Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[OH-].[Na+].[N:14]#[C:15]Cl>C(Cl)Cl.O>[NH:1]([CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)[C:15]#[N:14]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: N#CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(NC#N)CC(C)(C)N1

Procedure:
156 g (1 mole) of 4-amino-2,2,6,6-tetramethyl piperidine were dissolved in 500 ml of methylene chloride, 40 g (1 mole) of sodium hydroxide in 500 ml of water were introduced and 51 ml of cyanogen chloride were added dropwise at 0° to 5° C. The mixture was then stirred until it reached room temperature, after which 4-cyanamido-2,2,6,6-tetramethyl piperidine melting at 240° C was filtered off in a yield of 166 g (corresponding to 91.5% of the theoretical yield).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11](C4C=CN=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH3:28][O:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[N:10][C:11]([C:33]4[CH:32]=[N:31][C:30]([O:29][CH3:28])=[C:35]([O:36][CH3:37])[CH:34]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: C[C@@H](Oc1nc(-c2ccncc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cnc1OC
Yield: 60.3 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (217.8 mg, 0.82 mmol) as a starting material, to afford 70.0 mg (60.3%) of (R)-4-((R)-1-((3-cyclopropyl-6-(5,6-dimethoxypyridin-3-yl)-3H-imidazo[4,5-c]pyridin-4yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=2.4 Hz 1H), 8.287 (s, 1H), 7.90 (d, J=2.4 Hz 1H), 7.879 (s, 1H), 7.57 (s, 1H). 5.59-5.55 (m, 1H), 3.9 (d, J=2.4 Hz 6H), 3.71-3.66 (m, 1H), 3.38 (t, J=18 Hz, 1H), 3.25 (dd, J=12, 15 Hz, 1H), 2.89-2.82 (m, 1H), 2.36-2.3 (m, 2H), 1.43 (d, J=6.4 Hz, 3H), 1.119-1.09 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C22H25N5O4:423.19; found 424.08.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([F:12])=[CH:4][C:3]=1[CH2:13]OC1CCCCO1.P(Br)(Br)[Br:22]>C1(C)C=CC=CC=1>[Br:22][CH2:13][C:3]1[CH:4]=[C:5]([F:12])[C:6]2[O:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: Fc1cc(COC2CCCCO2)c(F)c2c1OCCO2
Solvent: Cc1ccccc1
Product: Fc1cc(CBr)c(F)c2c1OCCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 160 %

Procedure:
To a solution of 5,8-difluoro-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2,3-dihydro-1,4-benzodioxine (785 mg, 2.74 mmol) in toluene (5 mL) was added phosphorous tribromide (155 μl, 1.65 mmol) and the solution was stirred at room temperature for 15 hrs. The solution was concentrated in-vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford 700 mg, 2.64 mmol (96%) of 6-(bromomethyl)-5,8-difluoro-2,3-dihydro-1,4-benzodioxine as a pale yellow oil. 1H NMR (400 MHz, CDCl3): 6.68 (q, 1H), 4.33 (s, 2H), 4.35 (s, 4H); GC/MS (EI) for C9H7O2F2Br: 265 (M+).
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][N:17]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:5])[CH:3]=[CH2:4]>CO.C(Cl)Cl>[CH3:5][C:2]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][NH2:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:1])[CH:3]=[CH2:4]
Reactant: C=CC(C)(C)c1[nH]c2ccccc2c1CCN1C(=O)c2ccccc2C1=O
Solvent: CO
Solvent: ClCCl
Product: C=CC(C)(C)c1[nH]c2ccccc2c1CCN
Reaction time: 8 h

