Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][C@@H:19]([C:21]2[CH2:25][CH2:24][CH2:23][CH:22]=2)O)=[C:16]([CH2:26][CH3:27])[C:15]([CH3:28])=[C:14]2[C:10]=1[C:11](=[O:29])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C(C)(C)C.[C:37](OCC)([O:42]CC)([O:39][CH2:40][CH3:41])[CH3:38]>>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:21]2/[C@H:22]([CH2:38][C:37]([O:39][CH2:40][CH3:41])=[O:42])[CH2:23][CH2:24][CH2:25]/2)=[C:16]([CH2:26][CH3:27])[C:15]([CH3:28])=[C:14]2[C:10]=1[C:11](=[O:29])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C[C@H](O)C1=CCCC1)C(=O)OC2
Agent: CC(C)(C)C(=O)O
Product: CCOC(=O)C[C@@H]1CCC/C1=C\Cc1c(CC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 138 °C
Reaction time: 2.5 h

Procedure:
A mixture of (S)-2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-1-cyclopentenyl-1-hydroxyethane (2.8 g), pivalic acid (0.1 g) and triethyl orthoacetate (125 ml) was heated to 138° C. After 2.5 hours, more pivalic acid (65 mg) was added and the reaction was continued 1 hour more. The reaction mixture was cooled, the excess triethyl orthoacetate removed in vacuo, and the residue chromatographed on silica gel (20% ethyl acetate/hexane) to give ethyl (S)(E)-2-{2-[2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]cyclopent-1-yl}acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](C3C=CNN=3)[N:11]=[C:10]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:9]=2[C:29]([OH:31])=[O:30])[CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O)(=O)C>CN1C(=O)CCC1>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:11]=[C:10]([NH:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:9]=2[C:29]([OH:31])=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1c(Nc2ccc3[nH]ncc3c2)nc(-c2cc[nH]n2)nc1-c1cccc(O)c1
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C(O)c1c(Nc2ccc3[nH]ncc3c2)nc(N2CCOCC2)nc1-c1cccc(O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Resin bound 6-(3-hydroxyphenyl)-4-(1H-indazol-5-ylamino)-2-pyrazolylpyrimidine-5-carboxylic acid (100 mg, 0.055 mmol, 1 eq) was suspended in NMP, and morpholine (144 μL, 144 mg, 1.65 mmol, 30 eq) was added, followed by acetic acid (31 μL, 33 mg, 0.55 mmol, 10 eq). The reaction mixture was shaken at 90° C. overnight. The resin was filtered and washed with DMF, water, MeOH, CH2Cl2, then dried. The resin was treated with 95% TFA/H2O for 1.5 h at room temperature. Filtration and evaporation under reduced pressure afforded 6-(3-hydroxyphenyl)-4-(1H-indazol-5-ylamino)-2-morpholin-4-ylpyrimidine-5-carboxylic acid.
Reaction SMILES: NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(OC)=O)=CC=2)=CC=1.BrC1SC=CN=1.[S:30]1[C:34]2C=CC=C[C:33]=2[N:32]=[C:31]1[NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52](=[O:60])[CH2:53][C:54]([CH3:59])([CH3:58])[C:55]([OH:57])=[O:56])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1>>[CH3:58][C:54]([CH3:59])([CH2:53][C:52](=[O:60])[C:49]1[CH:48]=[CH:47][C:46]([C:43]2[CH:44]=[CH:45][C:40]([NH:39][C:31]3[S:30][CH:34]=[CH:33][N:32]=3)=[CH:41][CH:42]=2)=[CH:51][CH:50]=1)[C:55]([OH:57])=[O:56]
Reactant: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Agent: Brc1nccs1
Agent: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nccs3)cc2)cc1)C(=O)O
Yield: 24 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (64 mg, 0.21 mmol) and 2-bromothiazole (41 mg, 0.25 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 18.6 mg (24%) of the desired product. LC-MS m/z 381.4 (MH+), ret. time 2.53 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13]I)[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:22]([NH2:24])[CH3:23]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][NH:24][CH2:22][CH3:23])[CH2:7][CH2:6][CH2:5]2
Reactant: CCN
Reactant: Brc1ccc2c(c1)CCCN2CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCNCCN1CCCc2cc(Br)ccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (compound 3, 100 mg, 0.273 mmol) in acetonitrile (4.75 mL) and water (0.25 mL) in a 20 mL pressure vessel fitted with a stir-bar is treated with potassium carbonate (0.378 g, 2.73 mmol) and ethylamine hydrochloride (0.223 g, 2.73 mmol) and the sealed vessel stirred at 70° C. overnight. After 18 hours the mixture was partitioned between CH2Cl2 (50 mL) and water (10 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer extracted further with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a yellow residue. The residue was purified on silica gel eluting with 7.5% 2M NH3 in methanol/92.5% dichloromethane to yield a yellow oil/residue, 4 (55 mg, 71.1%). 1H-NMR (CDCl3) δ 7.09 (dd, 1H, J=8.7, 2.4 Hz), 7.06-7.01 (m, 1H), 6.51 (d, 1H, J=8.7), 3.36 (t, 2H, J=6.8 Hz), 3.29 (t, 2H, J=5.5 Hz), 2.82 (t, 2H, J=6.8 Hz), 2.80-2.65 (2×m, 4H), 1.96-1.88 (m, 2H), 1.11 (t, 3H, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1>ClCCl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OCc1nn(-c2ncccc2F)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)OCc1nn(-c2ncccc2F)cc1C=O
Yield: 82.2 %

