Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C([O:16][B:17](OC(C)C)[O:18]C(C)C)(C)C.Cl>CCOCC.C1COCC1.CCOCC>[F:2][C:3]([F:12])([F:11])[C:4]1[CH:9]=[CH:8][C:7]([B:17]([OH:18])[OH:16])=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
An oven dried Schlenk tube was charged with magnesium turnings (766 mg, 31.5 mmol), evacuated, and backfilled with argon. To the reaction vessel was added 10 mL of ether followed by 4-(trifluoromethyl)phenyl bromide (4.20 mL, 30.0 mmol). The reaction mixture was stirred without external heating for 1 hour, during which time an exotherm occurred and then subsided. The solution was diluted with ether (10 mL) and transferred via cannula to a flask containing triisopropylborate (13.8 mL, 60.0 mmol) in 1:1 THF/ether (20 mL) at −78° C. The resulting reaction mixture was kept at −78° C. for 15 minutes and then was allowed to warm to room temperature. After stirring at room temperature for 15 minutes, the reaction mixture was poured onto 2.0 M HCl (60 mL). The mixture was transferred to a separatory funnel, extracted with ethyl acetate (60 mL), washed with water (60 mL), and brine (60 mL). The organic solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was dissolved in 2:1 hexane/ethyl acetate (90 mL) and activated charcoal was added. The mixture was filtered and the product crystallized upon cooling. The crystals were collected by filtration to afford 1.98 g (35%) of pale yellow needles.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCC1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC3CCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 65.9 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 7.49 g (0.086 mol) of cyclopentylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 30 minutes. The reaction mixture is stirred for 1 hour below -10° C., then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 14.3 g (65.9%) of the title product as yellow crystals after recrystallization from ethanol, m.p.: 158°-160° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1)#[N:2]>[Au].CCOCC>[NH2:13][C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:10])[F:11])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Au]
Solvent: CCOCC
Product: N#Cc1ncc(N)cc1C(F)(F)F
Yield: 81.9 %

Procedure:
2-Cyano-5-nitro-3-trifluoromethylpyridine (0.065g, 0.3 mmol) was reacted in the same manner as described in example 762D to give the desired compound 763E (0.046g, 82%) as a gold colored solid after trituration with ether. HPLC: 100% at 2.07 min(YMC S5 ODS column) eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm. MS (ES): m/z 187.82 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCNCC1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2nccs2)CC1
Temperature: 100 °C

Procedure:
A mixture of methyl piperidine-4-carboxylate (2.045 g), 2-bromothiazole (1.64 g), and Cs2CO3 (5.86 g) in dimethylformamide (15 mL) was heated at 100° C. overnight. After it cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]=1[O:25][CH3:26])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][O:25][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:13]=[CH:14][C:9]=1[CH:8]=[CH:7][C:6]([OH:27])=[O:5]
Reactant: COc1cc(C=CC(=O)c2ccccc2)ccc1C=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C=CC(=O)c2ccccc2)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
3-[2-methoxy-4-(3-oxo-3-phenyl-propenyl)-phenyl]-acrylic acid tert-butyl ester (635 mg, 1.74 mmol) was dissolved in DCM (12 ml) and TFA (3 ml) was added to the resulting solution. After stirring for 2 h at room temperature the solvent was removed under vacuo giving 541 mg of 3-[2-methoxy-4-(3-oxo-3-phenyl-propenyl)-phenyl]-acrylic acid as yellow powder.
