Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH2:15][CH:16]1[O:18][CH2:17]1)(=O)=O>>[N:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:15][CH:16]3[O:18][CH2:17]3)[C:3]2=[CH:10][CH:9]=1
Reactant: Oc1cccn2nccc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Product: c1cc(OCC2CO2)c2ccnn2c1

Procedure:
4-Hydroxypyrazolo[1,5-a]pyridine (5) as obtained by the above procedure is reacted, in the form of alkali metal salt, with glycidyl tosylate to give 3-(pyrazolo[1,5-a]pyrid-4-yloxy)-1,2-epoxypropane (6). The reaction is preferably carried out in a solvent such as dimethylformamide under an atmosphere of argon gas.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([CH2:25][C:26]([NH2:28])=[O:27])[CH2:22][S:21](=[O:24])(=[O:23])[CH2:20]1>>[NH2:28][C:26](=[O:27])[CH2:25][C:19]1([NH:18][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:20][S:21](=[O:23])(=[O:24])[CH2:22]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Product: CC(CF)Oc1cc(C(=O)NC2(CC(N)=O)CS(=O)(=O)C2)ncc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer A) (example 287e) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (37.5 mg, 56%); MS (ESI, m/z): 400.3 (M+H+).
Reaction SMILES: C([C:3](=[CH:7][C:8]([CH3:13])=[CH:9][N:10]([CH3:12])C)[C:4]([O-:6])=[O:5])#N.[BrH:14].[C:15](O)(=O)[CH3:16].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:14][C:12]1[N:10]=[CH:9][C:8]([CH3:13])=[CH:7][C:3]=1[C:4]([O:6][CH2:15][CH3:16])=[O:5]
Reactant: CC(=CN(C)C)C=C(C#N)C(=O)[O-]
Reactant: CC(=O)O
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1cc(C)cnc1Br
Yield: 35 %

Procedure:
The crude 2-cyano-5-(N,N-dimethylamino)-4-methyl-2,4-pentanedienoate (15.9 g) was dissolved in acetic acid (50 ml) and the mixture heated at 40°. A solution of 30% HBr/acetic acid (100 ml) was added dropwise and then the mixture was heated to 55° with stirring. After heating for 3/4 of an hour, the solution was poured onto ice, neutralized with solid Na2CO3 and extracted with CH2Cl2 (4×200 ml). The organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was distilled at 114°-120° (0.4 mm) to yield 6.3 g (35% yield) of ethyl 2-bromo-5-methylnicotinate
Reaction SMILES: Cl[C:2]1[N:25]=[CH:24][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=1)[N:7]=3.Cl.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH3:29])[C:2]1[N:25]=[CH:24][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH2:22][OH:23])[N:15]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CNC
Reactant: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: Cl
Product: CC(C)n1nc(CO)nc1-c1cn2c(n1)-c1cnc(N(C)C)cc1OCC2

Procedure:
[5-(8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-methanol was reacted with dimethylamine-HCl to give 413 (10 mg) as a colorless solid. LCMS: 370.2. 1H NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 7.80 (s, 1H), 6.13 (s, 1H), 5.98-5.85 (m, 1H), 5.18 (t, J=6.0 Hz, 1H), 4.56-4.44 (m, 4H), 4.41 (d, J=6.0 Hz, 2H), 3.05 (s, 6H), 1.47 (d, J=6.6 Hz, 6H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)=[CH:5][N:4]=1.[I:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[NH:21][C:20](=[O:27])/[C:19]/2=[CH:28]/OC>CN(C)C=O>[O:12]1[CH:13]=[CH:14][C:10]([C:6]2[C:7]([OH:9])=[CH:8][C:3]([CH2:2][NH:1]/[CH:28]=[C:19]3\[C:20](=[O:27])[NH:21][C:22](=[O:26])[C:23]4[C:18]\3=[CH:17][C:16]([I:15])=[CH:25][CH:24]=4)=[N:4][CH:5]=2)=[CH:11]1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1cc(O)c(-c2ccoc2)cn1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1cc(O)c(-c2ccoc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.8 %

Procedure:
An amount of 64 mg (0.33 mmol) of 2-aminomethyl-5-furan-3-yl-pyridin-4-ol, is slurried in N,N-dimethylformamide (3 mL), followed by the addition of 110 mg (0.33 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione. After the mixture is stirred at room temperature for 6 hours, the solid is filtered and washed several times with N,N-dimethylformamide, then ether and dried to give 109 mg of the title compound as a light beige solid (67% yield); mp 213-228° C. dec,
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1.O.[NH2:12][NH2:13].O>C(O)C>[NH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[N:3]=1)[NH2:13]
Reactant: Cc1nc(Cl)ccc1C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(NN)ccc1C#N
Temperature: 80 °C
Yield: 59.9 %

