Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[CH:8]=[C:9](I)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[OH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC12CC3(C)OC(C)(CC(C)(O3)O1)P2C1C=CC=CC=1>O1CCCC1.O.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]>[C:1]([C:5]1[CH:6]=[C:7]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[CH:8]=[C:9]([C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([OH:22])[CH:24]=3)[CH:29]=2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Reactant: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C

Procedure:
In an embodiment, 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (1c) is reacted with 6-hydroxynaphthalen-2-ylboronic acid (compound (3a) in a mixture of tetrahydrofuran and water in the presence of potassium phosphate tribasic, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane, and tris(dibenzylideneacetone)dipalladium(0) to provide 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[CH:26]=[N:27][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:29](=[O:30])[C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[N:27][CH:26]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: COc1cncc(C(=O)O)c1
Product: COc1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2 ,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 5-methoxy-3-pyridinecarboxylic acid (CAN 20826-03-3) as starting materials; LC-MS (UV peak area/ESI) 97.8%, 438.0812 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([F:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Li+].O.[Al]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([F:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(F)cn2C(C)C
Agent: [Al]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1cc(F)c2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a 100 ml round bottom flask was added methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate (33.0 mg, 0.105 mmol), Methanol (700 μl), Tetrahydrofuran (THF) (1401 μl) and a magnetic stir bar. To the same was added lithium hydroxide, H2O (13.22 mg, 0.315 mmol) and the mixture was stirred at room temperature. Reaction progress was monitored by LCMS. LCMS(18 h) showed 60% conversion. The reaction was heated to 50° C. in an aluminum heating block with stirring. After complete conversion the solvent was removed in-vacuo and the remaining residue was dissolved with water (1 ml) and 1N HCl was added dropwise (9 drops) until precipitation stopped. The fine pale-yellow solid was collected by vacuum filtration. LCMS and HPLC showed 100% purity and NMR supports the desired structure. The product, 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylic acid (24 mg, 0.080 mmol, 76% yield), was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (br. s., 1H), 8.12 (t, J=1.89 Hz, 1H), 7.77 (d, J=2.27 Hz, 1H), 7.66 (d, J=1.77 Hz, 1H), 4.88 (qd, J=5.31, 6.65 Hz, 1H), 1.40 (d, 6H). MS(ES) [M+H]+ 300.1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]2[O:8][CH2:9][CH2:10][CH2:11][C:3]=12.C(N(CC)C(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>C(O)(C)C>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][C:2]1[N:7]=[N:6][CH:5]=[C:4]2[O:8][CH2:9][CH2:10][CH2:11][C:3]=12
Reactant: Clc1nncc2c1CCCO2
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(CNc2nncc3c2CCCO3)c(OC)c1
Temperature: 115 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture of 5-chloro-3,4-dihydro-2H-pyrano[2,3-d]pyridazine (150 mg, 0.879 mmol), N,N-diisopropylethylamine (0.154 mL, 114 mg, 0.879 mmol), and 2,4-dimethoxybenzylamine (294 mg, 1.76 mmol) in isopropanol (2 mL) was heated in a sealed tube 18 hours at 115° C. and then 4.5 hours at 145° C. before addition of excess 2,4-dimethoxybenzylamine (about 2 g, 12 mmol). The reaction was stirred at 145° C. for 18 hours. After cooling to room temperature, isopropanol was removed in vacuo. The crude was then treated with diethyl ether (30 mL). A tan solid was removed by filtration. The filtrate was washed twice with small amounts of saturated aqueous ammonium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography with a 0 to 10% methanol/dichloromethane gradient to afford the title compound (159 mg) as an amber foamy oil. MS (ESI) [m/e, (M)+]=301.8. 1H NMR (400 MHz, chloroform-d) δ ppm 8.22 (s, 1H), 7.35 (d, J=8.08 Hz, 1H), 6.36-6.56 (m, 2H), 4.73 (d, J=5.56 Hz, 2H), 4.37-4.56 (m, 1H), 4.11-4.24 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.27-2.31 (m, 2H), 2.04-2.11 (m, 2H).
Reaction SMILES: [F-].[K+].Br[CH2:4][C:5]([C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:14])=[O:6].C(OCC)(=O)C>CN(C)C=O>[CH3:13][C:12]1[C:7]2[C:5](=[O:6])[CH2:4][O:14][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(O)c1C(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2c1C(=O)CO2
Temperature: 25 °C
Reaction time: 96 h
Yield: 46.8 %

