Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([O:20]C)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylate (0.55 g, 1.8 mmol), MeOH (50 mL) and 2N aq. NaOH (4 mL) was stirred at 50° C. for 3 h. After cooling the mixture was concentrated in vacuo and acidified with 1N aq. HCl to pH<4 and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated to yield a white solid. LC-MS: 289.3 [M−1]−; 1H NMR (400 MHz, CDCl3): δ 8.61 (t, 1H, J=1.6 Hz), 8.59 (t, 1H, J=1.6 Hz), 8.39 (t, 1H, J=1.6 Hz), 7.58 (d, 2H, J=8.0 Hz), 7.33 (d, 2H, J=8.0 Hz), 3.15 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](Br)[CH:5]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17]C(=O)C)[CH3:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:21])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: CCOC(=O)CC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cc(C(=O)OC)ccc1C
Temperature: 90 °C
Yield: 10.7 %

Procedure:
3-Bromo-4-methyl-benzoic acid methyl ester (20.0 g, 87.31 mmol) was dissolved in 220 mL toluene, and 3-oxo-butyric acid ethyl ester (25.0 g, 192.08 mmol), K3PO4 (102 g, 480 mmol), biphen-2-yl-P(t-Bu)2 (2.60 g, 8.73 mmol), and palladium diacetate (980 mg, 4.36 mmol) were added. The reaction mixture was evacuated and purged with argon, and then heated to 90° C. for 15 hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (10%-15% EtOAc/hexanes) to provide 2.20 g of 3-ethoxycarbonylmethyl-4-methyl-benzoic acid methyl ester, MS (M+H)=237.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([CH3:21])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:16])=[O:15])[NH2:10].N1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[CH3:21][C:12]1[CH:11]=[C:9]([NH:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=[C:7]([CH3:6])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(NS(C)(=O)=O)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of 1.7 g (14.8 mmol) of methanesulphonyl chloride in 5 ml of anhydrous tetrahydrofuran is added dropwise to a solution, maintained under a nitrogen atmosphere, of 2.7 g (11.0 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline and 1.6 g (20.2 mmol) of pyridine, dried over potassium hydroxide, in 50 ml of anhydrous tetrahydrofuran. The mixture is stirred for 6 h 30 min at room temperature and is then refluxed for 4 h. 1.1 g (9.60 mmol) of methanesulphonyl chloride are then added and refluxing is continued for 1 h 30 min. A further 1.1 g (9.60 mmol) of methanesulphonyl chloride are added and refluxing is continued for 4 h. After cooling, the reaction medium is poured into ice-cold water and extracted with methylene chloride. The combined organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is crystallized from a cooled mixture of hexane and methylene chloride and is purified by recrystallization from a mixture of hexane and ethyl acetate, to give 1.1 g (yield=22%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]methanesulphonamide containing 14 mol % of ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:19]=[C:18]([CH3:26])[N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH:34]2[CH2:38][CH2:37][CH2:36][NH:35]2)[CH2:30][CH2:29]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:26][C:18]1[N:17]=[C:16]([C:10]2[N:11]=[C:12]3[C:13]4[CH:14]=[N:15][C:2]([N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH:31]5[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]5)=[CH:3][C:4]=4[O:5][CH2:6][CH2:7][N:8]3[CH:9]=2)[N:20]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:19]=1
Reactant: CN1CCC(C2CCCN2)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4C4CCN(C)CC4)cc2OCC3)n(CC(F)(F)F)n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 11.9 %

