Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:10][C@H:9]([NH2:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2)(=[O:3])[CH3:2].[CH3:24][C:25]([CH3:40])([C:29]([NH:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[O:30])[C:26](O)=[O:27]>>[C:1]([N:4]1[CH2:10][C@H:9]([NH:11][C:26](=[O:27])[C:25]([CH3:24])([CH3:40])[C:29]([NH:31][CH2:32][C:33]([F:38])([F:39])[C:34]([F:35])([F:36])[F:37])=[O:30])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CC(=O)N1C[C@H](N)C(=O)N(Cc2ccccc2)c2ccccc21
Product: CC(=O)N1C[C@H](NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F)C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d) and 27, the condensation of (S)-5-acetyl-3-amino-1-benzyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid [see Example 25 b)] yielded the title compound as a white solid; MS: m/e=553 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[OH-].[Na+]>ClCCl>[CH2:2]1[O:4][CH:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(CCl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
A solution of (+)-2-chloro-1-phenylethanol (156.6 mg, 1.0 mmol, 97.5% ee) in dichloromethane (2.0 ml) and a 2.0 M aqueous solution of sodium hydroxide (1.0 ml, 2.0 mmol) were mixed and stirred at room temperature for 4 hours. To the solution was added dichloromethane (2.0 ml), and the dichloromethane layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation. The residue was purified by silica gel column chromatography to give a desired compound, (+)-styrene oxide (115.2 mg; yield: 95.9%; optical purity: 97.5% ee).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Cl[CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1CCN2C(=NCCC2)CC1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:3]1=[O:8]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCCCCSc1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)N(CCCCSc2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 43 h
Yield: 56.8 %

Procedure:
To a solution of 2.56 g (20 mmol) of 5,5-dimethylhydantoin and 4.03 g (20 mmol) of 4-(4-chlorobutylthio)pyridine in 20 ml of N,N-dimethylformamide, 3.00 ml (20 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, and the mixture was stirred at room temperature for 43 hours, followed by further stirring at 70° C. for 10 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed three times with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to give 3.33 g of the desired compound (56.8% yield, colorless crystals).
Reaction SMILES: CO[C:3](=[O:30])[NH:4][C:5]1[NH:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.N12CCCN=C1CCCCC2>CN1CCCC1=O.O1CCCC1>[CH:31]1([NH:34][C:3](=[O:30])[NH:4][C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([O:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:22][CH:23]=4)(=[O:16])=[O:17])=[CH:13][C:7]=3[N:6]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)cc2[nH]1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1)NC1CC1
Temperature: 60 °C

