Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=1>CS(C)=O>[Br:21][C:22]1[CH:23]=[C:24]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:25]=[CH:26][CH:27]=1
Reactant: CN(C)c1ccc2c(=O)[nH]ccc2c1
Reactant: Brc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)c1ccc2c(=O)n(-c3cccc(Br)c3)ccc2c1
Temperature: 150 °C
Yield: 61.9 %

Procedure:
6-Dimethylamino-2H-isoquinolin-1-one (39 mg, 0.21 mmol), cuprous iodide (8.0 mg, 0.041 mmol), and potassium carbonate (29 mg, 0.21 mmol) were deposited in sealed vessel. 3 mL DMSO and 1,3-dibromobenzene (98 mg, 0.42 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 5 hours. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (25% ethyl acetate/hexanes) to yield 2-(3-Bromo-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (45 mg, 0.13 mmol). MS (ESI) 345.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:30]=[C:29]([O:31][CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[CH:28]=[CH:27][CH:26]=2)[N:4]=1)[CH3:2].[ClH:42]>C(OCC)(=O)C>[ClH:42].[ClH:42].[NH2:34][CH2:33][CH2:32][O:31][C:29]1[N:30]=[C:25]([CH2:24][N:5]2[C:6]3[C:11](=[C:10]([NH:12][C:13]([C:15]4[N:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]5=[N:17][CH:16]=4)=[O:14])[CH:9]=[CH:8][CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCc1nn(Cc2cccc(OCCNC(=O)OC(C)(C)C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2cccc(OCCN)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of tert-butyl 2-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yloxy)ethylcarbamate (21.9 mg, 0.0394 mmol) in ethyl acetate was added hydrogen chloride (1 mL; 4M in dioxane). The mixture was stirred for 30 minutes and the solvent was removed under reduced pressure to give N-(1-((6-(2-aminoethoxy)pyridin-2-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (14.3 mg; 69%). MS (APCI), positive scan, m/z=456.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH2:13].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1N
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Yield: 72.2 %

Procedure:
(E)-3-(2-Amino-5-chlorophenyl)-acrylic acid methyl ester (Gonzalez-Zamora, Eduardo et al Chem. Comm. (2001), (17), 1684-1685.) (1.7 g, 8.0 mmol) in THF (6.5 ml) was combined with (BOC)2O (6.98 g9 32.0 mmol) and refluxed for 4 hours. THF was evaporated and the residue purified via chromatography (SiO2, acetone/hexanes 5/95) followed by recrystallisation from hexanes to yield the title compound as yellow crystals (1.8 g; 72%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][C:33]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)c1ccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3ccccc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(4-(dimethylamino)phenyl)benzoate and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, ethyl acetate and water were added and pH was adjusted to pH 6.5 with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. Methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 3.8 mg of 2-(benzamido)-4-(4-(dimethylamino)phenyl)benzoic acid as pale yellow solid.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[CH3:12][O:13][C:14](=[O:19])[C:15]([NH2:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.O>[CH3:12][O:13][C:14](=[O:19])[C:15]([NH:18][CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)([CH3:17])[CH3:16]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: COC(=O)C(C)(C)N
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)NCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.4 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (11.0 g, 31.7 mmol) and 2-amino-2-methyl-propionic acid methyl ester (5.80 g, 49.5 mmol) in DMF (220 mL) was treated with triethylamine (9.0 mL, 18.5 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (400 mL) and then extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (3.87 g, 40%) as a light yellow solid: MS (ESI) m/e 302 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CON(C)C(=O)C1CCN(c2ccccn2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C1CCN(c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
A solution of 1,4-dibromobenzene (0.223 g, 0.944 mmol) in anhydrous THF (3.0 ml) was cooled to −78° C. To the cooled solution, n-butyllithium (1.6 M in hexanes, 0.47 ml, 0.746 mmol) was added dropwise, and the reaction stirred at −78° C. for 45 minutes. A solution of the 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid methoxy-methyl-amide (0.124 g, 0.497 mmol) in anhydrous THF (3.0 ml) was then added dropwise to the reaction. The reaction stirred at −78° C. for 3 hours and at 0° C. until complete. The reaction was quenched at 0° C. by the addition of 1 N HCl (5 ml) and saturated NaHCO3 (7.5 ml). The mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography using 3-10% acetone in hexanes, yielding the product (0.1220 g, 71%) as a colorless oi: 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=4.9, 1.2 Hz, 1H), 7.81 (m, 2H), 7.61 (m, 2H), 7.46 (m, 1H), 6.67 (d, J=8.7 Hz, 1H), 6.59 (dd, J=6.7, 5.1 Hz, 1H). 4.33 (dt, J=13.1, 3.1 Hz, 2H), 3.42 (m, 1H), 3.14 (m, 2H), 1.93 (d, J=13.2, 2.2 Hz, 2H), 1.82 (m, 2H); 13C NMR (100 MHz, CDCl3) 201.20, 159.20, 147.87, 137.53, 134.57, 132.28, 129.80, 128.20, 113.09, 107.34, 45.01, 43.76, 28.01; m/z calcd. for C17H17BrN2O: 344.05 found: (M+H)+347.1; HPLC retention time=3.205 min (wavelength 254 nm), purity=100%.
Reaction SMILES: C(O)=O.[C:4]1([CH:10]2[O:15]C(=O)CC(=O)[O:11]2)C=CC=CC=1.[CH:18](=O)[C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1>C(N(CC)CC)C>[CH3:23][O:22][C:21]1[CH:20]=[C:19]([CH2:18][CH2:4][C:10]([OH:15])=[O:11])[CH:28]=[CH:27][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C1CC(=O)OC(c2ccccc2)O1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1 were added to a mixture of 4.8 g (0.025 mol) of 2-phenyl-1,3-dioxane-4,6-dione (m.p.: 148° C.) and 4.15 g (0.025 mol) of veratraldehyde. The reaction was carried out according to Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=2)[NH:10][CH:11]([C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=2)[CH3:12])[C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC(C)c2cc(F)c(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2cc(F)c(F)c(F)c2)c2cccc(N)c2)cc1
Yield: 91.3 %

