Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:30]([CH3:32])[CH3:31])[CH2:5][CH2:6][C@H:7]([C:14]1[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:15]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH-:42].[Na+].OO>C1COCC1.O>[CH:30]([N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6][C@H:7]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][OH:42])[CH:17]=[CH:16][C:15]=1[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:32])[CH3:31]
Reactant: C=Cc1ccc(OCc2ccccc2)c([C@@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(CC[C@@H](c1ccccc1)c1cc(CCO)ccc1OCc1ccccc1)C(C)C
Temperature: 25 °C

Procedure:
(S)-N,N-Diisopropyl-3-(2-benzyloxy-5-ethenylphenyl)-3-phenylpropanamine (1 g, 2.34 mmol) in THF (25 mL) was added to 9-BBN (0.5 M in THF, 11.7 mL, 5.85 mmol) under nitrogen atmosphere at 0° C. Additional 9-BBN (2.3 mL, 1.2 mmol) was added after 3 hours of stirring, the temperature was raised to room temperature and the mixture was stirred for 0.5 hour. It was then cooled to 0° C. and 1 M sodium hydroxide (10 mL) was added followed by H2O2 (30% in H2O, 10 mL). After 1 hours stirring, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica (gradient of diethyl ether to 1% NH3 in diethyl ether). Yield 0.67 g (64%). 1H NMR (CDCl3) δ0.90 (d, 12H), 2.10-2.18 (m, 2H), 2.30-2.37 (m, 2H), 2.80 (t, 2H), 2.90-3.0 (m, 2H), 3.80 (br, 2H), 4.40 (t, 1H), 5.0 (s, 2H), 6.80 (d, 1H), 7.0 (m, 1H), 7.10-7.38 (m, 11H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:5]=1[O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)#[N:3]>O1CCOCC1>[NH:11]1[CH2:12][CH2:13][CH:8]([CH2:7][O:6][C:5]2[CH:21]=[CH:22][C:23]([B:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]3)=[CH:24][C:4]=2[C:2]#[N:3])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C#N)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(OCC3CCNCC3)c(C#N)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HCl in dioxane (50 ml) is added to a solution of tert-butyl 4-[2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxymethyl]piperidine-1-carboxylate (6.0 g, 0.0135 mol) in 1,4-dioxane (50 ml), and the mixture is stirred at room temperature for 16 h. The mixture is evaporated in a rotary evaporator and employed in the next step without purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]#[N:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: N#CCCc1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCCc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 555.6 %

Procedure:
The product of Example 41 (8.3 g, 10.5 mmol) dissolved in 25 ml of Et2O was added dropwise (15 min.) to a stirred slurry of lithium aluminium hydride (LAH) in 125 ml of dry Et2O under an Ar atmosphere at room temperature. After the addition was complete the reaction was stirred at room temperature an additional 18 h. With great care, 8.0 ml of water were added dropwise to the vigorously stirred reaction mixture. Following this, 8.0 ml of 4N NaOH were then carefully added. Finally 22 ml of H2O were added and the aluminum salts were filtered from the Et2O solution. The filtrate was concentrated to give 8.24 g of the title products which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:22]=[CH:21][C:9]2[N:10]([CH2:17][CH2:18][CH2:19][OH:20])[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[N:12][C:8]=2[CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[N:10]([CH2:17][CH2:18][CH2:19][OH:20])[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[N:12][C:8]=2[CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc2c(c1)nc(CC(C)C)n2CCCO
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc2c(c1)nc(CC(C)C)n2CCCO