Procedure:
A mixture of [1-(3-fluoro-2-pyridyl)-3-(isopropoxymethyl)pyrazol-4-yl]methanol (241 mg; 0.91 mmol) and manganese(IV) oxide (791 mg) are stirred in dichloromethane (5 mL) at room temperature overnight. After that time, the reaction mixture is filtered over celite and solvent evaporated to obtain 197 mg of the title compound that is used without further purification. MS (m/z): 264 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:7]([OH:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)COc2cc(F)ccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccc(F)cc2OCC1O
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 99.7 %

Procedure:
tert-Butyl 7-fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate (Intermediate 6, 2.22 g, 8.31 mmol) was dissolved in THF (20 mL) and cooled to −78° C. DIBAL-H (1 M in toluene, 10.8 mL, 10.8 mmol) was added at a rate to maintain the reaction temperature at below −70° C., and the reaction was thereafter stirred at −78° C. for 50 min. The cooling was removed and the reaction was quenched with NH4Cl (aq. sat. 10 mL). The mixture was allowed to reach rt. The reaction mixture was diluted with DCM and Rochelle's salt (30% aq., 100 mL) and extracted with DCM (2×100 mL). The organics were combined, washed with brine, dried over magnesium sulphate, filtered through a phase separator and concentrated to give the title compound (2.23 g, 100%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:21][CH:22]=1>CN(C)C=O>[O:23]([C:20]1[N:21]=[CH:22][C:17]([CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccc(Oc2ccccc2)nc1
Reactant: Nc1ncccc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(Oc3ccccc3)nc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
To an N,N-dimethylformamide (5.00 mL) solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20.0 mg, 0.125 mmol) described in Manufacturing Example 32-1-4 was added sodium hydride (5.50 mg, 0.138 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Thereafter, 5-chloromethyl-2-phenoxy-pyridine (49.7 mg, 0.226 mmol) described in Manufacturing Example 193-1-2 was added to the above mixture, which was stirred for 30 minutes at room temperature. The reaction mixture was partitioned into ethyl acetate and water at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1→ethyl acetate) to obtain the title compound (25.0 mg, 58.2%).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:9][CH2:10][C:11](Br)=[O:12]>C1COCC1>[Br:9][CH2:10][C:11]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:12]
Reactant: CCCCCCCN
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)CBr
Yield: 99.9 %

Procedure:
To a solution of n-heptylamine (2.30 g, 20 mmol) in THF (20 ml) was dropped a solution of bromoacetyl bromide (2.02 g, 10 mmol) in THF (10 ml) with ice-cooling and stirring and the mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated in vacuo, water was added to the residue and the mixture was extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom to provide 2.36 g (yield 99%) of crude 2-bromo-N-heptylacetamide as oil.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>>[CH:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)([CH3:13])[CH3:12]
Reactant: NC(=O)C1CCNCC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)N1CCC(C(N)=O)CC1
Yield: 94.1 %

Procedure:
Prepared from isonipecotamide (2.0 g, 15.6 mmol), 2-iodopropane (3.10 mL, 31.2 mmol) of potassium carbonate and (2.15 g, 5.6 mmol) according to the procedure used for Example 8 (Step A) to give 2.5 g of the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:33][C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:33][C:34]1[CH:39]=[C:38]([C:15]2[CH:14]=[CH:13][C:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)=[O:11])=[CH:17][CH:16]=2)[CH:37]=[N:36][CH:35]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(Br)c3)cc2)CC1

