Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17]C)(=[O:5])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.C(C1C=NC2C(C=1Cl)=CC=CC=2O)(=O)CCC.[F:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([CH3:48])[CH:42]=1>ClCCl.O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:45][C:44]1[CH:46]=[CH:47][C:41]([F:40])=[CH:42][C:43]=1[CH3:48])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(F)ccc1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Agent: BrB(Br)Br
Agent: CCCC(=O)c1cnc2c(O)cccc2c1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (131.9 g, 0.5 mol) in dichloromethane (1 liter) was cooled to -78°, then boron tribromide (142 ml, 1.5 mol) added slowly over 10 minutes. The mixture was warmed slowly to 0°, stirred 2 hours, then allowed to warm to room temperature overnight. After recooling in ice the reaction was quenched cautiously with water, then the resulting solid filtered off and dried. This was heavily contaminated with boron-containing impurities, but was used without purification. Crude 3-butyryl-4-chloro-8-hydroxyquinoline (64 g) and 4-fluoro-2-methylaniline (16.7 ml, 0.15 mol) were dissolved in dioxan (300 ml), heated on a steam bath for 2 hours, then left to stand overnight. The dioxan was evaporated, dichloromethane and aqueous sodium bicarbonate added, the mixture stirred until all the solid had dissolved, then the organic layer dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxy-quinoline (37 g), m.p. 121°-122°.
Reaction SMILES: CC(N=NC(C#N)(C)C)([C:4]#[N:5])C.C1C(=O)N(Br)C(=O)C1.[CH3:21][C:22]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24](OC)=[O:25]>C(Cl)(Cl)(Cl)Cl>[CH3:4][N:5]1[CH2:21][C:22]2[C:23](=[CH:28][CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=2)[C:24]1=[O:25]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CN1Cc2cc([N+](=O)[O-])ccc2C1=O
Temperature: 79 °C
Reaction time: 2 h

Procedure:
AIBN (84 mg, 0.51), NBS (1.1 gram, 6.4 mmol), and the methyl 2-methyl-4-nitrobenzoate (1 g, 5.1 mmol, as prepared in Step 1, Example 44) were suspended in CCl4 (12.8 ml), the vessel evacuated and backfilled with N2 (2×) and the mixture heated under N2 at 79° C. overnight. The solution was filtered, and concentrated in vacuum. One third of the crude material was dissolved in 2 N methylamine in methanol (18 ml), 2N methylamine in THF added (18 ml) and the solution stirred for 2 hours at RT. The volatiles were removed in vacuum and the product was purified by chromatography on SiO2 eluting with 10% acetone:DCM to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:13][C:3]1[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=1
Reactant: COC(=O)c1cc(N)c(Cl)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)c(Cl)cc1F
Reaction time: 120 h

Procedure:
To a solution of methyl 5-amino-4-chloro-2-fluorobenzoate (248 mg, 1.22 mmol) and pyridine (0.12 mL, 1.46 mmol) in 5 mL CH2Cl2 was added methanesulfonyl chloride (0.10 mL, 1.34 mmol). After 5 days at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCl3 to provide crude methyl 4-chloro-2-fluoro-5-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 280 (M−H)), which was hydrolyzed using aqueous NaOH to provide 4-chloro-2-fluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 266 (M−H)), which was used without further purification.
Reaction SMILES: C[C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11](C(F)(F)F)=[CH:10][N:9]=2)[CH2:3]1.[Br:18]C1C=CC(Br)=CN=1>>[Br:18][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH2:5][CH2:6][NH:7][CH2:2][CH2:3]2)=[N:9][CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[C@@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Product: Brc1ccc(N2CCNCC2)nc1
Yield: 73 %

