Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.[H-].[Na+].I[CH3:36]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([N:25]([CH3:36])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N(C)C(=O)OC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 36.7 %

Procedure:
(S)-tert-Butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.150 g, 0.341 mmol), prepared as described in Example 16, Part H, was taken up in DMF (1 mL) and cooled to 0° C. NaH (0.027 g, 0.683 mmol) was added and the reaction mixture was stirred for 45 min at 0° C. Iodomethane (0.107 mL, 1.706 mmol) was then added and reaction mixture was warmed to room temperature and stirred for 15 min. The mixture was quenched with ice and partitioned between ethyl acetate (4 mL) and water (2 mL). The organic layer was separated, washed with brine (2 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude which was purified by preparative HPLC to afford (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)(methyl)carbamate (60 mg, 0.125 mmol, 37% yield) as a light yellow solid. LC/MS (ESI) m/e 454.4 [(M+H)+, calcd for C26H36N3O2 454.3]; LC/MS retention time (method E): tR=1.21 min.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([OH:27])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[C:18]=1[CH3:26])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:40]([Si:44]([CH3:47])([CH3:46])Cl)([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([O:27][Si:44]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:47])[CH3:46])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[C:18]=1[CH3:26])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reaction time: 2.25 h

Procedure:
A solution of 1.153 g (2.445 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3-dimethyl-4-methoxyphenyl)methyl]hexanoic acid, 1.372 g (20.05 mmol) of imidazole and 1.709 g (11.0 mmol) of tert-butyldimethylchlorosilane in 8.7 ml of abs. DMF is stirred at RT for 18 h under argon. After that, the reaction mixture is poured onto ice-water and the whole is extracted with ethyl acetate. The organic phase is washed with cold 10% citric acid solution and saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a RE at approximately 30° C. The resulting product is dissolved in 28.8 ml of methanol and 11.2 ml of THF, and this solution is treated, at RT, with 1.962 g of potassium carbonate in 11.2 ml of water. After having been stirred for 2.25 h, the reaction mixture is concentrated down to half its volume at approximately 30° C. and the residue is treated with ethyl acetate and (cold) 10% citric acid solution, and the phases are separated. The organic phase is washed a further two times with saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by being chromatographed twice on silica gel (hexane:ethyl acetate, 1:1 and then 3:1), and the title compound is obtained. TLC Rf (hexane:ethyl acetate. 1:1)=0.42. FAB-MS (M+H)+ =586. IR (KBr) inter alia: 1711, 1485, 1260 and 1107 cm-1. 1H-NMR (CD3OD) inter alia: 7.30-7.06 (m, 5H); 6.91 and 6.65 (each d, each 1H); 6.00 and 5.41 (each d, in all 1H from NH); 3.75 (s, 3H); 2.21 and 2.12 (each s, each 3H); 1.31 and 1.21 (each s, in all 9H from Boc); 0.89 (s, 9H); 0.12 and 0.08 (each s, each 3H).
Reaction SMILES: [CH3:1]C1C=CC(C)=CC=1C(O)=O.F[C:13]1[CH:14]=[C:15]([C:22]([OH:24])=[O:23])[CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>>[CH3:1][C:14]1[CH:13]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1cc(F)cc(C(=O)O)c1
Reactant: Cc1ccc(C)c(C(=O)O)c1
Product: Cc1ccc(C(=O)O)cc1C(=O)O

Procedure:
The precursor compound was synthesized from 2,5-dimethylbenzoic acid following the procedure described for 5-fluoro-isophthalic acid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH2:33]>>[F:29][C:30]([F:35])([F:34])[CH2:31][CH2:32][NH:33][CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: NCCC(F)(F)F
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCCC(F)(F)F)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 3,3,3-trifluoropropan-1-amine via General Procedure E to give 8 mg of 293 following reverse phase purification. MS (Q1) 475.2 (M)+
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1)[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[Cl:16][C:15]1[C:10]([C:7](=[N:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:8][N:22]2[C:21](=[O:23])[C:20]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]3[C:18]2=[O:28])=[N:11][CH:12]=[C:13]([Cl:17])[CH:14]=1
Reactant: CC(C)(C)ON=C(CBr)c1ncc(Cl)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)ON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To 140 mg of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-(tert-butyl)oxime in 2 ml of N,N-dimethylformamide, 91 mg of potassium phthalimide was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (15 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 4:6) as the eluent to obtain 162 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:16])[CH2:14][Cl:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CN=C1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([O:16][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:14][Cl:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCC(CCl)O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 64 h
Yield: 81.5 %

