Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH2:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH2:28][CH2:29][CH3:30].[O-]CC.[Na+]>>[CH2:27]([NH:31][C:32]1[N:34]=[C:11]([C:10]2[C:9]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:8][N:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=23)[CH:12]=[CH:13][N:33]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCNC(=N)N
Reactant: C#CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Yield: 59 %

Procedure:
In a similar manner as described in Example 34 from 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (0.50 g, 1.7 mmol), N-butylguanidine sulfate and sodium ethoxide (0.81 mL, 21 wt % in ethanol, 2.2 mmol) at room temperature was obtained N-butyl-4-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (0.39 g, 59%) as a fluffy pale yellow solid. 1H NMR (CDCl3): δ 8.40 (d, 1 H), 8.07 (d, 1 H), 7.65 (m, 2 H), 7.29 (m, 1 H), 7.15 (t, 2 H), 7.06 (d, 1 H), 6.32 (d, 1 H), 5.16 (bs, 1H), 3.49 (q, 2 H), 1.71–1.41 (m, 4 H), 0.99 (t, 3 H); 19F NMR (CDCl3) δ −112.77; MS m/z 396 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:5]=[N:6][CH:7]=1.C([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH3:35])[CH:33]=2)[CH:28]=[C:27]1B(O)O)(OC(C)(C)C)=O>>[CH3:35][C:32]1[CH:33]=[C:34]2[C:29]([CH:28]=[C:27]([C:2]3[CH:3]=[C:4]([N:8]4[C:16](=[O:17])[C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:9]4=[O:18])[CH:5]=[N:6][CH:7]=3)[NH:26]2)=[CH:30][CH:31]=1
Reactant: Cc1ccc2cc(B(O)O)n(C(=O)OC(C)(C)C)c2c1
Reactant: O=C1c2ccccc2C(=O)N1c1cncc(Br)c1
Product: Cc1ccc2cc(-c3cncc(N4C(=O)c5ccccc5C4=O)c3)[nH]c2c1

Procedure:
2-(5-Bromo-pyridin-3-yl)-isoindole-1,3-dione and N-Boc-6-methyl-indoleboronic acid are processed according to the procedure described in Example 103 to give 2-[5-(6-methyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione. MS (ESI) m/z 354.1 (M+H)+
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19](O)=[O:20].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)CCl>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:16]([CH3:15])[CH:17]=3)=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[O:9]1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(C)c1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (2.1 g, 11 mmol) in ClCH2CH2Cl (70 mL), 3-methyl-4-nitrobenzoic acid (3.7 g, 20 mmol) and P2O5 (6 g) as an oily solid (1.4 g, 3.9 mmol, 35%). 1H NMR (CDCl3) 7.99 (d, J=8.2, 1H), 7.74 (s, 1H), 6.69 (d, J=8.2, 1H), 6.84 (s, 1H), 6.83 (s, 1H), 6.07 (s, 2H), 3.86 (s, 2H), 3.64 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:6]=1)[CH:3]=O.I.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][NH2:29])=[NH:27])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:28]=[N:29][CH:3]=[C:2]([C:5]3[CH:6]=[C:7]([N:11]4[CH2:15][CH2:14][CH2:13][C:12]4=[O:16])[CH:8]=[CH:9][CH:10]=3)[N:27]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=N)NN)cc1
Reactant: O=CC(=O)c1cccc(N2CCCC2=O)c1
Agent: I
Product: COc1ccc(-c2nncc(-c3cccc(N4CCCC4=O)c3)n2)cc1