Procedure:
The title compound was prepared following the procedure of the Intermediate 15, but starting from 2,5-dibromopyridine. Purification by chromatography (DCM/MeOH 80/20) gave the title compound as a brown powder (73%). M+(ESI): 244.2. HPLC (Condition A), Rt: 1.1 min (HPLC purity: 79.7%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.CCN(C(C)C)C(C)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(NS(=O)(=O)c2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
To 6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (8.2 mg, 0.021 mmol) and DIEA (5.4 mg, 0.042 mmol) in dichloromethane (1.0 ml) was added benzenesulfonyl chloride (3.7 mg, 0.021 mmol) at RT for 2 hrs. The reaction mixture was quenched with pH 7 phosphate buffer (2 ml), dried over Na2SO4, concentrated and purified by silica gel flash chromatography to isolate 377 as a yellow film (3 mg, 29%). [M+H]+=496.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1ccccn1
Agent: Br
Product: O=[N+]([O-])c1cc(OCc2ccccn2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-pyridine hydrobromide salt using the conditions described in Example 10C to provide 2-(4-Chloro-3-nitro-phenoxymethyl)-pyridine which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:13]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To suspension of sodium hydride (2.6 g; 62.6% in oil) in dimethylformamide (80 ml), a solution of 2-chloro-4-hydroxybenzaldehyde (10.0 g) in dimethylformamide (50 ml) was dropped over 15 minutes. The mixture was stirred for 30 minutes. Methyl iodide (4.2 ml) was dropped into the reaction mixture over 10 minutes at 0° C., and stirred for 1 hour. The reaction mixture was poured into water and extracted with hexane/ethyl acetate (1:1) The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (10.7 g) having the following physical data.
Reaction SMILES: [C:1]1([CH:7]([Ge:12](Cl)(Cl)Cl)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S>CC(C)=O>[C:1]1([CH:7]([GeH3:12])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Agent: S
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(O)CC([GeH3])c1ccccc1

Procedure:
16.4 g (0.05 mol) of 3-phenyl-3-(trichlorogermyl)propionic acid was dissolved in 200 ml of anhydrous acetone. 12.6 g (0.16 mol) of anhydrous pyridine was added to the solution under cooling with an ice bath, followed by stirring. Dry hydrogen sulfide was introduced into the mixture for one hour. The acetone was removed and the residue was dissolved in 50 ml of ethanol. The solution was added to 400 ml of water to precipitate the crystal. The crystal was recrystallized from a mixture of methyl acetate and benzene (1:3) to obtain 12.7 g of crystalline sesquisulfide of 3-phenyl-3-germylpropionic acid. ##STR14## sesquisulfide of 3-phenyl-3-germylpropionic acid (18).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:30])[CH2:28][CH3:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (71 mg, 74%), MS (ISP) m/z=385.4 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and propionic acid.
Reaction SMILES: [CH3:1][C@H:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][C@@H:3]1[NH2:11].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O.[CH3:50][N:51]([CH2:53][C@@H:54]([NH:62][CH2:63][C:64]1[CH:65]=[C:66]([CH:78]=[CH:79][CH:80]=1)[CH2:67][N:68]1[CH:72]([C:73](O)=[O:74])[CH2:71][CH2:70][S:69]1(=[O:77])=[O:76])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:52].C(N(CC)C(C)C)(C)C>CN(C)C=O.C[C@H]1C2C(C)(C)C(C2)C[C@@H]1N.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N[C@@H](CCSSCC[C@H](N)C(O)=O)C(O)=O>[CH3:1][C@@H:2]1[C@@H:3]([NH:11][C:73]([CH:72]2[CH2:71][CH2:70][S:69](=[O:77])(=[O:76])[N:68]2[CH2:67][C:66]2[CH:78]=[CH:79][CH:80]=[C:64]([CH2:63][NH:62][C@H:54]([CH2:53][N:51]([CH3:50])[CH3:52])[CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:65]=2)=[O:74])[CH2:4][C@H:5]2[CH2:6][C@@H:7]1[C:8]2([CH3:10])[CH3:9]
Reactant: C[C@H]1C2CC(C[C@@H]1N)C2(C)C
Reactant: CN(C)C[C@H](Cc1ccccc1)NCc1cccc(CN2C(C(=O)O)CCS2(=O)=O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N[C@@H](CCSSCC[C@H](N)C(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN[C@@H](Cc3ccccc3)CN(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Temperature: 25 °C
Yield: 244.9 %

