Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[F:17].O.[NH2:19][NH2:20]>CS(C)=O>[F:17][C:3]1[C:2](=[N:19][NH2:20])[N:7]=[C:6]([CH3:8])[NH:5][C:4]=1[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(NCc2ccccn2)n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(=NN)c(F)c(NCc2ccccn2)[nH]1
Reaction time: 8 h
Yield: 39 %

Procedure:
6-Chloro-5-fluoro-2-methyl-N-(2-pyridinylmethyl)-4-pyrimidinamine (0.2517 g, 0.999 mmol) was dissolved in 2 mL of DMSO and 1 mL of hydrazine monohydrate. The resulting reaction mixture was stirred overnight. Then the reaction mixture was purified by RP-HPLC to provide 5-fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4(1H)-pyrimidinone hydrazone as a beige solid (0.0954 g, 39%). LCMS: (M+H)+=249.3.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(Cl)Cl>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:2][C:3]([NH:5][CH2:6][C:7]#[CH:8])=[O:4])[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: C#CCNC(=O)CBr
Solvent: ClCCl
Product: C#CCNC(=O)CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
To a solution of 2-bromo-N-(prop-2-yn-1-yl)acetamide (0.7 g, 3.98 mmol) in DCM (10 mL) added N-methyl piperazine (0.66 mL, 5.96 mmol) drop wise. Reaction mixture stirred at rt for 16 h, diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude residue was triturated with ether-pentane, affording the title compound (0.38 g, 49%); LCMS: m/z=196.15 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=6.1 Hz, 1H), 3.86 (dd, J=5.9, 2.5 Hz, 2H), 3.07 (t, J=2.5 Hz, 1H), 2.91 (s, 2H), 2.47-2.25 (m, 8H), 2.15 (s, 3H).
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7](OCC)=[CH:6][C:3]=1[C:4]#[N:5].N([O:19][CH2:20][CH2:21]C(C)C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:20]([O:19][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:21]
Reactant: CCOc1cc(C#N)c(N)cc1C(F)(F)F
Reactant: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C(F)(F)F)ccc1C#N
Yield: 84.9 %

Procedure:
To a solution of 2-amino-5-ethoxy-4-trifluoromethyl-benzonitrile (31.62 g, 137.4 mmol, 1.0 equiv) in anhydrous THF (410 mL) was added isoamyl nitrite (40.4 mL, 302 mmol, 2.2 equiv) and the mixture was heated to reflux for 16 h. The solvent was removed by evaporation under reduced pressure to give an orange oil which was dissolved in a sat. solution of NaHCO3 and extracted three times with diethyl ether. The combined organic phases were washed with 1 N HCl and a sat. solution of sodium chloride and the organic phases dried over Na2SO4. Removal of the solvent by evaporation under reduced pressure left an orange oil which was purified by double Kugelrohr distillation (up to 160° C. bath temperature at 1.5 mbar) yielding 25.1 g (85%) of the title compound as a light yellow solid upon solidification. MS (EI): 185.1 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([C:20]4[N:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([NH2:25])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:26])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:26][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([C:20]5[N:21]=[CH:22][CH:23]=[CH:24][C:19]=5[O:18][C:17]([NH2:25])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:33]1[C:28]([F:27])=[N:29][CH:30]=[CH:31][CH:32]=1)=[CH:7][CH:6]=3
Reactant: NC1=NC2(c3cc(Br)ccc3Oc3cnc(Cl)cc32)c2ncccc2O1
Reactant: OB(O)c1cccnc1F
Product: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3cnc(Cl)cc32)c2ncccc2O1

Procedure:
The titled compound was prepared by using 7-bromo-3-chlorospiro[chromeno[2,3-c]pyridine-5,4′-pyrido[2,3-e][1,3]oxazin]-2′-amine and 2-fluoropyridine-3-boronic acid and following the procedures as described in Example 18, Step 4. MS m/z=446.0 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4]/[CH:5]=[CH:6]/[Cl:7].[OH-].[Na+].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>C1(C)C=CC=CC=1>[CH3:17][Si:18]([CH3:21])([CH3:20])[N:3]([CH3:2])[CH2:4]/[CH:5]=[CH:6]/[Cl:7]
Reactant: C[Si](C)(C)Cl
Reactant: CNC/C=C/Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C/C=C/Cl)[Si](C)(C)C
Temperature: 22.5 °C
Reaction time: 0.33 h