Procedure:
Oxo[3-(2-oxopyrrolidin-1-yl)phenyl]acetaldehyde was reacted with 4-methoxybenzenecarboximidic hydrazide hydriodide salt (0.72 g, 2.46 mmol) using the method described in Example 1 to give 1-{3-[3-(4-methoxyphenyl)-[1,2,4]triazin-5-yl]phenyl}pyrrolidin-2-one as a yellow solid (0.47 g): δH (400 MHz, d6-DMSO) 2.09-2.17 (2H, m), 2.57 (2H, t, J 8.0 Hz), 3.88 (3H, s), 3.99 (2H, t, J 7.0 Hz), 7.16-7.21 (2H, m), 7.64 (1H, t, J 8.0 Hz), 7.98-8.01 (1H, m), 8.18 (1H, d, J 8.2 Hz), 8.51-8.55 (2H, m), 8.66 (1H, t, J 1.8 Hz), 9.95 (1H, s); m/z (ES+) 347.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:11]=O)[CH2:6][CH2:5]2.O>[Zn].C(O)(=O)C>[NH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=NN1CCc2cc(Cl)ccc21
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: NN1CCc2cc(Cl)ccc21

Procedure:
To a stirred mixture of 50 g. (0.27 mole) of 5-chloro-1-nitrosoindoline, 80 g. (1.2 mole) of zinc and 250 ml. of water was added over a 45 minute period 100 ml. of glacial acetic acid. The mixture was filtered, the filtrate basified with 50% sodium hydroxide solution and the base-insoluble oil extracted with ether. The combined ether extracts were dried, concentrated and the residual oil distilled. 1-Amino-5-chloroindoline was distilled at 96°-98°C./0.1 mm. The oil solidified on standing at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[C:11]([N+:15]([O-:17])=[O:16])=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(F)cc(Br)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])c(Br)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
The method of Cheeseman, supra. was adapted. 5-Bromo-7-fluoro-1,4-dihydroquinoxaline-2,3-dione (77 mg, 0.30 mMol) was dissolved in concentrated H2SO4 (1 mL) at 0° C. for 30 min, and KNO3 (35 mg, 0.346 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then at room temperature for 30 h. The mixture was poured into ice water (10 g) and the precipitate was collected by filtration. The precipitate was dissolved in 1N NaOH (10 mL), then was acidified to pH=2 with 4N HCl to give cream precipitate, which was collected by filtration, and was dried in the air at 50° C. for 4 h affording pure (by NMR) 5-bromo-6-nitro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (81 mg, 90%), as a white amorphous solid; mp: 320°-25° C. (dec. from 290° C.). IR (KBr, cm-1): 3416, 3071, 2952, 1721, 1609, 1546. NMR (1H, DMSO-d6): δ 7.146 (d, J=10.2 Hz, 1H), 11.432 (s, 1H), 12.340 (s, 1H). HRMS: calcd. for C8H3N3O4BrF (M+) m/z: 302.9290, found: 302.9290.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[Br:17]Br>C(Cl)(Cl)Cl>[Br:17][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:16][C:6]=2[C:7]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrBr
Reactant: Cc1ccc2occ(-c3ccccc3)c2c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2oc(Br)c(-c3ccccc3)c2c1

Procedure:
To a solution of 119 g (0.816 mole) of 5-methyl-3-phenylbenzofuran in 1 l. of chloroform at 20° to 25° C. is added 143.5 g (0.895 mole) of bromine. The mixture is evaporated under vacuum and the residue is dissolved in diethyl ether. The ether solution is washed with water, 10% sodium bicarbonate solution and saturated sodium chloride solution. The dried mixture is filtered and the filtrate is evaporated under vacuum. The residue is suspended in hot petroleum ether, then the mixture is cooled to provide solid 2-bromo-5-methyl-3-phenylbenzofuran, m.p. 52°-57° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20].N1C=CN=CC1=O>>[N+:19]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:21])=[O:20]
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=c1cncc[nH]1
Product: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
5-Phenyl-2-(1H)-pyrazinone (56 g) was added in portions over 30 minutes to a stirred mixture of concentrated sulphuric acid (35 ml) and fuming nitric acid (200 ml). The temperature of the nitrating mixture was initially at -20° C. and care was taken to ensure that the temperature did not rise above -15° C. When the pyrazinone had completely dissolved the reaction mixture was allowed to warm to -10° C., stirred for a further 30 minutes, and poured slowly on to ice/water (1500 ml). A pale yellow solid precipitated which was collected by filtration, washed with a small amount of cold water and dried to afford 5-(4-nitrophenyl)-2-(1H)-pyrazinone (58.1 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=N[O-]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(F)c(C(F)(F)F)c1
Yield: 64390 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-61 by using 4-fluoro-3-(trifluoromethyl)aniline (3.0 g, 0.016 mmol), NaNO2 (1.73 g, 0.025 mmol), SnCl2.2H2O (9.39 g, 0.041 mmol) and conc. HCl (100 mL) to afford 2.0 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[OH:13].[H][H]>CO>[CH3:12][O:11][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[OH:13]
Reactant: [H][H]
Reactant: COc1cc(CO)cc(OC)c1O
Solvent: CO
Product: COc1cc(C)cc(OC)c1O
Yield: 65.7 %