Procedure:
3-[1-(3-hydroxy-propyl)-2-isobutyl-1H-benzimidazol-5-yl]-acrylic acid methyl ester (prepared according to the Example 1, step 1-3) (126.6 mg, 0.4 mmol) and 10% Pd/C (40 mg) in 10 mL of MeOH was hydrogenated using a hydrogen balloon overnight. After filtration through short-column silica gel, the filtrate was evaporated under reduced pressure to give 3-[1-(3-hydroxy-propyl)-2-isobutyl-1H-benzimidazol-5-yl]-propionic acid methyl ester (127 mg) in quantitative yield: MS m/z (M+H)+: 319; 1H NMR (400 MHz, MeOD) δ 0.95 (6H, d, J=6.4 Hz), 1.92 (2H, m), 2.19 (1H, m), 2.60 (2H, t, J=8.0 Hz), 2.74 (2H, d, J=7.2 Hz), 2.96 (2H, t, J=7.6 Hz), 3.50 (2H, t, J=4.1 Hz), 3.54 (3H, s), 4.25 (2H, t, J=7.2 Hz), 7.05 (1H, d, J=8.0 Hz), 7.30-7.40 (2H, m); 13C NMR (100 MHz, MeOD) δ 20.9 (2C), 27.3, 30.1, 31.5, 34.6, 35.3, 39.5, 50.1, 57.4, 109.1, 116.4, 122.1, 132.6, 134.2, 141.3, 154.2, 173.2.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:28])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15]C)[CH:10]=3.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:28])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3
Reactant: COc1cc2c(=O)c(Cc3cncc(C)c3)cn3c4cc(Br)ccc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cncc(Cc2cn3c4cc(Br)ccc4c4cc(O)cc(c2=O)c43)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
9-bromo-2-methoxy-5-(5-methyl-3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (302 mg) produced in Example 123 was suspended in anhydrous methylene chloride (80 ml), and boron tribromide (0.33 ml) was added dropwise at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice water (100 ml) and saturated aqueous solution of sodium hydrogencarbonate was added thereto until the termination of foaming. The crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with ethanol and ether in succession to obtain the title compound (227 mg, 78%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7][CH2:6][N:5]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH:4]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7][CH2:6][NH:5]1
Reactant: COCC1=NCCc2ccsc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCC1NCCc2ccsc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g (5.5 mmol) 7-methoxymethyl-4,5-dihydro-thieno[2,3-c]pyridine are dissolved in 10 ml of methanol and combined batchwise with 0.4 g (11.0 mmol) sodium borohydride while cooling with an ice bath. The ice bath is removed and the reaction mixture is stirred at RT for two hours. Then it is evaporated down and reacted further as the crude product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:10]([C:19]([OH:21])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:10]([C:19]([Cl:25])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCC1c1ccsc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CN(Cc2ccccc2)CCC1c1ccsc1

Procedure:
A solution of the product from step d) (4.68 g, 13.8 mmol) in CH2Cl2 (77 ml) was treated with DMF (3-4 drops) and oxalyl chloride (2.72 ml, 31 mmol) at 220C for 1 hour. Next, the solvent was evaporated providing the subtitle compound (4.38 g) that was used without further purification.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].OS(O)(=O)=O.N([O-])=O.[Na+]>CCO>[Br:8][C:7]1[CH:2]=[C:3]([OH:12])[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Nc1c(O)cc([N+](=O)[O-])cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a cooled solution (−10° C.) of 2-amino-3-bromo-5-nitro-phenol (643 g, 2.76 mol) in EtOH (13 L) was added conc. H2SO4 (515 mL, 9.97 mol) over a period of 35 min at −10 to −2° C. The reaction mixture was allowed to warm to rt then heated to 50-55° C. followed by portion-wise addition of NaNO2 (671 g, 9.72 mol) over 30 min then heated at reflux for 3 h. After completion of reaction (by TLC), the mixture was concentrated to 3 L and cooled to 0° C. followed by the addition of chilled water (5 L) and extraction with EtOAc (3×6 L). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a semi-solid residue. The residue was treated with 25% ether-hexane mixture (6 L) and stirred for 1 h. The solid was filtered and washed with hexane (3 L) to obtain the desired product (505 g, 84%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.[C:13]([C:16]([CH3:18])=O)([CH3:15])=O>C(O)(C)C>[ClH:1].[CH:4]([O:3][CH2:15][C:13]1[N:9]=[C:8]([C:7]2[CH:11]=[CH:12][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH:10][C:16]=1[CH3:18])([CH3:12])[CH3:5]
Reactant: CC(=O)C(C)=O
Reactant: COc1ccc(C(=N)N)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2nc(COC(C)C)c(C)[nH]2)cc1
Yield: 161.9 %