Procedure:
Into a reactor under an inert nitrogen atmosphere are introduced 80 g (0.56 mol) trans-1-methylamino-3-chloro-2-propene hydrochloride, 400 ml toluene, 160 ml 25% NaOH and the mixture is stirred for 20 minutes at 20-25° C. The organic phase is separated and the aqueous phase extracted with 100 ml toluene. To the combined organic phases are added 150 ml triethylamine (1.07 mol, 1.9 eq.) and 98 ml trimethylchlorosilane (0.77 mol, 1.4 eq.) are added dropwise at 20/25° C. over a period of 1 hour. Upon complete addition, the suspension thus obtained is stirred for 2 hours at 20°/25° C. The salts are filtered in an inert nitrogen atmosphere, washing them with 160 ml toluene; the organic solution is then concentrated to a small volume under vacuum and used as such in the subsequent step.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[O:19]=[C:20]1[NH:24][C:23]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:22]=2[O:21]1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:26]3[CH:27]=[CH:28][C:22]4[O:21][C:20](=[O:19])[NH:24][C:23]=4[CH:25]=3)[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: O=c1[nH]c2cc(B(O)O)ccc2o1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: O=c1[nH]c2cc(C=C3c4ccccc4CCc4cc(Cl)ccc43)ccc2o1

Procedure:
Following procedures essentially as described in Example 219 and using 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (200 mg, 0.630 mmol) and 2-oxo-2,3-dihydro-benzooxazole-5-boronic acid (134 mg, 0.750 mmol), provides the title compound. Purify by UV-guided semi-prep reverse-phase HPLC to obtain 14 mg (6%) of the Z-isomer (Example 222(a)) of title compound as a white solid (MS (ES) 391 (M+NH4), 372 (M−H); HPLC shows 94% purity) and 5 mg (2%) of the E-isomer (Example 222(b)) of the title compound as a white solid. MS (ES) 391 (M+NH4), 372 (M−H); HPLC shows 96% purity.
Reaction SMILES: C[Si]([I:5])(C)C.F[B-](F)(F)F.[F:11][S:12]([F:24])([F:23])([F:22])([F:21])[C:13]1[CH:18]=[CH:17][C:16]([N+]#N)=[CH:15][CH:14]=1>>[I:5][C:16]1[CH:17]=[CH:18][C:13]([S:12]([F:24])([F:23])([F:22])([F:21])[F:11])=[CH:14][CH:15]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C[Si](C)(C)I
Agent: F[B-](F)(F)F
Product: FS(F)(F)(F)(F)c1ccc(I)cc1
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
(Bowden, et al., Tetrahedron 2000, 56, 3393-3408) Trimethylsilyl iodide (15.0 mg, 0.0750 mmol) was added to a solution of 1 (11.0 mg, 0.0346 mmol) in [BMIM][BF4] (67.6 mg). After stirring for 5 min the mixture was extracted with hexane (0.5 mL×3) and the combined extracts was evaporated to give pure 25b as a colorless oil (4.6 mg, 40%): MS (GC, EI): m/z=330 [M+], 311 [M+ F], 222, 96. 1H NMR (500 MHz, CDCl3): δ=7.82 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=137.9 (2CH), 127.5 (2CH), 98.2 (C) ppm. 19F NMR (470 MHz, CDCl3): δ=83.5 (quint, J=151 Hz, 1 F), 62.8 (d, J=151 Hz, 4 F) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1(C)C(C)(C)OB([C:28]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:5]1[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:3][C:2]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:39][CH:40]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
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: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)cc(NC2CCOCC2)c1C
Temperature: 100 °C
Yield: 64.4 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (600 mg, 1.83 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (833 mg, 2.75 mmol) in dioxane (9 mL), aqueous 2M Na2CO3 solution (3.30 mL, 6.60 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (211 mg, 0.18 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (500 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:31](=[O:32])[CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)CN1CCOCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CN3CCOCC3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and 2-morpholinoacetic acid as a yellow solid (37%). MS 445 (MH+).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH2:15]([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ccccc1N
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: c1ccncc1
Product: CCCCOc1ccccc1Nc1ncc(C(=O)OCC)c(=O)[nH]1
Reaction time: 18 h
Yield: 60.1 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (21.5 g) and 2-butoxyaniline (24 g) are added to pyridine (50 ml), and the mixture is refluxed with stirring for 18 hours. The reaction mixture is concentrated to dryness. The residue is recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-butoxyanilino)-6-oxo-5-pyrimidinecarboxylate (20 g). M.p. 209°-211° C.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[Br:7].[CH3:8][S:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:7][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH3:8])=[CH:11][CH:12]=1
Reactant: BrC1=C(Br)CCC1
Reactant: CSc1ccc(B(O)O)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: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(C2=C(Br)CCC2)cc1
Yield: 32.6 %

