Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.CC[N:15](CC)CC.N>C1COCC1>[NH2:15][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([Cl:12])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Agent: N
Solvent: C1CCOC1
Product: Nc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of 2,4,6-trichloro-5-nitropyrimidine (94 mg, 0.413 mmol) in THF (5 mL) was cooled to −78° C. and treated with Et3N (110 μL, 0.757 mmol), followed by NH3 (7 N in MeOH, 50 μL, 0.344 mmol). The reaction was warmed to 0° C. Once TLC indicated complete consumption of the starting material, the crude product solution was immediately used in the reaction below (Scheme 40).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][Mg]Br.[CH3:7][O:8][C:9](=[O:32])[C:10](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[CH:10]([CH:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:18][CH:17]=1)[CH:1]=[C:2]([CH3:6])[CH3:3])[C:9]([O:8][CH3:7])=[O:32]
Reactant: CC(C)=C[Mg]Br
Reactant: COC(=O)C(=Cc1ccc(OCc2cccc(OC)c2)cc1)C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(C=C(C)C)c1ccc(OCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-methyl-1-propenylmagnesium bromide (3 mL, 0.5 M in THF) was added dropwise to a solution of compound 33.1 (1.0 mmol) in THF. The reaction mixture was stirred at room temperature for 1 hr and then quenched with saturated NH4Cl(aq) and the aqueous layer extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate=2/1) to give compound 33.2 as a white solid (0.93 mmol).
Reaction SMILES: [CH:1]1([NH:4][CH:5]([CH:8]([CH3:10])[CH3:9])[CH2:6][OH:7])[CH2:3][CH2:2]1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>C1COCC1>[CH:1]1([N:4]([CH:5]([CH2:6][OH:7])[CH:8]([CH3:10])[CH3:9])[C:20]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:11])([F:22])[F:23])=[O:21])[CH2:3][CH2:2]1
Reactant: CC(C)C(CO)NC1CC1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)C(CO)N(C(=O)Nc1ccccc1C(F)(F)F)C1CC1
Temperature: 60 °C
Yield: 61.7 %

Procedure:
To a solution of crude 2-cyclopropylamino-3-methyl-butan-1-ol (195 mg) in THF (10 mL) was slowly added a solution of 2-trifluoromethylphenylisocyanate (225 mg) in THF (3 mL) at 0° C. The mixture was then heated to 60° C. for 12 hours. After cooling, the solution was concentrated in vacuo and the residue was purified by flash chromatography using ethyl acetate/heptane 1:1 as an eluent to give the desired material as a colorless solid (245 mg). MS (ESI): 331.3 (MH+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:34])=O)(C)(C)C.[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])=[C:38]([CH3:52])[CH:37]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:34])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:39]3[CH:40]=[C:41]([F:42])[C:36]([F:35])=[CH:37][C:38]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)c(F)cc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)c(F)cc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 3.4 %

Procedure:
A mixture of E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol) and 1-(4,5-difluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (13 mmol) in toluene (13 mL) was heated at 60° C. for 3 h, and concentrated in vacuo. To the residue was added DCM (30 mL) and TFA (5 mL), and the resultant solution was stirred at room temperature for 3 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous diluted NaOH solution. The organic layer was washed with water to neutral, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (60 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1oc2cccc(NS(C)(=O)=O)c2c1C
Yield: 67 %

Procedure:
To the product of Example 20, Step 1, 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (800 mg, 2.27 mmol), in 25 mL of toluene were added methane sulfonamide (650 mg, 6.82 mmol, 3 eq), Pd2 (dba)3 (208 mg, 0.23 mmol, 0.1 eq), biphenyl-2-yl-di-tert-butyl-phosphane (68 mg, 0.23 mmol, 0.1 eq), and tribasic potassium phosphate (965 mg, 4.55 mmol, 2 eq) under nitrogen and the resulting mixture was heated at reflux for 3 h. After work up and trituration, 4-methanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 67% yield (450 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.7 (s, 3 H) 3.1 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 7.3 (dd, J=7.7, 0.9 Hz, 1 H) 7.5 (dd, J=8.3, 7.6 Hz, 1 H) 7.6 (m, 1 H) 9.5 (s, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH3:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:27])=[CH:5][C:6]=2[N:18]=[C:19]1[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(NC(=O)Cc2cccs2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCC[C@H]1n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Temperature: 130 °C
Yield: 74 %