Procedure:
310 g of 2,6-dimethoxyphenol, 300 g of 38 wt% formalin, and 810 g of 10% wt% aqueous sodium hydroxide were reacted for 60 hours at 25° C. under a pressure of 0 kg/cm2 -G, the reaction mixture was and then neutralized with sulfuric acid, to obtain 80 g of 2,6-dimethoxy-4-(hydroxymethyl)phenol. (Yield: 22 mol%) 25 g of the obtained 2,6-dimethoxy-4-(hydroxymethyl)phenol was reacted in 320 ml of methanol in the presence of 0.375 wt% of platinum-alumina catalyst and hydrogen for 4 hours at 200° C. at 199 kg/cm2 -G, and 15 g of 2,6-dimethoxy-4-methylphenol was obtained. (Yield: 66 mol%) The yield on the basis of the amount of the raw material was 15 mol%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].COCN[C:21]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: COCNC(=O)C1CCOCC1
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Product: COC(=O)c1sc(C(=O)C2CCOCC2)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and tetrahydropyran-4-carboxylic acid methoxymethylamide were reacted by method M. The product with the molecular weight of 365.33 (C14H14F3NO5S) was obtained in this way; MS (ESI): 366 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]2[C:9](=[S:13])[NH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1.[H-].[Na+].I[CH3:17]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[N:8]2[C:9]([S:13][CH3:17])=[N:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1
Reactant: CI
Reactant: COCc1ncc2cn[nH]c(=S)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ncc2cnnc(SC)n12

Procedure:
A slurry of 0.98 gm of 6-(methoxymethyl)-imidazo[1,5-d]-as-triazine-4(3H)-thione in 10 ml of N,N-dimethylformamide is treated with 0.28 gm of 50% sodium hydride in oil. Gentle warming is applied until the effervescence stops and then 0.41 ml of iodomethane is added. The resulting precipitate is collected, washed with ether, recrystallized from acetone then ethanol, to yield the above-noted desired product having a melting point equal to 179°-181° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:30])[CH2:16][N:17]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[CH2:35](Cl)Cl.CO>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:30][CH3:35])[CH2:16][N:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CN1CCN(Cc2ccccc2)CC1)Cn1c2ccccc2c2ccccc21
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CO
Product: COC(CN1CCN(Cc2ccccc2)CC1)Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 7 (0.200 g, 0.50 mmol) in 5 mL of THF are added NaH (0.068 g, 1.56 mmol) and methyl iodide (125 μL, 2.0 mmol). After 2 hr of stirring at rt the reaction is judged to be complete by tlc monitoring (SiO2, DCM:MeOH (100:3)) and is quenched with a saturated aqueous solution of Na2CO3 (5 mL). Extraction with DCM, drying over MgSO4, concentration in vacuo, flash chromatography on a 2.5×12 cm2 column of silica gel using DCM:MeOH (95:5) as eluting solvent and removal of the solvent in vacuo gives the title compound as an oil. Slow addition of HCl (4 eq, 1M in Et2O) into a solution of the above compound in EtOH (2 mL) gives the hydrochloride salt of the title compound (0.39 g) as white crystals in a 60% yield. M.p.: 272° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(OC)c1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.4 %