Procedure:
To a suspension of 6-chloro-2-methylnicotinonitrile (6.2 mmol) in 6.2 mL of ethanol, hydrazine monohydrate (9.3 mmol) was added. The resulting mixture was then heated to 80° C. overnight. The mixture was cooled to room temperature and 2 mL of water was added. It was heated to 80° C. again to a clear solution and then allowed to cool down to room temperature and finally in an ice-bath. The solid was collected by filtration, washed with cold 50% ethanol, and dried under vacuum to give 550 mg of the desired solid product. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H), 4.41 (s, 2H), 6.60 (br. s., 1H), 7.66 (d, J=8.59 Hz, 1H), 8.47 (s, 1H); ES-MS m/z 149 (M+H).
Reaction SMILES: FC1C=CC([N:8]([CH3:32])[C:9]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2OS(C(F)(F)F)(=O)=O)=[O:10])=CC=1.[F-:33].[K+].[Br-].[K+].[CH:37]1(B(O)O)[CH2:39][CH2:38]1>C1(C)C=CC=CC=1>[F:33][C:11]1[CH:16]=[CH:15][C:14]([CH2:32][NH:8][C:9](=[O:10])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2[CH:37]2[CH2:39][CH2:38]2)=[CH:13][CH:12]=1
Reactant: [F-]
Reactant: OB(O)C1CC1
Reactant: Cc1cc(N2CCOCC2)cc(OS(=O)(=O)C(F)(F)F)c1C(=O)N(C)c1ccc(F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)cc(C2CC2)c1C(=O)NCc1ccc(F)cc1
Yield: 28 %

Procedure:
A solution of trifluoro-methanesulfonic acid [2-[(4-fluorophenyl)-methyl-carbamoyl]-3-methyl-5-morpholin-4-yl-phenyl]ester (synthesized according to the methods described in sections a) to d) of example 17) (0.16 g, 0.34 mmol), potassium fluoride (0.08 g, 1.41 mmol), potassium bromide (0.05 g, 0.40 mmol) and cyclopropylboronic acid (0.06 g, 0.67 mmol) in dry toluene (3 ml) is degassed and flushed with argon for 20 min. To the reaction mixture is added tetrakis(triphenylphosphin)palladium(0) (0.039 g, 0.033 mmol) and subjected to microwave irradiation at 120° C. for 1 h. The reaction mixture is poured onto ice and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (20 ml), brine (20 ml) and dried over sodium sulfate. The solvent is evaporated to get the crude product. The reaction is repeated once and the combined fractions are purified by column chromatography (silica gel, 20% ethyl acetate/hexane) followed by preparative HPLC to afford N-[(4-fluorophenyl)-methyl]-2-cyclopropyl-6-methyl-4-morpholin-4-yl-benzamide (example 18) (0.12 g, 0.32 mmol, 28%). [M+H]+ 369.2.
Reaction SMILES: N1[CH:6]=[CH:5][C:4](N2C[CH2:10][CH:9]([O:12][Si](C(C)(C)C)(C)C)C2)=[CH:3][CH:2]=1.BrN1[C:25](=[O:26])[CH2:24]C[C:22]1=O>C(#N)C>[CH3:24][CH2:25][O:26][C:9]([CH3:10])=[O:12].[CH3:6][CH2:5][CH2:4][CH:3]([CH3:2])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2ccncc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCCC(C)C
Product: CCOC(C)=O
Reaction time: 8 h

Procedure:
1-(4-Pyridyl)-3-(t-butyldimethylsilyloxy)pyrrolidine (8.92 g, 32.1 mmol) was dissolved in acetonitrile (140 ml) and N-bromosuccinimide (6.00 g, 33.7 mmol) was added portionwise. After stirring overnight the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulphate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel, eluting sequentially with CH2Cl2; 5%MeOH CH2Cl2; 10%MeOH/CH2Cl2. Further purification by column chromatography on alumina, eluting sequentially with isohexane; 25%EtOAc/isohexane gave the product as a colourless oil.
Reaction SMILES: [N:1]([CH:4]([CH2:7][NH:8][C:9]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[O:10])[CH2:5][NH2:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[O:26]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[N:1]([CH:4]([CH2:7][NH:8][C:9]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[O:10])[CH2:5][NH:6][S:39]([C:36]1[CH:35]=[CH:34][C:33]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:38][CH:37]=1)(=[O:41])=[O:40])=[N+:2]=[N-:3]
Reactant: CCOP(=O)(OCC)C(=O)NCC(CN)N=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(=O)NCC(CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)N=[N+]=[N-]
Yield: 59.1 %

