Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[NH:16][CH2:17][CH3:18])[N:11]=[CH:10][C:9]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:26](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.N>CN(C=O)C.CO.C(Cl)Cl>[CH2:17]([NH:16][C:15](=[O:19])[NH:14][C:12]1[CH:13]=[C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([C:20]([NH2:26])=[O:22])=[CH:10][N:11]=1)[CH3:18]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8918.5 %

Procedure:
4-anilino-6-(ethylcarbamoylamino)pyridine-3-carboxylic acid (i) (70 mg, 0.23 mmol) was suspended in DMF (2 mL) and N,N-diisopropylethyl amine (0.16 mL, 0.93 mmol) was added, causing the solid to dissolve. The [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl-ammonium hexafluorophosphate (97 mg, 0.26 mmol) was added. After stirring at RT for 10 min, ammonia (1 mL, 25 mass %, 14.7 mmol) was added. The mixture was stirred overnight at RT. The mixture was quenched with NH4Cl and diluted with water and EtOAc. The mixture was extracted into EtOAc (3×20 mL), the organics combined and dried with brine then over MgSO4. The solvent was removed to afford a crude residue as a white solid. The solid was dissolved in MeOH/DCM and applied to a silica column, eluting with MeOH/DCM, to give Compound 6140 mg. 1H NMR (400 MHz, CD3OD) δ 8.46-8.39 (m, 1H), 7.44-7.37 (m, 2H), 7.29-7.23 (m, 2H), 7.22-7.14 (m, 1H), 6.84 (s, 1H), 3.29-3.24 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).
Reaction SMILES: C[Li].[CH3:3]COCC.[C:8]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[CH3:3][C:14]1[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:17]=[CH:16][N:15]=1
Reactant: CCOCC
Reactant: CC(C)(C)c1ccncc1
Agent: [Li]C
Solvent: ClCCl
Product: Cc1cc(C(C)(C)C)ccn1
Yield: 74.2 %

Procedure:
Cool a solution of methyl lithium in ether (200 mL, 1.6 M, 320.00 mmol) in an ice bath and add 4-tert-butyl-pyridine (20.28 g, 150.00 mmol) drop wise. Once the substrate is added, warm the reaction to ambient temperature for 3 hours. Concentrate the reaction to near dryness to remove the ether and then add anhydrous toluene (200 mL) and heat to reflux for 20-21 hours. Cool in an ice bath while slowly and cautiously adding ice to quench the reaction. Add water (200 mL) and then extract the aqueous with ethyl acetate (3×250 mL) and separate the layers. Pool, desiccate, filter and concentrate the organic extracts to an oil. Chromatograph the oil on silica using a gradient of 0→50% ethyl acetate hexanes over 25 minutes to yield the title compound (16.60 g, 111.23 mmol). MS(ESI), m/z 150 (M+1).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CCCCNCCc1ccc(C#N)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCc1ccc(C#N)cc1)c1nc2ccccc2o1
Yield: 24.5 %

Procedure:
A solution of 750 mg 4-(2-Butylamino-ethyl)-benzonitrile, 854 mg 2-chlorobenzooxazole and 0.95 ml N,N-diisopropylethylamine in 10 ml dimethylformamide were stirred under microwave irradiation at 200° C. for thirty minutes. The cooled reaction mixture was diluted by the addition of 60 ml ethyl acetate, then washed three times with 40 ml brine. The organic layer was dried over MgSO4, then the solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 290 mg 4-[2-(Benzooxazol-2-yl-butyl-amino)-ethyl]-benzonitrile as pale yellow amorphous solid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:21]1
Reactant: ClCc1nc2cccnc2s1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(2-methoxyphenyl)piperazine (229 mg, 1.2 mmol), and DIEA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.74 (m, 4H) 3.02 (m, 4H) 3.78 (s, 3H) 4.04 (s, 2H) 6.91 (m, 3H) 7.56 (dd, J=8.31, 4.75 Hz, 2H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 341 (M+H)+.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)C[C@H](N)C(=O)NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 67.9 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (108 mg, 0.37 mmol, 1.0 eq), triethylamine (156 uL, 1.11 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (53 uL, 0.41 mL, 1.1 eq), then with L-leucine N-benzylamide (123 mg, 570 umol, 1.5 eq). Workup as before provided 124 mg (68%) of L-leucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:16]=1.Cl.[CH2:18]([N:20]([CH2:33][CH3:34])[CH2:21][CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[O:23][CH2:22][CH2:21][N:20]([CH2:33][CH3:34])[CH2:18][CH3:19])[C:6]=2[CH:16]=1
Reactant: CCN(CC)CCOc1ccccc1C(=O)Cl
Reactant: Clc1ccc2oc(-c3ccccc3)cc2c1
Agent: Cl
Product: CCN(CC)CCOc1ccccc1C(=O)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
Acylation of 5 -chloro-2-phenylbenzofuran with 2-(2-diethylaminoethoxy)benzoyl chloride hydrochloride by the procedure described in Example 6 gives the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[H-].[Na+].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>C1COCC1.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:5]1[C@@H:4]([CH2:3][CH2:2][O:1][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[CH2:8][O:7][C:6]1([CH3:10])[CH3:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCOc2ccc(C(F)(F)F)cn2)COC1(C)C
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To a stirred solution of tert-butyl(S)-4-(2-hydroxyethyl)-2,2-dimethyloxazolidine-3-carboxylate (300 mg; CAS 147959-18-0) in THF (4 ml) under an argon atmosphere was added sodium hydride (59 mg, 60% dispersion in oil). The resulting suspension was heated at 50° C. for 20 min and then cooled to 0° C. A solution of 2-chloro-5-trifluoromethyl-pyridine (222 mg) in THF (2 ml) was then added dropwise and the resulting mixture was heated at 70° C. for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with saturated brine, the phases were separated and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-oxazolidine-3-carboxylic acid tert-butyl ester (393 mg, 82%) as a colourless oil. MS (ISP): 391.3 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:22][N:23]1[C:27](B(O)O)=[CH:26][CH:25]=[N:24]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][C:2]=1[C:27]1[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1nccc1B(O)O
Reactant: Brc1cc(-c2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1OCc1ccccc1
Yield: 63.9 %