Procedure:
A mixture of 12-chloro-4-[3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (50.0 mg, 0.130 mmol), 1-methyl-4-(pyrrolidin-2-yl)piperidine (30.0 mg, 0.178 mmol), Pd(P-t-Bu3)2 (6.00 mg, 0.0120 mmol), and NaOt-Bu (40.0 mg, 0.412 mmol) in toluene (20.0 mL) in a seal tube was stirred at 110° C. for 3 h. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.5% NH4HCO3 to afford 253 (8 mg, 12% yield) as white solid. LCMS (ESI): RT=4.70 min, m/z: 517.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.66 (s, 1H), 5.85 (s, 1H), 5.70 (dd, J=8.5 Hz, J=23.5 Hz, 2H), 4.46-4.43 (m, 4H), 4.06 (s, 1H), 3.38 (s, 1H), 3.26 (s, 1H), 2.09 (s, 3H), 1.95 (s, 9H), 1.84-1.72 (m, 2H), 1.52-1.34 (m, 3H), 1.19-1.12 (m, 2H)
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:23][C:24]1[N:25]([C:2]2[O:3][C:4]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:6]=2)[CH:26]=[CH:27][N:28]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-chloro-4-(4-trifluoromethylphenyl)-5-oxazolepropionate (1.33 g), 2-methylimidazole (1.33 g), potassium carbonate (2.00 g), and N-methylpyrrolidone (10 ml) was stirred at 110° C. for 2 hours. The reaction mixture was poured into ice water (100 ml). The precipitated crystals were filtered, washed with water and air-dried to give crystals of methyl 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropionate. Recrystallization from ethyl acetate-hexane gave pale yellow prisms (1.07 g, 71%). Melting point 94-95° C.
Reaction SMILES: Cl[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][Mg]Br.[Cl-].[NH4+].[OH-].[Na+]>C1COCC1.[Cu]Br>[F:12][C:11]1[C:2]([CH3:15])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2
Reactant: COc1ccc2cc(F)c(Cl)nc2c1
Reactant: C[Mg]Br
Agent: [Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2cc(F)c(C)nc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
2-Chloro-3-fluoro-7-methoxyquinoline (210 g, 1 mmol), (prepared as described for the starting material in Example 157), in anhydrous THF (1 ml) was added to a mixture of copper(I)bromide (570 mg, 4.0 mmol) and methylmagnesium bromide (3.0M solution in diethyl ether, 2.7 ml, 8 mmol) in anhydrous THF (20 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., allowed to warm to ambient temperature and then stirred for a further 18 hours. Saturated aqueous ammonium chloride solution and 5N aqueous sodium hydroxide solution (pH 12) were added and the product extracted with ethyl acetate (3×). The organic solution was washed with water, brine, dried (MgSO4) and evaporated to dryness to yield 3-fluoro-7-methoxy-2-methylquinoline (0.17 g, 91%).
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[N:11]1([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[N:11]1[CH2:16][CH2:15][N:14]([CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:13][CH2:12]1
Reactant: COC(=O)CCCC(C)=O
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCC(C)N1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A mixture of 1.10 g of methyl 5-oxo-hexanoate as synthesized in above step 7-14-A, 1.36 g of 2-piperazin-1-ylquinoline, 20 mg of p-toluenesulfonic acid and 50 ml of toluene was heated under reflux for 16 hours, and the formed water was azeotropically removed. The solvent was concentrated under reduced pressure. The residue was dissolved in 50 ml of tetrahydrofuran, and the solution was stirred at room temperature for an hour while hydrogen chloride gas was introduced thereinto. Then 380 mg of sodium cyanotrihydroborate as dissolved in 10 ml of methanol was added, followed by 2 hours' stirring. To the solution, 0.1N aqueous potassium hydroxide was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:n-hexane=1:1) to provide 977 mg (45%) of methyl 5-(4-quinoline-2-ylpiperazin-1-yl)hexanoate.
Reaction SMILES: C([C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:9]=1[OH:10])(O)=O.NC1C=CC=CC=1.Cl>O>[OH:10][C:9]1[N:8]2[N:11]=[CH:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[C:7]2[N:6]=[CH:5][CH:4]=1
Reactant: CC(C)(c1ccccc1)c1ccc(-c2cnn3c(O)c(C(=O)O)cnc23)cc1
Agent: Cl
Solvent: Nc1ccccc1
Solvent: O