Procedure:
To a solution of 38.4 g (0.206 mole) of p-methoxy-benzamidine hydrochloride in 1 liter of refluxing isopropyl alcohol is added 25 g (0.25 mole) of biacetyl. The mixture is stirred and refluxed for 72 hours. The solvent is removed to dryness under reduced pressure and the solid residue taken up in fresh hot isopropyl alcohol. Ether is added and, on chilling, pale yellow crystals form which are collected to give about 49.5 g (81% yield) of 4-isopropoxymethyl-2-(p-methoxyphenyl)-5-methylimidazole hydrochloride as very pale yellow crystals, m.p. 149°-150° C (dec.). Recrystallization twice from isopropyl alcohol-ether with charcoaling gives the product as white crystals, m.p. 149°-150° C (dec.).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:14]([C:24](=O)[CH3:25])=[CH:15][C:16]([Cl:23])=[C:17]4[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].O1CCCC1>CO.C(#N)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:14]([CH:24]([NH2:33])[CH3:25])=[CH:15][C:16]([Cl:23])=[C:17]4[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(N2CCCCC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(N2CCCCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(1,4′-bipiperidin-1′-yl)-5-chloroquinolin-7-yl]ethanone (0.0165 g, 0.0444 mmol) and ammonium acetate (0.0342 g, 0.444 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.11 mL, 0.11 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H30ClN4 (M+H)+: m/z=373.2; Found: 373.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>CN(C)C=O.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>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[CH:8]=[N:7][CH:6]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 76.8 %

Procedure:
81 mg (0.07 mmol)Pd(PPh3)4 was added under argon at room temperature to a solution of 1.0 g (4.63 mmol) methyl-5-bromo-pyridine-3-carboxylate in 23 ml N,N-dimethylformamide and the mixture was heated to 80° C. Then 2.26 g (6.94 mmol) cesium carbonate and 0.97 g (5.09 mmol) of 4-(trifluoromethyl)phenyl boronic acid were added and the mixture was stirred at 80° C. over night. The reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 1.0 g (68%) of 5-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1>>[OH:13][CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:7][CH2:8]1
Reactant: CCC(=O)Cl
Reactant: OCC1CCNCC1
Product: CCC(=O)N1CCC(CO)CC1

Procedure:
Prepared as in Example 24a from propionyl chloride and piperidin-4-ylmethanol as a colorless oil (40%). MS 172 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CC(C)=O>[CH2:38]([O:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4OCc4ccccc4)ncn3)cccc2s1
Temperature: 70 °C
Yield: 12.4 %

