Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:19](OCC)=[O:20].C(O)(=O)C>COCCOC>[CH:19]([CH:13]([CH2:12][C:5]1[C:4]([F:3])=[CH:9][C:8]([F:10])=[CH:7][C:6]=1[F:11])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20]
Reactant: CCOC(=O)CCc1c(F)cc(F)cc1F
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1c(F)cc(F)cc1F
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (1.240 g, 31.0 mmol) in DME (15 mL) was added dropwise a solution of ethyl 3-(2,4,6-trifluorophenyl)propanoate (1.8 g, 7.75 mmol) and ethyl formate (3.12 mL, 38.8 mmol) in DME (15 mL) at room temperature. The reaction mixture was then stirred overnight. It was neutralized with acetic acid (1.8 mL), then extracted with EA. The organic layer was collected, washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (2.017 g, 100% yield). LCMS: rt=2.98 and 3.67 min, [M+H+]=261.0, as a mixture of ketone (RT=2.98 min) and enol (RT=3.67 min) isomer.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([Br:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2c(Br)cccc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(Br)cccc5s4)cc3CC[C@@H]12
Yield: 78.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-bromobenzothiazole (114 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 142 mg (79%) of the title compound as an off white solid. mp 206°-210°. FDMS: m/e=474. α[D]589 =+56.25 (c=0.59, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([Cl:14])[C:3]=1[NH2:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52]C(=O)C)=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([OH:52])=[C:47]([CH:51]=2)[C:48]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=2[Cl:14])=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1c(Cl)cc(OC(F)(F)F)cc1Cl
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3c(Cl)cc(OC(F)(F)F)cc3Cl)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 33.1 %

Procedure:
2,6-Dichloro-4-trifluoromethoxyaniline (0.395 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:2) and then recrystallized from ether to obtain the titled compound (0.099 g, 0.177 mmol, 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([O-:3])=[O:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:24](=[O:26])[CH3:25])[CH:8]2[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2c1ccc(Cl)cc1
Product: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1c1ccc(Cl)cc1
Yield: 95 %

Procedure:
1-Nitro-5-(p-chlorophenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is treated with acetic anhydride as described in Example 27 to give 1-nitro-5-(p-chlorophenyl)-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline with a yield of 95%. M.p.: 183°-184° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>O1CCCC1>[CH2:14]([NH:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:18]=[CH:19][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)=[O:29])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNc1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CCCCNc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1

Procedure:
4-(4-Aminophenoxy)-2-butylaminopyridine (54 mg), p-fluorophenyl isocyanate (34.5 mg) and tetrahydrofuran (5 ml) were stirred at room temperature for 2.5 hours. After adding NH type silica gel to the reaction solution, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate). The solvent was distilled off under reduced pressure and the residue was solidified with ethyl acetate-hexane to obtain 15 mg of the target substance as a light yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH3:2].C([Li])CCC.CCCCCC.CN([CH:22]=[O:23])C>CCOCC>[CH2:1]([C:3]1[CH:7]=[C:6]([CH:22]=[O:23])[S:5][CH:4]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1ccsc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1csc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-ethylthiophene (2 g, 17.7 mmol) in ether (20 ml) under N2 at room temp is added butyl lithium, 2.5M in hexane solution (8.15 ml, 21.4 mmol) and the resulting straw coloured solution is heated to reflux for 20 minutes. The resulting cloudy solution is then cooled to room temperature before the slow addition of DMF (2 ml) over 2 minutes and the resulting solution is stirred at room temp for 1 hour. The reaction is quenched with aqueous saturated ammonium chloride (100 ml) and extracted with chloroform (100 ml). The organic layer is washed with brine, dried over magnesium sulphate and concentrated to give 4-ethyl thiophene-2-carbaldehyde as a light brown oil (2.48 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([N+:23]([O-])=O)=[C:16]2[N:15]=1.CO.C(Cl)Cl.[NH4+].[Cl-]>C(Cl)Cl.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1
Reactant: O=[N+]([O-])c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Product: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Yield: 99 %