Procedure:
A solution of benzyl 3-bromobiphenyl-4-yl ether (500 mg, 1.47 mmol) and (1-methyl-1H-pyrazol-5-yl)boronic acid (185 mg, 1.47 mmol) in dioxane (4 mL) was degassed with argon for 30 minutes. Tris(dibenzylideneacetone)dipalladium (0) (54 mg, 0.06 mmol) and tricyclohexylphosphine (33 mg, 0.12 mmol) were added to the mixture under an argon atmosphere. A degassed solution of tripotassium phosphate (626 mg, 2.95 mmol) in water (2 mL) was added and the mixture was stirred at reflux for 16 hours under an argon atmosphere. The cooled reaction mixture was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was dissolved in ethyl acetate (25 mL) and the solution was washed with water (2×10 mL), brine (10 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate in hexane) to afforded the title compound (320 mg).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:67][CH:68]5[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a suspension of 16.67 g (0.0379 mole) of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-38) in 500 mL of dimethylformamide was added 8.26 g (0.0612 mole) of 1-hydroxybenzotriazole, 22.44 g (0.0592 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred for 30 minutes and then 6.60 g (0.0580 mole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for an additional and then concentrated under reduced pressure. The residue was partitioned between 800 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted with twice with 300 mL of ethyl acetate. The combined organic extracts were washed successively three times with 1 M sodium hydroxide, twice with 200 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-isopropylamine (190:10:1-160:40:1) to give 15.32 g of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-39).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)[CH2:13][C:12]3([CH3:26])[CH3:25])=[C:8]([C:27]([NH2:29])=[O:28])[CH:7]=[N:6][N:5]2[CH:30]=1.[O:31]=[C:32]1[C@@H:36]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34][NH:33]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.CO.ClCCl.[Cu]I>[C:27]([C:8]1[CH:7]=[N:6][N:5]2[CH:30]=[C:2]([N:33]3[CH2:34][CH2:35][C@H:36]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42])[C:32]3=[O:31])[CH:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH2:13][C:12]1([CH3:25])[CH3:26])(=[O:28])[NH2:29]
Reactant: CC1(C)CN(c2ccc(C#N)cc2)CC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc3c(N[C@@H]4CCN(c5ccc(C#N)cc5)CC4(C)C)c(C(N)=O)cnn3c2)C1=O
Temperature: 100 °C
Reaction time: 0.18 h
Yield: 19.2 %