Procedure:
A solution of (4-isopropylpiperazin-1-yl)-(4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl) phenyl)-methanone (step 1) (1.0 eq, 778 mg) in DME (4 ml) and 2M sodium carbonate solution (2 eq, 2.2 ml) is treated with 3,5-dibromopyridine (1 eq, 514 mg) followed by PdCl2(dppf).DCM (0.1 eq, 159 mg). The resulting mixture is heated using microwave radiation at 90° C. for 1 h. The mixture is extracted with DCM and the organic extracts are washed with water. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with 0-100% EtOAc in iso-hexane followed by 0-5% MeOH in DCM to afford the title compound [M+H]+=388/390.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([S:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:29])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(Sc3ccccc3)ccn2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1csc(Nc2cc(S(=O)c3ccccc3)ccn2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 50 mL round bottom flask was charged with N-(4-methylthiazol-2-yl)-4-(phenylthio)pyridin-2-amine (0.050 g, 0.17 mmol) and dichloromethane (5 mL). The solution was cooled to 0° C., then MCPBA (0.029 g, 0.17 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. An additional 15 mg of MCPBA were added and the reaction mixture was stirred overnight. The reaction mixture was quenched with sodium bisulfite and extracted with dichloromethane. The organic layer was washed with a saturated solution of NaHCO3. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using preparative TLC with 35% EtOAc in hexanes as the solvent system to afford 4-methyl-N-(4-(phenylsulfinyl)pyridin-2-yl)thiazol-2-amine as a light yellow solid. 1H NMR (CDCl3) δ 8.34 (d, 1H), 7.48-7.73 (m, 5H), 7.25 (s, 1H), 6.93 (dd, 1H), 6.41 (s, 1H), 2.36 (d, 3H); Mass spectrum (apci) m/z=316 (100) (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:35])[C@@H:31]([NH:33][CH3:34])[CH3:32])[CH:24]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:37][N:38]([CH3:45])[CH2:39]/[CH:40]=[CH:41]/[C:42](O)=[O:43].Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)C(C)C)(C)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:35])[C@@H:31]([N:33]([CH3:34])[C:42](=[O:43])/[CH:41]=[CH:40]/[CH2:39][N:38]([CH3:45])[CH3:37])[CH3:32])[CH:24]=3)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)NC)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C)c1
Reaction time: 15 h
Yield: 57.2 %

Procedure:
To a solution of (S)-2-((4-cyanophenyl)amino)-N-(3-(2-(methylamino)propanamido)phenyl)-4-(propylamino)pyrimidine-5-carboxamide (E1) dihydrochloride (58 mg), 4-dimethylaminocrotonic acid hydrochloride (33 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (174 μL) was added at room temperature, and the mixture was stirred at the same temperature for 15 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure. The obtained solid matter was purified by basic silica gel column chromatography (eluent, 98 to 88% ethyl acetate in methanol) to obtain (S,E)-2-((4-cyanophenyl)amino)-N-(3-(2-(4-(dimethylamino)-N-methyl-2-butenamido)propanamido)phenyl)-4-(propylamino)pyrimidine-5-carboxamide (6-1, 41 mg) as white solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][C:11]([F:26])([F:25])[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:10][C:11]([F:25])([F:26])[C:12]([N:14]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Reaction time: 15 h
Yield: 61 %

Procedure:
tert-Butyl 2-bromoacetate was added to a solution of 52A (950 mg, 3.8 mmol) in DMF (8 mL) with Cs2CO3 (1.5 g, 4.6 mmol) and stirred 15 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 60% EtOAc in hexanes) to afford 52B (850 mg, 61%) as a clear oil. MS (ESI) m/z 361.3 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:9]1([N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cnn(C2CC2)n1
Temperature: 95 °C
Reaction time: 48 h
Yield: 18.4 %