Procedure:
To a yellowish solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine (2.3 g, 6.66 mmol), in a 1:1 mixture of MeOH/DCM (30 mL/30 mL) was added Zn dust (4.36 g, 66.6 mmol) [<10 micron, Aldrich] while stirring. Saturated NH4Cl aqueous solution (30 mL) was added drop-wise to this suspension with rapid stirring. After NH4Cl addition was complete, the reaction mixture was allowed to cool to ambient temperature and stirred for another 15 minutes. The reaction was diluted with DCM (50 mL) and filtered through a GF/F paper, rinsing the wet cake with DCM. The organic layer of the filtrate was separated, and the aqueous layer was extracted with DCM (2×50 mL). The organic layers were combined, washed with brine (100 mL), dried over Na2SO4, and concentrated, to provide the basically pure product as a brownish foamy solid (2.08 g, 99% yield), which was used without further purification.
Reaction SMILES: O(C1C=CC(C(O)=O)=CC=1)C1C=CC=CC=1.C(#N)CC#N.[C:22]([C:24]([C:40]#[N:41])=[C:25](O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)#[N:23].C[Si](C=[N+:47]=[N-:48])(C)C.O.NN>>[NH2:23][C:22]1[C:24]([C:40]#[N:41])=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[NH:48][N:47]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Agent: NN
Agent: O=C(O)c1ccc(Oc2ccccc2)cc1
Solvent: N#CCC#N
Solvent: O
Product: N#Cc1c(N)n[nH]c1-c1ccc(Oc2ccccc2)cc1

Procedure:
First, 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine may be prepared in accordance with procedures described in WO 2008/039218, for instance by converting 4-phenoxybenzoic acid to the corresponding acyl chloride (by using thionyl chloride), which latter product may be reacted with malononitrile to prepare 1,1-dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene. The methoxy moiety is then methylated using trimethylsilyldiazomethane, and that methylated product is the treated with hydrazine hydrate to provide 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole, which is reacted with formamide to provide 4-amino-3-(4-phenoxyphenyl)-1H-pyrazole[3,4-d]pyrimidine, as illustrated in the following scheme:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][C:9]=2[N:10]=1.[OH-].[Na+]>C(O)C>[Cl:23][C:22]1[CH:2]=[CH:3][C:4]([CH2:5][C:6]2[O:7][C:8]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][C:9]=3[N:10]=2)=[CH:20][CH:21]=1
Reactant: CC(C(=O)O)c1ccc2oc(Cc3ccc(Cl)c(Cl)c3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)c1ccc2oc(Cc3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[2-(3,4-dichlorobenzyl)-5-benzoxazolyl]propionic acid. (g) 2N-Sodium hydroxide solution (30 ml.) was added to the ethyl ester (5.8 g.) prepared in Example 1(g) in ethanol (40 ml). After 2 hours stirring at room temperature the volume was reduced by evaporation at 40° C and the solution diluted with water (120 ml.). It was then extracted with ether (x2) acidified with concentrated hydrochloric acid and then extracted with chloroform (x3). The combined chloroform extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to give an oil. This oil was purified using prep. tlc plates to give 2-[2-(4-chlorobenzyl)-5-benzoxazolyl]propionic acid, m.p. 135°-7° C, which was characterised by IR, UV and NMR spectroscopy and by micro analysis which gave C 64.41% H 4.71% N 4.57% C17H14Cl NO3 requires C 64.66% H 4.44% N 4.44% (h) A mixture of ethyl 3-amino-4-hydroxy-phenyl-propionate (4 g.), 4-fluoro-phenyl-acetic acid (3 g.), p-toluene sulphonic acid (0.1 g.) and xylene (50 ml.) was heated under reflux for 20 hours and the water which formed was removed using a Dean and Stark apparatus. The solution was evaporated to dryness and the residue dissolved in ether. The solution was washed with 2N-sodium hydroxide solution (x2) and water, then stirred with charcoal and anhydrous sodium sulphate, filtered and evaporated to dryness. The residual oil (3.7 g., ND22.5 1.5469) was dissolved in ethanol (30 ml.) and 2N-sodium hydroxide solution (30 ml) was added with stirring over 15 minutes. The reaction mixture was stirred for 21/2 hours during which time water (250 ml) was slowly added. The solution was extracted with ether (x2), acidified with concentrated hydrochloric acid and then extracted with ether (x3). These ethereal extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to give an oil. This oil was purified using prep. tlc plates to give 2-[2-(4-fluorobenzyl)-5-benzoxazolyl]propionic acid as a white solid, mpt 91°-93° C, which was characterised by IR UV and NMR spectroscopy and by microanalysis which gave C68.40% H 3.86% N 4.64% C17H14FNO3 requires C 68.23% H 4.68% N 4.68% (i) 2,6-Dichloro-phenyl-acetic acid (15.1 g.) was added portionwise with warming to thionyl chloride (30 ml.). The solution was heated on a steam bath for half an hour then allowed to stand at room temperature for 21/2 hours. The excess of thionyl chloride was removed by distillation under reduced pressure and the residue was distilled to give the acid chloride as a colourless oil, bpt 149°-150°/15 mm.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].C[O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](Cl)=[O:35])[CH:29]=1.N1C=CC=CC=1>C(Cl)Cl>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([CH2:9][C@@H:8]([NH:22][C:34](=[O:35])[C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([OH:37])=[O:26])[CH2:7][C@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:24])[CH3:23])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 29: 70 mg, 0.201 mmol) and 3-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 mL) is added pyridine (0.5 mL) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1M HCl and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid. Next, to a solution of N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (1.2 mL, 1.12 mmol) and the mixture is stirred at 50-60° C. for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1M HCl and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1.05 minutes (condition F); MS 432.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07 Hz, 3H), 1.60 (m, 1H), 1.89 (m, 1H), 2.47 (m, 1H), 2.86 (m, 2H), 4.27 (m, 1H), 7.27-7.35 (m, 3H), 7.34 (t, 1H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01-8.07 (m, 2H), 8.39 (s, 1H), 8.47 (d, J=8.46 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5].[CH:15](O)=O>>[CH3:1][N:2]([CH3:15])[CH:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5]
Reactant: CNC(CO)CCOc1ccccc1
Reactant: O=CO
Product: CN(C)C(CO)CCOc1ccccc1

