Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([O-])(O)=O.[Na+].[C:33](Cl)(Cl)=[S:34]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)([N:16]=[C:33]=[S:34])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(N=C=S)c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (0.132 g, 0.335 mmol) in chloroform (1 mL) was added H2O (1 mL) and NaHCO3 (84 mg, 1.01 mmol). To this vigorously stirred mixture was added thiophosgene (38.3 μl, 0.502 mmol) dropwise. The reaction was stirred at room temperature for 2 hours and diluted with CHCl3 and H2O. The organic layer was separated and washed with brine, dried over MgSO4 and concentrated. The crude mixture was purified by silica gel ISCO chromatography (12 g column) using hexanes/EtOAc (0-30% over 20 min) to give 5-chloro-2-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-isothiocyanato-2-phenylethyl)pyridine as a yellow oil (73 mg, 50% yield). LCMS: 4.3 min [M+1] 437.1 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (d, J=13.69 Hz, 2H), 4.07 (d, J=13.45 Hz, 2H), 6.89 (dd, J=7.83, 1.47 Hz, 3H), 7.16-7.22 (m, 5H), 7.24 (d, J=1.47 Hz, 1H), 7.37 (dt, J=4.22, 2.17 Hz, 2H), 7.40 (t, J=1.96 Hz, 1H), 7.52 (s, 2H), 7.66 (dd, J=8.31, 2.45 Hz, 2H), 8.65 (d, J=1.96 Hz, 2H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[F:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15].O.C1(C)C=CC=CC=1>C(O)(=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[N:15]1[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=2[C:4]1=[O:6]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F

Procedure:
A mixture of 3,4,5,6-tetrahydrophthalic anhydride (22.8 g, 150 mmol), 2-fluoro-5-nitroaniline (23.4 g, 150 mmol) in glacial acetic acid is heated at reflux for 23 hours, cooled and poured into a water/toluene mixture. The organic phase is separated, washed sequentially with water and saturated sodium hydrogen carbonate solution, dried and concentrated in vacuo to obtain a yellow solid. Recrystallization of the solid from ethanol gives the title compound as off-white plates (26.6 g, mp 154°-156° C.) which are identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:14]=[C:15]([OH:34])[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2[CH2:32][I:33])=[CH:17][C:18]=1[CH:19]([CH3:21])[CH3:20].[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2[CH2:32][I:33])=[C:15]([O:34][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)[CH:14]=1
Reactant: C1=COCCC1
Reactant: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CI)c(O)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CI)c(OC2CCCCO2)cc1F
Reaction time: 72 h

Procedure:
p-Toluenesulfonic acid (2.8 mg, 0.0145 mmol) was added to a solution of 4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-ol (63.4 mg, 0.145 mmol) and 3,4-dihydro-2H-pyran (60.8 mg, 66 μL, 0.723 mmol) in dry CH2Cl2 (7.2 mL) at room temperature under N2 and the reaction was stirred for 3 days. The reaction mixture was diluted with saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford 2-{[4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran. Rf=0.74 (10% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (d, J=8.3 Hz, 0.5H), 7.59 (d, J=8.3 Hz, 0.5H), 7.53 (t, J=7.3 Hz, 0.5H), 7.41 (s, 0.5H), 7.32 (d, J=7.9 Hz, 0.5H), 7.25 (d, J=7.9 Hz, 0.5H), 7.15 (t, J=9.4 Hz, 0.5H), 6.99 (d, J=12.2 Hz, 0.5H), 6.94 (d, J=12.2 Hz, 0.5H), 6.69 (d, J=11.0 Hz, 0.5H), 5.37 (s, 0.5H), 5.23 (s, 0.5H), 5.13 (s, 1H), 4.45 (d, J=9.6 Hz, 0.5H), 4.40 (d, J=9.6 Hz, 0.5H), 4.31 (d, J=9.6 Hz, 0.5H), 4.23 (d, J=9.6 Hz, 0.5H) 3.76 (m, 0.5H), 3.66-3.54 (m, 1.5H), 3.29-3.21 (m, 1H), 1.68-1.44 (m, 4H) 1.32-1.26 (m, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](O)=[O:24])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C1C=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][OH:24])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A stirred solution of 2-butyl-l-[(2'-carboxybiphenyl-4-yl)methyl]benzimidazole (1.50 g) in benzene (30 ml) was added dropwise to sodium dihydro-bis(2-methoxyethoxy)aluminate (70% toluene solution). The mixture was stirred for one hour at room temperature, and then heated for 10 minutes under reflux. The reaction mixture was cooled and poured into 2N-HCl, followed by extraction with dichloromethane. The extract was washed with water and dried (MgSO4), and the solvent was evaporated in vacuo. The residue was purified by silica gel (80 g) column chromatography to give the title compound (0.67 g, 46%) as an oil, which was crystallized from ethyl acetate--ether to afford pale yellow prisms, m.p.162°-163° C.