Procedure:
Following a similar procedure to that described in Example (1b), 3.34 g of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[1-(3,4,5-trifluorophenyl)ethyl]amine [prepared as described in step (a) above], 3.81 g of nickel chloride hexahydrate and 1.22 g of sodium borohydride were reacted, to obtain 2.83 g of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[NH:8][C:7](=[O:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:5]1=[O:18].N1C=CN=C1.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C=O)C.[Cl-].[Na+].O.C(OCC)C>[C:37]([Si:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[O:1][CH2:2][CH2:3][CH:4]1[NH:8][C:7](=[O:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:5]1=[O:18])([CH3:40])([CH3:38])[CH3:39]
Reactant: Cc1ccc(CN2C(=O)NC(CCO)C2=O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(CN2C(=O)NC(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 49.2 %

Procedure:
A solution of crude 5-(2-hydroxy-ethyl)-3-(4-methyl-benzyl)-imidazolidine-2,4-dione (24.68 g, 99.4 mmol) and imidazole (10.15 g, 0.149 mol) in DMF (250 mL) was treated dropwise with tert-butyldiphenylsilyl chloride (27.37 g, 99.6 mmol) and then stirred at room temperature under N2 for 7 h. The reaction was worked up extractively with aqueous 1 N HCl (300 mL), diethyl ether and brine and the organic layer was dried (MgSO4) and the solvent removed in vacuo to give crude product which was purified by flash chromatography using a gradient of 5:1 to 2:1 hexanes:EtOAc to afford 23.82 g (49%) of 5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-imidazolidine-2,4-dione. MS (ES+) Calc'd for C29H35N2O3Si (M+1) 487. Found m/z 487 (100%). 1H NMR.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1.[I:25]I>C1COCC1>[Cl:16][C:17]1[N:18]=[N:19][C:20]([O:23][CH3:24])=[C:21]([I:25])[CH:22]=1
Reactant: II
Reactant: COc1ccc(Cl)nn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nnc(Cl)cc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flask containing THF (350 mL) at −30° C. under nitrogen was added 26 mL (76.1 mmol. 2.93M n-BuLi in hexanes. 2,2,6,6-tetramethylpiperidine (12.9 mL, 76.1 mmol) was then added dropwise and the resulting solution was allowed to warm to 0° C. over 50 min. The solution was then cooled to −78° C. and there was added dropwise 3-chloro-6-methoxypyridazine (1) (5.0 g, 34.6 mmol) in 50 mL THF and the resulting solution stirred at −78° C. for 30 min. Iodine (9.3 g) was then added in three portions and the solution stirred at −78° C. for 2 hrs. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate solution and allowed to warm to room temperature, then diluted with CH2Cl2 and water, the CH2Cl2 layer separated, the aqueous layer extracted once more with CH7Cl2, and the combined CH2Cl2 layers washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica) eluting with hexane/ethyl acetate to give desired product 2, 5.6 g (60%), ˜95% desired regioisomer.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:31]1[CH2:32][CH2:33][N:28]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:29][CH2:30]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCN(Cc2ccccc2)CC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and N-benzylpiperazine (0.54 mL; 3.1 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(4-benzyl-piperazin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (50 mg, 38%) as an off-white powder. ES-HRMS m/e calcd for C26H35N5O (M+H+) 434.2915, found 434.2910.