Procedure:
Under nitrogen, 36.4 g (161 mmol) of 1,2-dibromocyclopentene (Aldrich) was reacted with 18.0 g (107 mmol) of 4-methylthiophenylboronic acid (Step 1) in 550 mL of toluene, 365 mL of ethanol, and 235 mL of 2M Na2CO3 in the presence of 6.0 g (5 mol %) of Pd(PPh3)4. The reaction was vigorously stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography (Waters Prep-500) with hexane gave 9.39 g (22%) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (38 in Synthetic Scheme X when R5 =SCH3 and R1, R2, R3, R4, R6, and R7 =H) as a solid: mp 52°-54° C.; NMR (CDCl3) d 1.98-2.09 (m, 2H) , 2.50 (s, 3H) , 2.70-2.78 (m, 2H) , 2.80-2.89 (m, 2H), 7.24 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[Br:1][CH2:2][C:3]([NH:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNC(=O)CBr
Yield: 70 %

Procedure:
A solution of bromoacetyl bromide (44.4 g; 0.22 mol) in CH2Cl2 (50 mL) was added dropwise in 2.5 h at 20° C. to a mixture of octadecylamine (59.3 g; 0.22 mol) and K2CO3 (30.4 g; 0.22 mol) in CH2Cl2 (600 mL) and H2O (600 mL). After 16 h at room temperature the organic layer was separated, washed with H2O, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography (CH2Cl2/MeOH=100/1 (v/v)) to give the desired product (60 g; 0.154 mol). Yield 70%. GC: 96% (area %), K. F.: <0.1%; 1H-NMR, 13C-NMR and MS spectra were consistent with the postulated structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.[OH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[H-].[Na+]>CN(C)C=O>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:9][CH2:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:7]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: Fc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(COc2cc(F)ccn2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To an N,N-dimethylformamide (15 mL) solution of 2-chloro-4-fluoropyridine (2.88 g, 21.9 mmol) and 4-(hydroxymethyl)benzonitrile (4.37 g, 32.9 mmol) was added sodium hydride (1.29 g, 32.9 mmol, 60% in oil) at room temperature. This mixture was stirred for 4 hours at 70° C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (4.08 g, 82%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCN1CCCCC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCN4CCCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 36 μl of 1-(2-aminoethyl)piperidine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 75 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)-3-(2-piperidin-1-ylethyl)urea, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2].[C:20]([O-])([O-])=O.[Cs+].[Cs+].IC>CC(C)=O>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccc(O)cc2)CC(=O)N1C
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)[C@H]1[C@@H](c2ccc(OC)cc2)CC(=O)N1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
To a solution of (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-hydroxyphenyl)pyrrolidin-2-one (prepared according to the procedure described for Intermediate W, 0.74 g, 2.81 mmol) in acetone (10 mL) was added Cs2CO3 (2.03 g, 5.62 mmol), followed by iodomethane (0.19 mL, 3.1 mmol). The reaction was stirred at room temperature for 72 h and filtered. The filtrate was concentrated under reduced pressure. The resulting oil was purified by flash chromatography (EtOAc) to yield (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-methoxy-phenyl)pyrrolidin-2-one (0.72 g, 93%) as a white solid: 1H NMR (DMSO-d6) δ 0.73 (t, J=6.0 Hz, 3H), 2.44-2.71 (m, 5H), 3.56-3.78 (m, 5H), 3.88 (q, J=8.8 Hz, 1H), 4.42 (d, J=8.8 Hz, 1H), 6.82-6.87 (m, 2H), 7.11-7.16 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:28])([CH2:25][CH2:26][SH:27])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[Cl:29][CH2:30][CH2:31]Cl.[OH-].[Na+]>O>[C:2]([CH2:25][CH2:26][S:27][CH2:31][CH2:30][Cl:29])([C:3]([C:4]([C:5]([C:6]([C:7]([C:8]([C:9]([F:12])([F:11])[F:10])([F:14])[F:13])([F:16])[F:15])([F:17])[F:18])([F:20])[F:19])([F:21])[F:22])([F:23])[F:24])([F:28])[F:1]
Reactant: ClCCCl
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCSCCCl
Reaction time: 5 h