Procedure:
To 8.32 g 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were added 40 ml of 4M hydrochloric acid in dioxane and the mixture was heated in four portions in a microwave reactor to 130° C. for 20 min. 2 ml of water were added to each vial and the reactions were heated to 130° C. for 40 min. The reactions were then combined and concentrated and the pH was adjusted to 6 by addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate and concentrated. The product precipitated upon treatment with diisopropylether and 5.65 g (76%) of 1-((1R,2R)-2-Methyl-cyclohexyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.[Li+].CC([N-]C(C)C)C.CN(C1C=CC=CC=1)[CH:31]=[O:32]>O1CCCC1.C(OC)(C)(C)C>[Br:13][C:14]1([CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH2:15]1)[CH:31]=[O:32]
Reactant: Fc1cccc(Br)c1
Reactant: CN(C=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: COC(C)(C)C
Product: O=CC1(Br)C=CC=C(F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a solution of diisopropylamine (2.27 mol, 320 mL) in anhydrous tetrahydrofuran (800 mL) in a 5 L flask at 0° C. add 1.6 M butyllithium (1.16 L, 1.86 mol) in hexanes dropwise over 1.5 h. Stir the resulting yellow solution at 0° C. for 30 min. In a separate 12 L flask dissolve 1-bromo-3-fluorobenzene (203 mL, 1.86 mol) in anhydrous tetrahydrofuran (650 mL) and cool to −78° C. Transfer the preformed LDA solution to an addition funnel via cannula and add dropwise to the 1-bromo-3-fluorobenzene solution over 2 h so the temperature does not rise above −70° C. Stir the resulting slurry at −78° C. for 30 min. Add a solution of N-methyl-N-phenyl formamide (230 mL, 1.86 moles, 1.00 equiv.) in anhydrous tetrahydrofuran (1.15 L) dropwise at −78° C. over one hour while maintaining the temperature below −70° C. Stir the reaction cold for 2 h while slowly allowing it to rise to room temperature overnight. Dilute the reaction with methyl tert-butyl ether (3 L), quench with 1M hydrochloric acid (4 L) and stir vigorously for 3 h. Separate the layers and extract the aqueous layer with methyl tert-butyl ether (1 L). Wash the combined organic phases with 1M hydrochloric acid (2×1 L), water (1 L), brine (1 L), dry over magnesium sulfate, filter and concentrate to an orange oil that slowly solidifies to obtain the title compound (394 g, 105%). 1H NMR (CDCl3) δ 10.37 (s, 1H), 7.50 (d, 1H), 7.44 (m, 1H), 7.17 (t, 1H).
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C:7]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[BrH:17]>O.[Cu](Br)Br>[Br:17][C:7]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: Br
Agent: Br[Cu]Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
An aqueous solution of sodium nitrate (2.21 g) in water (15 mL) is added dropwise to a stirred, ice-cooled mixture of 2-amino-4-chlorobenzoic acid (5.00 g, 29.1 mmol) and 48% hydrobromic acid (150 mL) in water (150 mL). The resultant mixture is stirred for 2 hr at 0° C. Then it is treated dropwise with an aqueous solution of copper bromide (7.81 g) in water (20 mL). Upon the completion of the addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred overnight. After extraction with ethyl acetate/hexanes (3:1; 2×400 mL), the combined organic layers are washed with brine (200 mL), dried, concentrated, and chromatographed on silica (1% methyl alcohol and 0.5% acetic acid in chloroform) to give the title compound (4.04 g, 59% yield). mp 154-155° C.; ES(−)MS m/z 233, (M−H)− consistent with 1 Br and 1 Cl.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[Li]CCCC.[C:17](O)(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2].CO.C(Cl)Cl>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[N:3]=[C:2]([C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:1][CH:5]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: c1ccc(-c2cocn2)nc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCC(=O)c1nc(-c2ccccn2)co1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
(163) A solution of 2-(oxazol-4-yl)pyridine (4 mg, 0.027 mmol) in anhydrous THF (1 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0;030 mmol, 12 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 0.054 mmol, 22 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.027 mmol, 5 mg) was added, and the solution was stirred for 10 min at 0° C. A separate flask was charged with oleic acid (2 equiv, 0.054 mmol, 15 mg) in anhydrous CH2Cl2 (0.5 mL), and to this solution cooled to 0° C. under N2 was added oxalyl chloride (5 equiv, 0.27 mmol, 34 mg, 24 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (0.5 mL). The solution of oleoyl chloride was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 1.5 cm×17.5 cm, 2% MeOH—CH2Cl2) afforded 1-(4-(pyridin-2-yl)oxazol-2-yl)octadec-9-en-1-one (163) (5 mg, 0.011 mmol, 42% yield) as a brown residue: 1H NMR (CDCl3, 250 MHz) d 8.66 (br d, J=4.8 Hz,1H), 7.90-7.68 (m, 4H), 5.40-5.25 (m, 2H), 3.10 (t, J=7.4 Hz, 2H), 2.10-1.93 (m, 4H), 1.80-1.72 (m, 2H), 1.47-1.17 (m, 20H), 0.86 (br t, J=6.6 Hz, 3H); IR (CDCl3) umax 2925, 2860, 1705, 1605, 1570, 1501, 1425, 1385 cm−1; MALDI-FTMS (DHB) m/z 411.3003 (C26H38N2O2+H+ requires 411.3006).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:20][C:21]1[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23][CH:22]=1.[ClH:34]>CO>[ClH:34].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13])[CH:6]=[C:5]2[CH2:20][C:21]1[CH2:26][NH:25][CH2:24][CH2:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C(Cc2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)C1
Agent: Cl
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1cc(CC2=CCCNC2)c2cc(F)ccc21