Procedure:
To a mixture of N-{4-[6-(2-hydroxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 137), (0.20 g, 0.50 mmol) and potassium carbonate (0.062 g, 0.45 mmol, Aldrich) in anhydrous acetone (2 mL) was added benzyl bromide (0.053 mL, 0.45 mmol, Aldrich) and the reaction mixture was heated at 70° C. for 2 h. The solvent was removed under vacuum and the residue was diluted with water (50 mL) and extracted with ether (2×100 mL). The combined organic extracts were washed with water (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by silica gel chromatography (gradient: 5–60% EtOAc/hexanes) to obtain the title compound (0.030 g, 13%) as a white solid. Mp: 201–203° C. MS (ESI, pos. ion.) m/z: 537 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](/[C:19](/[CH2:24][CH3:25])=[C:20](/[F:23])\[CH2:21][OH:22])=[CH:7][C:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1)[CH2:2][CH3:3].C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1>ClCCl.C(#N)C>[CH2:1]([O:4][C:5]1[C:6](/[C:19](/[CH2:24][CH3:25])=[C:20](/[F:23])\[CH:21]=[O:22])=[CH:7][C:8]2[C:9]([CH3:17])([CH3:18])[CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[C:13]=2[CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCCOc1cc2c(cc1/C(CC)=C(/F)C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-3-(3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enol (2.05 g, 6.13 mmol) in dichloromethane (81 mL) and acetonitrile (16 mL) was treated with tetrapropylammonium peruthenate (0.305 g, 0.92 mmol), 4 Å molecular sieves (0.442 g), and N-methylmorpholine-N-oxide (2.41 g, 15.3 mmol), and the solution was stirred for 0.5 h at ambient temperature. The mixture was filtered through a sintered glass funnel containing a bed of silica gel about 1 inch thick using 20% ethyl acetate in hexane as the eluent. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[O:39]1[C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=[N:40]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:44]([C:43]1[O:39][N:40]=[CH:41][CH:42]=1)=[O:45])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: O=C(Cl)c1ccno1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)c1ccno1
Yield: 45 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 45% yield. LCMS for C22H18ClN6O2(M+H)+: m/z=433.1. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 9.52 (s, 1H), 9.49 (s, 1H), 8.75 (d, 1H), 8.12 (s, 1H), 7.84 (m, 1H), 7.56 (m, 1H), 7.48 (m, 1H), 7.27 (m, 1H), 7.20 (d, 1H), 7.06 (dd, 1H), 6.85 (m, 1H), 6.82 (m, 1H), 2.84 (m, 4H).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[C:15]([C:21]([O:23]C)=O)=[C:16]([CH3:20])[NH:17][C:18]=2[CH3:19])=O)=[CH:7][C:6]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26]>C(O)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:14]3[C:15](=[C:16]([CH3:20])[NH:17][C:18]=3[CH3:19])[C:21](=[O:23])[NH:2][N:3]=2)=[CH:7][C:6]=1[C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]1)=[O:26]
Reactant: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
Hydrazine hydrate (0.021 mL, 0.28 mmol) was added to methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (57) (0.108 g, 0.25 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material (0.033 g, 31.9% yield). 1H NMR (399.902 MHz, DMSO) δ 1.30 (1H, m), 1.44 (1H, m), 1.72 (1H, m), 1.87 (1H, m), 2.27 (3H, s), 2.51 (3H, s), 3.05 (1H, m), 3.26 (3H, s), 3.32 (2H, m), 3.42 (1H, m), 3.92 (1H, m), 4.08 (2H, s), 7.14-7.30 (3H, m), 11.08 (1H, s), 11.94 (1H, s); m/z (LC-MS, ESI+), RT=1.44 min (M+H=413.36).
Reaction SMILES: [Na].Cl[CH2:3][C:4]([CH:6]=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH:26]([O:29][CH2:30]C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)([CH3:28])[CH3:27]>CCC(O)CC>[CH:26]([O:29][CH2:30][CH2:3][C:4]([CH:6]=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])([CH3:28])[CH3:27]
Reactant: CC(C)OCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Agent: [Na]
Solvent: CCC(O)CC
Product: CC(C)OCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 3.04 g of sodium in 100 ml of 3-pentanol is reacted with 25.0 g of chloromethylcarbonylmethylenetriphenyl phosphorane analogously to the production of isopropoxymethylcarbonylmethylenetriphenyl phosphorane. The title compound is obtained as crystallized oil with a melting point of 66°-70° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C(Cl)C([C:32]([F:35])([F:34])[F:33])=CN=1.NC1C=C(O)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([C:32]([F:35])([F:34])[F:33])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(C(F)(F)F)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-trifluoromethylpyrimidine and 3-aminophenol were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.82 (bs, 1H), 8.88 (bs, 1H), 8.36 (s, 1H), 7.18–7.11 (m, 2H), 6.96 (m, 4H), 6.63 (dd, 1H, J=2.4 and 8.1 Hz), 6.38 (d, 1H, J=8.1 Hz); 19F NMR (DMSO-d6): −16979; LCMS: ret. time: 19.04 min.; purity: 95%; MS (m/e): 363 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([C@H:28]2[CH2:30][C@@H:29]2[C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(Cl)Cl.CO>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:31]([C@H:29]3[CH2:30][C@@H:28]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:32])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)[C@H]1C[C@@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)[C@H]4C[C@@H]4c4ccccc4)cc1c23
Yield: 22 %

Procedure:
Preparation of example 62 from the title compound of Example 7 (79 mg, 0.28 mmol), (1S,2S)-2-phenylcyclopropanecarboxylic acid (60 mg, 0.37 mmol; as described by A. Thurkauf, et al., J. Med. Chem. 43, 3923–3932, (2000)), triethylamine (0.160 mL, 1.14 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (141 mg, 0.37 mmol) in N,N-dimethylformamide (10.0 mL) was carried out analogously to Example 11. Silica gel chromatography (5% methanol in CH2Cl2), also in an analogous manner, followed by trituration with methanol afforded the title compound (26 mg, 0.06 mmol) as a yellow powder in 22% yield.