Procedure:
To a solution of 2-[2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione (1.10 g, 3.07 mmol) in 3:1 MeOH/CH2Cl2 (20 mL) at rt under argon was added N2H4.H2O (0.52 mL). The reaction mixture was stirred overnight, concentrated in vacuo, diluted with CHCl3, then extracted with H2O. The CHCl3 layer was separated. The H2O layer was extracted further with CHCl3. The combined CHCl3 extracts were washed, dried, filtered, and concentrated to give the title compound: MS (ESI+) m/z 229.2.
Reaction SMILES: C[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][C:8](C(O)=O)=[CH:7][CH:6]=1.[C:17](=O)=O>>[CH3:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]([CH:2]=1)[CH2:4][C:5]1[O:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C=O
Reactant: Cc1ccccc1Cc1ccc(C(=O)O)o1
Product: Cc1cccc(Cc2ccco2)c1

Procedure:
A mixture of 5-(2-methylbenzyl)-2-furoic acid [prepared as described in (d) or (f) above; 26.2 g.] and cupric oxide (1 g.) was heated at 200° C. for 4 hours until evolution of carbon dioxide almost ceased. The residue was cooled and distilled to give 2-(5-methylbenzyl)furan (16.5 g.), b.p. 118° C./20 mm.Hg, in the form of a pale yellow coloured oil.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH3:41])[C:3](=[O:40])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:37]=[CH:36][C:20]([CH2:21][N:22]([CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])C(=O)OC(C)(C)C)=[C:19]([CH3:38])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:39].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:40])[C:2]([CH3:1])([CH3:42])[CH3:41])=[C:7]([CH3:39])[CH:8]=1)([C:17]1[CH:37]=[CH:36][C:20]([CH2:21][NH:22][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:19]([CH3:38])[CH:18]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(CN(CCS(C)(=O)=O)C(=O)OC(C)(C)C)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CNCCS(C)(=O)=O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Yield: 95.1 %

Procedure:
To a mixture of t-butyl (4-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}-2-methylbenzyl)-(2-methanesulfonylethyl)carbamate (0.25, g, 0.41 mmol) and CH2Cl2 (5 mL) is added TFA (5 mL,), stirred for 10 m, and concentrated. The residue is diluted with EtOAc (100 mL), washed with sat.d NaHCO3 (2×30 mL); MgSO4 dried, and chromatographed (90% EtOAc) to give the title compound (0.19 g, 0.39 mmol, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of mixture of cis isomer of methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (4 g, 9.09 mmol) in acetonitrile (50 mL) was added cesium carbonate (5.9 g, 18.18 mmol) and methyl iodide (6.45 g, 45.45 mmol). The resulting reaction mixture was heated at 80° C. for 7 h. On completion, the reaction mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and filtrate was concentrated to afford desired crude compound which then purified by column chromatography giving desired compound (1.4 g, 34%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:32]([N:35](CC2C=CC(OC)=CC=2OC)[C:36]2[S:40][N:39]=[CH:38][N:37]=2)(=[O:34])=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:26]1[CH:31]=[CH:30][N:29]=[N:28][CH:27]=1)#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([S:32]([NH:35][C:36]2[S:40][N:39]=[CH:38][N:37]=2)(=[O:33])=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=2)=[CH:12][C:11]=1[C:26]1[CH:31]=[CH:30][N:29]=[N:28][CH:27]=1)#[N:2]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1-c1ccnnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.7 %

