Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[S:10][C:9]3[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=3[CH:3]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Reactant: CC1(C)OB(c2ccnc(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2sc(-c3ccnc(F)c3)cc2N1
Temperature: 70 °C
Yield: 68.5 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.052 g, 0.20 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.085 g, 0.60 mmol), 2 M sodium carbonate (0.30 mL, 0.60 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.033 g, 0.040 mmol) in 1,4-dioxane (2 mL) was degassed with nitrogen and heated at 70° C. for 15 h. Then, the reaction was cooled to room temperature, and concentrated with silica gel (2 mL), and the residue was purified by flash chromatography (silica gel, ethyl acetate to 80:20 ethyl acetate/methanol) to give the title compound (0.038 g, 69%) as a yellow solid:
Reaction SMILES: C([N:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:41])(=O)C1C=CC=CC=1>[OH-].[Na+].O1CCOCC1.[Cl-].[Na+].O>[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[NH:9][C:10]1=[O:41])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(c1ccccc1)n1c(=O)ccn(CCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1ccn(CCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 48 h

Procedure:
Compound (15) (231 mg; 0.42 mmol) was stirred for 48 hours at room temperature in a mixture of NaOH 1M and Dioxane 1:1 (8 ml). After 48 hours, Brine (8 ml) was added to the solution, and then extracted with EtOAc (3×8 ml). The organic phase was dried over MgSO4; the solvent was removed in vacuo and the crude residue was purified by flash chromatography using DCM/MeOH 90:10 as eluent. The title compound was obtained as a colourless oil which precipitated after treatment with a mixture of Water/EtOH 1:1 which gave the title compound as a white solid (112 mg, 60%). Rf: 0.64 in DCM/MeOH 90:10.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:7]=[C:6]([NH:16][C@H:17]([CH2:19][CH3:20])[CH3:18])[CH:5]=1.[OH-].[Li+].Cl>CO>[C@@H:17]([NH:16][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:7]=1)[C:3]([OH:21])=[O:2])([CH2:19][CH3:20])[CH3:18]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(C2OCCCO2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(C2OCCCO2)n1

Procedure:
Dissolve (S)-2-sec-butylamino-6-[1,3]dioxan-2-yl-isonicotinic acid methyl ester (100 mg, 0.35 mmol) in methanol (4 mL). Slowly add 1 N lithium hydroxide (0.46 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 with 5 N HCl and concentrate. Dilute with ethyl acetate (15 mL), wash the organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].O.[CH2:14]([NH2:17])[CH2:15][NH2:16].C(N)CN.Cl>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:15][CH2:14][NH2:17])=[C:3]([O:11][CH3:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCN
Agent: Cl
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1NCCN
Yield: 86.1 %

Procedure:
31 g (0.165 mole) of 2-chloro-5-nitro-anisole is added to 130 cm3 (1.65 mole) ethylenediamine hydrate. The reaction mixture is heated at reflux for five hours, and the excess of ethylenediamine driven off under vacuum. The residue is treated with 200 cm3 of a 5N hydrochloric acid solution, and dried, yielding 30 g of 4-nitro-2-methoxy-N(β-aminoethyl) aniline, which is washed with acetone.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)#[N:17].P(Cl)(Cl)(Cl)=O>O>[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:2]([CH3:1])[C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[N+:13]([O-:15])=[O:14])=[O:23])=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(N(C)C(=O)c2ccc(C#N)cc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 13.1 g of methyl 4-methylamino-3-nitro-benzoate, 10.3 g of 4-cyano-benzoylchloride and 75 ml of phosphorusoxychloride is stirred for 8 hours at 100° C. After cooling, the mixture is decomposed with water and the aqueous phase is extracted with ethyl acetate. The ethyl acetate phases are washed with soda solution and concentrated by evaporation. The residue is dissolved in a little acetone and ether is slowly added. The quantities precipitated initially (about 1.2 g) are discarded. After further ether has been added the desired substance is precipitated. Yield: 10.2 g (48% of theory), Rf value: 0.54 (silica gel; ethyl acetate/petroleum ether =7:3)
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CSC.B(F)(F)F.CCOCC.CCOC(C)=O>ClCCl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CSC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
Methyl 2-[(4-{3-[4(benzyloxy)phenoxy]propyl}phenoxy)methyl]benzoate (0.70 g, 1.45 mmol) was dissolved in dichloromethane (10 ml). Dimethylsulfide (1.08 g, 17.4 mmol) and borontrifluoride etherate (2.06 g, 14.5 mmol) was added and the mixture was stirred at room temperature for six hours. EtOAc (10 ml) was added and the organic phase was washed with water (3×10 ml), dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). After removing the solvent by evaporation 0.328 gram of methyl 2-({4-[3-(4-hydroxyphenoxy)propyl]-phenoxy}methyl)benzoate (yield 57.6%) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[O:17]([CH2:16][CH2:15][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1CCNCC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1CCN(CCOc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
4-Hydroxypiperidine (5.06 g, 50 mmol) was dissolved in N,N-dimethylformamide (200 mL), potassium carbonate (13.8 g, 100 mmol) and (2-bromoethoxy)benzene (12.9 g, 60 mmol) were added thereto, and the mixture was stirred at 70° C. for 18 hours. The reaction solution was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 1-(2-phenoxyethyl)piperidin-4-ol (8.48 g).
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37](=[O:39])[CH3:38])[CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37](=[O:39])[CH3:38])[CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4cccc(C(C)=O)c4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)c1cccc(-c2cc(-c3cnn(CC#N)c3-c3cc(C)cc(O)c3)ccn2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.7 mg, 0.12 mmol) prepared in Example 36 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (32 mg, 65%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]3)=[N:15][N:16]=2)[CH:3]=1.[CH3:27][O:28][C:29]1[C:34]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:11][N:8]1[C:9]2[C:5](=[C:4]([C:12]3[O:13][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]4)=[N:15][N:16]=3)[CH:3]=[C:2]([C:32]3[CH:33]=[C:34]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[C:29]([O:28][CH3:27])=[N:30][CH:31]=3)[CH:10]=2)[CH:6]=[N:7]1
Reactant: CC(C)N1CCN(Cc2nnc(-c3cc(Br)cc4c3cnn4C)o2)CC1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4CCN(C(C)C)CC4)o3)c3cnn(C)c3c2)cc1NS(C)(=O)=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 38.9 %

