Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9].Cl.O>O1CCOCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C(OCC)C>[CH3:5][C:4]([N+:1]([O-:3])=[O:2])([CH3:6])[CH2:9][CH2:8][C:7]([O:11][CH3:12])=[O:10]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCC(C)(C)[N+](=O)[O-]
Temperature: 70 °C
Yield: 71.1 %

Procedure:
According to the method of R. B. Moffett, Organic Syntheses, Coll. Vol. 4, p. 652 (1963), a 250-mL three-necked flask was fitted with a dropping funnel, and a thermometer placed so that the bulb was near the bottom of the flask. A solution of 2-nitropropane (45.5 mL, 0.5 mol) in dioxane (25 mL) and a 40% aqueous solution of benzyltrimethylammonium hydroxide (Triton B, 5 mL, 0.013 mmol) were added to the flask. The flask was heated to 70° C. in an oil bath and methyl acrylate (45 mL, 0.5 mol) was added via a dropping funnel over 15 minutes. The temperature rose to about 100° C. during the addition then dropped to ˜85° C. The mixture was then heated at 100° C. for 4 h. The reaction mixture was cooled to room temperature and acidified with 1 N hydrochloric acid (10 mL). Water (200 mL) and diethyl ether (400 mL) were added to the reaction flask. The mixture was poured into a separatory funnel and organic layer was washed with water (2×200 mL), brine (200 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow liquid. The product was distilled through a short path distillation apparatus to give a pale yellow liquid (62.3 g, 71.1%). 1H NMR (CDCl3, 400 MHz): δ 1.60 (s, 6H), 2.22-2.38 (m, 4H), 3.70 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[O:28]CC3C=CC=CC=3)[CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O>CCO.[Pd].C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[OH:28])[CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2cccc(-c3cc(F)ccc3OCc3ccccc3)c2C1
Agent: [Pd]
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2cccc(-c3cc(F)ccc3O)c2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution under N2 of 8-(2-benzyloxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (208 mg, 0.45 mmol, 1.0 eq.) in EtOH (10 mL), palladium on activated carbon (10 wt. %, 21 mg) was added. The flask was evacuated and refilled with H2. The black suspension was stirred at r.t. under an H2-atmosphere for 6 hours. The black suspension was filtered through Celite and the filtrate was concentrated in vacuo to give a beige foam. To an-ice cooled suspension of the residue and triethylamine (93 μL, 0.67 mmol, 1.5 eq.) in DCM (10 mL), benzyl chloroformate (67 μL, 0.45 mmol, 1.0 eq.) was added dropwise. Upon completion of the addition, the mixture was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (10 mL). The layers were separated. The aq. phase was extracted with DCM (3×10 mL). The comb. org. phases were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (10 mL) and 1M aq. NaOH (2 mL) was added. The mixture was stirred at r.t. for 64 hours. The org. solvent was removed in vacuo and the aq. layer was acidified with 2N aq. HCl. The aq. layer was extracted with DCM (3×10 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by CC (SiO2, Hept/AcOEt 7:3) to give the title compound as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCNc1ccc([N+](=O)[O-])cc1

Procedure:
4.2 g (29.7 mmol) of N-tert.butoxycarbonyl-ethylenediamine, 5.0 g (31.2 mmol) of 4-fluoro-nitrobenzene and 7.0 g (50.6 mmol) of potassium carbonate are stirred in 25 ml of DMSO for 9 hours at 60° C. After cooling the mixture is diluted with water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is stirred with petroleum ether, decanted off and evaporated down again. The product is stirred with ether and suction filtered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])=[CH:7]2.[Li]CCCC.[CH:18]1[C:30]2[CH:29]([Si:31](Cl)([CH3:33])[CH3:32])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.O>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[CH:5]=[C:6]2[C:10]=1[CH:9]=[C:8]([CH3:11])[CH:7]2[Si:31]([CH:29]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:30]1=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:32])[CH3:33]
Reactant: CC1=Cc2cc(F)cc(Br)c2C1
Reactant: C[Si](C)(Cl)C1c2ccccc2-c2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1=Cc2c(Br)cc(F)cc2C1[Si](C)(C)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.41 g (15.0 mmol) of 7-bromo-5-fluoro-2-methyl-1H-indene in 80 ml of ether, 6.00 ml (15.0 mmol) of 2.5 M nBuLi in hexanes was added. The reaction mixture was stirred for 12 h at room temperature; then, this solution was added dropwise to a solution of 3.88 g (15.0 mmol) of (9H-fluoren-9-yl)chlorodimethylsilane in 80 ml of ether over 1 h at room temperature. The resulting mixture was stirred for 12 h, and then 100 ml of water was added. The organic layer was separated, dried over Na2SO4, and evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 30 mm, l 400 mm, eluent: hexanes). Yield 3.71 g (55%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:24])[O:21]2)=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](=[N:9]\[H])/[NH2:8].[BrH:31].CCOCC>C(O)(=O)C>[BrH:31].[BrH:31].[NH2:1][C@H:2]([C:11]([NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:20](=[O:24])[O:21]2)=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: [H]/N=C(/N)NCCC[C@H](N)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc2cc(-c3ccccc3)c(=O)oc2c1