Procedure:
A mixture of 2-methoxy-2-(4-hydroxyphenyl)acetic acid methyl ester (see Example 10) (8g; 40 mmol), potassium carbonate (11.04 g; 80 mmol) and 2-chloromethylpyridine hydrochloride (6.56 g; 40 mmol) in DMF (150 ml) was stirred at room temperature for 16 h, and then poured into icy water. The product was extracted with ethyl acetate, the acetate layer was washed with water, brine, dried with magnesium sulfate ans concentated in vacuo. The residue was purified by column chromatography (hexane-ethyl acetate 3:1) to afford 2.0 g of 2-methoxy-2-[4-(2-pyridylmethoxy)phenyl]acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=O)[C:7]3[CH:8]=[C:9]4[C:23]([CH3:25])([CH3:24])[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:10]4=[CH:11][C:12]=3[C:13](=O)[C:14]=2[CH:15]=1.I.O.II>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[CH:13][C:12]1[CH:11]=[C:10]3[C:17]4[C:22]([C:23]([CH3:25])([CH3:24])[C:9]3=[CH:8][C:7]=1[CH:6]=2)=[CH:21][CH:20]=[CH:19][CH:18]=4
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)C(=O)c1ccc(Br)cc1C3=O
Agent: I
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)c2ccccc2-c2cc3cc4cc(Br)ccc4cc3cc21
Reaction time: 48 h
Yield: 59.5 %

Procedure:
8-bromo-13,13-dimethyl-6H-indeno[1,2-b]anthracene-6,11(13H)-dione (20 g, 0.05 mol) was dissolved in acetic acid (200 ml) and added with 57% HI (50 ml), followed by reflux-stirring for 48 hours. After the reaction was completed, the resultant solution was added with distilled water 500 ml. The produced solid was filtered and dissolved in toluene 200 ml and iodine (4.05 g, 0.016 mol) was added thereto, followed by reflux-stirring for 3 hours. After the reaction was completed, through extraction and column chromatography, 8-bromo-13,13-dimethyl-13H-indeno[1,2-b]anthracene (11.1 g, yield 60%) was obtained.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[N:4]=1)#[N:2].Cl>[Pd].CO>[NH2:2][CH2:1][C:3]1[N:4]=[C:5]([O:11][CH3:12])[N:6]=[C:7]([O:9][CH3:10])[N:8]=1
Reactant: COc1nc(C#N)nc(OC)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1nc(CN)nc(OC)n1
Reaction time: 4 h
Yield: 36.6 %

Procedure:
A mixture of 6.4 g of the product from Example 3, 0.69 g, 10% palladium-on-carbon catalyst, and 3 ml of concentrated hydrochloric acid in 140 ml methanol was shaken under an atmosphere of hydrogen at 50 p.s.i. on a Parr Hydrogenation Apparatus. After approximately 4 hours, the solution was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was diluted with water and, after being washed with several small portions of ether, the aqueous layer was made strongly basic to pH paper by the addition of 50% sodium hydroxide solution with ice-water cooling. A yellow solid precipitated from the basic solution and was isolated by filtration. Drying in vacuo for 24 hours gave 2.4 g of 2-aminomethyl-4,6-dimethoxy-1,3,5-triazine as a light yellow solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:30]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:31]
Reactant: CCBr
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
This compound was made in the following manner: 50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equ. of bromoethane and 2 equ. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as the free base. Treatment with 1 equ. 1M HCl in dioxane and concentration in vacuo afforded 29.5 mg of the corresponding hydrochloride salt. Yield 51%, ES MS m/z 419/421.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1([F:24])[CH2:12][C:11]1([C:14]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:15])[CH3:13]>CS(C)=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:14]2([C:11]3([CH3:13])[CH2:12][C:10]3([F:9])[F:24])[CH2:2][O:15]2)=[CH:22][CH:21]=1
Reactant: CC1(C(=O)Cc2ccc(F)cc2)CC1(F)F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C2(Cc3ccc(F)cc3)CO2)CC1(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.8 %