Procedure:
6-Bromo-1-methyl-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1H-indazole (40 mg, 0.095 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (31.3 mg, 0.095 mmol), sodium carbonate (30.3 mg, 0.286 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (6.98 mg, 9.54 μmol) were added to a microwave vial and dissolved in 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 15 mins. The reaction mixture was evaporated under a stream of nitrogen and the residual solid was dissolved in DMSO (1 ml), filtered through a frit and purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was evaporated under a stream of nitrogen and the residue was dissolved in 1,4-dioxane (1 ml) and water (1 ml), frozen in a cardice bath and placed on the freeze-drier for 18 h to afford the title compound as a white solid (20 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([F:12])[CH:19]=[C:18]([F:20])[CH:17]=1)=[O:9]
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(F)cc(F)c1)c1cc(Br)ccc1O
Yield: 36.3 %

Procedure:
Using 5-bromosalicylic acid and 3,5-difluoroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].Cl[C:23]1[N:28]=[C:27]([Cl:29])[CH:26]=[CH:25][N:24]=1>>[Cl:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([Sn:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH3:21])[N:28]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Yield: 44.7 %

Procedure:
Using the procedure described in Example 1, Step 1, use LDA, tributyltin hydride (10.8 g, 37.2 mmol) and 2,4-dichloropyrimidine (5.2 g, 34.9 mmol)) to obtain the desired compound (6.3 g). 1H NMR (CDCl3) δ8.52 (d, 1H), 7.18 (d, 1H), 1.58 (m, 6H), 1.30 (q, 6H), 1.18 (t, 6H), 0.86 (t, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH3:21][N:22]([CH3:36])[C:23]1[CH:35]=[CH:34][C:26]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>>[CH3:20][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2([N:27]([C:26]3[CH:25]=[CH:24][C:23]([N:22]([CH3:36])[CH3:21])=[CH:35][CH:34]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:13])[O:8]2)=[CH:18][CH:19]=1
Reactant: CN(C)c1ccc(Nc2ccccc2)cc1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Product: CN(C)c1ccc(N(c2ccccc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3ccccc32)cc1
Yield: 49.2 %

Procedure:
Following a procedure similar to that described in Example 1 but employing 2.6 g of 2-[4-(dimethylamino)benzoyl]benzoic acid and 2.1 g of 4-(dimethylamino)-N-phenylaniline there was obtained 2.2 g of 3-[4-(dimethylamino)phenyl]-3-{[4-(dimethylamino)phenyl]phenylamino}phthalide, m.p. 163°-166° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a brown-colored image.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH4+:15]>C(O)C>[NH2:15][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Reactant: [NH4+]
Solvent: CCO
Product: NCC(O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
A sealed vessel was charged with 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (1.5 g, 7.9 mmol) and ammonium in ethanol (50 mL) was then added and the vessel sealed and heated at 80° C. for 2 h. After cooling to room temperature, solvents were evaporated to afford the desired product as a colorless oil (1.2 g, 73.7% yield). It was used in the next step without further purification. LCMS (m/z): 207.1 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3c(F)cccc3OC)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)O)c2)c1

Procedure:
This compound is prepared by hydrolysis of 23g using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[C@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:59][N:60](C=O)C>[C-]#N.[C-]#N.[Zn+2].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]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:59]#[N:60])=[C:3]([C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[C@H:12]2[CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][N:21]=2)=[O:10])[CH:4]=1
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(C#N)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Temperature: 150 °C