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:11]1[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[S:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>O.C1COCC1.CO>[CH2:4]([C:11]1[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCc1csc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCc1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
A solution of lithium hydroxide hydrate (1.20 g, 28.3 mmol) in water (50 mL) was added to a solution of compound 1017 (2.4 g, 9.4 mmol) in THF (50 mL) and methanol (30 mL). The reaction mixture was stirred at room temperature for 12 hours. After removal of organic solvent, the aqueous solution was acidified to pH 4.0 with 6 N hydrochloric acid solution and extracted with EtOAc. The organic layer was dried and concentrated to give 4-heptylthiophene-2-carboxylic acid (1018, 2.1 g) which was directly used in the next step without further purification. Rf=0.03 (10% EtOAc in hexane).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O.[OH-].[K+]>[C:13]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1cc2ccccn2n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CC(=O)c1c(C(C)C)nn2ccccc12
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of 4.2g of 2-isopropylpyrazolo[1,5-a]-pyridine, 10.2g of acetic anhydride and 2-3 drops of concentrated sulfuric acid was refluxed for 7 hr. After cooling, the mixture was added to 200 ml of 4M potassium hydroxide solution and stirred for 1 hr. The solution was extracted with chloroform and the chloroform solution was dried over sodium sulfate. The dried chloroform solution was concentrated and the residue was columnchromatographed over alumina to isolate objective product. Recrystallization from n-hexane gave 4.3g of colorless needles, mp 74° C. Yield 67%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.Cl[C:10]1[C:14]2[CH:15]=[C:16]([CH:28]=[O:29])[C:17]([N:20]3[CH2:25][C@H:24]([CH3:26])[O:23][C@H:22]([CH3:27])[CH2:21]3)=[C:18]([F:19])[C:13]=2[O:12][N:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:27][C@H:22]1[O:23][C@@H:24]([CH3:26])[CH2:25][N:20]([C:17]2[C:16]([CH:28]=[O:29])=[CH:15][C:14]3[C:10]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)=[N:11][O:12][C:13]=3[C:18]=2[F:19])[CH2:21]1
Reactant: OB(O)c1cn[nH]c1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(Cl)noc3c2F)C[C@H](C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: C[C@@H]1CN(c2c(C=O)cc3c(-c4cn[nH]c4)noc3c2F)C[C@H](C)O1

Procedure:
1H-pyrazole-4-boronic acid pinacolate ester, 3-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzoxazole-5-carbaldehyde (Intermediate 534), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-phos), and tris(dibenzylideneacetone) dipalladium(0) were reacted using a method similar to the one described for the synthesis of Intermediate 554.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[F:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([N:46]([CH3:48])[CH3:47])[N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:36]4[C:31]([O:30][CH3:29])=[N:32][C:33]([N:46]([CH3:47])[CH3:48])=[N:34][CH:35]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cn1)N(c1cccc(Cl)c1F)C2=O
Reactant: COc1nc(N(C)C)ncc1B1OC(C)(C)C(C)(C)O1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N(C)C)ncc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cn1)N(c1cccc(Cl)c1F)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(3-chloro-2-fluorophenyl)-6-(5-chloropyridin-2-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Intermediate BT) and 4-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Intermediate W) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. The title compound was obtained as a brown solid. ESI-MS: tR=1.32 min, [M+H]+ 555/557/559 (LC-MS 1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[OH:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[OH:29])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:38]1([SH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O.CN(C)C=O>[OH:21][C:15]1[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=1[C:12]1[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=2[OH:29])[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:3][CH:4]=2)[N:13]=1
