Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[N:22]1([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:21][CH:20]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(N3CCCC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCCC2)ccc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 1-tert-butyloxycarbonyl-4-[(4-pyrrolidinophenyloxy)methyl]piperidine (0.55 g) obtained in Example 15 was added trifluoroacetic acid (2 ml), followed by stirring at room temperature for 10 minutes. The mixture was worked up according to the same manner as that described in Example 14 to obtain a fumarate and the fumarate was recrystallized from water/ethanol (1/2) to obtain 4-[(4-pyrrolidinophenyloxy)methyl]piperidine fumarate (0.5 g) as colorless crystals, m.p. 200°-205° C.
Reaction SMILES: [C:1]12([N:11]3[C:15](=[O:16])[C:14]([CH2:23][C:24]4[CH:28]=[CH:27][O:26][CH:25]=4)([CH2:17][C:18]4[CH:22]=[CH:21][O:20][CH:19]=4)[NH:13][C:12]3=[O:29])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:32]I>C1COCC1>[C:1]12([N:11]3[C:15](=[O:16])[C:14]([CH2:23][C:24]4[CH:28]=[CH:27][O:26][CH:25]=4)([CH2:17][C:18]4[CH:22]=[CH:21][O:20][CH:19]=4)[N:13]([CH3:32])[C:12]3=[O:29])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C1NC(Cc2ccoc2)(Cc2ccoc2)C(=O)N1C12CC3CC(CC(C3)C1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)N(C23CC4CC(CC(C4)C2)C3)C(=O)C1(Cc1ccoc1)Cc1ccoc1
Reaction time: 1.5 h
Yield: 100.9 %

Procedure:
Under a N2 atmosphere was combined 3-adamantan-1-yl 5,5-bis-furan-3-ylmethyl-imidazolidine-2,4-dione (0.100 g, 0.25 mmol) in 2 ml of dry THF. To this solution was added a 60% dispersion of sodium hydride (11.1 mg, 0.28 mmol) and the suspension was allowed to stir for 1.5 hours. To this reaction mixture was then added methyl iodide (32 μl, 0.508 mmol) and the reaction mixture was allowed to stir for 30 minutes and quenched with water and extracted with 2×30 ml of methylene chloride (CH2Cl2). The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to yield 0.103 g of the title compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](=O)(OC)OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:9][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: COC(=O)OC
Reactant: Oc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(O)cc1
Yield: 97 %

Procedure:
22 parts of hydroquinone, 18 parts of dimethyl carbonate and one part of triphenylphosphine are kept for 15 hours at 190° C. Working up takes place as described in Example 23. 3 parts (97% of theory, based on converted hydroquinone) of hydroquinone monomethyl ether of boiling point 57° C. are obtained. The conversion is 12 percent.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C@H:14]([O:29][CH3:30])[CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C.CO>C(Cl)Cl>[C:31]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[C@H:14]([O:29][CH3:30])[CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl cis(±)-2-amino-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (185b) (300 mg) was dissolved in methylene chloride (25 ml). Acetyl chloride (0.1 ml) and triethylamine (0.2 ml) were added, and the mixture was stirred at room temperature for one hour. Methanol was added to the reaction solution, followed by concentration under reduced pressure. Then, the residue was diluted with ethyl acetate, washed with water, and then concentrated under reduced pressure to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].N[C@@H:23]1C2C(=CC=CC=2)CC[C@H]1O>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:23][CH2:14][C@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: N[C@@H]1c2ccccc2CC[C@H]1O
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(N[C@@H]2c3ccccc3CC[C@H]2O)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (trans)-1-amino-1,2,3,4-tetrahydronaphthalen-2-ol and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.27–1.34, 2.01, 2.24, 2.64, 2.84, 2.93, 4.03, 4.76, 5.06, 5.17, 7.19–7.21, 7.25–7.27, 7.34–7.37, 7.66;
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:30]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(C)(=O)=O)cc1I
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-1-methyl-4-(methylsulfonyl)benzene (Intermediate 17), the title compound was obtained as a colorless oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][C:27]=1[Cl:28])[NH:24][N:23]=[CH:22]2.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][C:19]=1[NH:18][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[NH:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: Nc1cc2cn[nH]c2cc1Cl
Reactant: O=C(O)c1ccccc1NCc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc2cn[nH]c2cc1Cl)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
194 mg (0.85 mmol) of 2-(4-pyridylmethyl)aminobenzoic acid is mixed in 8 ml of dimethylformamide with 283 mg (1.69 mmol) of 5-amino-6-chloroindazole. Under argon and in a moisture-free environment, 215 mg (2.13 mmol) of N-methylmorpholine and 386 mg (1.02 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophophate are added to this solution. This mixture is stirred for 4 hours at room temperature. It is then diluted with about 40 ml of water and extracted three times with 30 ml of ethyl acetate each. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol-10:1 as an eluant. 97 mg (30.2% of theory) of N-(6-chloroindazol-5-yl)-2-[(4-pyridyl)methyl]amino-benzoic acid amide with a melting point of 222.8° C. is obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C2(O)CCNCC2)cc1
Reaction time: 20 h