Product: CC(C)(c1ccccc1)c1ccc(-c2cnn3c(O)ccnc23)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To 6-carboxy-7-hydroxy-3-[4-(2-phenylpropan-2-yl)phenyl]pyrazolo[1,5-a]pyrimidine (950 mg) was added aniline (7.0 ml), and the mixture was stirred at 100° C. for 3 hours. To the reaction mixture was added water (20 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtration, washed with 30% methanol-water to give the title compound (830 mg) at a quantitative yield.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1>CO.C(Cl)Cl.[Pt](=O)=O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccnc(-c2ccc(Cl)cc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCNC(c2ccc(Cl)cc2)C1
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Methyl 2-(4-chlorophenyl)isonicotinate hydrochloride (4.46 g, 15.69 mmol) was dissolved in MeOH (40 mL) and platinum(IV) oxide (0.356 g, 1.57 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 1 h. The catalyst was filtered off and washed with MeOH and the eluate evaporated leaving a brown solid. The solid was dissolved in DCM and washed with 1 M K2CO3 and brine. The organic layer was dried through a phase-separator and evaporated. The residue was dissolved in DCM and added onto SCX-2 cation exchange columns (4*10 g columns. Each column was washed with DCM, MeOH and then eluted with NH3/MeOH (1 CV each). The NH3/MeOH layer was evaporated yielding methyl 2-(4-chlorophenyl)piperidine-4-carboxylate (3.13 g, 79%). MS m/z 254 (M+H)+
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:12]=2)[C:7](F)=[N:8][CH:9]=1.[NH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:12]=2)[C:7]([NH:38][C:39]2[CH:44]=[N:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[N:8][CH:9]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(OC(F)F)cnc3F)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(OC(F)F)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of 4-(5-(difluoromethoxy)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.030 g, 0.059 mmol) and 5-amino-2-methoxypyridine (Aldrich) (8.06 μL, 0.065 mmol), in THF (1 mL) was cooled to 0° C. under N2 and treated with lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydriofuran (Aldrich) (0.039 mL, 0.235 mmol). The dark red mixture was stirred at 0° C. for 1 h and then partitioned between EtOAc and sat. NH4Cl. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (12 g, 10% to 20% EtOAc in hexanes) to give the product as a yellow solid (0.022 g). m/z (ESI, +ve ion) 616.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.65 (s, 1H); 8.63 (br. s., 1H); 8.26 (s, 1H); 8.17 (br. s., 1H); 7.89 (d, J=8.77 Hz, 1H); 7.11-7.25 (m, 4H); 6.78-6.95 (m, 4H); 6.72 (d, J=8.77 Hz, 1H); 6.11-6.69 (m, 1H); 4.74-4.93 (m, 4H); 3.94 (s, 3H); 3.81 (d, J=8.48 Hz, 6H); 2.59 (s, 3H).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH2:21][CH2:22][NH2:23])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].[CH2:24]([CH2:28][C:29](=O)[CH3:30])[C:25]([CH3:27])=O.[Al]>CN(C)P(=O)(N(C)C)N(C)C>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH2:21][CH2:22][N:23]2[C:29]([CH3:30])=[CH:28][CH:24]=[C:25]2[CH3:27])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: CC(=O)CCC(C)=O
Reactant: NCCc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Al]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ccc(C)n1CCc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 3-sulphamoyl-4-phenoxy-5-[β-aminoethyl]-benzoic acid (5.0 g=1.35 mmols; see Example 3 for the preparation), acetonylacetone (1.85 g, approximately 16.2 mmols) and hexamethylphosphoric acid triamide (Hexametapol; 25 ml) is warmed at 100° for 30 minutes under N2 in an apparatus which has been protected against incident light by covering it with aluminium foil, and the reaction solution is worked up as follows, with strict exclusion of light throughout: pouring into ice-water (50 ml) and extracting with ethyl acetate, washing the extract with water, drying and filtering and evaporating the filtrate. The crude product is recrystallised from chloroform/cyclohexane with the addition of active charcoal and gives pale orange-coloured, light-sensitive crystals, melting point>210° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)(=[O:11])[CH3:10]
Reactant: Cc1ccnc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C)ccn1