Reactant: Oc1ccc(-c2nc(-c3ccc(Cl)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
To a 500 mL round bottomed flask equipped with a magnetic stirrer, condenser, Dean-Stark trap and nitrogen atmosphere are charged 16.1 g (0.0394 mol) of 6-(p-chlorophenyl)-2,4-bis-(2,4-dihydroxyphenyl)-s-triazine, 2.72 g (0.0197 mol) of potassium carbonate, 600 mg of potassium iodide and 150 mL of N,N-dimethylformamide. A pre-heated oil bath (150° C.) is then applied to the stirred brown solution. Thiophenol (4.04 mL, 0.00394 mol) is added all at once through a syringe. The mixture is stirred at 150° C. for 4.5 hours and then allowed to cool to room temperature. The solution is diluted with water and extracted thrice with ethyl acetate. The combined organic layers are washed twice with 0.1N hydrochloric acid and then dried over anhydrous magnesium sulfate. The solvent is then removed under reduced pressure to give a yellow product. There is some unsolubilized material found at the interface in the ethyl acetate extractions of the reaction mixture which is washed with water and triturated with heptane. Both crops of yellow solid are the title compound and are combined to afford the title compound in a yield of 17.5 g (92%); mp>250°.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1C[N:13]([C:33]1[S:34][CH:35]=[CH:36][N:37]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:28]=2)=[CH:19][N:18]=1)(=[O:16])=[O:15].C(Cl)Cl>>[C:29]([C:27]1[N:28]=[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([S:14]([NH:13][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:16])=[O:15])=[N:18][CH:19]=2)[S:25][CH:26]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Nc3nc(C(C)(C)C)cs3)cn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1csc(Nc2ccc(S(=O)(=O)Nc3nccs3)nc2)n1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic Acid (49.4 uL, 0.641 mmol) was added to a solution of 5-(4-tert-Butyl-thiazol-2-ylamino)-pyridine-2-sulfonic acid (2,4-dimethoxy-benzyl)-thiazol-2-yl-amide (35 mg, 0.064 mmol) in Methylene chloride (0.39 mL, 6.1 mmol). After 30 min, the reaction mixture was concentrated in vacuo. The residue was dissolved in DMSO and purified on Gilson (semi-prep, reverse phase, Phenomenex 100×21.2 mm 10 micron C18 column, 20 mL/min, Gradient 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). Fractions were checked by LC/MS and then dried on a lyophilizer to give the desired product as a pale yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Br[CH2:45][CH2:46][CH2:47][Cl:48].BrCC1OC(C(F)(F)F)=CC=1>>[Cl:48][CH2:47][CH2:46][CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: ClCCCBr
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(CCCCl)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 1-bromo-3-chloropropane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (22%) as a colorless solid: mp 144-146° C.; 1H NMR (300 MHz, CDCl3) δ 7.31 (dt, 1H), 7.14-7.12 (m, 2H), 7.01(t, 1H), 6.65 (s, 1H), 6.23 (s, 1H), 5.89 (s, 2H), 4.68 (ABq, 2H), 3.85-3.79 (m, 2H), 3.67 (t, 2H), 2.06 (t, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 155.8, 148.7, 142.9, 142.2, 132.4, 129.3, 124.1, 123.3, 120.3, 109.3, 103.6, 101.7, 80.3, 57.8, 43.4, 30.6; MS(ES+) m/z 358.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[N:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17]([C:23]#[N:24])=[C:16]3OC(C)C)[C:9](=[O:11])[N:10]=1.C(O[Na])(C)=O.O=C1C(=CC2N=C3C(=CC=2)N=CC(C#N)=C3)SC(NCC2SC=CC=2)=N1>CC(O)=O>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[N:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17]([C:23]#[N:24])=[CH:16]3)[C:9](=[O:11])[N:10]=1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)nc12
Agent: CC(=O)O[Na]
Agent: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)nc2c1
Temperature: 120 °C
Yield: 30.1 %

Procedure:
