Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]([O:9][C:10]1[CH:32]=[CH:31][C:13]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=2[O:29][CH3:30])=[O:15])=[CH:12][CH:11]=1)[CH2:6][CH:7]=[CH2:8]>O1CCCC1>[Cl:1][Si:2]([Cl:4])([Cl:3])[CH2:8][CH2:7][CH2:6][CH2:5][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:18]=2[O:29][CH3:30])=[O:15])=[CH:31][CH:32]=1
Reactant: C=CCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OC)cc2OC)cc1
Reactant: Cl[SiH](Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC[Si](Cl)(Cl)Cl)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 ml of trichlorosilane are added while stirring to a solution of 0.1 g of H2PtCl6 in 20 ml of dry tetrahydrofuran. A solution of 14.8 g of 2-methoxy-4-[(E)2-methoxycarbonylvinyl]phenyl 4-(3-butenyloxy)benzoate dissolved in 20 ml of dry tetrahydrofuran is cautiously added dropwise thereto. Thereafter, the mixture is stirred at room temperature for 5 hrs. and then at 50° C. for 16 hrs. The reaction mixture is concentrated in a water-jet vacuum and completely freed from residual solvent and trichlorosilane on an oil pump with a cooling trap under reduced pressure. This gives crude 2-methoxy-4-[(E)2-methoxycarbonylvinyl]phenyl 4-(4-trichlorosilanylbutyloxy)benzoate, which is dissolved in dry tetrahydrofuran for storage.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26]([NH:9][C:5]1[C:4]([O:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=1)(=[O:28])=[O:27]
Reactant: Nc1nc(Cl)c(Cl)nc1OCc1cccnc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1nc(Cl)c(Cl)nc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 121a) (0.27 g) and 2,3-dichlorobenzenesulphonyl chloride (0.27 g). Yield 0.17 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][N+:14]([O-])=O>[Ni].CO>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][NH2:14]
Reactant: COCOCc1ccccc1C(C[N+](=O)[O-])c1ccccc1
Agent: [Ni]
Solvent: CO
Product: COCOCc1ccccc1C(CN)c1ccccc1
Yield: 122.1 %

Procedure:
Raney nickel (3.4 g) was placed in Parr flask and was washed with MeOH (3×), then 1-((methoxymethoxy)methyl)-2-(2-nitro-1-phenylethyl)benzene (2.93 g, 9.72 mmol) in MeOH (150 mL) was added. The flask was installed on a Parr shaker, purged first with argon (3×) then H2 (3×) then pressurized to ˜35 psi and shaken over a weekend. The reaction was depressurized, then was filtered and concentrated to give 3.22 g of an oil. The residue was dissolved in CHCl3, dried (MgSO4), filtered through Celite and concentrated to afford the product (2.57 g) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.35 (s, 4H), 7.13-7.31 (m, 5H), 4.70 (d, J=11.87 Hz, 3H), 4.66 (s, 3H), 4.51 (d, J=11.62 Hz, 2H), 4.35 (t, J=6.06 Hz, 1H), 3.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18])=[C:5]2C.[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH2:32]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17]([CH:19]1[CH2:20][CH2:21]1)=[O:18])=[C:5]2[NH:32][CH2:31][CH:30]([O:33][CH3:34])[O:29][CH3:28]
Reactant: COC(CN)OC
Reactant: Cc1c(C(=O)C2CC2)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)c(OS(=O)(=O)O)c12
Solvent: C1CCOC1
Product: COC(CNc1c(C(=O)C2CC2)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
6-Chloro-3-cyclopropanecarbonyl-4-methylsulfoxy-8-trifluormethyl-2-quinolinone (377 mg, 1 mmol) and 2,2-dimethoxyethylamine (105 mg, 1 mmol) were dissolved in tetrahydrofurane (20 ml) and stirred for 24 hr at room temperature. After completion of reaction, solvent was removed under reduced pressure and residue was recrystallized from ethanol to give desired product (335 mg, yield: 80%).
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[C:14]([O:16]CC)=[O:15])=[N+:2]=[N-:3].O>[OH-].[Na+]>[N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15])=[N+:2]=[N-:3]
Reactant: CCOC(=O)c1cnc2ccccc2c1N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [N-]=[N+]=Nc1c(C(=O)O)cnc2ccccc12
Temperature: 0 °C

