Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]#[N:43])[CH2:37][CH2:36]1>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=[C:26]2[NH:34][CH:35]2[CH2:36][CH2:37][N:38]([CH2:41][C:42]#[N:43])[CH2:39][CH2:40]2)=[O:8])=[CH:2]1
Reactant: N#CCN1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: O=C(O)c1ccoc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN1CCC(Nc2nc3ccccc3n2C(=O)c2ccoc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a stirred mixture of 3.14 parts of 3-furancarboxylic acid, 6 parts of N,N-diethylethanamine and 390 parts of dichloromethane were added 7.2 parts of 2-chloro-1-methylpyridinium iodide. After stirring for 10 minutes at room temperature, 7 parts of 4-[(1H-benzimidazol-2-yl)amino]-1-piperidineacetonitrile were added and the whole was stirred for 1 hour at room temperature. The reaction mixture was washed with water. The organic phase was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 7 parts (74%) of 4-[[1-(3-furanylcarbonyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile (129).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18](C3COC3)[CH:17]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.I[CH:35]1[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1.Cl.N[C@@H]1CCCC[C@H]1O.C[Si](C)(C)N[Si](C)(C)C.[Na].[NH4+].[Cl-]>CC(O)C.[Ni](I)I.CCOC(C)=O>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([C:18]2[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:16]([C:15](=[O:30])[N:14]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:32][CH3:33])[CH3:31])[CH:17]=2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C2COC2)cc(C(F)(F)F)c1
Agent: I[Ni]I
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
To a suspension of 3-((4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)(methyl)carbamoyl)-5-(trifluoromethyl)phenylboronic acid (0.1 g, 223 μmol, example 235, intermediate) in 2-propanol (1.0 mL) were added tert-butyl 3-iodoazetidine-1-carboxylate (63.2 mg, 223 μmol), (1R,2R)-2-aminocyclohexanol hydrochloride (2.03 mg, 13.4 μmol, CAS RN 13374-31-7), nickel(II) iodide (4.18 mg, 13.4 μmol) and sodium hexamethyldisilazan (40.9 mg, 223 μmol) and the suspension was heated in a microwave oven at 80° C. for 50 minutes. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product (light brown solid, 0.048 g) was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.008 g; 6%). MS (ESI): m/z=560.22 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:8]=[CH:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].C(O)(=O)/C=C/C1C=CC(OC)=C(O)C=1.P(Cl)(OCC)(OCC)=O.[Cl-].[CH3:42][C@H:43]1[CH2:48][CH2:47][C@H:46]([NH3+:49])[CH2:45][CH2:44]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:42][C@H:43]1[CH2:48][CH2:47][C@H:46]([NH:49][C:10](=[O:12])[CH:9]=[CH:8][C:7]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:45][CH2:44]1
Reactant: C[C@H]1CC[C@H]([NH3+])CC1
Reactant: COc1ccc(C=CC(=O)O)cc1OC(C)=O
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: COc1ccc(/C=C/C(=O)O)cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC(C)=O

Procedure:
Using 5.9 g of 3-acetoxy-4-methoxycinnamic acid derived from isoferulic acid by the acetylation thereof, 4.34 ml of diethyl chlorophosphate, 8.35 ml of triethylamine, 500 ml of methylene chloride, 3.74 g of trans-4-methylcyclohexylammonium chloride, and 0.18 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 104 was carried out. As a result, 6.3 g of N-(trans-4-methylcyclohexyl)-3-acetoxy-4-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties: Proton nuclear magnetic resonance spectrum (δ ppm in CDCl3):
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:21]1([CH3:24])[CH:22]=[CH:23][C:18]([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(I)cc1
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1ccc(NCc2ccccc2)cc1
Yield: 85.7 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 4-iodotoluene (218 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.5) afforded N-(4-tolyl)benzylamine (169 mg, 86% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]([C:9]1[O:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=1)=O)=[O:5])[CH3:2].[BH4-].[Na+].C(O)(=O)C>C(O)C.O.[Pd]>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH:13]=[C:9]1[CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc2ccccc2o1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1cc2ccccc2o1
Reaction time: 2 h