Procedure:
To a solution of 2-amino-4-methylpyridine (20 g) in acetic acid (80 ml) was added acetic anhydride and the resulting solution was refluxed for 3 h. The solution was concentrated in vacuo and the solid obtained was triturated with about 50 ml of water and carefully neutralised with solid sodium bicarbonate. The solid was filtered, washed with water and dried under vacuum to give the crude title compound as a white solid (20 g).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:18])[N:6]([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[C:5](=[O:18])[N:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1cccc([N+](=O)[O-])c1=O

Procedure:
3.73 g (14.7 mmol) of tert-butyl 2-(3-nitro-2-oxopyridin-1(2H)-yl)acetate are dissolved in 10 mL of dichloromethane and treated with 40 mL of trifluoroacetic acid. It is stirred at
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=O)[CH2:10][N:11]([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:12][N:11]([CH3:13])[CH2:10][CH2:9][NH:8][C@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: CN(C)CC(=O)N[C@H]1CC[C@@H](C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCN[C@H]1CC[C@@H](C)CC1

Procedure:
Using 4.8 g of N-(cis-4-methylcyclohexyl)-2-dimethylaminoacetamide (Example 109), 1.8 g of lithium aluminum hydride, 150 ml of THF, and 5 g of sodium sulfate decahydrate, a reaction similar to that performed in Example 78 was carried out. As a result, 2.9 g of N-(2-dimethylaminoethyl)-cis-4-methylcyclohexylamine was obtained as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: CCN=C=NCCCN(C)C.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[CH3:29][NH:30][O:31][CH3:32].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:30]([O:31][CH3:32])[CH3:29])=[O:19])=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(O)c(CN2CCOCC2)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(O)c(CN2CCOCC2)c1
Reaction time: 48 h

Procedure:
EDCI (4.44 g, 23.18 mmol) was added portionwise to a solution of 4-hydroxy-3-(morpholinomethyl)benzoic acid (5 g, 21.07 mmol), N,O-dimethylhydroxylamine (2.67 g, 27.40 mmol), DIPEA (4.05 mL, 23.18 mmol) and HOBt (3.55 g, 23.18 mmol) in DMF (25 mL) whilst maintaining the temperature below 10° C. The mixture was stirred for 48 h, diluted with EtOAc (200 mL), washed with saturated NaHCO3 (200 mL), water (2×100 mL) & brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography on silica with EtOAc as eluent to give the sub-title compound as a colourless oil. Yield: 3.20 g
Reaction SMILES: C[Si](C)(C)O[C:4]([CH3:20])=[C:5]([C:13]([O:15][Si](C)(C)C)=[CH2:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl[C:24]1[C:25](=[O:36])[C:26]2[C:31]([C:32](=[O:34])[CH:33]=1)=[CH:30][CH:29]=[CH:28][C:27]=2[OH:35]>C1(C)C=CC=CC=1>[OH:15][C:13]1[C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:20])[C:24]2[C:25](=[O:36])[C:26]3[C:31]([C:32](=[O:34])[C:33]=2[CH:14]=1)=[CH:30][CH:29]=[CH:28][C:27]=3[OH:35]
Reactant: O=C1C=C(Cl)C(=O)c2c(O)cccc21
Reactant: C=C(O[Si](C)(C)C)C(C(=O)OC(C)(C)C)=C(C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)OC(C)(C)C)c(O)cc2c1C(=O)c1c(O)cccc1C2=O
Temperature: 25 °C
Yield: 44.9 %