Procedure:
The hydrochloride salt from Example VIII, above (0.247 g, 0.438 mmol), was treated with 3 ml of 32% hydrogen bromide in acetic acid for 75 min at room temperature. Addition of 70 ml ether gave crude 7-(L-arginamido)-3-phenylcoumarin dihydrobromide that was precipitated twice from methanol/ether yielding 0.221 g (91%) of an off white powder: mp 168°; TLC (SiO2 : ethyl acetate/2-butanone/formic acid/water-5:3:1:1) Rf=0.30. This material, without further purification, was dissolved in 4 ml of dry pyridine containing 0.11 ml (0.80 ml) of triethylamine and 0.436 g (1.99 mmol) of N-benzoyloxy-succinimide. The reaction proceeded overnight at room temperature. The pyridine was removed in vacuo and the crude product was purified by preparative layer chromatography on silica gel with several developments in ethyl acetate/formic acid/water (32:1:1). The purified material was taken up in 1000 ml ethyl acetate/1-butanol (1:1) and washed with 200 ml volumes of N HCI, brine (3x), and water (2x). The organic layer was evaporated in vacuo yielding 0.139 g (65.4%) of II as the hydrochloride salt: mp 251°; TLC (SiO2 : ethyl acetate/2-butanone/formic acid/water-5:3:1:1) Rf=0.67.
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.I[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].C[NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][C:26](I)=[C:25]([N+]([O-])=O)[CH:24]=1.C[Si](C)(C)CC#C>>[C:22]([NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([C:5]#[CH:6])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=1)(=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNC(=O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: C#C[Si](C)(C)C
Agent: C#CC[Si](C)(C)C
Product: C#Cc1ccc(C(=O)NC(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
Compound I-14, Compound I-15, Compound I-16, Compound I-17, Compound I-18, Compound I-19, Compound I-20, Compound I-21, Compound I-22, Compound I-23, Compound I-24 and Compound I-25 were prepared sequentially according to the methods of Example 14, Example 15 and Example 16, by selecting appropriate amines and trimethylsilylacetylene, using the Compound 4-iodo-3-nitrobenzoic acid (Compound VI-1) as starting material; Compound I-26 was prepared sequentially according to the methods of Example 15 and Example 16, using the compound N-methyl-4-iodo-3-nitrobenzamide (Compound VII-1) and trimethylpropargylsilane as starting materials:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=2)=[N:13][CH:14]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: COc1ccccc1Br
Product: COc1ccccc1-c1ccc(-c2cnc(N)nc2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 1-bromo-2-methoxybenzene. MS (ESI): mass calcd. for C16H14N4O. C2HF3O2, 278.12; m/z found, 279.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.00 (s, 2H), 8.81 (d, J=2.2, 1H), 8.28 (dd, J=8.4, 2.2, 1H), 8.02 (d, J=8.4, 1H), 7.48-7.41 (m, 2H), 7.16 (d, J=8.4, 1H), 7.11 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:37])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:36]=[CH:35][C:25]([CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[S:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[OH:37])(=[O:11])=[O:10])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)benzylcarbamate (569 mg, 1.00 mmol) in methylene chloride (9 mL) was added TFA (3 mL). The reaction mixture was stirred at rt for 2 h, and then concentrated. The residue was dissolved in with methylene chloride (100 mL) and washed with saturated aq sodium bicarbonate solution, brine, dried over MgSO4, and concentrated to give the title compound (446 mg, 95%) as a tan solid. MS (ESI): m/z 468.9 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C@@H:8]([C:31]([O:33][CH3:34])=[O:32])[N:9]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=1)(=O)=O.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CO>[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42]([C:7]2[C@@H:8]([C:31]([O:33][CH3:34])=[O:32])[N:9]([C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:11]=2)=[CH:41][CH:40]=1
Reactant: COC(=O)[C@@H]1C(OS(=O)(=O)C(F)(F)F)=CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C(c2ccc(C(F)(F)F)cc2)=CCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 85 °C
Yield: 62.5 %