Reaction SMILES: C([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11])(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:35](=[O:36])[C:34]1[C:33]([Cl:32])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:42])[CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)CCCN2)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)CCCN2C(=O)c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A solution of methyl (S) 2-(N-boc-amino)-3-(1,2,3,4-tetrahydro-quinolin-6-yl)-propionate [500 mg, Reference Example 19(a)] in tetrahydrofuran (20 ml) was treated successively with triethylamine (360 mg) and 2,6-dichlorobenzoyl chloride (380 mg). The mixture was stirred at 40° C. for 2 hours and then partitioned between ethyl acetate (100 ml) and dilute hydrochloric acid (100 ml). The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated. The residue was dissolved in trifluoroacetic acid (2 ml) and the clear solution was left at room temperature for 30 minutes then evaporated. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The organic phase was washed with sodium bicarbonate solution, then dried and then evaporated to give the title compound (200 mg) as a colourless oil.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O.[F:22][C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[C:32](=[O:33])[N:31]([C:34]3[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=3)[CH:30]=[N:29]2)=[CH:25][CH:24]=1.[NH2:45][CH2:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[N:50]([CH3:52])[CH3:51]>>[CH3:51][N:50]([CH3:52])[C:49]1[CH:48]=[C:47]([CH:55]=[CH:54][CH:53]=1)[CH2:46][NH:45][C:40]([C:36]1[S:35][C:34]([N:31]2[C:32](=[O:33])[N:28]([CH2:27][C:26]3[CH:43]=[CH:44][C:23]([F:22])=[CH:24][CH:25]=3)[N:29]=[CH:30]2)=[N:38][C:37]=1[CH3:39])=[O:42]
Reactant: CN(C)c1cccc(CN)c1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccc(N(C)C)c1
Yield: 50 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)-N,N-dimethylaniline, the title compound was obtained as a colourless solid in 50% yield: mp 149-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.9 Hz, 1H), 8.71 (s, 1H), 7.35 (dd, J=8.5, 5.6 Hz, 1H), 7.15 (d, J=8.9 Hz, 1H), 7.09 (dd, J=7.9, 6.9 Hz, 2H), 6.66 (s, 1H), 6.58 (dd, J=7.7, 7.7 Hz, 2H), 4.96 (s, 2H), 4.35 (d, J=5.8 Hz, 2H), 2.83 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ163.7, 161.3, 160.5, 151.6, 151.2, 150.9, 150.1, 140.3, 132.7 (d, 3JC-F=11 Hz), 132.4, 130.4 (d, 2JC-F=33 Hz), 129.2, 123.1, 115.9 (d, 1JC-F=86 Hz), 115.6, 111.7, 111.4, 48.2, 43.6, 40.5, 17.3; MS (ES+) m/z 467.16 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]([C:36]([O:38][CH3:39])=[O:37])[N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:24]3[CH:25]=[C:26]([C:36]([O:38][CH3:39])=[O:37])[N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=3)[CH:7]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cc(Oc3ccc(N)cc3)ccn2)cn1C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
A 100 ml flask was charged with 4-((2-chloropyridin-4-yl)oxy)aniline (150 mg, 0.68 mmol), 1-tert-butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2-dicarboxylate (260 mg, 0.81 mmol), 2M Na2CO3 solution (0.5 ml, 1.0 mmol), PdCl2(PPh3)2 (5 mg, 0.007 mmol), 10 ml of 1,4-dioxane and 3 ml of water. The mixture was flushed with nitrogen and heated at 70° C. for 30 minutes. The mixture was cooled to room temperature and poured into 100 ml of water. The precipitates were filtered and dried to give the crude, which was further purified by silica gel chromatography eluting with 2-3% MeOH/CHCl3 to give 1-tert-butyl 2-methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]-1H-pyrrole-1,2-dicarboxylate as light brown oil.
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[C@H:11]([NH2:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3].[CH2:26]([N:28]=[C:29]=[S:30])[CH3:27].C(N(CC)CC)C>CC#N>[C:2]([O:5][C@H:6]1[C@H:11]([NH:12][C:29]([NH:28][CH2:26][CH3:27])=[S:30])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCN=C=S
