NH4+]
Reactant: Cc1ccc(F)c(C2CC(=O)CC(=O)C2)c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(F)c(C2CC(=O)C=C(N)C2)c1
Yield: 87.1 %

Procedure:
A solution of 5-(2-fluoro-5-methylphenyl)cyclohexane-1,3-dione (1.5 g) and ammonium acetate (1.6 g) in ethanol (23 ml) was refluxed for 20 hours. Under reduced pressure, the solvent was evaporated, and precipitated crystals were washed with water and toluene, and dried to give 1-amino-5-(2-fluoro-5-methylphenyl)cyclohexen-3-one (1.3 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].B1(C=C)OB([CH:32]=[CH2:33])OB(C=C)O1.C1C=CN=CC=1.O>C1COCC1.[Cl-].[Na+].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>[CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH:32]=[CH2:33])=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1OC(F)(F)F
Reactant: C=CB1OB(C=C)OB(C=C)O1
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: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1ccc(C(=O)N(CC)CC)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To a stirring degassed solution of N,N-diethyl-4-bromo-2-(trifluoromethoxy)benzamide (2373 mg, 7 mmol) in THF (40 mL) was added tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.08 mmol). After 15 min., potassium carbonate (2898 mg, 21 mmol), 2,4,6-trivinylcyclotriboroxane pyridine complex (2663 mg, 7 mmol), and water (8 mL). The reaction was heated to reflux for 3 h and then cooled to room temperature. The reaction was diluted with brine and extracted with EtOAc (3×25 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pale yellow oil. The oil was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to give 1783 mg of the desired product as a colorless oil. MS (ESI) 288 (M+H).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14](OCCNC(C2C=CC3N=C(C(C4NC5CCNCC=5N=4)C)N(C)C=3C=2)=O)=[C:15]([CH:19]=1)C(O)=O)=[O:10])C1C=CC=CC=1.[BrH:47]>C(O)(=O)C>[BrH:47].[C:9]([OH:10])(=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:19]=1
Reactant: CC(c1nc2c([nH]1)CCNC2)c1nc2ccc(C(=O)NCCOc3ccc(C(=O)OCc4ccccc4)cc3C(=O)O)cc2n1C
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1
Temperature: 10 °C

Procedure:
A solution comprising 5-benzyloxycarbonyl-2-(2-{3-methyl-2-[1-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)ethyl]-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid (0.561 g, 0.90 mmol) in glacial acetic acid (2 mL) was heated under nitrogen in a water bath to 10° C., treated with hydrogen bromide in acetic acid (2 mL of a 30% solution) and allowed to warm to 20° C. and, one hour later, concentrated with a stream of nitrogen. The residue was dissolved in a small quantity of ethanol and the solution was added dropwise to stirring ether to give a pale brown precipitate. The precipitate was isolated by filtration and dried to provide 2-(2-{3-methyl-2-[4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)ethyl]-3H-benzoimidazol-5-ylcarbonylamino}ethoxy)benzoic acid hydrobromide (0.651 g); 1H-NMR (300 MHz, DMSO-d6) d ppm: 9.31 (br s, 2H), 8.63 (m, 1H), 8.24 (s, 1H), 7.79 (d, 1H, J=7.9 Hz), 7.63 (m, 2H), 7.47 (t, 1H, J=7.9 Hz), 7.21 (d, 1H, J=7.9 Hz), 7.00 (t, 1H, J=7.9 Hz), 5.21 (q, 1H, J=6.3 Hz), 4.29 (s, 2H), 4.21 (s, 2H), 3.91 (s, 3H), 3.68 (m, 2H), 3.43 (m, 2H), 2.89 (s, 2H), 1.79 (d, 3H, J=6.3 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH:6]/[C:7](=[CH:13]\[C:14]([O:16]CC)=O)/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=[N:2]1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:16]=[C:14]1[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:6][C:4]2[CH:5]=[N:1][NH:2][C:3]1=2
Reactant: CCOC(=O)/C=C(\Nc1cn[nH]c1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cc(=O)c2[nH]ncc2[nH]1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
Diethyl 2-(pyrazol-4-ylamino)fumarate (7.74 g, 30 mmol) was added to boiling Dowtherm A (250 ml). The solution was heated under reflux for 10 min, and then allowed to cool to room temperature. 60°-80° petrol (250 ml) added and the solid was collected and washed well with petrol, to give the title compound as pale yellow needles (5.77 g, 99%), m.p. 287°-292° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:40]=[N:39][C:38]([CH3:41])=[N:37][CH:36]=2)[CH:30]=1)=O)(C)(C)C>>[CH3:41][C:38]1[N:39]=[N:40][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:36][N:37]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1ncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Product: Cc1ncc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (83 mg, 0.3 mmol) and 3-[3-(3-methyl-[1,2,4]triazin-6-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K46) (113 mg, 0.36 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (18 mg).