Procedure:
2-(methylamino)-4-phenoxy-1-butanol, described in Example 4, with formic acid, followed by reduction, gives 2-(dimethylamino)-4-phenoxy-1-butanol,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Li+].CC([N-]C(C)C)C.[C:19](=[O:21])=[O:20]>C1COCC1.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: COc1cncc(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cncc(OC)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A solution of 3,5-dimethoxypyridine (600 mg, 4.3 mmol) (prepared according to the method of Testaferri, L. et al Tetrahedron, 1985, 41, 1373) in THF (2.6 ml) was added to a solution of LDA [generated from n-BuLi (1.9 ml, 2.5 M in hexane, 4.73 mmol) and diisopropylamine (0.6 ml, 5.16 mmol)] in THF (2.6 ml) at −78° C. under nitrogen. The reaction mixture was stirred for 30 minutes at −78° C., transferred via cannula to a suspension of crushed solid CO2 (30 g) in toluene (100 ml) under vigorous stirring and warmed to room temperature. The reaction is quenched by addition of water (20 ml) to and 1M NaOH (10 ml) and the aqueous layer separated, acidified to pH 4 with glacial acetic acid and extracted with 10% MeOH in dichloromethane (3×50 ml). The combined organic layers were dried (MgSO4) and the solvent removed under vacuum to give the title compound (502 mg, 63%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([N:13]([CH3:20])C3C=CC=CC=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2].[S:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31](CN)=[CH:30][CH:29]=2)=[CH:24]1>CCO>[CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([NH:13][CH2:20][C:31]3[CH:30]=[CH:29][C:28]([C:25]4[CH:26]=[CH:27][S:23][CH:24]=4)=[CH:35][CH:34]=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:2])[CH3:3]
Reactant: CSc1nc(N(C)c2ccccc2)n2ncc(C(C)C)c2n1
Reactant: NCc1ccc(-c2ccsc2)cc1
Solvent: CCO
Product: CSc1nc(NCc2ccc(-c3ccsc3)cc2)n2ncc(C(C)C)c2n1
Yield: 74 %