Procedure:
232 g of compound 3 are dissolved in 500 ml of ethanol. Cool in ice-bath and add 100 g of sodium borohydride in 500 ml of water. Stir for 2 hours. Add acetic acid until the sodium borohydride has been neutralized. Cool the solution in ice-bath under an atmosphere of nitrogen and add 10 g of 10% Pd/C catalyst. Stir under a hydrogen atmosphere at 15PSI until the reaction is complete, as judged by TLC. Filter through celite and evaporate organic solvents. Extract with ethyl acetate. Dry over sodium sulfate. Filter. Evaporate solvent.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH3:28])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O-:23])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].FC(F)(F)C([O-])=O.[C:37]([O:43][CH2:44]I)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].C(OCC)(=O)C>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH3:28])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 90.4 %

Procedure:
To a solution of 45 mg of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (prepared from the corresponding trifluoroacetate) in 1 ml of dimethylacetamide were added, at -15° C., 27 mg of iodomethyl pivalate and the mixture was allowed to react for 15 minutes. At the end of this time, 20 ml of ethyl acetate were added to the reaction mixture, and the mixture was washed, in turn, with water, an aqueous solution of potassium bisulphate and an aqueous solution of sodium bicarbonate. The organic phase was separated and concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through silica gel eluted with a 3:1 by volume mixture of ethyl acetate and hexane, to give 49 mg of the title compound, whose properties were identical with those of the compound obtained in Example 1.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[NH:12]1[CH2:17][CH:16]([C:18]([NH2:20])=[O:19])[O:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]1(=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH:12]1[CH2:17][CH:16]([C:18]([NH2:20])=[O:19])[O:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(=O)C1CNCCO1
Solvent: CC(C)=O
Product: O=C1CCCc2ccccc21

Procedure:
2-Tetralone-6-morpholinamide, ethylene ketal (323 mg, 1.06 mmol) and catalytic p-toluenesulfonic acid were stirred in acetone (50 mL) at ambient temperature for 48 hours. TLC indicated a mixture of 2-tetralone-6-morpholinamide, ethylene ketal and desired product, so the solution was heated to reflux for 16 hours. The volatiles were removed in vacuo and the residue applied to a silica flash chromatography column and eluted with 50–100% EtOAc in hexanes to yield 27 mg (10%) of 2-tetralone-6-morpholinamide a slowly crystallizing solid, pure by NMR, TLC. MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.[BrH:19].BrBr>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[Br:19]
Reactant: CSc1ccc(CC(=O)c2ccccc2F)cc1
Reactant: Br
Agent: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccccc2F)cc1
Reaction time: 0.83 h

Procedure:
A 100 mL three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with 1-(2-fluorophenyl)-2-(4-methylthiophenyl)ethanone from Step 2, (4.36 g, 16.7 mmol), acetic acid (30 mL) and 33% HBr in acetic acid (0.5 mL). The solution was stirred and treated with bromine (17 mL, 16.8 mmol, 1.0M in acetic acid) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca, 15 min. After an additional 50 minutes at room temperature, the solution was concentrated in vacuo to give a brown oil. The crude haloketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 1-(2-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone as an oil that solidified upon standing (4.83 g, 85%): mp 58°-63° C. 1H NMR (CDCl3) 300 MHz 7.87 (td, J=7.6, 1.8Hz, 1H), 7.52 (m, 1H), 7.39 (d, J=8.3Hz, 2H), 7.27-7.03 (m, 4H), 6.34 (s, 1H), 2.45 (s, 3H). 19F NMR (CDCl3) -108.51 (m). Mass spectrum M+ =338.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:33])=[N:30][CH:31]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:4]([C:3]1[C:6]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:33])=[N:30][CH:31]=1)=[O:5]
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=Cc1c(Br)cc(C(F)(F)F)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2C=O)cn1
Temperature: 100 °C