Procedure:
4-Azido-3-carbethoxyquinoline (1.4 g; 0.006 M) was suspended in 10% aq. NaOH at ambient temperatures and the mixture stirred until complete solution had been obtained. The solution was filtered, cooled to 0° C. and acidified to pH 4 with 5 M HCl. The resulting precipitate was filtered, washed well with H2O and dried in vacuo over P2O5 to yield the product, 1.3 g (93%), as a monohydrate, m.p. 284° C. (dec.) (Found: N, 24.53%, C10H8N4O3 requires: N, 24.46%), νmax (nujol) 3200-3700(br), 2200-2600(br), 2110, 1700, 1492, 1327, 1215, 760cm-1, δ[(CD3)2SO] 7.45-3.1(m), 8.9(s) (aromatic protons). 14-16 (broad) (CO2H*+H2O),
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]4[NH:27][N:26]=[CH:25][CH:24]=4)=[CH:18][C:17]=3[Cl:28])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[OH:31][C:32]([CH3:39])([CH3:38])/[CH:33]=[CH:34]/B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2](/[CH:34]=[CH:33]/[C:32]([OH:31])([CH3:39])[CH3:38])[CH:30]=[CH:29][C:5]=2[N:6]=1
Reactant: CC(C)(O)/C=C/B(O)O
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccc(Br)cc3c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)/C=C/c1ccc2nc(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)c3cc[nH]c(=O)c3c2c1
Temperature: 80 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1H-pyrazol-5-yl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (Example 100, Step 4) (125 mg, 0.25 mmol) in THF (4 mL) was added [(1E)-3-hydroxy-3-methylbut-1-en-1-yl]boronic acid (65 mg, 0.45 mmol), Pd(Ph3P)4 (58 mg, 0.05 mmol) and sodium carbonate (0.125 mL, 0.25 mmol, 2M in water). The reaction was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF and methanol, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [Cl-:1].[F:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:4]=1C(F)(F)F.[CH2:16]([Cl:18])[Cl:17]>>[F:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:4]=1[C:16]([Cl:1])([Cl:18])[Cl:17]
Reactant: [Cl-]
Reactant: Fc1cc(C(F)(F)F)c(F)c(F)c1F
Reactant: ClCCl
Product: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Temperature: 0 °C

Procedure:
85 g (0.64 mol) of aluminiumn chloride (anhydrous) are initially introduced into 500 ml of methylene chloride, and 109 g (0.5 mol) of 2,3,4,5-tetrafluoro-benzotrifluoride are added dropwise at room temperature, while stirring. The, mixture is then subsequently stirred at 40° C. for 1 hour, allowed to cool and poured onto 600 g of ice, the organic phase is separated off, the aqueous phase is extracted with ether and the combined phases are washed with water and dried over anhydrous magnesium sulphate. After concentration, the residue is distilled. 108.3 g (81% of theory) of product are obtained; boiling point: 89-90° C./22 mbar.
Reaction SMILES: C([O:14][C:15](=[O:44])[C@H:16]([CH2:35][S:36][CH2:37][C@H:38]([OH:43])[C@H:39]([OH:42])[CH2:40][OH:41])[NH:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(C1C=CC=CC=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(Cl)Cl>[C:18]([NH:17][C@H:16]([C:15]([OH:44])=[O:14])[CH2:35][S:36][CH2:37][C@H:38]([OH:43])[C@H:39]([OH:42])[CH2:40][OH:41])(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@H](O)[C@H](O)CO)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@H](O)[C@H](O)CO)C(=O)O
Reaction time: 2 h