Procedure:
20 ml of absolute dimethyl sulphoxide are added dropwise to a mixture of 5.31 g (0.0241 mol) of trimethylsulphoxonium iodide and 0.79 g (0.0329 mol) of sodium hydride (80%) at 10° C. under a nitrogen atmosphere. When the addition is complete, the mixture is allowed to warm to room temperature in the course of 10 minutes, and a solution of 5 g (0.0219 mol) of 4-fluorobenzyl 2,2-difluoro-1-methyl-cyclopropyl ketone in 10 ml of absolute dimethyl sulphoxide is then added dropwise with stirring. Stirring is continued for 4 hours at 40° C. The reaction mixture is then poured onto ice-water. The mixture which forms is extracted three times using cyclohexane. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. In this manner, 6.3 g of 2-(4-fluoro-benzyl)-2-(2,2-difluoro-1-methyl-cyclopropyl)-oxirane are obtained, which is used for further reaction without additional purification. ##STR31##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][NH2:22]>CO>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([NH:21][NH2:22])=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
Ethyl 4-benzyloxy-3-chlorobenzoate [c.f., Jones & Robinson, J. Chem. Soc. 3845 (1955)] (32.0 g., 0.11 mole), 25 ml. methanol and 20 ml. 95% hydrazine are stirred under reflux for 8 hours and cooled to room temperature. The mixture is filtered and the resulting solid dried in vacuo to give 29.4 g. 4-benzyloxy- 3-chlorobenzoic acid hydrazide (96.7% yield), m.p. 168°-171° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][N:14]([CH3:16])C)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=C[CH:26]=[C:25](N)[CH:24]=1.Cl>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][NH:14][C:16]2[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)N1CCN(C(=CN(C)C)C(=O)OC)CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)N1CCN(C(=CNc2cccc(OC)c2)C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of step (ii) (6.3 g), m-anisidine (2.5 ml), ethanol (65 ml) and concentrated hydrochloric acid (2.2 ml) was stirred at room temperature for 2 hours then evaporated. The residue was basified by careful addition of aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by flash chromatography on silica by elution with 70% v/v ether/hexane to yield 1-ethoxycarbonyl-4-(1-(3-methoxyphenyl)amino-2-methoxycarbonylethen-2-yl)piperazine (5.15 g) as an off-white solid: m.p. 120°-122° C.; NMR (CDCl3) δ 1.28 (3H, t), 2.90 (4H, m), 3.50 (4H, m), 3.71 (3H, s), 3.81 (3H, s), 4.18 (2H, q), 6.52 (3H, m), 7.21 (1H, t), 7.39 (1H, d), 7.80 (1H, d); m/Z 364 (H+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])C.CON(C)[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1)=[O:27]>C1COCC1>[CH3:9][O:11][C:12](=[O:22])[CH:13]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([S:34][CH3:35])[N:29]=1)=[O:27]
Reactant: CON(C)C(=O)c1ccnc(SC)n1
Reactant: CCOC(=O)COc1ccccc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccccc1C)C(=O)c1ccnc(SC)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 12.9 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (31.5 mL of 1.8 M solution in THF, 56.6 mmol) in THF (180 mL) is added dropwise a solution of ethyl-(2-methylphenoxy)acetate (10.0 g, 51.5 mmol) in THF (30 mL). After stirring for 1 h at −78° C. a solution of 2-methylsulfanyl-pyrimidine-4-carboxylic acid methoxy-methyl-amide (10.4 g, 48.9 mmol) in THF (30 mL) is added dropwise to the reaction mixture. After stirring 20 min at −78° C., the reaction mixture is warmed to 0° C. and stirred for an additional 30 min. The reaction is quenched by pouring into aqueous saturated NH4Cl. The aqueous phase is extracted with EtOAc (×2). The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified by silica gel chromatography (10% EtOAc/hexanes, followed by 30% EtOAc/hexanes) to afford 2.1 g (32%) of the desired product. 1H NMR (300 MHz, CDCl3) (observed 3:1 mixture of keto:enol tautomers) keto tautomer: δ 8.80 (d, J=4.2 Hz, 1H), 7.57 (d, J=4.8 Hz, 1H), 7.20-7.14 (m, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.29 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 2.27 (s, 3H), 1.26 (t, J=7.2 Hz, 3H); ESI+ MS: m/z (rel intensity) 347.1 (100, M++H).