Procedure:
3-Cyano-N-(2,4-dimethoxybenzyl)-4-{[3-pyridazin-4-yl-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 26, 210 mg, 0.29 mmol) was dissolved a in 4M solution of hydrogen chloride in 1,4-dioxane (7 mL) and stirred at room temperature for 5 hours. A precipitate formed which was collected by filtration and purified by trituration with dichloromethane followed by silica gel column chromatography (0%-15% methanol in dichloromethane gradient elution) to afford the title compound as a solid (77 mg, yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(CC)CC.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccnc(NC(=O)C(C)(C)C)c1
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of 4-methylpyridin-2-amine (25.0 g, 0.230 mol) and Et3N (35.0 g, 0.350 mmol) in CH2Cl2 (200 ml) was added pivaloyl chloride (33.1 g, 0.270 mol) drop-wise. The mixture was stirred for 4 h under N2 atmosphere. The reaction mixture was quenched with water and was extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous Na2SO4, evaporated under vacuum and purified by chromatography on silica gel (20% ethyl acetate in petroleum ether) to afford N-(4-methylpyridin-2-yl)pivalamide (36.2 g, 82%). 1H NMR (CDCl3, 300 MHz) δ 8.08-8.09 (m, 2H), 8.00 (br s, 1H), 6.83 (dd, J=4.8, 0.6 Hz, 1H), 2.33 (s, 3H), 1.30 (s, 9 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([CH3:6])[CH3:5].[C:7]([N:15]=[C:16]=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[C:7]([NH:15][C:16]([N:2]([CH3:1])[CH2:3][CH:4]([CH3:6])[CH3:5])=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNCC(C)C
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)CN(C)C(=S)NC(=O)c1ccccc1
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
To a stirring solution of N-methylisobutylamine (3.21 g, 36.8 mmol, 4.45 mL) in 40 mL of CHCl3 was added benzoyl isothiocyanate (6.0 g, 36.8 mmol, 4.95 mL). After stirring for 45 min, the solution was concentrated to yield the title compound as a pale yellow solid (9.22 g, 100%). 1HNMR (400 MHz, CDCl3; 2:1 mixture of rotamers) δ 7.86 (d, 2 H), 7.60 (t, 1 H), 7.50 (t, 2 H), 3.90 (d, 2 H), 3.44 (s, 3 H), 3.41 (d, 2 H), 3.27 (s, 3 H), 2.35-2.32 (m, 1 H), 2.13 (m, 1 H), 1.06 (d, 6 H), 0.90 (d, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]([C:18]([OH:20])=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:44]([NH:51][C:18]([C:10]1[C:11]([CH:15]([CH3:16])[CH3:17])=[C:12]([CH:13]=[O:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:20])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)c1c(C(=O)O)nn(-c2ccc(F)cc2)c1C=O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid (1.25 g, 4.52 mmol) in CH2Cl2 (50 mL) at 25° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.30 g, 6.79 mmol; commercially available from Sigma Aldrich) followed by 1-hydroxybenzotriazole hydrate (1.04 g, 6.79 mmol; commercially available from Sigma Aldrich) and the reaction was stirred for 5 min at 25° C. Subsequently, benzyl amine (0.533 g, 4.98 mmol; commercially available from Sigma Aldrich) was added and the reaction was stirred for an additional 4 hrs as a fine white precipitate developed. The organic layer was washed with 1 N HCl, saturated NaHCO3 and brine. After drying and concentration, the product was purified by silica gel chromatography (20% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid benzylamide (0.65 g, 39%): MS(APCI+): m/z366.1 (M+H).
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH2:13]([O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[CH3:28])[CH3:14]>O.C(#N)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:13]([O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[CH:28]=[O:2])[CH3:14]
Reactant: CCOC(=O)CCCOc1cccc(C)c1C
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCOc1cccc(C)c1C=O
Temperature: 64 °C
Yield: 205.6 %

Procedure:
A mixture of copper(II) sulfate pentahydrate (21.98 g, 88.06 mmol) and potassium persulfate (71.42 g, 264 mmol) in water (396 mL) was heated to 63-65° C. to obtain a blue colored solution. Then, a solution of 4-(2,3-dimethyl-phenoxy)-butyric acid ethyl ester (20.81 g, 88.06 mmol) in acetonitrile (220 mL) was added at the above temperature. The resulting light green solution was refluxed for 40 minutes. Then, the reaction mixture was cooled to ˜5° C. in order to precipitate most of the inorganic solids. The resulting solids were collected by filtration and the solid cake was washed with dichloromethane (1.0 L). The two layers of filtrate were separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a brown oil. The crude mixture was purified by using a Biotage™ (40 L) column chromatography eluting with 5-10% ethyl acetate in hexanes to obtain 4-(2-formyl-3-methyl-phenoxy)-butyric acid ethyl ester (45.32 g, 94%) as a colorless oil: EI(+)-HRMS m/e calculated for C14H18O4 (M+)+ 250.1205, found 250.1202.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: Sc1ccc(Cl)cc1
Product: CN1CCN(c2cc(Sc3ccc(Cl)cc3)nc(-c3ccccc3)n2)CC1
Temperature: 160 °C