Procedure:
To a solution of 2-azido-3-[diethylphosphonoformamido]propylamine (1.26 g, 4.5 mmol) and triethylamine (1.2 eq, 1.46 g, 5.4 mmol) in 15 ml CH3CN was added dropwise 4-phenoxybenzenesulfonyl chloride solution (1.5 eq, 68 mmol, 5.25 ml) in 15 ml CH3CN at 0° C. with stirring. After the addition, the reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by silica gel chromatography [eluent: DCM/1% MeOH] to yield 1.36 g (60%) a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([C:17]([CH3:19])=[CH2:18])[CH2:15][C:14](=[O:20])[CH2:13][CH:12]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:28]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@:6]3([C@@H:12]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:13][C:14](=[O:20])[NH:28][CH2:15][C@H:16]3[C:17]([CH3:19])=[CH2:18])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(C)C1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CNC(=O)C[C@H](c2cccc(Cl)c2)[C@@]12C(=O)Nc1cc(Cl)ccc12
Yield: 20.8 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-iso-propenylspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (120 mg, 0.3 mmol) was reacted with NaN3 (39 mg, 0.6 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.3 mL) (Aldrich) in acetonitrile (10 mL) followed by chiral chromatography separation to give (3S,4R,5R)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (25.9 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, Found: 415.0974; (3R,4S,5S)-6′-chloro-5-(3-chlorophenyl))-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethenylspiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (28.8 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, found: 415.0975; (3S,4R,5R)-4′-chloro-3-(3-chlorophenyl))-1,1′,2,2′,3,5,6,7-octahydro-5-(1-methylethenylspiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (20.7 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, found: 415.0974; and (3R,4S,5S)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-(1-methylethenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (21.6 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, found: 415.0974.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])C.BrC[C:24]1[CH:29]=[CH:28][C:27](CBr)=[CH:26][CH:25]=1>C(#N)C>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][CH2:7][C:2]2[CH:3]=[CH:4][C:21]([CH2:20][NH:17][CH:18]([C:19]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:8][CH:1]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(CBr)cc1
Solvent: CC#N
Product: c1ccc(C(NCc2ccc(CNC(c3ccccc3)c3ccccc3)cc2)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 18.3 g of benzhydrylamine, 10 g of triethylamine and 60 ml of acetonitrile is added dropwise to a boiling mixture of 13.2 g of 1,4-bis-(bromomethyl)-benzene in 60 ml of acetonitrile. The mixture is left to boil overnight, is greatly concentrated, and partitioned between 200 ml of ether and 200 ml of 10% sodium hydroxide solution, concentrated by evaporation and recrystallised from diethyl ether. N,N'-bis-(diphenylmethyl)-p-xylylenediamine having a melting point of 92°-94° C. is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([CH2:21][O:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].C(N(CC)CC)C.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([O:22][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 88.4 %

Procedure:
To a solution of 4-(t-butoxycarbonyl)piperazine (1.50 g, 8.05 mmol) in methylene chloride (68 ml) were added chloroformic acid p-nitrobenzyl ester (1.90 g, 8.86 mmol) and triethylamine (1.24 ml, 8.86 mmol) in an ice bath. The mixture was stirred in the ice bath for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate=(1:3) as the eluant to afford 1-(t-butoxycarbonyl)-4-(p-nitrobenzyloxycarbonyl)piperazine (2.60 g, yield 89%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2([C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=4)=[CH:21][CH:20]=3)[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1CCC(C(=O)Nc2cc(Cl)cc(Cl)c2)(c2ccc(I)cc2)CC1
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: CN1CCC(C(=O)Nc2cc(Cl)cc(Cl)c2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Temperature: 25 °C
Yield: 400 %

Procedure:
To a flask containing 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid (3,5-dichloro-phenyl)-amide (175 mg, 0.35 mmol) was added Pd(PPh3)4 (13 mg, 0.035 mmol, 10 mol %), 3-cyanophenylboronic acid (78 mg, 0.53 mmol, 1.5 eq.) and Na2CO3 (0.53 g, 5 mmol). The mixture was suspended in toluene (5 mL), EtOH (2.5 mL) and H2O (2.5 mL) and heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by HPLC to give 4-(3′-cyano-biphenyl-4-yl)-1-methyl-piperidine-4-carboxylic acid (3,5-dichloro-phenyl)-amide as a white solid (0.066 g, 1.4 mmol, 14%). 1H NMR (300 MHz, CDCl3): δ 7.95 (M, 1H), 7.91 (M, 1H), 7.62 to 7.76 (m, 6H), 7.51 (d, 2H), 7.19 (br, 1H), 7.15 (t, 1H), 2.71 (m, 6H), 2.42 (s, 3H), 2.30 (m, 2H). MS (ESI): 464.2/466.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4cnn(CC)c4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1cc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)cn1
Yield: 75.4 %