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[NH:7][CH2:8][CH3:9].[CH3:16][CH:17]([CH2:21][S:22][CH3:23])[C:18](O)=[O:19].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClC(Cl)C>[Cl:1][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N:7]([CH2:8][CH3:9])[C:18](=[O:19])[CH:17]([CH3:16])[CH2:21][S:22][CH3:23]
Reactant: CSCC(C)C(=O)O
Reactant: CCNc1sc(-c2cccnc2)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCN(C(=O)C(C)CSC)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
To a solution of (4-chloro-2-pyridin-3-yl-thiazol-5-yl)-ethylamine (800 mg, 3.33 mmol) in dichloroethane (30 mL) was added 2-methyl-3-methylsulfanyl-propionic acid (prepared according to literature reference J. Org. Chem. 1996, 51, 1026-1029) (894 mg, 6.66 mmol) and N,N-dimethylaminopyridine (814 mg, 6.66 mmol) followed by triethylamine (0.2 mL, 1.44 mmol). To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 9.99 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford a beige solid (715 mg, 60%): mp 79-81° C.; 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.7 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.27-8.13 (m, 1H), 7.42 (dd, J=8.0, 4.9 Hz, 1H), 3.90 (bs, 1H), 3.69 (bs, 1H), 2.80 (bs, 2H), 2.47 (bs, 1H), 2.02 (s, 3H), 1.21 (q, J=7.3 Hz, 6H); ESIMS m/z 356 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH3:17]>>[CH2:16]([N:18]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15])[CH3:17]
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CCNCc1ccncc1
Product: CCN(Cc1ccncc1)C(=O)c1cnoc1-c1ccc(C)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-(ethylaminomethyl)-pyridine (8.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (7.8 mg). HRMS calcd for C19H19N3O2: 321.1477, found 321.1485.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:7]1.Cl.[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[CH2:13][CH:8]1[C:9](=[O:12])[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[Cl:2])[CH2:7]1
Reactant: CO
Reactant: O=C(O)CC1CN(Cc2ccccc2Cl)CCC1=O
Agent: Cl
Product: COC(=O)CC1CN(Cc2ccccc2Cl)CCC1=O

Procedure:
A solution of 30 g. of this hydrochloride in 300 cc. methanol saturated with gaseous hydrogen chloride is stirred at ambient temperature for 3 hours. The reaction mixture is then evaporated in a vacuum at a temperature below 50° C. and the residue is poured into water, rendered basic by the addition of sodium bicarbonate and extracted with methylene chloride. The organic extracts are washed with water, dried with anhydrous sodium sulphate and evaporated to dryness. The yellow resin obtained is used, without further purification, for the following stage.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:20][CH:19]=1)([C:11]([O:13]CC)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].O>C(O)C>[CH2:9]([O:8][C:6]([C:5]([CH2:3][CH3:4])([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:22][CH:23]=1)[C:11]([OH:13])=[O:12])=[O:7])[CH3:10]
Reactant: CCOC(=O)C(CC)(CCc1ccc(OCCCCc2ccccc2)cc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC)(CCc1ccc(OCCCCc2ccccc2)cc1)C(=O)O
Yield: 53.4 %