Procedure:
2-bromo-4,6-bis(trifluoromethyl)benzaldehyde (100 mg, 0.31 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (119 mg, 0.34 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol), and 2M K2CO3 (0.31 mL, 0.62 mmol), were dissolved in 1,4-dioxane (1.0 mL) and heated to 100° C. After 70 min the resulting mixture was cooled to room temperature, diluted with DCM, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:5](=[O:7])[CH3:6])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (2.32 g, 24.6 mmol) was added dropwise to a cold (0° C.) solution of (4-fluorophenyl)(piperidin-4-yl)methanone (5.00 g, 20.5 mmol) in DCM (33 mL) and triethylamine (10.0 mL, 71.8 mmol). The resulting mixture was removed from the ice bath after 5 minutes and stirred at room temperature for 2 hours. The reaction was then added to a mixture of 1 M aqueous K3PO4 (100 mL), H2O, and DCM was added. The layers were separated and the aqueous layer again extracted with DCM. The combined organic layers was dried (Na2SO4), filtered, concentrated under reduced pressure and chromatographed (CH2Cl2/EtOAc) to provide the title compound as a clear oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:53][N:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[NH2:55]>CN(C=O)C.O1CCCC1>[CH3:53][N:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[NH:55][C:12](=[O:14])[C:11]1[CH:15]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=1
Reactant: CN(N)c1ccccc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCOCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCOCC2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
In a 10 mL two-necked flask, the above prepared 5-(tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (50 mg, 164 μmol, Eq: 1.00) was combined with tetrahydrofuran (1.0 mL) and DMF (1 mL) to give a colorless solution. TBTU (78.9 mg, 246 μmol, Eq: 1.5) and N,N-diisopropylethylamine (106 mg, 143 μl, 819 μmol, Eq: 5) were added and the reaction mixture stirred for 10 min at rt before 1-methyl-1-phenylhydrazine (24.0 mg, 23.1 μl, 197 μmol, Eq: 1.2, CAN 618-40-6) was added and the reaction mixture kept overnight at rt. Work up: The reaction mixture was quenched with 1 M HCl (10 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with 1 M NaOH, then with H2O/NaCl sol., the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 10 g, 15% to 50% EtOAc in heptane) delivered eventually 62 mg of the title compound as white foam; MS (EI) 410.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([C:15]1([OH:30])[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[S:26][C:25](B(O)O)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:31]([N:35]1[C:39](=[O:40])[CH:38]=[C:37](Cl)[S:36]1(=[O:43])=[O:42])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([C:15]1([OH:30])[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[S:26][C:25]([C:37]3[S:36](=[O:42])(=[O:43])[N:35]([C:31]([CH3:33])([CH3:32])[CH3:34])[C:39](=[O:40])[CH:38]=3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Reactant: OB(O)c1ccc(CN2CCC(O)(Cc3ccccc3)CC2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CN3CCC(O)(Cc4ccccc4)CC3)s2)S1(=O)=O
Temperature: 80 °C
Yield: 17 %

Procedure:
A solution of 4.12-A (100 mg, 0.2 mmol), 9-A (55 mg, 0.25 mmol), potassium carbonate (190 mg, 1.3 mmol) in 1,4-dioxane (1.5 mL) was added to a vial and degassed with nitrogen. Then [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (28 mg, 0.034 mmol) was added, degassed with nitrogen and the vial capped and heated at 80° C. overnight. The reaction mixture was filtered through silica gel and eluted with copious amounts of EtOAc. The solvent was concentrated and crude sample purified by reverse phase HPLC to afford 20 mg (15%) of 4.12-B. LCMS found for C24H30N2O4S2 (M+H)+: m/z=475.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 280 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 96 mg of 2-butyn-1-ol, to which 55 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 212 mg of 4-(2,3-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (83)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[N:6]([CH:13]([CH3:15])[CH3:14])[CH2:5]2.CC1(C)C(C)(C)[O:20][B:19](B2OC(C)(C)C(C)(C)O2)[O:18]1>>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][N:6]([CH:13]([CH3:15])[CH3:14])[C:7]2=[O:12])=[CH:3][C:2]=1[B:19]([OH:20])[OH:18]
Reactant: CC(C)N1Cc2cc(Br)c(F)cc2C1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)N1Cc2cc(B(O)O)c(F)cc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 7 starting from 5-bromo-6-fluoro-2-isopropylisoindolin-1-one and 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl]. LCMS: (M+H)+=238.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH2:12])[CH3:11].Cl[C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:37][C:24]2=[CH:25][C:26]3[C:27](=[O:36])[N:28]([CH:33]([CH3:35])[CH3:34])[C:29](=[O:32])[C:30]=3[CH:31]=[C:23]2[N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:22][C:23]2=[CH:31][C:30]3[C:29](=[O:32])[N:28]([CH:33]([CH3:35])[CH3:34])[C:27](=[O:36])[C:26]=3[CH:25]=[C:24]2[N:37]=1)[CH3:11]
Reactant: CC(N)Cc1cc(F)ccc1F
Reactant: CC(C)N1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Yield: 98.8 %