Procedure:
A mixture of (R)-6-bromo-4-((1-(4-cyanophenyl)-3,3-dimethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.039 mmol), (S)-tert-butyl (2-oxopyrrolidin-3-yl)carbamate (21.6 mg, 0.108 mmol), copper(I) iodide (1.5 mg, 7.70 mmol), potassium carbonate (16.0 mg, 0.116 mmol) in dioxane (0.5 mL) was pumped under vacuum and backfilled with nitrogen twice. N1,N2-dimethylethane-1,2-diamine (8.3 μl, 0.077 mmol) was added. The reaction tube was sealed and heated at 100° C. for 17 h. The mixture was diluted with a 1:1 mixture of methanol-dichloromethane (2 mL) and filtered. The filtrate was concentrated to give crude product (48.3 mg) as brown solid. Part of the material (15.6 mg) was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water; Mobile Phase B: acetonitrile; Buffer: 20-mM ammonium acetate; Gradient: 15-100% B over 10.9 minutes, then a 4.0 minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give tert-butyl ((S)-1-(3-carbamoyl-4-(((R)-1-(4-cyanophenyl)-3,3-dimethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-2-oxopyrrolidin-3-yl)carbamate (4.4 mg, 20% yield). 1H NMR (500 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.11 (s, 1H), 7.79 (s, 1H), 7.47 (d, J=8.9 Hz, 2H), 7.27 (s, 1H), 6.94 (d, J=8.9 Hz, 2H), 4.41 (t, J=9.4 Hz, 1H), 4.09 (dd, J=10.2, 3.7 Hz, 1H), 3.91-3.72 (m, 3H), 3.57 (d, J=12.9 Hz, 1H), 3.25-3.16 (m, 1H), 2.95 (d, J=13.4 Hz, 1H), 2.66-2.57 (m, 1H), 2.25-2.07 (m, 2H), 1.96-1.84 (m, 1H), 1.44 (s, 9H), 1.16 (s, 3H), 1.08 (s, 3H); MS (ES+) m/z: 587.1 (M+H); LC retention time: 1.78 min (analytical LCMS Method I).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22][C:23]([CH3:29])([CH3:28])[CH:24]=[CH:25][CH:26]=[CH2:27].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(O)=O.[Na+]>C(#N)C.CCN(CC)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:27]=[CH:26][CH:25]=[CH:24][C:23]([CH3:29])([CH3:28])[CH3:22])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: C=CC=CC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C=CC=Cc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 100 °C
Yield: 74.5 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (500 mg, 1.40 mmol) in acetonitrile (15 mL) and NEt3 (3.2 mL) was added 5,5-dimethyl-hexadiene (0.5 g, 4.54 mmol), palladium acetate (35 mg, 0.16 mmol) and tri-o-tolylphosphine (175 mg). The reaction mixture was heated in a sealed tube at 100° C. for 16 h. After cooling to room temperature, saturated NaHCO3 was added. The mixture was extracted with EtOAc (2×). The combined organic layers were dried (MgSO4), concentrated and chromatographed (silica gel; hexane/EtOAc, 5:1 to 2:1) to afford an oil (403 mg, 75%): 1H NMR (CDCl3, 300 Hz) δ 1.48 (s, 9H), 1.82-1.92 (m, 2H), 2.00-2.08 (m, 2H), 3.30-3.50 (m, 2H), 3.90 (br, 1H), 4.08-4.26 (m, 2H), 5.93 (d, 1H, J=15.5 Hz), 6.15 (dd, 1H, J=10.0, 15.0 Hz), 6.42 (d, 1H, J=16.0 Hz), 6.90 (m, 1H), 8.12 (s, 2H), 8.20 (s, 1H); MS (CI/NH3) m/z 387 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1.[F:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.[Cu]Cl.C(OCC)(=O)C.CCCCCC>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][C:2]1[CH:3]=[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1
Reactant: Brc1csc(C2OCCO2)c1
Reactant: Oc1cccc(F)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1cccc(Oc2csc(C3OCCO3)c2)c1
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 24.4 %

Procedure:
2-(4-Bromo-thiophen-2-yl)-[1,3]dioxolane (1.0 g, 4.3 mmol), 3-fluorophenol (0.95 g, 8.6 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.078 g, 0.43 mmol), copper(I) chloride (0.21 g, 2.7 mmol) and cesium carbonate (2.8 g, 8.6 mmol) were suspended in N-methylpyrrolidone (10 mL) under a nitrogen stream, and the mixture was stirred for 4.5 hours at 120° C. To this suspension was added 2,2,6,6-tetramethyl-3,5-heptanedione (0.12 g, 0.65 mmol), and the solution was further stirred for 8 hours at 140° C. The reaction mixture was filtered through Celite pad, then, water and ethyl acetate were added for partitioning, and the organic layer was washed with water twice. NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption to NH silica gel, purification was carried out by NH silica gel column chromatography (hexane, then hexane:ethyl acetate=30:1), and the title compound (280 mg, 1.05 mmol, 24.4%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl.C(OCC)(=O)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccn(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere: to a solution of 1H-indole-6-carboxylic acid methyl ester (for synthesis see example 2a), 2.47 g, 14.1 mmol) in NMP (140 mL) was added Cs2CO3 (10.1 mg, 31 mmol) at 0° C. After stirring for 15 min 2-picolyl chloride hydrochloride (2.77 g, 16.9 mmol) was added and the mixture was stirred at room temperature for 18 h. Ethyl acetate (200 mL) was added and the mixture was washed with saturated aqueous ammonium chloride (3×150 mL) and brine (200 mL). The organic phase was dried (Na2SO4) and concentrated. The crude product was purified using column chromatography (ethyl acetate/heptane 1:3) to give the title compound as a colourless oil, which slowly crystallised on standing (2.72 g, 10.2 mmol, 72%).
Reaction SMILES: CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]1.CCN(CC)CC>CC(O)(C)C.ClCCCl.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([NH:24][C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[N:12]=1
Reactant: Cn1cc(N)cn1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cn1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Reaction time: 0.17 h