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (2.04 g, 5.19 mmol) in CH3CN (80 mL) was added ethyl isothiocyanate (1.36 g, 15.57 mmol), followed by triethylamine (0.94 g, 9.31 mmol). The reaction mixture was heated to reflux and stirred for 3 h. The organic layer was concentrated, and redissolved in CH2Cl2. The reaction was then washed with a minimal amount of saturated aqueous NaHCO3 solution. The aqueous layer was extracted an additional two times with CH2Cl2. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The desired (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-ethylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate was obtained as a yellow oil (2.21 g, 98% yield) following flash chromatography (EtOAc/hexanes, 1:1). 1H NMR (500 MHz, CDCl3) δ 1.19 (m, 3H), 1.81 (d, 1H, J=4.0 Hz), 2.05 (s, 3H), 2.08 (s, 3H), 2.10 (s, 3H), 2.14 (s, 3H), 3.40 (s, 1H), 3.85 (m, 1H), 4.12 (m, 1H), 4.28 (m, 1H), 4.81 (s, 1H), 5.19 (m, 1H), 5.73 (d, 1H, J=7.7 Hz), 6.00 (s, 1H), 6.12 (d, 1H, J=15.0 Hz); 13C NMR (125 MHz, CDCl3) δ 14.39, 20.81, 20.96, 21.07, 21.25, 57.84, 60.67, 61.95, 68.08, 72.99, 73.31, 93.12, 163.03, 169.60, 170.97, 171.88.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>ClCCl.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)Nc1ncc(Br)cc1I
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(Br)cc1C#C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
To a suspension of N-(5-bromo-3-iodo-pyridin-2-yl)-acetamide (6.42 g, 18.83 mmol) in dichloromethane (90 ml) was added triethyl amine (3.15 ml, 22.6 mmol), then the mixture was cooled to 0° C. and dichlorobis(triphenylphosphino)palladium (II) (66 mg, 0.094 mmol) and copper(I) iodide (36 mg, 0.188 mmol) were added sequentially. Finally trimethylsilylacetylene (2.93 ml, 20.71 mmol) was added dropwise, and the ice bath was removed. After stirring at room temperature for 17 hours, the crude mixture was directly adsorbed on silica gel. Purification by flash chromatography on silica gel with a gradient of ethyl acetate/hexane afforded the title compound as light yellow solid (4.75 g, 81% yield). 1H NMR (DMSO-d6): δ 9.99 (s, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.95 (d, J=2.5 Hz, 1H), 1.82 (s, 3H), 0.00 (s, 9H); HPLC/MS m/z: 311, 313 [MH]+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][O:8][CH:9]=[CH:10][CH:11]=[CH2:12]>C(=O)([O-])O.[Na+]>[CH3:7][O:8][CH:9]1[CH:10]=[CH:11][CH2:12][CH:2]([C:1]([O:5][CH3:6])=[O:4])[O:3]1
Reactant: COC(=O)C=O
Reactant: C=CC=COC
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)C1CC=CC(OC)O1
Temperature: -70 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
The above-obtained solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 0.168 g (2 mmole) of 1-methoxy-1,3-butadiene. Reaction was then allowed to proceed at -30° C. for 3 hours, and 10 ml of a sodium hydrogencarbonate aqueous solution was added to the reaction mixture to terminate the reaction. This reaction mixture was filtered through Celite and then subjected to extraction once with a 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate=10/1), thereby obtaining 0.12 g of desired optically active 2-methoxy-6-methoxycarbonyl-5,6-dihydropyran (yield: 79%).
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(=[O:14])[CH2:13][CH2:12][CH:11]=[CH:10]1.CN(C1CCCCC1)C1CCCCC1>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:8][C:3]1[C:2]([C:11]2[CH2:12][CH2:13][C:9](=[O:14])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: O=C1C=CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2F)CC1
Temperature: 23 °C
Reaction time: 21 h

Procedure:
A solution of 3-bromo-2-fluoropyridine (4 g, 22.73 mmol), 2-cyclopenten-1-one (7.35 mL, 91 mmol), n-methyldicyclohexylamine (12.05 mL, 56.8 mmol) and bis(tri-tert-butylphosphine)palladium (0) (0.581 g, 1.136 mmol) in 1,4-dioxane (50 mL) was heated to 105° C. in a capped vessel. After 21 h, the reaction was cooled to 23° C., diluted with EtOAc (400 mL) and washed with water (150 mL) and brine (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 15-50% EtOAc/hexane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 178.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1Br)([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:7]=[C:6]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)c1ccccc1Br
Product: CC(C)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-isopropylbromobenzene. MS (ESI): mass calcd. for C19H18FN3, 307.15; m/z found, 308.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.49-7.34 (m, 2H), 7.27-7.17 (m, 4H), 6.71 (s, 2H), 3.06-2.97 (m, 1H), 1.14 (d, J=6.8, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