Procedure:
Potassium hydroxide (14 g) was added to a solution of diethyl 2-ethyl-2-(2-(4-(4-phenylbutyloxy)phenyl)ethyl)malonate (46 g) in ethanol (300 ml) and the mixture was refluxed under heating for 3.5 hours. The reaction mixture was poured into water and washed with isopropyl ether. After being acidified to pH 1 with concentrated hydrochloric acid, the aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure to give the subject compound (23 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(Cl)Cl.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>CC#N.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([O:1][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[C:8]([CH3:10])[C:5]=1[CH:6]=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(O)cc(C)c1C=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cc(Oc2ccccc2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A suspension of 4-hydroxy-2-methoxy-6-methyl-benzaldehyde (1.00 g, 6.02 mmol), powdered 4A molecular sieves (4 g) in CH3CN (40 mL) and DCM (40 mL) was treated with phenylboronic acid (1.47 g, 12.06 mmol), followed by copper (II) acetate (1.09 g, 6.00 mmol). Pyridine (2.40 mL, 29.70 mmol) was added to the green suspension and the resulting mixture was stirred at rt overnight in an open flask. The mixture was filtered through a pad of Celite and the filtrate was concentrated to a green oil. The residue was purified by column chromatography (SiO2, EtOAc/hexanes; 1:9) to afford 2-methoxy-6-methyl-4-phenoxy-benzaldehyde (0.92 g, 63%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 7.41 (t, J=7.42 Hz, 2H), 7.22 (t, J=7.42 Hz, 1H), 7.08 (d, J=7.42 Hz, 2H), 6.43 (d, J=2.34 Hz, 1H), 6.31 (d, J=2.34 Hz, 1H), 3.83 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: ClC1C=CC(C2C(C3C=CN=C(N[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:21]=4)N=3)=CNN=2)=CC=1.[CH3:35][C:36]([O:39][C:40]([NH:42]C1C=CC(O)=CC=1)=[O:41])([CH3:38])[CH3:37]>>[C:36]([O:39][C:40](=[O:41])[NH:42][C:25]1[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[CH:23][CH:24]=1)([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: CN1CCC(COc2cccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)c2)CC1
Product: CN1CCC(COc2ccc(NC(=O)OC(C)(C)C)cc2)CC1

Procedure:
[4-(1-Methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester is prepared as described for [3-(1-methyl-piperidin-4-ylmethoxy)-phenyl]-carbamic acid tert-butyl ester (see Example 27) using 4-N-BOC-Aminophenol (AstaTech; B56686). Title compound: ES-MS: 321.1 [M+H]+; single peak at tR=4.55 min (System 1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[C:11](=O)([O-])[O-].[Cs+].[Cs+].BrCBr>CN(C=O)C>[O:10]1[C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[O:1][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Cs+]
Solvent: BrCBr
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a stirred solution of 3,4-dihydroxybenzaldehyde (10 g, 72.40 mmol, 1.00 equiv) in DMF (150 mL) was added cesium carbonate (35.4 g, 108.31 mmol, 1.50 equiv) and dibromomethane (18.7 g, 107.57 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 110° C. The solution was cooled to room temperature and the solid was removed by filtration. The filtrate was diluted with H2O (300 mL). The resulting solution was extracted with EtOAc (2×300 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with with EtOAc/petroleum ether (1:9) to afford 8 g (74%) of the title compound as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ ppm 9.81 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.34 (s, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.08 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])=[CH:23][C:22]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[C:36](Cl)([Cl:38])=[O:37]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:36]([Cl:38])=[O:37])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([C:28]#[N:29])([CH3:30])[CH3:31])=[CH:23][C:22]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, 2-{4-[rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-phenyl}-2-methyl-propionitrile (example 17) was reacted with phosgene in the presence of triethylamine to give the title compound.