Procedure:
A well blended mixture of the above prepared 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine (2.0 g.) and 5.0 g. of p-chlorothiophenol is heated in an oil bath maintaining the temperature at 160°C. for 3 hours. After being cooled to room temperature, the reaction mixture is triturated with 60 ml. of 30°/o sodium hydroxide. The product is collected on a sintered glass funnel and washed with water repeatedly. It amounted to 2.9 g. and melted at 145°-150°C. Upon recrystallization from absolute ethanol, there is obtained 4-(4-chlorophenylthio)-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine, m.p. 152°-154°C.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[CH2:13]([CH:17]([C:21](=O)[CH3:22])[C:18](=O)[CH3:19])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:17]1[C:18]([CH3:19])=[N:3][N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[C:21]=1[CH3:22])[CH2:14][CH2:15][CH3:16]
Reactant: NNc1ccc(CCO)cc1
Reactant: CCCCC(C(C)=O)C(C)=O
Agent: Cl
Product: CCCCc1c(C)nn(-c2ccc(CCO)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 3-n-butyl-2,4-pentanedione: MS (ESI) m/z 273 [M+H]+, 1H-NMR (CDCl3) δ 7.37-7.26 (4H, m), 3.87 (2H, t, J=6.8 Hz), 2.91 (2H, t, J=6.6 Hz), 2.39 (2H, t, J=7.6 Hz), 2.25 (3H, s), 2.22 (3H, s), 1.53-1.26 (4H, m), 0.94 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH2:1][C:12]([O:13][CH2:14][CH3:15])=[O:16])=[O:3])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 20 °C

Procedure:
To potassium t-amylate (25 wt %, 50.8 kg, 99.26 mol) in toluene (15.2 kg) cooled to 5° C. under mechanical stirring and under nitrogen was added a mixture of 4-methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene over 1 hour maintaining the temperature below 10° C. The reaction mixture was heated to 60° C. for 8 hours until no 4-methoxyacetophenone was detected by HPLC. The mixture was cooled to 20° C. and quenched by adding to a mixture of acetic acid (8 kg) and water (90 kg) over 30 minutes while maintaining the temperature at <20° C. The layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50° C. during the distillation. The yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg (94%).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:12]=[CH:11][C:5]=2[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CCOC(=O)c1ccc(Br)cc1-c1ccc(OC)c(OC)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(-c2ccc(F)cc2)cc1-c1ccc(OC)c(OC)c1
Yield: 89.4 %