Procedure:
Potassium fluoride (0.85 g, 14.7 mmol) was added to a solution of 2-bromo-1-(2-hydroxy-6-methylphenyl)ethan-1-one (26b) (1.5 g, 6.5 mmol) in anhydrous dimethylformamide (25 mL). The reaction mixture was stirred at room temperature for 4 days. Ethyl acetate (75 mL) was added and the mixture was washed with brine (3×100 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5 to 80/20) to provide the desired benzofuran-3-one (26c) (450 mg, 3.04 mmol, 46%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[O:5][C@H:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:3]1[CH2:16][CH2:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[N:19]1.[O:29]1CCCC1.I([O-])(=O)(=O)=O.[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(C)(C)C>[CH:6]([O:5][C@H:4]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:3]([CH2:16][CH2:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[N:19]1)[C:2]([OH:1])=[O:29])=[O:7]
Reactant: O=c1c2ccccc2nnn1CC[C@@H]1[C@H](O)[C@H](O)O[C@@H]1CCc1ccccc1
Reactant: C1CCOC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=CO[C@H](CCc1ccccc1)[C@H](CCn1nnc2ccccc2c1=O)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the compound obtained from step b above (0.3 g) in tert-butanol:tetrahydrofuran (3 mL:3 mL) at 0° C., a solution of sodium metaperiodate (0.673 g in 3 mL of water) was added. The reaction mixture was stirred for 2 hours at the same temperature and potassium permanganate (0.025 g) was added at 0° C. After stirring the reaction mixture for an additional 6 hours at room temperature, the reaction mixture was evaporated and the residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure, to afford the title compound (0.3 g).
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>CC(C)=O>[OH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:2][CH2:3][CH3:4])[CH2:8][CH2:7]1
Reactant: CCCI
Reactant: OC1CCNCC1
Solvent: CC(C)=O
Product: CCCN1CCC(O)CC1

Procedure:
1-Iodopropane (22 ml) was added dropwise during 15 minutes to a stirred suspension of 4-hydroxypiperidine (20 g) in acetone (250 ml) and the resultant mixture was stirred at ambient temperature for 20 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and 2N aqueous sodium hydroxide solution. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to give 4-hydroxy-N-propylpiperidine as an oil (19.6 g); NMR Spectrum: (DMSOd6) 0.82 (t, 3H), 1.16 (m, 4H), 1.66 (m, 2H), 1.91 (m, 2H), 2.06 (t, 2H), 2.64 (m, 2H), 3.38 (m, 1H), 4.45 (d, 1H); Mass Spectrum: M+H+ 144.
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[H-].[Na+].[CH2:15](Br)[CH2:16][CH2:17][CH3:18].O>C1(C)C=CC=CC=1>[CH2:15]([O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCBr
Reactant: CCC=C(C)C(O)CCCCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC=C(C)C(CCCCC)OCCCC
Temperature: 80 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
20 g of 4-methyl-3-decen-5-ol dissolved in 100 ml of toluene are added dropwise at 80° C. over a period of 30 minutes to 6.2 g of a 55-60% sodium hydride dispersion in 100 ml of toluene. The mixture is stirred at 80° C. for 12 hours, then cooled to 50° C. and treated dropwise with a solution of 24.1 g of n-butyl bromide in 50 ml of toluene. The mixture is subsequently held at reflux temperature for 6 hours. For the working-up, the mixture is treated at room temperature with water, the organic layer is separated and washed neutral with water, dried and, after the addition of 0.2 g of potassium carbonate, fractionally distilled There are obtained 20.7 g of 5-butoxy-4 methyl-3-decene of boiling point 60° C./0.03 Torr, nD20 =1.4378. Odour: caramel-like, delicate, fatty-fruity.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:10])[CH:3]=1.Cl.Cl.BrC1C=CC(CN)=C(F)C=1.[C:23](Cl)(Cl)=[O:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]=[C:23]=[O:24])=[C:4]([F:10])[CH:3]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NCc1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A solution of 4-bromo-2-fluorobenzylamine (20.4 g, 0.10 mol) in toluene (300 ml) is saturated with gaseous hydrochloric acid at 25° C. The resulting suspension of the 4-bromo-2-fluorobenzylamine hydrochloride is heated at 100° C. Phosgene is passed in at this temperature. Stirring of the solution, which has eventually become clear, is continued at 100° C. for 1 hour, and the mixture is then refluxed to remove the gases phosgene and hydrogen chloride. The batch is worked up by distillation. 21.2 g of 4-bromo-2-fluorobenzyl isocyanate (boiling point 109° C. at 4 mbar) are obtained. Yield: 92.1% of theory.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[CH2:9][CH2:8][NH:7]1.[CH3:15][N:16]=[C:17]=[S:18]>C(#N)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[CH2:9][CH2:8][N:7]1[C:17](=[S:18])[NH:16][CH3:15]
Reactant: c1coc(C2NCCc3[nH]cnc32)c1
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)N1CCc2[nH]cnc2C1c1ccco1