Procedure:
10 mg of methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) were combined with 25 μl cyclopropylamine and 10 μl 1,8-diazabicyclo[5.4.0]undec-7-ene in 2 ml N-methylpyrrolidone/tetrahydrofuran (0.8/1.2) in a 24 well Inox plate for high pressure reaction. The reaction mixture was put under a 10 Bars argon pressure and then heated to 60° C. for 40 hours, and then cooled to room temperature. Compounds were put in an assay tube, tetrahydrofuran was evaporated under reduced pressure and compound in N-methylpyrrolidone was directly purified by LC/MS trigged purification yielding 8.7 mg title compound. (LC/MS analysis: retention time=3.66 min., mass spectrum: 456.36, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[CH2:22][OH:23]>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a suspension of N-(4-chloro-3-hydroxymethyl-phenyl)-2-methyl-6-trifluoromethyl-nicotinamide (3.29 g; 9.56 mmol) in dichloromethane (300 ml) was added manganese dioxide (8.31 g; 95.6 mmol) and the resulting mixture stirred at room temperature for 30 minutes. Analysis after this time showed a 60% conversion to product. Further manganese dioxide (8 g; 92 mmol) was added in three portions over the next 90 minutes. The reaction mixture was then filtered through celite and the filtrate evaporated to give N-(4-chloro-3-formyl-phenyl)-2-methyl-6-trifluoromethyl-nicotinamide (3.2 g, 97%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][S-:16].[Na+].CCOC(C)=O.Cl>C1COCC1>[CH3:15][S:16][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: C[S-]
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1cc(C(=O)O)cc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a suspension of 2-chloro-6-(trifluoromethyl)isonicotinic acid (0.1 g, 443 μmol, prepared according to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) in THF (5 mL) was added sodium thiomethoxide (155 mg, 2.22 mmol, CAS RN 50615-16-2) and the reaction mixture was heated to 70° C. (oil bath temperature) for 15 hours. After cooling down to room temperature, EtOAc (5 mL) and 1M aqueous HCl (2 mL) were added and the reaction mixture was stirred at room temperature for 30 min. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give the desired compound as an off-white solid (0.105 g; 99%) which was used in the next step without further purification. MS (ESI): m/z=236.01 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([C:14](=[O:16])[CH3:15])[CH2:3]1>CO.[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:17])([CH3:1])[CH2:3][N:4]2[C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
10% Pd—C (0.2 g) was added to a suspension of 1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone (2.1 g, 9 mmol) in MeOH (20 mL). The reaction was stirred under H2 (40 psi) at room temperature overnight. Pd—C was filtered off and the filtrate was concentrated under vacuum to give a crude product, which was purified by column chromatography to yield 1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (DC-8) (1.3 g, 61%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:18])[CH2:11]2)[CH:3]=1.[CH3:26][C:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=2)[NH:29][N:28]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[CH:20]1([NH:19][C:17]([C@H:12]2[CH2:13][CH2:14][C@@H:15]([CH3:16])[N:10]([C:4]3[CH:3]=[C:2]([C:32]4[CH:31]=[C:30]5[C:35]([C:27]([CH3:26])=[N:28][NH:29]5)=[CH:34][CH:33]=4)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=3)[CH2:11]2)=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Reactant: Cc1n[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2ccc3c(C)n[nH]c3c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 35 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (440 mg, 1.20 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (466 mg, 1.80 mmol, 1.5 equiv), tricyclohexylphosphine (50 mg, 0.18 mmol, 0.15 equiv), Pd2(dba)3 (83 mg, 0.09 mmol, 0.075 equiv) and K3PO4 (434 mg, 2.04 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (4.5 mL) and water (1.5 mL). The mixture was bubbled with argon for 10 minutes, followed by capping and heating at 100° C. for 20 hours. The mixture was filtered through celite, and rinsed with EtOAc (50 mL). The filtrate was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and brine (20 mL). The organic was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient elution with 1% EtOAc in CHCl3 to 100% EtOAc. This purified material was combined with purified product from a duplicate run. The combined residue was triturated in a mixture of CHCl3 (1 mL) and hexane (6 mL). Drying under vacuum at 65° C. for 20 hours afforded the title compound (194 mg) as a beige solid. LC-MS (ES) m/z=462 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.20-1.34 (m, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.35-1.45 (m, 2H), 1.64-1.71 (m, 1H), 1.73-1.83 (m, 5H), 1.85-1.95 (m, 2H), 1.95-2.07 (m, 1H), 2.35-2.45 (m, 1H), 2.59 (s, 3H), 2.98 (s, 3H), 3.07-3.17 (m, 1H), 3.63-3.73 (m, 1H), 4.45-4.65 (bs, 1H), 6.48 (s, 1H), 7.66 (dd, J=8.5, 1.1 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 8.02 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 84.1 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (180 mg, 1.17 mmol), tetrahydrofuran (7 mL), oxalyl chloride (152 μL, 1.74 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (242 mg, 84%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)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.O>[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:2]3[C:10]4[N:5]([NH:6][CH:7]=[N:8][C:9]=4[NH2:11])[CH2:4][CH:3]=3)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncnn2ccc(Br)c12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)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: CN(C)C=O
Product: NC1=C2C(c3ccc4cn(Cc5ccccc5)nc4c3)=CCN2NC=N1
Yield: 37.9 %

Procedure:
A stirred mixture of 5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.47 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (188 mg, 0.56 mmol), sodium carbonate (119 mg, 1.13 mmol), N,N-dimethylformamide (4 mL) and water (0.3 mL) was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.04 mmol) was added, and the reaction was irradiated in a microwave reactor at 150° C. for 15 minutes. The reaction mixture was filtered through Celite®, the pad washed with methanol, and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane and 1N aqueous hydrochloric acid. The dichloromethane extracts were washed with 5% aqueous sodium bicarbonate solution, then brine, dried (anhydrous sodium sulfate); filtered and concentrated in vacuo to afford 61 mg (38% yield) of yellow solid. 1H-NMR (CD2Cl2): δ 8.04 (d, 1 H), 7.86 (s, 1 H), 7.77 (dd, 1 H), 7.75 (d, 1 H), 7.65 (d; 1 H), 7.40-7.32 (m, 5 H), 7.21 (dd, 1 H), 6.77 (d, 1 H), 6.91 (br s, 2 H), 5,61 (s, 2 H). MS: LC/MS (+esi), m/z=341 [M+H]. RT=2.44 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55]C(OC(C)(C)C)=O)[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH2:55])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reaction time: 1 h

Procedure:
[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.211 g, 0.244 mmol) was dissolved in DCM (2.439 mL). HCl in dioxane (4N, 0.610 mL, 2.44 mmol) was added at room temperature and the resulting solution was stirred for approximately one hour. Upon completion, the reaction was concentrated in vacuo to giving [1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester as a white solid (assumed 0.244 mmol) that was used without further purification in subsequent reactions. LCMS-ESI+: calc'd for C45H48N8O4: 764.43 (M); Found: 765.31 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:20])[CH2:4][O:3]1.I[CH3:27]>>[CH3:27][N:17]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]3[NH:6][C:5](=[O:20])[CH2:4][O:3][C:2]([CH3:1])([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)[C:8]=3[CH:9]=2)=[CH:14][CH:15]=[C:16]1[C:18]#[N:19]
Reactant: CI
Reactant: CC1(c2ccsc2)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccsc1)OCC(=O)N2