A solution of 4-bromophenyl sulphonyl chloride (53.76 g) in dichloromethane (700 ml) was added to a stirred solution of ethyl piperidine-4-carboxylate (32.97 g) in dichloromethane (500 ml) containing triethylamine (36 ml) at 0° C. and under argon over 0.75 hours. The reaction was stirred for 18 hours. The reaction mixture was washed with water (2×500 ml), saturated brine (1×500 ml), dried and evaporated. The residual solid was triturated in isohexane (500 ml) for 1 hour, collected by filtration and dried to give, as a colourless solid, ethyl 1-(4-bromophenylsulphonyl)piperidine-4-carboxylate (79 g); mp 132-3° C.; NMR (CDCl3): 1.21(t, 3H), 1.70-1.90(m, 2H), 1.90-2.05(m, 2H), 2.18-2.33(m, 1H), 2.45-2.60(m, 2H), 3.53-3.67(m, 2H), 4.10(q, 2H), 7.55-7.70(m, 4H); EI-MS m/z 376 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:6]2[N:7]=[CH:2][C:3]([NH2:8])=[N:4][CH:5]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Nc1nccnc1Br
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
Bromopyrazin-2-amine (2.0 g, 11.49 mmol), (4-methylsulfonylphenyl)boronic acid (2.758 g, 13.79 mmol) and K3PO4 (4.878 g, 22.98 mmol) were combined in MeCN (40 mL)/Water (10 mL) and Pd[P(tBu)3]2 (216 mg, 0.4227 mmol) was added. The reaction was heated at 60° C. for 1 hour. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with water, then Et2O then dried in vacuo to give the sub-title compound as a beige solid which was used without further purification (2.53 g, 88% Yield). 1H NMR (400.0 MHz, DMSO) δ 3.20 (s, 3H), 6.80 (br s, 2H), 7.94 (d, 2H), 8.00 (d, 1H), 8.17 (d, 2H) and 8.64 (d, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:18])[CH:3]=1.S(Cl)(Cl)=O.Cl.CN.C[CH2:27][N:28](C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([NH:28][CH3:27])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([F:18])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cnccc1-c1cc(F)c(Cl)cc1F
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1cnccc1-c1cc(F)c(Cl)cc1F
Temperature: 65 °C
Reaction time: 7 h
Yield: 41.9 %

Procedure:
4-(4-chloro-2,5-difluorophenyl)nicotinic acid (170 mg, 0.630 mmol) was taken in thionyl chloride (0.14 mL, 1.89 mmol) and heated at 65° C. for 1 h. The solvent was evaporated under reduced pressure to afford a crude oil which was dissolved in dichloromethane and added to a mixture of methanamine hydrochloride (63.9 mg, 0.946 mmol) and DIEA (0.11 mL, 0.63 mmol) in DCM (8 mL) dropwise at 0° C. The reaction mixture was then allowed to warm to room temperature and stirred for 7 h. The reaction mixture was diluted with DCM (5 mL) and washed with water (3×5 mL) followed by brine (1×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to provide the crude product which was purified by preparative thin layer chromatography (3:2 Ethyl acetate:hexane) to afford 4-(4-chloro-2,5-difluorophenyl)-N-methylnicotinamide (90 mg, 0.264 mmol, 42% yield) as a white solid. LC/MS (ESI) m/e 283.0 [(M+H)+, calcd for C13H10ClF2N2O 283.0]; LC/MS retention time (method A): tR=1.46 min.
Reaction SMILES: [N:1]1C=CC=CC=1C(=O)CC(=O)CC(C1C=CC=CN=1)=O.[N:21]1([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32](=O)[CH2:33][C:34](=[O:49])[CH2:35][C:36]([C:38]3[CH:43]=[C:42]([N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH:41]=[CH:40][N:39]=3)=O)[CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>CO>[N:21]1([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]3[NH:1][C:36]([C:38]4[CH:43]=[C:42]([N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)[CH:41]=[CH:40][N:39]=4)=[CH:35][C:34](=[O:49])[CH:33]=3)[CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(CC(=O)c1cc(N2CCCC2)ccn1)CC(=O)c1cc(N2CCCC2)ccn1
Reactant: O=C(CC(=O)c1ccccn1)CC(=O)c1ccccn1
Solvent: CO
Product: O=c1cc(-c2cc(N3CCCC3)ccn2)[nH]c(-c2cc(N3CCCC3)ccn2)c1

Procedure:
This compound is prepared in a manner analogous to that described in Example 1, Step 2 for 1,5-di-pyridin-2-yl-pentane-1,3,5-trione, but instead the pyrrolidine-substituted triketone from Example 21 is used. Pure 4,4″-di-pyrrolidin-1-yl-1′H-[2,2′;6′,2″]terpyridin-4′-one can be obtained by recrystallisation from methanol in the form of an almost colourless solid. 1.81–2.05 (m, 8H); 3.17–3.33 (m, 8H); 6.32 (dd, 2H, J=5.7, 2.3 Hz); 6.84 (d, 2H, J=2.3 Hz); 6.90 (s, 2H); 8.19 (d, 2H, J=5.7 Hz). MS (EI pos., 70 eV), m/z=387 ([M+]), 359 (100); 358 (85); 330 (20); 28 (60).