Procedure:
Operating as in Example 14, 12 g of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (oil) are obtained from 18.4 g of histamine dihydrochloride and 16.6 ml of furfural. A solution of 1.89 g of 4-(2-furyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 1.1 g of methyl isothiocyanate in 20 ml of acetonitrile is refluxed for 5 h. The solution is cooled and filtered: 1.54 g of the title compound, m.p. 200°, are collected.
Reaction SMILES: Cl.C([NH:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:16][CH2:15]1)=[O:12])(=O)C1C=CC=CC=1>[OH-].[Na+]>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([NH:13][C:11]([NH2:10])=[O:12])[CH2:19][CH2:18]2)=[CH:23]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
1-benzoyl-3-[1-(2-[3-indolyl]ethyl)piperid-4-yl]urea hydrochloride (1.180 g.) was refluxed in 2N sodium hydroxide solution (20 ml) for 1 hour. The reaction mixture was cooled and the title compound was filtered off, (0.678 g., 86%) m.p. 212.2° (dec).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[C:7]([C:23]([OH:25])=O)=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:10][N:11]=1>C(Cl)(Cl)Cl.CN(C=O)C>[NH2:5][C:6]1[C:7]([C:23]([Cl:3])=[O:25])=[N:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:10][N:11]=1
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)Cl)n2)CC1
Temperature: 25 °C

Procedure:
Thionyl chloride (1.887 g, 1.157 mL, 15.86 mmol) was added to a solution of 3-amino-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carboxylic acid (1.25 g, 3.964 mmol) in chloroform (50 mL) and DMF (1 mL) and the resulting dark solution heated under reflux for 1 hour. The reaction mixture was allowed to cool to RT, concentrated in vacuo and taken through crude to the next stage.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6]2[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:3]=[C:2]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[CH:7]=2)[CH:9]=1
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Reactant: NCCc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Oc1ccc(CCNc2cc(-c3cccnc3)nc(-c3ccccn3)n2)cc1

Procedure:
4-Chloro-6-pyridin-3-yl-2-pyridin-2-yl-pyrimidine (Intermediate A) (1 eq, 0.74 mmol, 200 mg) and 4-(2-amino-ethyl)-phenol (1.2 eq, 0.89 mmol, 123 mg) are dissolved in iPrOH (3 ml). Then DIPEA (2 eq, 1.49 mmol, 196 mg) is added and the resulting mixture is heated using microwave radiation at 130° C. for 20 min. The solvent is removed in vacuo and the crude residue is purified by flash chromatography eluting with 0-5% MeOH in DCM yielding the title compound [M+H]+=370.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][N:22]=C[CH:20]=1)[C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]#[N:17].ClC1C=CC([N+:36]([O-])=O)=C2C=1C=CC=C2C#N.N1C=CC=C(N)N=1>>[CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[N:36][CH:20]=1)[C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]#[N:17]
Reactant: CN(Cc1ccncc1)c1ccc([N+](=O)[O-])c2c(C#N)cccc12
Reactant: N#Cc1cccc2c(Cl)ccc([N+](=O)[O-])c12
Agent: Nc1cccnn1
Product: CN(Cc1ccnnc1)c1ccc([N+](=O)[O-])c2c(C#N)cccc12
Yield: 24 %

Procedure:
5-(Methyl-pyridazin-4-ylmethyl-amino)-8-nitro-naphthalene-1-carbonitrile (24) was prepared in a manner analogous to that described above for the preparation of compound (10), except that compound (9) and pyridazyl amine compound (48) were used as starting materials. Compound (24) (24% yield) was isolated as a yellow foam by flash chromatography on silica, eluting CH2Cl2 :MeOH (25:1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:24][C:11]5([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]5)[CH2:10]4)[O:8][C:5]3=[CH:6][N:7]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)nc4)ncc3O1)C2

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 6-methylsulfonyl-pyridine-3-boronic acid pinacol ester following a procedure analogous to that described for Example 1; the reaction is conducted in a microwave oven at 140° C. LC (method 3): tR=1.07 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.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>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]([O:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:4][CH:5]=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Reactant: OB(O)c1ccc(Cl)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: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Temperature: 100 °C