Procedure:
0.9 g of N-palmitoyl-S-[2(R),3(R),4-trihydroxybutyl]-(L)-cysteine-benzhydryl ester in a mixture of 3 ml of trifluoroacetic acid and 12 ml of methylene chloride is allowed to stand for 2 hours at room temperature. The reaction mixture is then evaporated to dryness; the residue is triturated with ice-water, filtered off with suction and the solid substance is dried. It is then extracted with ligroin, and recrystallised from acetone to yield colourless crystals of N-palmitoyl-S-[2(R),3(R),4-trihydroxy-butyl]-(L)-cysteine, m.p. 76°-76.5°, having the specific rotation [α]D20 =-5° (c=0.819, dioxane).
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=1)C)C>C(O)(=O)C.O1CCOCC1.O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=1
Reactant: CCOC(C)Oc1ccc(C(C)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 700 ml of a mixed solvent of acetic acid/dioxane/water (10/5/5) was dissolved 0.35 mole of a each R-form of fatty acid ester of 1-(4-(1-ethoxyethoxy)phenyl)ethanol, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled under reduced pressure to give an R-form of fatty acid ester of 1-(4-hydroxyphenyl)ethanol.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[OH:16][CH2:15][C@H:14]([CH3:17])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1COc2ccccc2N1
Reactant: C[C@@H](CO)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](CO)CN1C(=O)COc2ccccc21
Temperature: 40 °C
Reaction time: 48 h
Yield: 147.7 %

Procedure:
A 25 mL flask was charged with 4H-benzo[1,4]oxazin-3-one (0.100 g, 0.670 mmol), (S)-3-bromo-2-methylpropanol (0.103 g, 0.670 mmol) and cesium carbonate (0.208 g, 0.670 mmol) in MeCN (10 mL) and stirred at 40° C. for 2 days. The reaction mixture was quenched with water (5 mL), and the product extracted into EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4) and evaporated to give the crude title compound (108LM40-37) (0.219 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([CH3:16])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])O1.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22](I)=[CH:21][C:20]=1[CH3:27]>>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([C:9]2[C:10]([CH3:16])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:21][C:20]=1[CH3:27]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Product: Cc1cc(-c2c(C)nn(C)c2C)cc(C)c1Br

Procedure:
The title compound is prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3,5-trimethyl-pyrazole and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=1.09 min; Mass spectrum (ESI+): m/z=293/295 (Br) [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[C:25]=1[F:33].Cl.[OH-].[Na+]>C(O)C>[NH2:30][C:26]1[C:25]([F:33])=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:3]1[C:4]([C:18]([F:20])([F:21])[F:19])=[CH:5][C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:7][C:2]=1[Br:1])=[O:34]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 104.7 %

Procedure:
0.940 g (1.63 mmol) of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-nitrobenzamide and 0.960 g (5.05 mmol) of stannous chloride (anhydrous) were added to 10 ml of ethanol, and 1.02 ml (9.78 mmol) of concentrated hydrochloric acid was added thereto, followed by stirring at 60° C. for 4 hours. The reaction mixture was adjusted to pH 10 by the addition of an aqueous sodium hydroxide solution, and the precipitated insolubles were removed by filtration using Celite. The filtrate on Celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with a 20% aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=4:1) to prepare 0.930 g (yield 99%) of a target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 16.3 g. of ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate, 16.3 g. of potassium hydroxide and 200 ml. of 95% ethanol is refluxed for 3 hours. The mixture is diluted with 100 ml. of water brought to pH 6 with concentrated hydrochloric acid. Chilling and filtering gave 15 g. of white crystals. Recrystallization from ethanol gave 8.6 g. of white crystals, m.p. 191°-192° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].COO[CH:17](OOC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COOC(OOC)N(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)s1

Procedure:
A 0.3M solution of methyl 5-methyl-4-nitrothiophene-2-carboxylate in dry DMF was treated with N,N-dimethylformamide dimethoxy acetal (10 eq.) overnight at 110° C. Evaporation to dryness gave a residue that was used as such. 1H-NMR (300 MHz, CDCl3, 300 K, δ) 8.32 (s, 1H), 7.53 (d, 1H, J 13.4), 6.77 (d, 1H, J 13.4), 4.08 (s, 3H), 3.29 (s, 6H); MS (ES+) m/z 257 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[H][H]>[Pd].CO.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(C(F)(F)F)c(O)c1
Yield: 86 %