Procedure:
(+)-Isopinocampheylamine (Aldrich; 29 mg, 0.19 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (available from Aldrich; 58.4 mg, 0.18 mmol), N-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 24.3 mg, 0.18 mmol) were added to a cooled (0° C.) solution of 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (100 mg 80% pure, 0.18 mmol) in dry N,N-dimethylformamide (3 mL) under argon. N,N-Diisopropylethylamine (70 μL, 0.4 mmol) was then added. The solution was then stirred at room temperature. After 30 minutes more (+)-isopinocampheylamine (6 mg, 0.04 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (available from Aldrich; 6 mg, 0.002 mmol) and N-hydroxybenzotriazole (available from 3B Scientific Corporation, Libertyville, Ill. 60048, USA; 3 mg, 0.002 mmol) were added. After 90 minutes all of the starting material had been consumed. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1N NaOH (3×15 mL), and brine (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give the crude product (132 mg). This material was combined with the crude product from an identical experiment using 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (250 mg). The combined lots were chromatographed, eluting with 0-10% methanol/dichloromethane to give 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicylo[3.1.1]hept-3-yl)amide (256 mg, 60%) as a tan foam.
Reaction SMILES: [CH3:1][N:2]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3](=[O:13])[CH2:4][NH:5]C(OC(C)(C)C)=O.C(O)CC.[BrH:32]>C(OCC)(=O)C>[BrH:32].[CH3:1][N:2]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[C:3](=[O:13])[CH2:4][NH2:5]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)n1cccc1C(=O)c1ccccc1Cl
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CN(C(=O)CN)n1cccc1C(=O)c1ccccc1Cl

Procedure:
1-(N-Methyl-(t-butoxycarbonylamino)acetamido]-2-(2-chlorobenzoyl)pyrrole (24 g, 61.2 mmol) was dissolved in 100 ml of ethyl acetate, and 60 ml of n-propanol solution containing 12 ml of 48% HBr was added thereto with stirring. After 1 hour at 35° the solution was evaporated and the residue triturated with ether to give 23.2 g of powder. This powder was recrystallized from isopropanol-ether to give 22 g (96%) of flocculent crystals, m.p. 193°-195°.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH3:29])=[C:21]([C:23](N(OC)C)=[O:24])[N:22]=4)[CH:19]=3)[C:10](=[O:30])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:33][Mg]Br>C1COCC1>[C:23]([C:21]1[N:22]=[C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=4)=[CH:9][C:10]3=[O:30])=[CH:19][N:18]2[C:20]=1[CH3:29])(=[O:24])[CH3:33]
Reactant: CON(C)C(=O)c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn2c1C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-(4-((4-fluorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-N-methoxy-N,3-dimethylimidazo[1,2-a]pyridine-2-carboxamide (150 mg) in THF (10 ml) was added methylmagnesium bromide (3 M ether solution, 344 μl) at −78° C., and the resulting mixture was stirred at the same temperature for 2 h. The reaction mixture was then quenched with saturated aqueous NH4Cl (40 ml) at −78° C., and slowly warmed to room temperature. The reaction mixture was concentrated in vacuo and diluted with EtOAc (100 ml). The EtOAc layer was washed with brine (40 ml), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (55 mg) as a white solid.
Reaction SMILES: N1(CCN2CCC(N[C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])CC2)CCCCCC1.Cl.Cl.Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][N:45]2[CH:50]3[CH2:51][CH2:52][CH:46]2[CH2:47][CH:48]([OH:53])[CH2:49]3)[CH2:39][CH2:38]1>>[OH:53][CH:48]1[CH2:49][CH:50]2[N:45]([CH2:44][CH2:43][N:40]3[CH2:41][CH2:42][CH:37]([NH:36][C:17]([C:19]4[NH:20][C:21]5[C:26]([CH:27]=4)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=5)=[O:18])[CH2:38][CH2:39]3)[CH:46]([CH2:52][CH2:51]2)[CH2:47]1
Reactant: NC1CCN(CCN2C3CCC2CC(O)C3)CC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4C5CCC4CC(O)C5)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 24.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([F:13])[F:12])[CH:3]=1.[Li+].[Cl-].[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([F:13])[F:12])[CH:3]=1)[CH:17]=[CH2:16]
Reactant: N#Cc1ccc(Br)cc1OC(F)F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc(C#N)c(OC(F)F)c1

Procedure:
To a solution of 4-bromo-2-(difluoromethoxy)benzonitrile (620 mg, 2.5 mmol) in 30 ml of toluene was added LiCl (322 mg, 7.5 mmol), Pd(PPh3)4 (60 mg), Allyl tributyltin (990 mg, 3.0 mmol), and then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-(difluoromethoxy)benzonitrile.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[N:6]3[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: CON(C)C(=O)c1nc2cccc(C)n2c1Br
Reactant: OB(O)c1cc(F)cc(F)c1
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: C1COCCO1
Solvent: O
Product: CON(C)C(=O)c1nc2cccc(C)n2c1-c1cc(F)cc(F)c1
Temperature: 95 °C
Yield: 81.1 %