Procedure:
A mixture of 1-benzyl-4-p-tolyl-piperidin-4-ol (350 mg, 1.243 mmol), and Pd—C 10% (55 mg) in EtOAc (7 mL) is hydrogenated at room temperature and atmospheric pressure for 20 h. The mixture is filtered over Celite, and the filtrate is evaporated to provide the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C@H:18]4[O:22]C(C)(C)[N:20](C(OC(C)(C)C)=O)[C@@H:19]4[CH2:32][F:33])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3]1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[C:37]([OH:39])([C:36]([F:41])([F:40])[F:35])=[O:38].[NH2:20][C@H:19]([CH2:32][F:33])[C@@H:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]3[CH2:5][S:2](=[O:1])(=[O:34])[CH:3]=3)=[N:11][CH:10]=2)=[CH:17][CH:16]=1)[OH:22]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C4=CS(=O)(=O)C4)nc3)cc2)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3=CS(=O)(=O)C3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product of step 4, Example 18 (0.15 g, 0.233 mmol, 1 eq) in methylene chloride (5 mL) is added trifluoroacetic acid (0.4 mL) at 0° C. Resulting reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo and stripped with methylene chloride (3×10 mL) to afford crude TFA salt of title compound (0.185 g), which is used as such in next step. LCMS (m/z): [M+H] 349.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].CCN=C=NCCCN(C)C>O1CCCC1.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1Cl
Yield: 91.6 %

Procedure:
A solution of 4-bromo-2-chlorobenzoic acid (2.00 g, 8.5 mmol), N-hydroxysuccinimide (1.07 g, 9.3 mmol) and EDCI (1.79 g, 9.3 mmol) in tetrahydrofuran/N,N-dimethylformamide (3:1; 40 Ml) was stirred at room temperature for 18 h. The reaction was concentrated and water (50 Ml) was added. The mixture was extracted with ethyl acetate (3×50 Ml) and the combined organic layers were washed with brine, dried (Na2SO4), concentrated, and dried in vacuo to give 1-[(4-bromo-2-chlorobenzoyl)oxy]-2,5-pyrrolidinedione (2.59 g, 92%) as an off-white solid which was used directly in the next step without further purification.
Reaction SMILES: C([O:3][C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:29])[NH:15][C:16]2[C:17](=[O:28])[O:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[CH:20]=3)[C:6](=[O:30])[CH:5]=1)C>C1COCC1.C(Cl)Cl.Cl.O>[CH3:27][O:26][C:21]1[CH:20]=[C:19]2[C:24]([CH:25]=[C:16]([NH:15][C:14](=[O:29])[O:13][CH2:12][CH2:11][CH2:10][CH:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][C:6]3=[O:30])[C:17](=[O:28])[O:18]2)=[CH:23][CH:22]=1
Reactant: CCOC1=CC(=O)C(CCCOC(=O)Nc2cc3ccc(OC)cc3oc2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(NC(=O)OCCCC3CCC(=O)CC3=O)c(=O)oc2c1
Yield: 59.2 %

Procedure:
Compound 5 (240 mg, 0.58 mmol) was stirred in a mixture of THF/DCM (3/1 v/v, 4 mL) and 3N HCl (4 mL) for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous MgSO4 and reduced to dryness to yield the crude product, which was purified by flash column chromatography (EtOAc/acetone 4/1) to yield 7 as an off-white solid (133 mg, 59.4%). Rf 0.62 (hexanes/EtOAc/MeOH 6/3/1); Mp. 154-156° C.; 1H NMR (300 MHz, CDCl3) δ 8.25 (1H, s), 7.42 (1H, s), 7.39 (1H, d, J=8.7 Hz), 6.88 (1H, dd, J=8.6 Hz, 2.1 Hz), 6.83 (1H, d, J=2.1 Hz), 4.23 (2H, t, J=6.5 Hz), 3.86 (3H, s), 3.44 (2H, d, J=5.1 Hz), 2.78-2.69 (1H, dt, J=16.4 Hz, 4.4 Hz), 2.67-2.51 (2H, m), 2.24-2.15 (1H, dq, J=14.1 Hz, 4.8 Hz), 2.03-1.95 (1H, m), 1.88-1.47 (6H, m); 13C NMR (75 MHz, CDCl3) δ 204.2, 203.8, 161.2, 158.9, 153.5, 151.3, 128.4, 122.0, 121.8, 113.3, 113.2, 100.9, 65.6, 58.5, 55.9, 49.1, 39.9, 26.6, 25.7, 24.8; ESI MS m/z 410 (M++Na+), 388 (M++H+); CHN calc. for C20H21NO7.0.5H2O, C, 60.59; H, 5.61; N, 3.53; found C, 61.31; H, 5.56; N, 3.48.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]2)=[CH:8][C:7]=1[C:22]#[N:23])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)=[CH:8][C:7]=1[C:22]#[N:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(-n2cc(C(=O)OCC)cn2)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 54.9 %