Procedure:
10% Pd/C (590 mg) was added to 3-benzyloxy-4-trifluoromethyl-benzoic acid in a methanol-ethyl acetate mixed solvent (1:1), and the mixture was stirred at room temperature for two days in a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give 3-hydroxy-4-trifluoromethyl-benzoic acid (582 mg, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=[O:13].[CH3:15][Si:16]([CH3:21])([CH3:20])[CH2:17][CH2:18]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C1COCC1.CN(C)C1C=CN=CC=1>[CH3:15][Si:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][O:13][C:12]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])=[O:14]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(O)c1c(O)ccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)c1c(O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 2-hydroxynaphtoic acid (2.02 g, 10.7 mmol) in dichloromethane (45 mL) and THF (2 mL) were added 2-trimethylsilylethanol (4.6 mL, 32.2 mmol) and 4-dimethylaminopyridine (1.07 g, 8.9 mmol) under N2. The mixture was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (2.33 g, 11.3 mmol) was added. After removal of the ice bath, the mixture was stirred for 3 h at room temperature. 2N HCl was added to adjust the pH to 2, and the mixture was filtered to remove urea. After the separation of layers the organic phase was washed with water and brine, dried (Na2SO4), and concentrated to dryness. Purification by chromatography gave 2.92 g of 2-hydroxy-naphthalene-1-carboxylic acid 2-trimethylsilanyl-ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([C:26]2[CH:30]=[C:29]([C:31]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[NH:32])[S:28][C:27]=2[S:41][CH3:42])(=[O:25])=[O:24])[CH:18]=1)=[O:8])C.[Li+].[OH-]>CO>[C:37]([O:36][C:34]([NH:33][C:31](=[NH:32])[C:29]1[S:28][C:27]([S:41][CH3:42])=[C:26]([S:23]([C:19]2[CH:18]=[C:17]([C:11]3[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:7](=[O:8])[CH2:6][CH2:5][C:4]([OH:43])=[O:3])[CH:22]=[CH:21][CH:20]=2)(=[O:25])=[O:24])[CH:30]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)CCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-{3′-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-succinamic acid ethyl ester (Example 133: step a) and LiOH were dissolved into MeOH and stirred at RT for 2 hours. The solvents were removed in vacuo yielding the title compound that was used with out further purification or characterization.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=2)[N:9]=1.[C:22]1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOCC>CC#N>[Br-:1].[Cl:18][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[CH:17][C:8]([CH2:7][O:6][C:5]3[CH:4]=[C:3]([CH2:2][P+:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=[CH:20][CH:19]=3)=[N:9]2)=[CH:14][CH:13]=1
Reactant: Clc1ccc2ccc(COc3cccc(CBr)c3)nc2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: Clc1ccc2ccc(COc3cccc(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)c3)nc2c1
Product: [Br-]
Reaction time: 20 h
Yield: 98.5 %

Procedure:
The bromide of Step 3 (26.45 g, 72.9 mmol) and triphenylphosphine (28.7 g, 109 mmol) were heated to reflux in CH3CN (250 mL) for 7 hours. At r.t., ether was added and an oil separated, which crystallized on trituration. The solid was filtered and was swished with ether for 20 hours to yield 44.87 g (98%) of the title phosphonium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CCN(Cc5ccccn5)CC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.066 mmol) in DMF was added 2-(bromomethyl)pyridine hydrogen bromide (26.0 mg, 0103 mmol). The mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-(pyridin-2-ylmethyl)piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=544)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[C:9]([N+:18]([O-:19])=[O:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]=O
Reactant: Cc1ccc(C(C)(C)C)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 4-tert-butyl toluene (33.7 mmol) in acetonitrile (150 mL) at 0° C. was added nitronium tetrafluoroborate (40.5 mmol). After 30 min at room temperature, the reaction was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine and dried (MgSO4). Removal of the volatiles in vacuo left a residue; flash chromatography using 10% methylene chloride/petroleum ether as eluent provided 4-tert-butyl-2-nitrotoluene.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH:25]1(C2NN=C(N)N=2)[CH2:28]C[CH2:26]1>>[CH:1]1([C:2]2[N:24]=[C:5]3[N:6]=[C:7]([C:16]4[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=4)[C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:9][N:4]3[N:3]=2)[CH2:28][CH2:25][CH2:26]1
Reactant: Nc1n[nH]c(C2CCC2)n1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Product: O=Cc1ccc(-c2nc3nc(C4CCC4)nn3cc2-c2ccccc2)cc1

Procedure:
This compound was prepared in a manner according to 4-(2-methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde by using 5-cyclobutyl-1,2,4-triazol-3-amine in the first step.