Procedure:
To a mixture of 3-chloro-2-hydroxypropyl 4-methylbenzenesulfonate (17.4 g) and imidazole (13.4 g) in DMF (130 mL) was added tert-butyl(chloro)dimethylsilane (14.9 g), and the mixture was stirred for 64 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with hexane. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (20.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:23])[CH:18](Cl)[O:19][CH2:20][CH3:21])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:23])[CH:18]([O:19][CH2:20][CH3:21])[N:11]1[CH:12]=[CH:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:10]1)[CH3:15]
Reactant: COc1ccc(-c2cc[nH]n2)cc1
Reactant: CCOC(=O)C(Cl)OCC
Product: CCOC(=O)C(OCC)n1ccc(-c2ccc(OC)cc2)n1

Procedure:
3-(4-Methoxyphenyl)pyrazole (CAS 27069-17-6) was reacted with 2-chloro-2-ethoxy-acetic acid ethyl ester according to general procedure A to give (RS)-ethoxy-[3-(4-methoxy-phenyl)-pyrazol-1-yl]-acetic acid ethyl ester. Colorless oil. MS 305.1 ([M+H]+)
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:20]1[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH:22]([CH2:30][CH:31]([CH3:41])[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:33])[CH2:21]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH2:8]([N:20]1[CH2:29][CH2:28][C:23]2([O:24][CH2:25][CH2:26][O:27]2)[CH:22]([CH2:30][CH:31]([CH3:41])[C:32]([NH:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:33])[CH2:21]1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCc1ccccc1
Reactant: CC(CC1CN(C(=O)OCc2ccccc2)CCC12OCCO2)C(=O)Nc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(CC1CN(CCc2ccccc2)CCC12OCCO2)C(=O)Nc1ccccc1
Yield: 92 %

Procedure:
Phenylacetaldehyde (0.87 mL, 7.40 mmol) was added to a solution of (8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (96) in MeOH (49.4 mL, 0.03M) in a hydrogenation flask. 20% Pd/C (0.53 g) was added, and the mixture was shaken under 40 psi H2 until the consumption of H2 ceased and the reaction was judged complete by TLC (3.5 h). The crude reaction mixture was passed through a column of Celite, concentrated in vacuo, and purified by flash column chromatography (60:38:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain pure (8-phenethyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-ylmethyl)-N-phenylpropionamide (97) (0.59 g, 92%). 1H NMR (CDCl3): 7.42-7.12 (10H, m), 4.08 (1H, dd, J=13.4, 9.5 Hz), 3.96-3.77 (4H, m), 3.65 (1H, broad d, J=10.9 Hz), 2.92-2.80 (1H, m), 2.80-2.64 (3H, m), 2.64-2.51 (2H, m), 2.33 (2H, broad t, J=10.3 Hz) 2.20-1.94 (3H, m), 1.72 (1H, dt, J=13.3, 13.2, 3.7 Hz), 1.58 (1H, ddd, J=13.1, 10.9, 4.3 Hz), 1.03 (3H, t, J=7.4 Hz) ppm. LRMS: 408.86.
Reaction SMILES: C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(CC(F)(F)F)N=CC=13)C2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[N:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1.[N:55]([C:58]1[CH:63]=[CH:62][C:61]([C:64]2[N:69]=[C:68]3[N:70]([CH2:73][C:74]([F:77])([F:76])[F:75])[N:71]=[CH:72][C:67]3=[C:66]([N:78]3[CH2:84][CH:83]4[O:85][CH:80]([CH2:81][CH2:82]4)[CH2:79]3)[N:65]=2)=[CH:60][CH:59]=1)=[C:56]=[O:57]>ClCCl.C(N(CC)CC)C>[N:45]1([C:48]2[N:53]=[CH:52][C:51]([NH:54][C:56]([NH:55][C:58]3[CH:63]=[CH:62][C:61]([C:64]4[N:69]=[C:68]5[N:70]([CH2:73][C:74]([F:76])([F:77])[F:75])[N:71]=[CH:72][C:67]5=[C:66]([N:78]5[CH2:84][CH:83]6[O:85][CH:80]([CH2:81][CH2:82]6)[CH2:79]5)[N:65]=4)=[CH:60][CH:59]=3)=[O:57])=[CH:50][CH:49]=2)[CH2:46][CH2:47][O:42][CH2:43][CH2:44]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: O=C=Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1)Nc1ccc(N2CCOCC2)nc1
Reaction time: 8 h