Procedure:
To a stirred mixture of (S)-methyl 3-(trifluoromethylsulfonyloxy)-1-trityl-2,5-dihydro-1H-pyrrole-2-carboxylate ((Tetrahedron Lett. 2001, 8571) 1.71 g, 3.3 mmol), 4-(trifluoromethyl)phenylboronic acid (1.3 g, 6.6 mmol), K2CO3 (0.68 mg, 5.0 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) DCM adduct (0.12 g, 0.16 mmol) was added toluene (10 mL) and MeOH (1.0 mL). The mixture was stirred under nitrogen at 85° C. 15 hours. The mixture was cooled and evaporated in vacuo. The residue was dissolved in DCM, adsorbed onto silica gel and purified by flash column chromatography (eluting first with 1:5 EtOAc in hexanes and second with a gradient of hexanes to 30% DCM in hexanes) to give (S)-methyl 3-(4-(trifluoromethyl)phenyl)-1-trityl-2,5-dihydro-1H-pyrrole-2-carboxylate as a white solid (1.06 g, 62%). LCMS (M+H) 514.5 calc. for C32H27F3NO2 514.2. 1H NMR (400 MHz, CDCl3): δ ppm 6.67-8.21 (a series of m, 19H) 5.85 (s, 1H) 5.01 (d, J=4.11 Hz, 1H) 4.39 (dd, J=17.61, 2.54 Hz, 1H) 3.82 (dd, J=17.70, 2.64 Hz, 1H) 3.64 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]3)=[CH:16][C:15]=2[O:33][CH3:34])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
Zinc chloride (1.0 M in Et2O) (8.56 mL, 8.56 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.06 mL, 7.85 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under nitrogen. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (I26) (1.97 g, 7.13 mmol) in 1:1 DCE/tBuOH (30 mL) was added. A solution of triethylamine (600 μL, 0.432 mmol, 1.1 eq) in 1:1 DCE/t-BuOH (10 mL) was next added drop-wise at 0° C. The reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final addition and then at room temperature for 24 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-45% EtOAc in petroleum benzine 40-60° C.) to give a pale yellow oil which solidified upon standing. This was triturated sequentially with water, 1:1 water/MeOH and MeOH and the precipitate was filtered to afford a white solid. The solid was recrystallised from water to give the title compound (I34) (0.92 g, 30%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 6.86 (dd, J=8.4, 1.7 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.25 (s, 2H), 3.91 (s, 3H), 2.81 (t, J=11.8 Hz, 2H), 2.64 (tt, J=12.1, 3.6 Hz, 1H), 1.83 (d, J=13.5 Hz, 2H), 1.69-1.57 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 7.00 min; m/z=487.0 [M+H]+, 431.0 [M-tButyl+H]+, 485.0 [M−H]−.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])#[N:8].I[C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)=[N:24][CH:25]=1>O1CCOCC1.CN(C=O)C.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>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:20]2[CH:25]=[N:24][C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[N:22][CH:21]=2)=[CH:11][C:10]=1[F:18])#[N:8]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(I)cn3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(-c4ccc(C#N)c(F)c4)cn3)CC2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Under argon atmosphere 0.1 mL sat. Na2CO3-solution and 3 mg (0.004 mmol) bis(triphenylphosphine)-palladium(II) chloride are added to a mixture of 16 mg (0.10 mmol) 4-cyano-3-fluorophenylboronic acid and 45 mg (0.10 mmol) (S)—N-(1-{4-[1-(5-iodopyrimidin-2-yl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 4.43) in 2 mL dioxane/1 mL MeOH. The mixture was stirred at 70° C. for 6 h. After that time, the mixture was diluted with DMF and filtered. The filtrate was purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14])CCC.[CH2:17]([C:20]#[N:21])[C:18]#[N:19].[CH2:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH3:23]>C1C=CC=CC=1>[CH2:11]([O:10][C:9]1[C:6](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[C:7](=[O:16])[C:8]=1[O-:15])[CH2:12][CH2:13][CH3:14].[CH2:22]([NH+:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH3:23]
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Reactant: N#CCC#N
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCOC1=C([O-])C(=O)C1=C(C#N)C#N
Product: CC[NH+](CC)CC
Yield: 56.4 %