Procedure:
To a solution of 4-nitro-2H-1,2,3-triazole (1.0 g, 8.77 mmol), cyclopropylboronic acid (1.51 g, 17.5 mmol), copper (II) acetate (1.59 g, 8.77 mmol) and N,N-dimethylpyridin-4-amine (3.21 g, 26.3 mmol) in toluene (20 ml) was added sodium 1,1,1,3,3,3-hexamethyldisilazan-2-id (14.6 ml, 0.6M toluene solution) under oxygen atmosphere, and the mixture was stirred at 95° C. for 2 days. The reaction solution was cooled to room temperature, water was then added, the mixture was extracted with chloroform, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=5:1 to 3:1) to give 2-cyclopropyl-4-nitro-2H-1,2,3-triazole (249 mg, yield: 18%) as a yellow oily substance.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:25]([C:26]([O:28]CC)=O)=[C:9]2[CH2:10][CH2:11][C:12]3[CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16][C:17]=3[C:8]2=[N:7]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[NH:18]([C:15]1[N:14]=[CH:13][C:12]2[CH2:11][CH2:10][C:9]3=[C:25]4[C:26](=[O:28])[NH:2][CH2:3][CH2:4][CH2:5][N:6]4[N:7]=[C:8]3[C:17]=2[N:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c2c(nn1CCCN)-c1nc(Nc3ccccc3)ncc1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: O=C1NCCCn2nc3c(c21)CCc1cnc(Nc2ccccc2)nc1-3
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
185 mg (0.43 mmol) of ethyl 2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate hydrochloride were dissolved in 10 mL of methanol and 400 mg of cesium carbonate were added. After 3 hours under stirring at room temperature the solvent was removed at reduced pressure. Water was then added to the residue and the solid collected by filtration and washed with water and acetone to give 100 mg (70% yield) of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:30])[CH:8]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:6][C:7]1[CH:8]=[C:9]([CH3:30])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH:26]=[O:27])=[CH:28][CH:29]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)(=[O:4])=[O:3]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(OS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride was dropwise added under ice-cooling to a mixture of 4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, triethylamine and ethyl acetate, followed by stirring at 0° C. for 2 hours to obtain 3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl methanesulfonate.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.S1C=CC=[C:22]1C(C1C=CC(O)=CC=1)=O.S(=O)(=O)(O)O>CO>[C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:17])([CH3:18])[C:14]([O:16][CH3:22])=[O:15])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccc(O)cc1)c1cccs1
Reactant: CC(C)(Oc1ccc(C(=O)c2cccs2)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C(C)(C)Oc1ccc(C(=O)c2cccs2)cc1

Procedure:
2-[4-(2-Thenoyl)-phenoxy]-2-methyl-propionic acid (M.p. 157° C.; 29 g; obtained according to the procedure described in Example 2 from 2-thienyl(4-hydroxy-phenyl)ketone) is dissolved in anhydrous methanol (300 ml), concentrated sulfuric acid (2 ml) is then added thereto and the mixture is heated for 6 hours at the reflux temperature. The solvent is then evaporated off under reduced pressure and the residue is dissolved in ethyl ether; the organic phase is washed with an aqueous sodium hydroxide solution. After neutralization and drying, the ether is evaporated off and the methyl ester is recrystallized from ethanol, to give 29 g of product which melts at 85° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]#[C:26][C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]#[C:26][C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC(C)(O)CCCCCc1cccc(C#Cc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCCc1cccc(C#Cc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 3(i), by reacting 250 mg (0.42 mmol) of 7-{3-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenylethynyl]phenyl}-2-methylheptan-2-ol with 0.93 ml of tetrabutylammonium fluoride 1M/THF, after purification on a silica column (ethyl acetate 70-heptane 30), white crystals (m=132 mg; Y=86%) are obtained. m.p.=52-5° C.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[C:1]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:8][CH2:9][N:10]([C:29]([C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:23]4[N:22]=[C:21]([C:20]([F:35])([F:19])[F:36])[O:25][N:24]=4)[CH:27]=3)=[O:30])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2cccc(-c3ccccc3)c2)CC1
Yield: 40 %

Procedure:
This compound was synthesized from 1-([1,1′-biphenyl]-3-yl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (110 mg, yield 40%). 1H NMR (400 MHz, MeOD) δ 8.27-8.25 (m, 1H), 8.22-8.21 (m, 1H), 7.75-7.70 (m, 2H), 7.60-7.58 (m, 2H), 7.43-7.40 (m, 2H), 7.53-7.30 (m, 2H), 7.22-7.21 (m, 1H), 7.14-7.12 (m, 1H), 7.02-6.00 (m, 1H), 3.99 (m, 2H), 3.67 (m, 2H), 3.37 (m, 2H), 3.24 (m, 2H). MS (ESI) m/z: Calculated for C26H21F3N4O2: 478.16. found: 479.1 (M+H)+