Procedure:
A mixture of (2-bromo-5-methylphenyl)((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone (synthesized from Example A3, 0.35 g, 0.744 mmol), Zn(CN)2 (0.105 g, 0.818 mmol), Pd2(dba)3 (0.068 g, 0.074 mmol) and 2-dicyclohexylphophino-2′,6′-dimethoxybiphenyl (S-Phos; 0.076 g, 0.186 mmol) in wet DMF (DMF:H2O 10:1, 20 mL) was degassed and sealed and heated in a microwave reactor for 1 h at 150° C. The reaction was cooled to rt and the solvent was removed in vacuo. The crude was dissolved with EtOAc, washed with satd. aq. NaHCO3 and brine and dried over Na2SO4. The solvent was removed and the crude was purified in silica gel with 0˜100% EtOAc/Hex to obtain the title compound. ESI-MS (m/z): 417 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
A slurry of 10% palladium on carbon (10 g) in a solution of 4-tert-butoxycarbonyl-1-(2-methoxy-5-nitrophenyl)piperazine (D2) (124.5 g) in ethanol (3.5L) and water (50 ml) was stirred with hydrogen at ambient temperature and atmospheric pressure for 18 h. The reaction mixture was filtered and the filtrate concentrated to afford the title compound (D3) as a gum (112 g, 99%). MH+ 308.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:13][N:12]2[C:14]3[C:9]([C:10]([S:15]([C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])=[N:11]2)=[CH:8][CH:7]=[CH:6][C:5]=3[O:4]1.[CH3:28][NH:29][CH3:30].Cl.CCOCC>CS(C)=O.O>[ClH:1].[CH3:28][N:29]([CH3:30])[CH2:2][CH:3]1[O:4][C:5]2=[C:14]3[C:9](=[CH:8][CH:7]=[CH:6]2)[C:10]([S:15]([C:18]2[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[N:11][N:12]3[CH2:13]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn2c3c(cccc13)OC(CCl)C2
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN(C)CC1Cn2nc(S(=O)(=O)c3cccc4ccccc34)c3cccc(c32)O1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 7-chloromethyl-2-(naphthalene-1-sulfonyl)-7,8-dihydro-6-oxa-1,8a-diaza-acenaphthylene (0.075 g, 0.18 mmoles) and dimethylamine (0.56 ml, 1M solution in THF, 0.56 mmoles) in DMSO was stirred under nitrogen at 100° C. for 4 hours, cooled to room temperature, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum. The resultant residue was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, treated with 1M HCl in ether (0.2 ml, 0.2 mmoles) and evaporated to dryness to afford the title compound, MS: (ES) m/z 407.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]#[N:31])=[CH:24][C:23]=2[CH2:32][CH:33]([CH3:35])[CH3:34])[CH:11]=[CH:12][C:13]=1OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([C:40]1[CH:41]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[CH:37]([CH3:39])[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]#[N:31])=[CH:24][C:23]=2[CH2:32][CH:33]([CH3:35])[CH3:34])[CH:11]=[CH:12][C:13]=1[C:42]1[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:40]([CH2:36][CH:37]([CH3:38])[CH3:39])[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CC(C)C
Reactant: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)cc1CC(C)C
Temperature: 80 °C
Yield: 88.9 %

Procedure:
134.6 mg (0.27 mmol) Trifluoro-methanesulfonic acid 3-benzyl-4′-(2-Cyano-ethyl)-2′-isobutyl-biphenyl-4-yl ester (54), 96.9 mg (0.33 mmol, 1.24 eq.) 2-(3-isobutyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (11) and 46.7 mg (40 μmol, 0.15 eq.) Pd(Ph3P)4 were dissolved in 7 ml DME/EtOH (9+1). To this yellow solution 0.27 ml (0.54 mmol, 2.00 eq.) of a 2 M aq. Na2CO3-solution was added and the resulting mixture was heated at 80° C. for 19 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (6+1)) yielded 122.9 mg (0.24 mmol, 88.26%) 3-(3′-Benzyl-2,3″-diisobutyl-4″-methoxy-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (55) as a clear oil. Rf (hexanes/EtOAc (6+1))=0.20. 1H-NMR (500 MHz, CDCl3): δ=0.69 (d, 6H, J=6.62 Hz, 2*CH3), 0.84 (d, 6H, J=6.62 Hz, 2*CH3), 1.63 (m, 1H, CH), 1.83 (m, 1H, CH), 2.42 (d, 2H, J=7.25 Hz, CH2), 2.44 (d, 2H, J=7.25 Hz, CH2), 2.61 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.93 (t, 2H, J=7.41 Hz, CH2CH2CN), 3.81 (s, 3H, OCH3), 3.98 (s, 2H, CH2Ph), 6.81 (d, 1H, J=8.51 Hz), 6.96 (m, 2H), 7.00-7.18 (m, 10H), 7.24-7.26 (d, 1H, J=7.57 Hz). MS (EI): m/z=517 (10), 516 (45), 515 (100), 472 (10), 381 (8), 91 (20). HR-MS (EI): Calcd. for C37H41NO: 515.318814. Found: 515.319235.