Procedure:
A solution of tert-butyl 5-{[5-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl]methyl}-3,6-dihydro-1(2H)-pyridinecarboxylate (320 mg, 0.68 mmol) in methanol and HCl (1M in Et2O, 1.0 ml) is heated at reflux temperature under nitrogen for 18 hr, cooled and concentrated in vacuo. The resultant residue is treated with ether and filtered. The filtercake is dried in vacuo to afford the title compound as a brown solid, 211 mg, mp 96° C. (dec.), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:17]([O-])=O)[CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:6])[CH:2]=[CH2:3].Cl[Sn]Cl>CO>[NH2:17][C:15]1[CH:16]=[C:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: C=CCOC(=O)c1cc([N+](=O)[O-])c2ncccc2c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: C=CCOC(=O)c1cc(N)c2ncccc2c1
Temperature: 40 °C
Yield: 96.2 %

Procedure:
To a solution of 6-allyloxycarbonyl-8-nitroquinoline (4 g; 15.5 mM) in methanol (80 ml) was added SnCl2. (17.8 g-77.5 mM). The mixture was heated at 40° C. for 1 hour. After evaporation of the solvent, the residue was partitioned between an aqueous solution of NaHCO3 (10%) and ethyl acetate. The organic phase was concentrated and purified by subjecting to flash chromatography, eluting with ethylacetate/petroleum ether (30/70) to give 8-amino-6-allyloxycarbonylquinoline (3.4 g; 96%).
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH3:7].C([O:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)=[C:15]2[CH:14]=1)=O)C.C([O-])(=O)C(C(C([O-])=O)O)O.[Na+].[K+]>C(Cl)Cl>[CH3:5][N:6]([CH3:7])[C:11]([C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)=[C:15]2[CH:14]=1)=[O:10]
Reactant: CNC
Reactant: CCOC(=O)c1ccn2nc(-c3ccccn3)c(-c3ccnc4ccccc34)c2c1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)C(=O)c1ccn2nc(-c3ccccn3)c(-c3ccnc4ccccc34)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Add trimethylaluminium (0.54 mL, 1.08 mmoL) dropwise to a solution of dimethylamine (0.45 mL, 0.90 mmoL) in methylene chloride (1 mL) at 0° C. Warm to room temperature and stir for 1 hour. Add 2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (177 mg, 0.45 mmol) in methylene chloride (4 mL), and stir at room temperature for 1 hour and at 80° C. for 24 hours. Cool the reaction mixture to room temperature. Add aqueous solution of potassium sodium tartarate (20 mL) and stir the solution for 1 hour. Separate the organic layers and extract the aqueous solution with methylene chloride (2×20 mL). Dry the combined organic layers with sodium sulfate and concentrate. Purify by flash column chromatography (SiO2, 20-30% methanol/methylene chloride) to give the title compound 54 mg (31%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH:13]=O)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1cc(N)c(Cl)cc1CCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(N)c(Cl)cc1CCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of 5-amino-4-chloro-2-(4-oxobutyl)benzonitrile (35 mg, 0.157 mmol) in THF (0.5 mL) at room temperature was added morpholine (24.65 mg, 0.283 mmol), sodium cyanoborohydride (19.76 mg, 0.314 mmol), and a drop of acetic acid. The reaction was stirred at room temperature for 1 h at which point LCMS indicated full conversion. The reaction was quenched with aq. Na2CO3, extracted w/ DCM, concentrated and purified by flash column chromatography (0-10% MeOH/DCM) to give 5-amino-4-chloro-2-(4-morpholinobutyl)benzonitrile (29 mg) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N:17]1[CH:21]=[N:20][C:19]([NH2:22])=[N:18]1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:22][C:19]3[N:20]=[CH:21][N:17]([CH3:16])[N:18]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Cn1cnc(N)n1
Product: Cc1cn(-c2ccc(Nc3ncn(C)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-methyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless solid (Yield=36%). MS ISP (m/e): 280.1 (100) [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O-:12].[Na+]>CO>[CH3:11][O:12][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(C)=O)cn1
Temperature: 160 °C