Procedure:
2-(Perfluorooctyl)ethanethiol (RF =C8F17, 4.80 g, 10.0 mmle) and 1,2-dichloroethane (29.67 g, 300 mmole) and 10 ml of water was stirred by magnet bar under nitrogen at ambient temperature, while sodium hydroxide (0.67 g, 16.7 mmole) in 20 ml of water was added dropwise during a half hour. An exotherm carried the temperature from 24.0° to 25.2°. A thick, white slurry was formed. After 5 hours of stirring at 23.5°, the white slurry had not separated into two liquid layers as in the procedures used above. Stirring was continued for 29 hours and a sample removed for analysis. After 39 hours the thick white paste was made acidic by the addition of 5.0 ml of 6N hydrochloric acid, and the white solid collected on a Buchner funnel, and washed with water. When dry the solid weighed 3.45 g, mp (sinter 82°) 83°-88°, 70% of theory for C8F17CH2CH2SCH2CH2SCH2CH2C8F17. A 1.00-g sample was recrystallized from hot chloroform, that was first filtered while hot, from insoluble salt; 0.54 g, mp (sinter 90°) 92°-94°. The filtrate deposited 0.26 g of less pure solid. The original filtrate containing water and 1,2-dichloroethane (above) was separated into layers, and the organic layer evapd off to give white solid, mp 30°-33°, 1.18 g, 21.7% of theory for C8F17CH2CH2SCH2CH2Cl.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH2:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Nc1ccc(Oc2ccc(CCN)cc2)cc1
Reactant: O=Cc1ccccc1
Solvent: CO
Product: CC(=O)Nc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
Combine N-{4-[4-(2-amino-ethyl)-phenoxy]-phenyl}-acetamide (100 mg, 0.37 mmol), benzaldehyde (47 mg, 0.44 mmol), 3 Å molecular sieves (300 mg), and methanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (28 mg) to the reaction and stirred at room temperature for 2 hours. Concentrate on a rotary evaporator and purified by radial chromatography on silica gel eluting with 10% conc. ammonium hydroxide in ethanol and chloroform to yield N-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-acetamide, (61 mg): 1H NMR (CDCl3, 300.00 MHz): 7.51-6.88 (m, 13H), 3.84 (s, 2H), 2.97-2.78 (m, 4H), 2.21 (s, 3H), 1.55 (s, 1H); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][N:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:30][C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1cc(N)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Yield: 41 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of 2-aminoethyl isopropylether, to the title compound (102 mg, 41%) which was obtained as a white solid. MS: m/e=388.1 [M−H]−.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:18][C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:13]=2[C:12]2[O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)ccc1c3ccccc3oc21
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cc2c3ccccc3oc2c2ccccc12
Temperature: 60 °C
Yield: 82 %

Procedure:
32.7 g of benzo[b]naphtho[2,1-d]furan was dissolved in 300 mL of N,N-dimethylformamide. Then, 50 mL of a N,N-dimethylformamide solution of 28.0 g of N-bromosuccinimide was added, and the resulting reaction solution was stirred with heating at 60° C. for 5 hours. After cooling to room temperature, the reaction solution was poured in 2 L of water. Solids thus obtained were sequentially washed with methanol, water and methanol. The resulting crude product was purified by means of silica gel column chromatography, whereby 36.5 g (yield: 82%) of 5-bromobenzo[b]naphtho[2,1-d]furan was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:15]2[C@H:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C@@H:14]2O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:32])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]2[C@@H:15]([C@@H:14]([Cl:32])[CH2:13][CH2:12][C:11]2([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2Cl

Procedure:
A solution of 1 g of (3aR, 4S, 7aR)-2-tert-butyloxycarbonyl-7,7-diphenyl-4-perhydroisoindolol in 10 cm3 of thionyl chloride is stirred for 3 hours at 80° C. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa). 1.03 g of (3aR, 7S, 7aR)-2-tert-butyloxycarbonyl-7-chloro-4,4-diphenylperhydroisoindole are obtained in the form of a solid which is used in the crude state in the following test.