Procedure:
2.16 ml (10 mmol) of 3,4-dibutoxy-3-cyclobutene-1,2-dione (2b) was dissolved in 20 ml of anhydrous benzene, and 660 mg (10 mmol) of malonodinitrile was added under stirring. Then, 1.65 ml (12 mmol) of triethylamine was added dropwise for 5 min followed by 10 ml of anhydrous benzene. The obtained emulsion is stirred for 30 min at room temperature. The solvent is removed using a rotary evaporator. The yellow oiled residue is treated three times with ether to give crude product 2d (1.8 g, 56%), 1H-NMR (DMSO-d6): δ 10.15–9.55 (1H, broad s, NH+), 4.59 (2H, t, 6.7 Hz, OCH2), 3.07 (6H, q 7.4, 14.5 Hz, N(CH2CH3)3), 1.77–1.58 (2H, m, CH2), 1.48–1.26 (2H, m, CH2), 1.18 (9H, t, 7.3 Hz, N(CH2CH3)3), 0.90 (3H, t, 7.4 Hz, CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](N)=[N:6][CH:7]=1.[CH3:9][Si:10]([CH3:14])([CH3:13])[C:11]#[CH:12].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.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>[CH3:15][C:5]1[CH:4]=[CH:3][C:2]([C:12]#[C:11][Si:10]([CH3:14])([CH3:13])[CH3:9])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(Br)cn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(C#C[Si](C)(C)C)cn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-pyridin-2-ylamine and 2.3 mL (16.3 mmol) 1-trimethylsilyl-ethyne using 68 mg (0.36 mmol) CuI, 305 mg (1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl2(PPh3)2 and 18 mL (127 mmol) triethylamine in 18 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:8][C:5]1[CH:4]=[N:3][C:2]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[N:7][CH:6]=1
Reactant: OC1CCNCC1
Reactant: Cc1cnc(Cl)nc1
Product: Cc1cnc(N2CCC(O)CC2)nc1

Procedure:
The title compound is prepared from 2-chloro-5-methyl-pyrimidine and 4-hydroxy-piperidine following a procedure analogous to that described in Intermediate 37. LC (method 1): tR=0.48 min; Mass spectrum (ESI+): m/z=194 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)=[N:28][CH:29]=2)O1>>[NH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[N:34][C:33]([NH2:36])=[N:32][CH:31]=3)=[N:28][CH:29]=2)[N:10]=1
Reactant: Nc1ccnc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: Nc1ccnc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)nc2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidin-4-amine and 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H15N7O, 357.13; m/z found, 358.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 2H), 8.64 (dd, J=2.3, 0.8, 1H), 7.95 (dd, J=8.3, 2.3, 1H), 7.78-7.72 (m, 2H), 7.53-7.45 (m, 2H), 7.38 (m, 1H), 7.23 (dd, J=8.1, 1.2, 1H), 6.11 (d, J=5.9, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.C1S(=O)(=O)CCC1>C(OCC)(=O)C>[Br-:11].[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][N+:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(=O)c1ccc(C)cn1
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: CC(=O)c1ccc(C)c[n+]1Cc1ccc2ccccc2c1
Product: [Br-]

Procedure:
Twenty-six grams (0.192 m) of 2-acetyl-5-methylpyridine and 40 g (0.181 m) of 2-bromomethylnaphthalene was added to 78 ml of tetramethylene-sulfone. After heating the mixture for two hours on a steam bath, the mixture was allowed to stand at room temperature for twenty days. The reaction mixture was diluted with 700 ml of ethyl acetate and product oiled out. This first portion of ethyl acetate was decanted and the gum was extracted with 3×100 ml portions of ether. A total of 58 g (85-90%) of gum remained and after storing in the cold for one week some solid formed; however no attempt was made to purify this material further.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([C:29]1[CH:30]=[N:31][C:32]([CH3:35])=[N:33][CH:34]=1)[CH2:7][CH2:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][NH:21][C:20]=3[N:19]=2)[C:11]1=[O:28])C.O.[OH-].[Li+]>O1CCCC1.O>[CH3:35][C:32]1[N:33]=[CH:34][C:29]([C@@H:6]([CH2:7][CH2:8][CH2:9][N:10]2[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[CH2:24][CH2:23][CH2:22][NH:21][C:20]=4[N:19]=3)[C:11]2=[O:28])[CH2:5][C:4]([OH:36])=[O:3])=[CH:30][N:31]=1
Reactant: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NCc2ccc3c(n2)NCCC3)C[C@H]1C)c1cnc(C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc([C@@H](CCCN2C(=O)[C@@H](NCc3ccc4c(n3)NCCC4)C[C@H]2C)CC(=O)O)cn1
Reaction time: 16 h

Procedure:
To a stirred solution of 5-6 (110 mg) in tetrahydrofuran (4.5 mL) was added lithium hydroxide monohydrate (45 mg) in water (4.5 mL) and the mixture was stirred for 16 h. The reaction mixture was concentrated at reduced pressure and the resulting oil was purified by flash column chromatography (silica gel, 30:3:3 to 50:5:5% ethanol/ammonium hydroxide/water in ethyl acetate) to give 5-7 as a white solid.