Procedure:
A mixture of ethyl {4-[4-({4-[({4-[(E)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (52 mg), 1N aqueous sodium hydroxide solution (2 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was heated under reflux for 30 min. After cooling, 1N hydrochloric acid was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine; dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from tetrahydrofuran-hexane gave {4-[4-({4-[({4-[(E)-2-(1-ethyl-1H-pyrazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (37.6 mg, yield 77%). melting point: 165-166° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1.[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][C:17]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:18]2[C:19]3[C:24](=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:16]([CH3:15])=[C:17]2[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Product: COC(=O)c1ccc(OCCn2c(-c3cccnc3)c(C)c3cc(C#N)ccc32)cc1

Procedure:
4-(2-Bromo-ethoxy)-benzoic acid methyl ester and 5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 6) are processed according to the method described in Example 59 to give 4-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester. 1H NMR (400 MHz, MeOD) δ ppm 2.28 (s, 3H), 3.87 (s, 3H), 4.24 (t, J=5.1 Hz, 2H), 4.61 (t, J=5.1 Hz, 2H), 6.73-6.79 (m, 2H), 7.58 (dd, J=8.5, 1.6 Hz, 1H), 7.66 (ddd, J=7.9, 5.0, 0.8 Hz, 1H), 7.77 (dd, J=8.6, 0.5 Hz, 1H), 7.85-7.88 (m, 1H), 7.88-7.90 (m, 1H), 8.03 (dt, J=8.1, 1.9, 1.8 Hz, 1H), 8.07 (dd, J=1.5, 0.6 Hz, 1H), 8.52-8.84 (m, 2H). HRMS (ESI) m/z 412.1660 [(M+H)+ Calcd for C25H22N3O3: 412.1661].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:13]1([C:19]2[C:32]3[C:23](=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=[N:25]4)[N:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[C:2]1([C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]3[C:24](=[C:23]4[C:32](=[CH:31][CH:30]=3)[C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:20][CH:21]=[N:22]4)[N:25]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)ccnc4c3n2)cc1
Temperature: -78 °C
Yield: 37.2 %

Procedure:
To a three-necked flask of 250 ml, 0.97 g (6.16 mmol) of bromobenzene and 70 ml of THF were charged, then 3.9 ml (22 mmol) n-butyllithium (1.6M in Hexane solution) was dropped under stirring at −78° C. in a nitrogen atmosphere. The mixture was stirred for one hour at −78° C., and a solution of 1.86 g (5.6 mmol) 4,7-diphenyl-1,10-phenanthroline in 30 ml THF was dropped. Then the mixture was stirred at room temperature for overnight and was added with water. The organic layer was extracted with Dichloromethane and dried with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation. The product was purified by column chromatography on alumina using Dichloromethane/Hexane as eluent and dried in vacuo, obtaining white powder compound 0.85 g (yield of 37.21%).
Reaction SMILES: OC([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(C)C(=O)C.[CH3:13][C:14](=[O:18])[C:15](=[O:17])[CH3:16].C1([Mg]Br)C=CC=CC=1>>[CH3:16][CH:15]([C:14](=[O:18])[CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:17]
Reactant: CC(=O)C(C)(O)c1ccccc1
Reactant: CC(=O)C(C)=O
Agent: Br[Mg]c1ccccc1
Product: CC(O)C(=O)Cc1ccccc1
Yield: 30 %

Procedure:
The preparation of 3-hydroxy-3-phenylbutan-2-one by reaction of 2,3-butanedione with an appropriate Grignard reagent is described in an article by Lapkin and Golovkova in Zuhr. Obshchei Khim (J. Gen. Chem.) 19, 701-6 (1949) and abstracted in Chemical Abstracts 44, 1057h (1950). The reaction of biacetyl with phenylmagnesium bromide (31.4 g) gave 30% methylphenylacetylcarbinol. The reaction conditions are not specifically described but earlier in the abstract the solvent used was diethyl ether and the reactants were heated for 10 hours. The preparation is also referred to in Beilsteins Handbook (1969) at page 458.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2N)cc1
Yield: 88.5 %

Procedure:
1.56 g (4.5 mmol) of tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)phenylcarbamate are dissolved in 300 ml of a 1:1 ethanol:ethyl acetate mixture. The solution was mixed with H2 was passed through a cartridge containing Pd/C in a H-cube apparatus, then was evaporated to provide 1.26 g (88% yield) of tert-butyl 4-(2,3-diaminopyridin-4-yloxy)phenylcarbamate as a white foamy solid.