Procedure:
Racemic 1-(2,5-difluorophenyl)propan-2-amine (0.051 g) and 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-isopropylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.2965 mmol) were submitted to general procedure A to give 0.144 g the title compound. 1H NMR (500 MHz, DMSO-d6) δ13.04 (s, 1H), 11.20 (d, 1H), 11.10 (d, 1H), 8.13 (s, 1H), 7.82 (t, 2H), 7.36-7.31 (m, 2H), 7.22-7.14 (m, 1H), 7.09-7.03 (m, 1H), 6.17 (d, 1H), 4.51-4.42 (m, 3H), 4.18-4.10 (m, 1H), 3.09-2.93 (m, 2H), 1.32 (d, 3H), 1.25 (d, 6H). APCI MS: m/z 489.9 (M+1).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:22])([F:21])[CH2:12]OS(C(F)(F)F)(=O)=O.[C:23]1([S:29]([N:32]2[C:36]3[CH:37]=[N:38][C:39]([C:48]#[N:49])=[C:40]([CH2:41][CH:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)[C:35]=3[C:34]3[CH:50]=[CH:51][CH:52]=[N:53][C:33]2=3)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([S:29]([N:32]2[C:36]3[CH:37]=[N:38][C:39]([C:48]#[N:49])=[C:40]([CH2:41][CH:42]4[CH2:47][CH2:46][N:45]([CH2:12][C:11]([F:10])([F:21])[F:22])[CH2:44][CH2:43]4)[C:35]=3[C:34]3[CH:50]=[CH:51][CH:52]=[N:53][C:33]2=3)(=[O:31])=[O:30])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#Cc1ncc2c(c1CC1CCNCC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc2c(c1CC1CCN(CC(F)(F)F)CC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
N,N-Diisopropylethylamine (100 mg, 0.77 mmol) and trifluoromethane sulfonic acid 2,2,2-trifluoroethyl ester (100 mg, 0.43 mmol) in THF (1 mL) were added to a solution of 9-benzenesulfonyl-5-piperidin-4-ylmethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile in THF (4 mL) and resultant mixture stirred at ambient temperature for 30 min. The mixture was then filtered through a 2 g Sill SPE cartridge, eluting with THF. The THF washings were concentrated in vacuo and the resultant residue was purified by flash chromatography (silica, 2 g column, Si H SPE, 0-20% ethyl acetate in DCM) to afford title compound as a white solid (0.16 g, 85%). 1H NMR (CDCl3, 400 MHz): 9.81 (d, J=2.9 Hz, 1H), 8.81-8.75 (m, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.28 (d, J=7.9 Hz, 2H), 7.66-7.59 (m, 1H), 7.55-7.45 (m, 3H), 3.35-3.27 (m, 2H), 3.02-2.88 (m, 5H), 2.32-2.21 (m, 2H), 1.86-1.60 (m, 4H).
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([NH2:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:10]([C:6]1[C:5]2[S:1][N:2]=[N:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)#[N:12]
Reactant: NC(=O)c1cccc2nnsc12
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1cccc2nnsc12
Temperature: 3 °C
Reaction time: 22 h

Procedure:
4.0 g (0.022 mol) of benzo-1,2,3-thiadiazol-7-ylcarboxylic acid amide are dissolved in 35 ml of tetrahydrofuran, and 3.6 ml (0.045 mol) of pyridine are added. The batch is then cooled to 3° C. and a solution of 3.9 ml (0.028 mol) of trifluoroacetic acid anhydride in 12 ml of tetrahydrofuran is added dropwise. The reaction mixture is subsequently stirred for 22 hours at room temperature and then poured onto ice/water and extracted twice with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate and filtered through a layer of silica gel. Concentration by evaporation gives 3.5 g (99% of the theoretical yield) of crystalline product having a melting point of 119°-122° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([Br:18])=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=O.O.[NH2:20][NH2:21]>C(O)C>[Br:18][C:16]1[CH:15]=[N:14][C:9]2[NH:10][C:11]3[CH:12]=[N:13][C:5]([C:3]([NH:20][NH2:21])=[O:2])=[CH:6][C:7]=3[C:8]=2[CH:17]=1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (582 mg, 1.90 mmol) and hydrazine hydrate (2.29 mL, 47.0 mmol) in ethanol (4.6 mL) was heated under reflux in an inert atmosphere. After 1 h, the reaction mixture was allowed to cool to ambient temperature. The resultant precipitate was collected by filtration, washed with ethanol, and left to air-dry to afford the title compound as a tan-yellow solid.