Procedure:
According to the same conditions resulting in the preparation of the compound IIa.1, the compound IIa.3 is prepared from 8-isopropyl-4-(N-methyl-N-phenylamino)-2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazine and from 4-(thiophen-3-yl)benzylamine. Yield=74%. Mp=141-143° C. (EtOH). 1H NMR (300 MHz, CDCl3): δ 7.73 (s, 1H, Harom), 7.57 (d, 2H, J=8.3 Hz, Harom), 7.45-7.36 (m, 5H, Harom), 6.78 (bs, 1H, NH), 4.81 (d, 2H, J=6.0 Hz, CH2), 3.16 (hept, 1H, J=7.0 Hz, CH), 2.58 (s, 3H, CH3), 1.33 (d, 6H, J=7.0 Hz, 2 CH3). MS (ESI): m/z 396 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[H][H]>[Pd].CO>[C:8]([C:5]1[CH:4]=[C:3]([NH2:12])[CH:2]=[CH:7][CH:6]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cccc(N)c1

Procedure:
1-Bromo-4-tert-butyl-2-nitro-benzene (18 g) was reduced as described in General Method 3 using 10% palladium on charcoal (1 g) and MeOH (100 mL) in a hydrogen atmosphere (50 psi). The catalyst was filtered, and the solvents were evaporated. The residue was taken in EtOAc (100 mL) and washed with saturated sodium bicarbonate solution and H2O. The solution was dried and concentrated. The residue was purified by flash chromatography to give 3-tert-butyl-phenylamine. MS (APCI): 150 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:13][C:12]=2[C:24]([NH2:26])=[O:25])=[CH:7][CH:6]=1.[CH3:27][NH:28]CC1C=CC=CC=1>CO.[Pd]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:14]1[O:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:28][CH3:27])=[CH:6][CH:7]=2)=[C:12]([C:24]([NH2:26])=[O:25])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCCCl)cc1
Reactant: CNCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCOc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1

Procedure:
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide with N-methylbenzylamine, according to the procedure described in example S-1, step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 60° C., 0.05M in MeOH). 1H NMR (DMSO) δ 2.35 (3H, s), 2.87 (2H, t), 4.10 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.55 min; m/z (ES+) 374.
Reaction SMILES: Cl[Si:2]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH2:5][CH3:6].C(=O)=O.Br[C:19]([F:22])([F:21])[F:20].C(N(CC)P(N(CC)CC)N(CC)CC)C>CC(C)=O.ClCCl>[CH2:3]([Si:2]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[C:19]([F:22])([F:21])[F:20])[CH2:4][CH2:5][CH3:6]
Reactant: FC(F)(F)Br
Reactant: CCCC[Si](Cl)(CCCC)CCCC
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCC[Si](CCCC)(CCCC)C(F)(F)F
Temperature: -78 °C
Yield: 67.1 %

Procedure:
A flask equipped with a dry ice condenser was flame dried under a nitrogen sream, and charged with 5.0g (20 mmol) of chlorotri-n-butylsilane and 10 mL of dichloromethane. After cooling the resulting solution to -78° C. and charging the condenser with dry ice and acetone, 6.2 mL (66 mmol) of bromotrifluoromethane (Freon 13Bl) that had been condensed into a graduated tube was warmed to room temperature and allowed to distill into the flask. The cooling bath was removed and the mixture was allowed to warm to the temperature of the refluxing Freon (-59° C.). To this cold solution was added, dropwise, 8.0 mL (29 mmol) of hexaethylphosphorous triamide. The resulting solution was stirred at reflux for 1 hour. Removal of the condenser and continued stirring for 1 hour resulted in evaporation of excess Freon and warming of the solution to room temperature. Dilution with 30 mL of dichloromethane, water (three 30 mL portions) and lN HCl (two 30 mL portions) washing, drying (MgSO4), and concentration afforded a residue which was short path distilled to give 3.6 g (64% yield) of tri-n-butyltrifluoromethylsilane: bp 53°-58° C. at 0 5 torr; 1H NMR (CDCl3)δ0.60-1.10 (m, 5H), 1.10-1.56 (m, 4H); 19F NMR (CDCl3, relative to CFCl3) -61.6 ppm (s); IR (neat) 2956, 2925, 2872, 1214, 1058 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 199 (30, M-CF3), 143 (80), 105 (30), 101 (27), 87 (30), 77 (66), 63 (43), 59 (41), 55 (54), 47 (25), 43 (20), 41 (100). Anal. Calcd. for C13H27F3Si: C, 58.16; H, 10.14. Found: C, 58.26; H, 10.09.