Procedure:
A solution of 4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine (50 mg, 0.12 mmol) in dichloromethane (4 mL) was treated with triethylamine (0.16 mL), followed by a solution of triphosgene (19 mg, 0.064 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 6-morpholinopyridin-3-amine (86 mg, 0.48 mmol)—was added to the 3-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After being left overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile over 30 minutes to provide 1-(6-morpholin-4-ylpyridin-3-yl)-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea.TFA (18 mg, 21%). MS (ES+): 610.2 (M+H)+
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl.CN(C=O)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:1])([F:13])[F:12])[CH3:21]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of 2-trifluoromethylbenzoic acid (20.0 g, 105 mmol) in 500 mL of methylene chloride was added oxalyl chloride (18.4 mL, 210 mmol) followed by ˜8 drops of DMF. The reaction was allowed to stir at ambient temperature for 4 h and then was concentrated in vacuo to a solid. The solid was taken up in 500 mL of methylene chloride and then there was added diethylamine (24 mL, 231 mmol) dropwise as a solution in 50 mL of methylene chloride. The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc, washed sequentially with 1N HCl, sat'd. aq. NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 22 g (85%) of the title compound as an oil. 1H NMR (CDCl3): δ 7.68 (d, 1H, J=7.7 Hz), 7.57 (t, 1H, J=7.4 Hz), 7.49 (t, 1H, J=7.7 Hz), 7.32 (d, 1H, J=7.1 Hz), 3.90-3.82 (m, 2H), 3.29-3.22 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.03 (t, 3H, J=7.2 Hz). LRMS (ESI): 246.12 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[C:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:29]([F:32])([F:31])[F:30])=[C:20](Cl)[N:19]2[N:34]=[CH:35][N:36]=[C:18]2[N:17]=1>ClCCl>[Cl:15][C:16]1[C:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[C:29]([F:32])([F:30])[F:31])=[C:20]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[N:19]2[N:34]=[CH:35][N:36]=[C:18]2[N:17]=1
Reactant: Fc1ccc(C(F)(F)F)c(-c2c(Cl)nc3ncnn3c2Cl)c1
Reactant: CC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCN(c2c(-c3cc(F)ccc3C(F)(F)F)c(Cl)nc3ncnn23)CC1
Yield: 57.9 %

Procedure:
A mixture of 4-methylpiperidine(1.42 mmoles), triethylamine (1.42 mmoles) and dichloromethane (10 ml) is added to a mixture of 5,7-dichloro-6-(5-fluoro-2-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-α]pyrimidine (1.42 mmol) and dichloromethane (30 ml) under stirring. The reaction mixture is stirred 48 hours at room temperature and subsequently washed with dilute hydrochloric acid (5%). The organic layer is separated, dried with anhydrous sodium sulfate and filtered. The filtrate is evaporated under reduced pressure to yield 0.34 g of white crystals having a melting point of 149° C.
Reaction SMILES: [O-]S([O-])(=O)=O.[Na+].[Na+].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16].[OH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>CC(C)=O>[C:14]([OH:19])(=[O:18])[C:15]([OH:17])=[O:16].[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[O:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1
Reactant: OCCc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: O=C(O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Oc1ccc(CCOC2CCCCO2)cc1