Procedure:
20.1 g (58.5 mmol, 2.0 eq.) of tert-butyl 3-trimethylsilanyloxy-2-(1-trimethylsilanyloxyvinyl)but-2-enate and 5.05 g (24.3 mmol) of 2-chloro-8-hydroxy-1,4-naphthoquinone (Giles & Roos, J. Chem. Soc Perkin 11976, 2057-2060) were dissolved in 125 ml of anhydrous toluene and heated at reflux for 24 hours. The solvent was then removed on a rotary evaporator, and 150 ml of THF were added to the brown oily residue. After the addition of 10 ml of water, the mixture was stirred at RT for 1d. About 50 ml of silica gel were then added, and the mixture was freed from the solvent. The crude product, absorbed on the silica gel, was then filled into a frit filled with silica gel and eluted using DCM as mobile phase. The product band, which has an intensive yellow color and is easy to isolate, was collected separately, and, after removal of the solvent, it was possible to isolate 3.8 g (10.9 mmol, 45%) of the brown tert-butyl 3,8-dihydroxy-1-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate which still contained small amounts of impurities; however, these could be removed completely in the next synthesis step.
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(c1ccc(O)cc1)C1CCCCCC1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1

Procedure:
In analogy to the procedure of Example III, the title compound is prepared from 10 g (45.8 mmol) of the compound from Example XII, 10.3 g (48.1 mmol) of 2-chloromethylquinoline hydrochloride and 13.8 g (0.10 mol) of potassium carbonate.
Reaction SMILES: C1(C2N=CN(C3CCNCC3)C=2C2C=CN=CN=2)C=CC=CC=1.ClCC1N=CC=CN=1.F[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:40]=[CH:41][N:42]([CH:51]3[CH2:56][CH2:55][N:54]([CH2:57][C:58]4[N:63]=[CH:62][CH:61]=[CH:60][N:59]=4)[CH2:53][CH2:52]3)[C:43]=2[C:44]2[CH:49]=[CH:48][N:47]=[C:46](N)[N:45]=2)=[CH:35][CH:34]=1>>[C:36]1([C:39]2[N:40]=[CH:41][N:42]([CH:51]3[CH2:56][CH2:55][N:54]([CH2:57][C:58]4[N:63]=[CH:62][CH:61]=[CH:60][N:59]=4)[CH2:53][CH2:52]3)[C:43]=2[C:44]2[CH:49]=[CH:48][N:47]=[CH:46][N:45]=2)[CH:35]=[CH:34][CH:33]=[CH:38][CH:37]=1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ncccn3)CC2)n1
Agent: ClCc1ncccn1
Agent: c1ccc(-c2ncn(C3CCNCC3)c2-c2ccncn2)cc1
Product: c1ccc(-c2ncn(C3CCN(Cc4ncccn4)CC3)c2-c2ccncn2)cc1

Procedure:
The title product was prepared by reaction of 4-(4-phenyl-1-piperidin-4-yl-1H-imidazol-5-yl)pyrimidine (C23) with 2-(chloromethyl)pyrimidine according to the general procedure for the synthesis of 4-{4-(4-fluorophenyl)-1-[1-(pyrimidin-2-ylmethyl)piperidin-4-yl]-1H-imidazol-5-yl}pyrimidin-2-amine (3) in Example 3. In this case, after the reaction mixture was concentrated, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification was effected via silica gel chromatography (Eluant: 25% methanol in ethyl acetate) to provide the product as a white solid. Yield: 63 mg, 0.16 mmol, 62%. APCI m/z 398.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.11-2.20 (m, 4H), 2.23-2.32 (m, 2H), 3.13 (br d, J=12 Hz, 2H), 3.87 (s, 2H), 4.78 (tt, J=11, 4.5 Hz, 1H), 7.18 (dd, J=5.3, 1.5 Hz, 1H), 7.22 (t, J=4.9 Hz, 1H), 7.29-7.34 (m, 3H), 7.41-7.44 (m, 2H), 7.85 (s, 1H), 8.53 (br d, J=5.4 Hz, 1H), 8.76 (d, J=4.9 Hz, 2H), 9.29 (br d, J=1.5 Hz, 1H).