Procedure:
To a solution (15 ml) of ethyl 1-(4-butoxy-3-cyanophenyl)pyrazole-4-carboxylate (1.5 g) in ethanol was added 1.5 N aqueous sodium hydroxide solution (4 ml) with stirring, and the mixture was heated at 80° C. for 1 hour. After the completion of the reaction, the reaction mixture was poured into water and the mixture was neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.75 g of 1-(4-butoxy-3-cyanophenyl)pyrazole-4-carboxylic acid, melting point 200-202° C.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[C:3]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:2]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([N:6]2[CH2:7][CH2:8][C:9]3[O:1][N:2]=[C:3]([C:10]([N:12]4[CH2:17][CH2:16][N:15]([C:18]5[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=5)[CH2:14][CH2:13]4)=[O:11])[C:4]=3[CH2:5]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3noc4c3CNCC4)CC2)cc1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3noc4c3CN(S(=O)(=O)c3ccc(C)cc3)CC4)CC2)cc1
Yield: 28.1 %

Procedure:
In a manner similar to the general method, 170 mg (0.42 mmol) of 1-[4-[4-(4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carbonyl)-piperazin-1-yl]-phenyl]-ethanone were reacted with 120 mg (0.63 mmol) of p-toluenesulfonic acid chloride to yield 60 mg (28% of theoretical) of 1-(4-{4-[5-(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine-3-carbonyl]-piperazin-1-yl}-phenyl)-ethanone (86), which were obtained in the form of a colourless solid.
Reaction SMILES: C(C1C=CC=CN=1)(=O)C.[I-].BrC1N=C(C(=O)C[N+]2C=CC=CC=2)C=CC=1.[C:27]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[N:36]=[C:35]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47](Br)[N:46]=2)[CH:34]=1.[CH:58]1[C:70]2[C:69]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[NH:63][C:62]=2[CH:61]=[CH:60][N:59]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.[Cu].ClC1C=CC=CC=1Cl.CS(C)=O>[C:27]1([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[N:36]=[C:35]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([N:63]3[C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][C:69]=4[C:70]4[CH:58]=[N:59][CH:60]=[CH:61][C:62]3=4)[N:46]=2)[CH:34]=1
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Reactant: Brc1cccc(-c2cc(-c3ccccc3-c3ccccc3)cc(-c3ccccn3)n2)n1
Agent: [Cu]
Agent: CC(=O)c1ccccn1
Agent: O=C(C[n+]1ccccc1)c1cccc(Br)n1
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: c1ccc(-c2ccccc2-c2cc(-c3ccccn3)nc(-c3cccc(-n4c5ccccc5c5cnccc54)n3)c2)cc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
As in Example 1,3-(biphenyl-2-yl)-1-(pyridin-2-yl)propenone was synthesized from 2-biphenylcarboxyaldehyde and 2-acetylpyridine, and further subjected to a reaction with [2-(6-bromopyridin-2-yl)oxoethyl]pyridinium iodide to synthesize 4′-(biphenyl-2-yl)-6-bromo[2,2′;6′,2″]terpyridine. To 4.6 g of the resulting 4′-(biphenyl-2-yl)-6-bromo[2,2′;6′,2″]terpyridine were added 1.7 g of 5H-pyrido[4,3-b]indole, 0.3 g of a copper powder, 4.2 g of potassium carbonate, 0.3 mL of dimethyl sulfoxide, and 20 mL of o-dichlorobenzene, followed by heating and stirring at 140° C. for 5 hours. After cooling to room temperature, 60 mL of chloroform was added thereto to remove an insoluble matter by filtration, and the filtrate was concentrated under a reduced pressure to obtain a concentrate. The concentrate was dissolved in chloroform, and subjected to adsorptive purification with NH silica gel and to concentration under a reduced pressure to obtain a crude product. The crude product was washed with methanol and further washed with ethyl acetate to obtain 2.6 g (yield, 46%) of 4′-(biphenyl-2-yl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine (Compound 135) as a white powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:6])[CH2:3][C:4]#[N:5].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>C1(C)C=CC=CC=1.O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(B(O)O)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[C:8]1([NH:1][C@@H:2]([CH3:6])[CH2:3][C:4]#[N:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccccc1
Reactant: C[C@H](N)CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](CC#N)Nc1ccccc1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
(3S)-3-aminobutanenitrile (8.6 g, 102 mmol, may be prepared as described in PCT Int. Appl., WO2005/100321), bromobenzene (16.16 ml, 153 mmol) and cesium carbonate (50.0 g, 153 mmol) were combined in Toluene (100 ml) under nitrogen were stirred for 45 mins. Phenylboronic acid (0.187 g, 1.534 mmol, Aldrich), palladium (II) acetate (0.188 g, 0.837 mmol, available from Aldrich) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.443 g, 1.125 mmol, available from Aldrich) were combined in tetrahydrofuran (THF) (6.67 ml) under nitrogen and stirred for 45 mins. The THF solution was added to the toluene solution and the reaction heated to 80° C. overnight. The reaction mixture was cooled and partitioned between EtOAc (500 ml) and water (300 ml). The aqueous layer was reextracted with EtOAc (200 ml). The combined organic layers were washed with water and brine (500 ml each) and then dried with Na2SO4, filtered and concentrated to yield an orange oil. The crude product was taken up in the minimum of DCM, applied to a 330 g Companion XL column and eluted with 5% ethyl acetate in cyclohexane for 1 CV then 5-30% Ethyl Acetate over 12 CV then held at 30% for 3 CV; UV collection; 450 ml fractions. The product was isolated as an off-white solid (11.3526 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.C(N(CC)C(C)C)(C)C.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:33]([C:29]1[O:28][CH:32]=[CH:31][CH:30]=1)=[O:34]
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H]1CN(C(=O)c2ccco2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Reaction time: 0.08 h
Yield: 53.8 %