Procedure:
1,2-Dimethoxyethane (30 ml) which has been degassed with argon is introduced into a 250 ml three-necked flask, then ethyl 4-bromo-2-(3,4-dimethoxyphenyl)benzoate (3.65 g; 0.010 mole; compound 209), palladium tetrakis(triphenyl)phosphine (0.1 g), 4-fluorophenylboronic acid (1.7 g; 0.012 mole) and 2M sodium carbonate (20 ml) are added. After refluxing for 8 hours, the reaction mixture is poured into distilled water (100 ml). The mixture is then extracted with dichloromethane (2×100 ml), washed with water (100 ml), dried over magnesium sulphate, passed over a layer of silica and then evaporated. Ethyl 2-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)benzoate (3.4 g; yield: 89.5%) is thus obtained, m.p. 127° C. (compound 233).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([Cl:19])[C:3]=1[NH2:4].C(N(CC)CC)C.[F:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].[OH-].[Na+]>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:10]([F:13])([F:12])[F:11])[C:14]([F:15])([F:16])[F:17])[CH:6]=[C:5]([Cl:19])[C:3]=1[NH:4][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:36]([N+:37]([O-:39])=[O:38])[C:28]=1[F:27]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1F
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1F
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
In a dried 4.5 l reactor equipped with mechanical stirrer, thermometer, reflux condenser, 1 liter dropping funnel, under inert atmosphere, was dissolved 2-bromo-6-chloro-4-(1,1,1,2,3,3,3-heptafluoro-prop-2-yl)aniline (described in WO/10127926) (177 g, 0.473 mol, 1 equiv.) in anhydrous tetrahydrufurane (800 ml) at 20° C. Triethylamine (143 g, 1.418 mol, 3 equival.) and 4-dimethylaminopyridine (0.58 g, 4.73 mmol, 0.01 equiv.) were added. To the dark red solution was added, under stirring, a solution of 2-fluoro-3-nitro-benzoyl chloride (0.993 mol, 2.1 equiv.) in tetrahydrofurane (800 ml). After the addition, the orange suspension was heated with an oil bath to reflux temperature for four days. The reaction progression was monitored by LC-MS analysis of the reaction mixture. After almost complete conversion to the corresponding imide, the reaction mixture was concentrated under reduced pressure and the residue was taken up in dichloromethane (1 l) and carefully treated, under stirring, with a saturated aqueous solution of sodium hydrogenocarbonate (500 ml). After the gas evolution had ceased, the layers were separated and the organic layer was concentrated under reduced pressure. The residue was taken up in tetrahydrofurane (1 l) and treated with 2 N aqueous sodium hydroxide (470 ml, 0.94 mol, 2 equiv.) at 20° C. in order to hydrolyze the intermediate imide. The reaction was followed by LC-MS analysis. After 30 minutes, the reaction mixture was concentrated under reduced pressure and the resulting aqueous mixture was extracted with ethyl acetate (1 l). The aqueous phase was further extracted with three portions of ethyl acetate (200 ml each) and the combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude product was dissolved in methanol (1.5 l) at 50° C. Water (600 ml, at 50° C.) was added. A suspension formed, that was stirred until cooled to 20° C., then filtered. The residue was washed three times with 300 ml of a mixture of methanol/water:5/1. After drying, the titel compound was isolated as brown crystals with a melting point of 177-180° C.
Reaction SMILES: CN[C:3]([C:5]1[N:6]([CH2:20][CH3:21])[CH:7]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=1)=[O:4].[CH3:22][CH2:23][Mg+].[Br-]>C1COCC1>[CH2:20]([N:6]1[CH:7]=[C:8]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=[C:5]1[C:3](=[O:4])[CH2:22][CH3:23])[CH3:21]
Reactant: CC[Mg+]
Reactant: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)NC
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1cc(C#Cc2cccc(OC)c2)cn1CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere to a cold (0° C.) solution of 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid methyl amide (2.48 g, 7.93 mmol) in THF (40 ml) was added EtMgBr solution (1 molar in THF, 16 mL) over 10 minutes. The mixture was allowed to warm to room temperature and stirred for 18 hours, then poured into ice/1 N HCl solution and extracted with ether. The combined ether extracts were washed with brine, dried over MgSO4 and evaporated to dryness. The resultant residue was purified by flash chromatography (hexane/ethyl acetate 9.5/0.5) to give the title compound as an off white solid (1.8 g, 80% yield), mp 64° C., 1H NMR (400 MHZ, CDCl3) δ 1.16 (t, 3H), 1.35 (t, 3H), 2.8 (q, 2H), 3.79 (s, 3H), 4.35 (q 2H), 6.85 (m, 1H), 6.99-7.03 (m, 2H), 7.05 (m, 2H), 7.08 (m, 1H), MS m/e (M+H)+ 282.1.