To a mixture of 2-(2-chloro-benzylamino)-thiazol-4-one (40.9 mg, 0.17 mmol) (see Example 2), AcONa (160 mg, 1.95 mmol), and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (53.1 mg, 0.22 mmol) (see Example 11) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 120° C. (oil bath) for 2 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water acetone and ether to give 6-[2-(2-chloro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-[1,5]naphthyridine-3-carbonitrile as a dark brown solid (20.8 mg, 30.1%). HR-ES (+) m/e calcd for C20H12ClN5OS (M+H)+ 406.0524. found 406.0525.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=2)=[N:5][C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].Cl.CN.C(Cl)CCl.[CH3:42][N:43]1CCOCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]1[C:4]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([NH:43][CH3:42])=[O:32])=[CH:28][CH:27]=2)=[N:5][C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(C#N)c(OCc3ccc(C(=O)O)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Reactant: CN1CCOCC1
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)c1ccc(COc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(C)cc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dried round bottom flask was added the product of Example 122 (0.030 g; 0.0613 mmol), methylamine hydrochloride (0.005 g; 0.0675 mmol), EDC (0.018 g; 0.0919 mmol), DMAP (0.007 g; 0.0613 mmol), N-methylmorpholine (0.028 mL; 0.251 mmol), and methylene chloride (0.5 mL). The reaction mixture was stirred at room temperature overnight. The volatiles were removed, and the residue was taken up in ethyl acetate, washed with saturated NaHCO3 (2×), water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-50% ethyl acetate:hexane) to afford the desired product: m/e=502 (M+1); Rt=4.2 min on LCMS. HPLC/MS: 502 (M+1); Rt=4.20 min
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Cl:57][C:58]1[C:63]([F:64])=[C:62](I)[CH:61]=[CH:60][N:59]=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].O.C1(C)C=CC=CC=1>[Cl:57][C:58]1[C:63]([F:64])=[C:62]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:61]=[CH:60][N:59]=1
Reactant: Fc1c(I)ccnc1Cl
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 123.6 %

Procedure:
tert-Butyl carbamate (215 mg), cesium carbonate (1.14 g), Pd2(dba)3 (240 mg), and Xantphos (303 mg) were added to a toluene solution (9 ml) containing 2-chloro-3-fluoro-4-iodopyridine (450 mg), followed by stirring at 100° C. for 3 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline, dried over anhydrous sodium sulfate. Next, the solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 3:1). A yellow oily matter of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate (533 mg) was thus obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O[Na])(C)(C)C>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(N2CCNCC2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
The mixture of 1-bromo-4-(trifluoromethyl)benzene (15 g, 67 mmol), piperazine (28.8 g, 334.4 mmol, 5 eq.), Pd2(dba)3 (1.4 g, 1.53 mmol, 2 mol %), BINAP (420 mg, 0.67 mmol, 1 mol %) and t-BuONa (12.9 g, 134.2 mmol, 2 eq.) in toluene (200 ml) was stirred for 2 hours at 70° C. under nitrogen. Then the solids were filtered off and the mixture was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1% 5% methanol in dichloromethane to afford 1-[4-(trifluoromethyl)phenyl]piperazine as a dark red solid (10.5 g, 68%). (ES, m/z): [M+H]+ 231.1; 1H NMR (300 MHz, CDCl3): δ 7.48 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 3.32-3.20 (m, 4H), 3.04-3.01 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1([C:24]#N)[CH2:8][CH2:7][CH:6]([CH:9]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.[C:27]1([Mg]Cl)[CH:32]=[CH:31]C=[CH:29][CH:28]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:22]([O:21][CH:19]([O:18][CH:9]([CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:26])[CH3:1])([C:24]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)[CH2:4][CH2:5]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:20])[CH3:23]
Reactant: CCOC(C)OC(COc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OC(COc1ccccc1)C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanecarbonitrile (871 mg, 2.4 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise to a 2 M solution of phenylmagnesium chloride in tetrahydrofuran (3.6 ml, 7.3 mmol), while cooling with ice. The mixture was stirred at room temperature overnight and saturated ammonium chloride solution and water (5 ml of each) were then added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated in vacuo.