Procedure:
5-Bromo-6-cyclobutoxy-nicotinic acid (example 78 a; 1.531 g, 5.63 mmol), 4-chloro-phenylboronic acid (968 mg, 6.19 mmol), potassium carbonate (1.56 g, 11.3 mmol) and tetrakis(triphenylphosphine)palladium (325 mg, 281 μmol) were suspended in THF (38 mL) and water (38 mL). The reaction mixture was stirred at reflux temperature (100° C.) over the weekend. THF was removed and the residue was partitioned between water (pH=2) and ethyl acetate; the organic phases were combined, dried with MgSO4 and concentrated in vacuo to obtain the title compound (quant.) as off-white solid; MS (ESI) 302.2 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].Cl.C1COCC1>O>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Reactant: Brc1c[nH]nc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.5 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, 5N aqueous HCl (1.25 mL/g of bromophenyl pyrazole starting material) was added followed by THF (12.5 mL/g) and water (2.5 mL/g). The mixture was heated to 50° C. to dissolve the precipitates, then cooled to 25° C. and filtered twice through a Darco zeta pad. To the filtrate was added TMT (5 mol %). The mixture was stirred at ambient temperature for 14 h and filtered again four times through the same Darco zeta pad employed in the previous filtration. The THF was removed by evaporation, and water (2.5 mL/g) and ethanol (2.5 mL/g) were added to precipitate the product, affording 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing 146 ppm of palladium.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:23][C:24](Cl)=[O:25]>C(Cl)Cl>[C:24]([C:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:1]=[CH:2][CH:3]=1)(=[O:25])[CH3:23]
Reactant: c1ccc2c(c1)c1ccccc1c1ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cccc2c3ccccc3c3ccccc3c12
Reaction time: 3 h
Yield: 97 %

Procedure:
Triphenylene (1 equivalent) is reacted at 0° C. with 2.1 equivalents of AlCl3 and 21.0 equivalents of CH3COCl in CH2Cl2. After stirring at room temp. for 3 hours, the reaction product (acetyltriphenylene) was obtained in 97% yield, and is used in step b).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:32])[CH:11]=1>>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:4]3[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:11][C:12]=2[F:32])=[O:17])[CH2:23][CH2:22]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 27.8 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (101 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (196 mg) described in Preparation Example 116 and by the reaction and treatment in the same manner as in Example 4, the title compound (62 mg) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][O:10][CH2:9]1)(C)(C)C.[ClH:16].O1CCOCC1>>[ClH:16].[CH3:13][C:12]1([CH3:14])[CH2:11][O:10][CH2:9][CH:8]1[NH2:7]
Reactant: CC(C)(C)OC(=O)NC1COCC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)COCC1N
Temperature: 25 °C

Procedure:
(4,4-Dimethyl-tetrahydro-furan-3-yl)-carbamic acid tert-butyl ester (70 mg, 0.32 mmol) was dissolved in 3 mL of cold 4M HCl/dioxane and gradually warmed to room temperature with stirring. After the starting material was judged to be consumed by thin layer chromatography, the reaction mixture was concentrated to afford 4,4-dimethyl-tetrahydro-furan-3-ylamine hydrochloride which was used with further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2].[CH:10](=O)[CH3:11].C(O)(=O)C.C([O-])(=O)C.[NH4+]>CN(C)C=O.[C].[Pd]>[C:1]([CH:3]([CH2:10][CH3:11])[C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])#[N:2]
Reactant: CC=O
Reactant: N#CCC(=O)NC(N)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCC(C#N)C(=O)NC(N)=O

Procedure:
Cyanoacetylurea (38.7 g) was suspended in N,N-dimethylformamide (77.4 ml), and acetaldehyde (18.8 ml), acetic acid (3.43 ml) and ammonium acetate (2.31 g) were added. This suspension was subjected to catalytic hydrogenation in the presence of 10% palladium carbon (0.78 g, 50% wet product) under normal pressure at 30° C. for 5 hours. The catalyst was filtered off. Water (350 ml) was added to the filtrate to allow precipitation of crystals. The crystals were collected by filtration to give crystals of N-(2-cyanobutanoyl)urea (yield 24.2 g). 1H-NMR(270 MHz, DMSO-d6)δ 0.99(3H,t), 1.75-1.95(2H,m), 3.86(1H,t), 7.42(2H,br), 10.50(1H,br)