Procedure:
A mixture of 15 mL of methanol, 500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone and 1.17 g (21.69 mmol) of sodium methoxide is heated in a microwave reactor at 160° C. for 4 hours. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, t 5 min 20% B, t 30 min 40% B), 230 mg of 1-(6-methoxypyrid-3-yl)ethanone were obtained, corresponding to the following characteristics:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C:18]3([CH3:28])[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:35]([N:49]2[CH2:61][CH2:60][N:52]3[C:53]4[CH2:54][CH2:55][CH2:56][CH2:57][C:58]=4[CH:59]=[C:51]3[C:50]2=[O:62])=[N:36][CH:37]=[CH:38][C:39]=1B1OC(C)(C)C(C)(C)O1)(=[O:31])[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:49]2[CH2:61][CH2:60][N:52]3[C:53]4[CH2:54][CH2:55][CH2:56][CH2:57][C:58]=4[CH:59]=[C:51]3[C:50]2=[O:62])=[N:36][CH:37]=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:24][O:25][CH2:26]4)[CH2:19][C:18]3([CH3:27])[CH3:28])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3(C)C)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4(C)C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-bromo-3-(5-(2,2-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 190e (200 mg, 1.0 eq., 0.45 mmol), (2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate 113i (345 mg, 2 eq., 0.90 mmol), PdCl2(dppf) (36 mg, 0.1 eq., 0.045 mmol), K3PO4 (191 mg, 2 eq., 0.90 mmol), sodium acetate (74 mg, 2.0 eq., 0.90 mmol), acetonitrile (15 mL), and water (0.1 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/ethanol to afford 187a (100 mg, 31%) as yellow solid. MS-ESI: [M+H]+ 707.4.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6](=[O:19])[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH:8]=1)([CH3:3])[CH3:2].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][N:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:8][N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]([F:16])([F:18])[F:17])[C:6]2=[O:19])[CH2:24][CH2:23]1
Reactant: CC(C)c1cn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Reactant: BrCC1CC1
Product: CC(C)c1cn(-c2ccccc2C(F)(F)F)c(=O)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isopropyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 19, 50 mg) by alkylation with bromomethylcyclopropane (25 mg). 3-Cyclopropylmethyl-4-isopropyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a colorless oil (11 mg). MS (ESI): 325.3 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[N:6]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=1)[CH3:2].P(=O)(O)(O)O.Cl.[OH-].[Na+]>ClCCl.O>[CH2:1]([C:3]1[N:4]=[C:5]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[N:6]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=1)[CH3:2]
Reactant: CCc1cn(CCN2CCCC2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCc1cn(CCN2CCCC2)c(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Combine tert-butyl 4-(4-ethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate; phosphoric acid (18.27 g, 38.50 mmol) and water (9.1 mL). Add 12 M hydrochloric acid in water (9.63 mL, 3.0 eq) dropwise and stir at room temperature. After one hour, adjust the pH of the reaction mixture with 2 M aqueous sodium hydroxide to 10. Dilute with dichloromethane. Separate the layers. Wash the aqueous phase with dichloromethane. Wash the organics with aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give 4-(4-ethyl-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine (7.70 g, 72%). MS (ES) m/z=277 [M]+.