Procedure:
A 1.0 M solution of ZnCl2 in Et2O (5.07 mL, 5.07 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 4.61 mmol) in t-BuOH (25 mL) and DCE (25 mL) and the mixture was stirred for 10 minutes. The mixture was diluted with t-BuOH (25 mL) and DCE (25 mL) before 1-methyl-1H-pyrazol-4-amine (492 mg, 5.07 mmol) and Et3N (1.93 mL, 13.83 mmol) were added and stirring was continued at room temperature overnight. The volatiles were removed in vacuo and the resultant residue suspended in water (250 mL) and sonicated for 10 minutes. The solid was collected by vacuum filtration and the filter cake washed with water and then air dried. The solid was dissolved in DCM, adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A64 as a white solid (182 mg, 14%). LCMS-A: rt 6.113 min; m/z 278.1 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CCOC(C)=O.[Cu]I.CS(C)=O>[N:23]1([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1I
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-n1ccnc1
Temperature: 90 °C
Reaction time: 66 h

Procedure:
A mixture of 3-iodo-4-methyl-N-(4-(trifluoromethoxy)phenyl)benzamide (100 mg, 0.237 mmol), imidazole (64.6 mg, 0.95 mmol), CuI (9.04 mg, 0.048 mmol), L-proline (10.94 mg, 0.094 mmol), K2CO3 (131.2 mg, 0.95 mmol) and DMSO (250 μL) were stirred under argon for 66 h at 90° C. The RM was cooled to, diluted with DCM/EtOAc, filtered, washed with 10% aq. NaCO3 solution and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® 4 g silica gel, DCM/MeOH+1% NH3 from 0% B to 10% DCM/MeOH+1% NH3) to afford the title compound. UPLC-MS (Condition 2) tR=0.9 min, m/z=362.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 3H) 7.12 (d, J=0.78 Hz, 1H) 7.36 (d, J=8.99 Hz, 2H) 7.49 (d, J=0.78 Hz, 1H) 7.58 (d, J=7.82 Hz, 1H) 7.84-7.90 (m, 2H) 7.90-7.93 (m, 1H) 7.93-7.95 (m, 1H) 7.98 (dd, J=7.82, 1.56 Hz, 1H) 10.41 (s, 1H).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=[O:15])[NH:7][CH2:8][C:9]2[C:14]/1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:3].[NH:16]1[CH:20]=[C:19]([C:21]2[CH:27]=[CH:26]C(N)=[CH:23][CH:22]=2)[N:18]=[CH:17]1>C1(C)C=CC=CC=1>[NH:16]1[CH:20]=[C:19]([C:21]2[CH:27]=[CH:26][C:3]([NH:2]/[CH:4]=[C:5]3\[C:6](=[O:15])[NH:7][CH2:8][C:9]4[C:14]\3=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:23][CH:22]=2)[N:18]=[CH:17]1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CN(C)/C=C1/C(=O)NCc2ccccc21
Solvent: Cc1ccccc1
Product: O=C1NCc2ccccc2/C1=C/Nc1ccc(-c2c[nH]cn2)cc1
Temperature: 110 °C
Yield: 27.8 %

Procedure:
A toluene (3 mL) solution containing (4E)-4-[(dimethylamino)methylene]-1,4-dihydro-3(2H)-isoquinolinone (300 mg, 1.48 mmol) and 4-(1H-imidazol-4-yl)aniline (265 mg, 1.66 mmol) is heated at 110° C. for 4 h. Using the same workup as example 1, 0.13 g (28%) orange solid is obtained: mp 151-152° C. (dec.); HRMS (ESI) m/z calcd for C19H16N4O 317.13969. found 317.13894 (M+H)+1.