Procedure:
A solution of 3-bromo-N-methoxy-N,5-dimethylimidazo[1,2-a]pyridine-2-carboxamide (0.48 g, 1.6 mmol), (3,5-difluorophenyl)boronic acid (0.33 g, 2.1 mmol), and sodium carbonate (0.26 g, 2.4 mmol) in 1,4-dioxane (10 mL) and water (1.9 mL) was degassed with nitrogen and treated with tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol). The reaction mixture was degassed with nitrogen and heated at 95° C. for 19 h. The reaction mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude solid. Purification by flash column chromatography gave the desired product (0.43 g, 80%). LCMS for C17H16F2N3O2 (M+H)+: m/z=332.1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:39]=[C:38]([CH3:40])[C:31]3[N:32]([CH2:36][CH3:37])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:36]([N:32]1[C:31]2[C:38]([CH3:40])=[CH:39][C:28]([C:26]([C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35])[CH3:37]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CCn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(C)c21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)oc2cc(C(=O)c3cc(N4CCC(n5c(=O)[nH]c6ncccc65)CC4)ncn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
47 mg (0.20 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 50 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-ethyl-4-methyl-3H-benzoxazol-2-one and 0.11 mL (0.64 mmol) DIPEA were combined in 2.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined, the organic solvent was evaporated down and the residue was neutralised with 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.C([O-])(=O)C.[K+].[O:29]=[C:30]1[NH:35][C:34](=[O:36])[C:33](B(O)O)=[CH:32][NH:31]1>CN(C)C=O.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>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:33]5[C:34](=[O:36])[NH:35][C:30](=[O:29])[NH:31][CH:32]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: O=c1[nH]cc(B(O)O)c(=O)[nH]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3c[nH]c(=O)[nH]c3=O)cc1-2
Temperature: 25 °C

Procedure:
9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 (500 mg, 1.3 mmol) and potassium acetate (380 mg, 3. 8 mmol) were suspended in N,N-dimethylformamide (5 mL) and water (5 mL) and degassed by bubbling N2 for 5 min. Charged with 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylboronic acid (250 mg, 1.6 mmol) and then tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.13 mmol). The reaction was microwaved at 300 watts, 140° C. for 20 minutes. Subsequently after cooling to r.t. and diluting with water (20 mL), the mixture was extracted with ethyl acetate. The combined organics portions were concentrated and purified by reverse phase HPLC to provide 506 as a white crystalline compound (70 mg, 10% yield). LC/MS (ESI+): m/z 423.1 (M+H). 1H NMR (500 MHz, DMSO) δ 1.22 (s, 2H), 8.71 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 5.92-5.81 (m, 1H), 4.38 (s, 2H), 3.45 (s, 2H), 1.55 (d, J=6.5 Hz, 4H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:22]=[C:21]([O:23][C:24]3[CH:25]=[N:26][C:27]([N+:30]([O-])=O)=[CH:28][CH:29]=3)[CH:20]=[CH:19][N:18]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.C1COCC1.[Zn]>[NH2:30][C:27]1[N:26]=[CH:25][C:24]([O:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:14]([N:11]3[CH2:10][CH2:9][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)=[O:15])[CH:22]=2)=[CH:29][CH:28]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1)N1CCN(Cc2ccccc2)CC1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(Cc4ccccc4)CC3)c2)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 66.4 %

Procedure:
To a stirring solution of 4-benzyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (0.574 g, 1.321 mmol) in MeOH/THF (1:1, 30 mL) at RT was sequentially added ammonium formate (0.833 g, 13.21 mmol) and zinc powder (0.864 g, 13.21 mmol). The resulting suspension was stirred briskly at RT. After 75 min, the reaction was filtered through diatomaceous earth, rinsing with THF. The combined filtrates were concentrated and purified by silica gel chromatography (0-10% MeOH/DCM) to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-4-benzylpiperazine-1-carboxamide (0.355 g, 64%) as a brittle pink foam. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 8.05 (d, J=5.7 Hz, 1H), 7.75 (d, J=2.9 Hz, 1H), 7.30-7.29 (m, 5H), 7.24-7.23 (m, 2H), 6.52 (dd, J=5.7, 2.4 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 5.99 (s, 2H), 3.46 (s, 2H), 3.40 (t, J=4.7 Hz, 4H), 2.31 (t, J=4.7 Hz, 4H); MS (ESI) m/z: 405.2 (M+H+).