Procedure:
A 100 mL round bottomed flask fitted with a nitrogen inlet was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (1.54 g, 4.77 mmol), 1,2-dichloroethane (45 mL), and N,N-diisopropylethyl amine (2.497 mL, 14.30 mmol). The mixture stirred for 5 min and then furan-2-carbonyl chloride (0.940 mL, 9.53 mmol) was slowly added. The reaction stirred at room temperature for 2 h and was then concentrated. The residue was purified via column chromatography (eluting with 3:2 hexanes/ethyl acetate) to afford (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (1.07 g, 54%) as an off-white solid. MS (ESI, pos. ion) m/z 417, 419 [M+1]+.
Reaction SMILES: C([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:19]2[CH:20]=[C:21]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][O:27][CH2:26]3)[CH:22]=[CH:23][CH:24]=2)=[N:4]1)=C.C[N+]1([O-])CCOCC1.[O-]S([O-])=O.[Na+].[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[NH:3][N:4]=[C:5]([C:19]3[CH:20]=[C:21]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:28][O:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)[CH:6]=2)=[CH:10][CH:11]=1
Reactant: C=Cn1nc(-c2cccc(C3(NC(=O)OC(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)[nH]n3)c2)COC1
Reaction time: 3.5 h

Procedure:
A stirred solution of tert-butyl {3-[3-(1-ethenyl-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}carbamate (1.02 g, 2.03 mmol) in 14 mL of 2.5:1 acetone:water was cooled in an ice bath. To the stirred solution was added OsO4 (2.6 mL of a 5.5 weight % solution in water, 0.2 mmol) and N-methylmorpholine N-oxide (2.4 g, 2.1 mmol). The mixture was stirred for 3.5 h. 10% Aqueous Na2SO3 solution was added. The mixture was stirred for 5 min, then extracted with EtOAc. The combined organic phases were washed with water and brine, then dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give tert-butyl {3-[3-(5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}carbamate as a dark solid. Calcd (M+1)+: 476.5. Found: 476.2
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=2)O1.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH3:21][Si:18]([CH3:19])([CH3:20])[CH2:17][CH2:16][O:15][CH2:14][N:12]1[CH:13]=[C:9]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[CH:10]=[N:11]1
Reactant: N#Cc1cccc(Br)c1
Reactant: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)cn1
Temperature: 80 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole (150.0 mg, 0.0004625 mol) and 3-bromobenzonitrile (0.10 g, 0.00056 mol) in toluene (2.0 mL, 0.019 mol) and ethanol (0.3 mL, 0.005 mol) was treated with sodium carbonate (98 mg, 0.00092 mol) in water (0.5 mL, 0.03 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.000046 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a microwave at 80° C. for 30 min, then allowed to cool to rt and taken up in water and ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to give a crude product, which was purified by FCC on silica gel, eluting with EtOAc/Hexanes (1:5) to give 3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazol-4-yl)benzonitrile, as an oil, LC/MS (M+H)+: 300.