Procedure:
Prepared from 5-[5-methyl-2-oxo-5-(3-thienyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-2-carbonitrile and iodomethane generally according to the procedure of example 3. 1H-NMR (DMSO-d6) δ 10.16 (s, 1H), 7.56 (dd, J=2.92, 5.02 Hz, 1H), 7.42 (dd, J=1.90, 8.42 Hz, 1H), 7.28-7.23 (m, 3H), 7.09 (dd, J=1.06, 4.83 Hz, 1H), 7.01 (d, J=4.06 Hz, 1H), 6.30 (d, J=4.08 Hz, 1H), 4.20 (d, J=15.95 Hz, 1H), 4.05 (d, J=15.93 Hz, 1H), 3.65 (s, 3H), 1.96 (s, 3H); MS (ES) m/z 362 ([M−H]−, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(-c3ccncc3)cccc21
Product: CC1c2cccc(-c3ccncc3)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1O[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[CH3:1][C:2]1[N:24]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1
Reactant: Cc1nc2c(=O)c3ccccc3ccc2o1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(Cn2c(C)nc3c(=O)c4ccccc4ccc32)cc1
Temperature: 100 °C

Procedure:
A stirred mixture of the product from step (i) (5.07 g) and 4-methoxybenzylamine (12 ml) was heated at 100° C. for 24 h. The excess 4-methoxybenzylamine was distilled off under reduced pressure. The remaining residue was purified by recrystallisation from ethyl acetate to give the subtitle product as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[CH:12]=[CH2:11]
Reactant: CC(=O)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C(C)=O
Yield: 98.6 %

Procedure:
2′-Hydroxyacetophenone (1I-3) (14.0 g, 0.103 mol), allyl bromide (20.4 g, 0.169 mol) and potassium carbonate (14.2 g, 0.103 mol) in acetone (140 ml) were refluxed for 16 h. The solvent was removed under reduced pressure and water was added. The layers were extracted with ether and the organic extracts were washed with water, dried over magnesium sulfite and concentrated under reduced pressure leaving 17.9 g of 2′-allyloxyacetophenone as a colorless oil. 8.6 g of allyl ether thus obtained was refluxed in 1,2-dichlorobenzene (40 ml) in an oil bath heated at 210° C. for 18 h. The solvent was removed under reduced pressure to give 8.9 g of 3′-allyl-2′-hydroxyacetophenone. Without purification, the product was dissolved in DMF (60 ml) and was added dropwise to a suspension of sodium hydride (60% oil dispersion, 2.4 g, 0.06 mol) in DMF (25 ml) at a rate keeping the reaction temperature between 40 to 45° C. After stirring for additional 20 min, a solution of benzyl bromide (8.6 g, 0.05 mol) in DMF (10 ml) was added dropwise. After 2 h and 4 h, each 0.7 g of additional benzyl bromide was added. After 6 h, the reaction mixture was poured into ice water and extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was removed to give 14.0 g of an orange oil. This was purified by 250 g of silica gel chromatography (ethyl acetate/hexane=1:4) to give compound (II-4) (9.6 g) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH:19]([N:21]([CH3:35])[S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH3:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl>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]>[C:2]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[CH:19]([N:21]([CH3:35])[S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(c1nc2ccccc2c(=O)n1-c1ccc(Br)cc1)N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CC(c1nc2ccccc2c(=O)n1-c1ccc(-c2ccccc2)cc1)N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 70 °C
Yield: 70.6 %

Procedure:
An oven-dried flask charged with N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzenesulfonamide (103 mg, 0.19 mmol) was diluted with 2 mL of a nitrogen-purged solution of DME/H2O (1:1). The resulting reaction mixture was then treated with K2CO3 (78.8 mg, 0.57 mmol) and phenyl boronic acid (46.3 mg, 0.38 mmol) at room temperature under a nitrogen atmosphere. In a separate oven dried vial containing triphenyl phosphine (43.9 mg, 0.17 mmol) and Pd2 dba3:CHCl3 (17 mg, 0.019 mmol) was placed 1 mL of the nitrogen purged DME/H2O solution (1:1). The contents of the vial were stirred until the Pd(0) was completely dissolved. The premixed palladium solution was then added to the reaction mixture and heated to 70° C. under nitrogen for 16 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was then taken up in EtOAc and filtered through a plug of silica. The filtrate was concentrated under vacuum to afford a crude residue that was purified by chromatography (silica gel, 0-75% EtOAC:Hex) to afford the desired product as a white solid (74 mg, 71% yield). 1H-NMR (CDCl3): δ 8.26 (d, 1H), 7.88 (d, 1H), 7.76 (d, 1H), 7.67 (m, 4H), 7.45 (m, 7H), 7.23 (m, 3H), 4.99 (q, 1H), 3.20 (s, 3H), 1.33 (d, 3H), 1.16 (s, 9H); MS (ESI) 552 (MH+).