Procedure:
Alternatively, suitable 4-(hydroxyalkyl)phenols or 4-(hydroxyalkyl)thiophenols may be protected in one step by combining a solution of the selected 4-(hydroxyalkyl)phenol or 4-(hydroxyalkyl)thiophenol in acetone with Na2SO4, dihydropyran, and a catalytic amount of oxalic acid. For example, 4-(2-hydroxyethyl)phenol in acetone is reacted with Na2SO4, distilled dihydropyran, and a catalytic amount of oxalic acid for three hours to yield 4-(2-tetrahydropyran-2-yloxyethyl)phenol (9).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6]>C(OCC)(=O)C>[CH2:1]([NH:4][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: C=CCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Step 1′ A 3-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a nitrogen inlet adapter, and a 500-mL pressure-equalizing addition finnel fitted with a glass stopper was purged with nitrogen. The flask was charged with allylamine (K) 33.9 g (0.593 mol), 50 mL of ethyl acetate, triethylaamine 60.0 g (0.593 mol), and then cooled with an ice-water bath. The addition funnel was charged with 3-nitro-benzoyl chloride (J) 100.0 g (0.539 mol) and 230 mL ethyl acetate, and this solution was then added dropwise to the reaction mixture over 1 h while the reaction mixture was maintained at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then filtered. The filtrate was transferred to a separatory finnel and washed with 150 mL of a 10% (by volume) HCl aqueous solution, 100 mL of saturated sodium chloride solution, dried over magnesium sulfate, and the solvent volume was reduced to one-third the original volume under reduced pressure. The clear solution was cooled to 0° C. overnight. The resulting yellow solid was collected by filtration and dried in a vacuum oven at 50° C. for 6 h to afford 89.4 g (80% yield) of N-allyl-3-nitrobenzamide (L) as a yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
To a solution of Example 7 (0.095 g, 0.240 mmol) in methanol (1.4 ml), lithium hydroxide (0.028 g, 1.20 mmol) in water (0.36 ml) was added and stirred at RT. After 12 h, the pH was adjusted to (approx) 7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.070 g, 76%). M.P.: 245-247° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.18 (s, 1H), 8.88 (dd, J=4.1, 1.7 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.39 (d, J=1.1 Hz, 1H), 8.36 (d, J=8.5 Hz, 2H), 8.21 (d, J=8.7 Hz, 1H), 8.10 (d, J=8.5 Hz, 2H), 8.03 (d, J=9.2 Hz, 2H), 7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.22 (s, 2H). MS (m/z): 381.88 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:17])=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.[CH2:47]([NH2:51])[CH2:48][CH2:49][CH3:50]>CN(C)C=O>[CH2:47]([NH:51][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12])[CH2:48][CH2:49][CH3:50]
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Reactant: CCCCN
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccccc1C=C(C)C(=O)OCC
Yield: 78.1 %

Procedure:
Ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate is prepared as described in Example 30, starting with 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide, a solution of 0.69 cm3 (5.0 mmol) of triethylamine, 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide and a second solution consisting of 366 mg (5.0 mmol) of n-butylamine and 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide. 1.13 g of ethyl 3-(2-butylcarbamoylphenyl)-2-methylacrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: CN(C)CCO.C([Li])CCC.[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Br)(Br)(Br)[Br:25]>CCCCCCC.O>[Br:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:19]=1
Reactant: BrC(Br)(Br)Br
Reactant: c1ccc(-c2ccccn2)cc1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: O
Product: Brc1cccc(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To N,N-dimethylethanolamine (0.8 mL, 8.00 mmol) in heptane (10 mL) cooled externally to 0° C. was added dropwise a 2.5 M n-butyllithium solution (6.40 mL) and the reaction mixture stirred for 30 minutes. 2-Phenylpyridine (12) (412 mg, 2.66 mmol) in heptane (5 mL) was then added and the reaction mixture stirred for a further 1 hour. The reaction was then cooled and carbon tetrabromide (3.18 g, 9.60 mmol) was added whilst maintaining the temperature at −78° C. The reaction was kept at −78° C. for 1 hour and then allowed to warm to ambient temperature. Water was cautiously added and extracted with TBME (×2), dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was purified by column chromatography eluting with 5% EtOAc in heptane to give the title compound. Yield: 300 mg, 48%; LC-MS tr 1.63 min; HPLC Purity: 97%; MS (ES+) m/z 234, 236 (M+H)
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:15]=1[CH2:16]Cl.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:11][C:9]1[N:10]=[C:3]2[C:2]([O:1][CH2:16][C:15]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:14]=3[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[C:8]=1[CH3:12]
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1nc2c(O)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cccc(C)c1COc1cccn2c(C)c(C)nc12
Yield: 33.7 %

Procedure:
A mixture of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine (1.2 g, 7.41 mmol), 2,6-dimethylbenzylchloride (1.145, 7.41 mmol), sodium iodide (0.3 g), sodium carbonate (2.0 g) and acetone (50 ml) was refluxed for 3 h. After the addition of methylene chloride the reaction mixture was filtered. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was chromatographed on silica, eluting with CH2Cl2—MeOH (100:5) to give 0.70 g of the desired product (from ethyl acetate-ether).