Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:25][CH2:26]Br>O>[CH3:12][O:11][C:8]1[C:9]2[O:10][CH2:25][CH2:26][O:1][C:2]=2[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=1
Reactant: COc1cc(C=O)cc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc2c1OCCO2
Temperature: 100 °C
Yield: 42.9 %

Procedure:
In a vial was placed 0.5 g (3.0 mmol) of 3,4-dihydroxy-5-methoxybenzaldehyde, 414 mg (3.0 mmol) of K2CO3, and 3 mL of anhydrous DMF. To this mixture was added, 0.56 g (3.0 mmol) of 1,2-dibromoethane dropwise. The vial was sealed and heated to 100° C. overnight. Water was added to the reaction and the mixture was extracted with diethyl ether. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to give the crude product. The material was purified by silica gel chromatography using 50% ethyl acetate/hexane as the eluent to afford 0.25 g (43%) of the pure aldehyde 10.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=[N:13][CH:14]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])#[CH:24]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([C:24]#[C:23][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])[CH:12]=[N:13][CH:14]=1
Reactant: O=S(=O)(Oc1cncc(F)c1)C(F)(F)F
Reactant: C#Cc1cccc(C#N)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C#Cc2cncc(F)c2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
Add triethylamine (0.79 mL, 5.64 mmol), copper (I) iodide (15.43 mg, 0.08 mmol) and bis(triphenylphosphine)palladium (II) dichloride (49.48 mg, 0.07 mmol) to a solution of trifluoromethanesulfonic acid 5-fluoropyridin-3-ylester, (prepared as described in PREPARATION 6), (345 mg, 1.41 mmol) and 3-ethynylbenzonitrile, prepared as described in PREPARATION 8), (230 mg, 1.41 mmol) in ethyl acetate (2 mL). Stir in a sealed tube at 70° C. for 18 h. Concentrate and purify by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to give the title compound (109 mg, 35%).
Reaction SMILES: [C:1](=[O:45])([O:16][CH2:17]/[C:18](/[C:35]1[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1)=[C:19](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:20][O:21][Si](C(C)(C)C)(C)C)[O:2][CH2:3][CH2:4][CH2:5][CH:6]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][O:8][N+:9]([O-:11])=[O:10]>C(#N)C.C1(C)C=CC=CC=1>[C:1](=[O:45])([O:16][CH2:17]/[C:18](/[C:35]1[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:37][CH:36]=1)=[C:19](/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)\[CH2:20][OH:21])[O:2][CH2:3][CH2:4][CH2:5][CH:6]([O:12][N+:13]([O-:15])=[O:14])[CH2:7][O:8][N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.7 %

Procedure:
To a solution of 18 ml of phosgene (1.93 M /toluene) at −78° C. under N2, was added 3 g of 3,4-bis(nitrooxy)butyl alcohol. The resulted mixture was stirred at 25° C. for 24 h. Distillation of excess phosgene was done under low vacuum at 50° C. to afford 4.2 g of the desired compound as an orange oil. The crude compound was used directly in the next reaction. To a solution of 3.5 g of (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-ol, 1.0 g of DMAP and 1.8 mL of Hünig's base in 40 mL of CH2Cl2 at −78° C. was added 3.3 g of 4,5-bis(nitrooxy)pentyl chloridocarbonate. The reaction mixture was stirred for 2 h at 25° C. and then filtered through a pad of silica gel, washed with EtOAc and evaporated. Purification by flash chromatography afforded 5.4 g of the titled compound as a yellowish oil. The compound was used directly in the next step. To a solution of 5.4 g of 4,5-bis(nitrooxy)pentyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-yl carbonate in 50 mL of acetonitrile was added 2.5 mL of HF.pyr and the mixture was stirred at 25° C. for 1.5 h. The reaction mixture was diluted with 200 mL of toluene, loaded on silica gel and washed with EtOAc. Purification by flash chromatography afforded 4.6 g of the titled compound as a colorless oil. 1H NMR (acetone-d6, 500 MHz): δ 7.69 (d, 2H), 7.34 (d, 2H), 7.14-7.08 (m, 5H), 5.30 (s, 2H), 5.01 (dd, 1H), 4.73 (dd, 1H), 4.64 (d, 2H), 4.17-4.11 (m, 3H), 4.04 (q, 4H), 3.03 (s, 3H), 1.91-1.81 (m, 4H).
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:12]([CH2:13][CH:14]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[O:11][C:10]([CH3:35])([CH3:34])[N:9]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([Sn](CCCC)(CCCC)CCCC)=[N:48][CH:49]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@H:8]1[C@H:12]([CH2:13][CH:14]([NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:47]3[CH:46]=[CH:45][C:44]([CH3:43])=[CH:49][N:48]=3)=[CH:18][CH:17]=2)[O:11][C:10]([CH3:35])([CH3:34])[N:9]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccccc2)[C@H](CC(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)OC1(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(CC(C[C@@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]3Cc3ccccc3)NC(=O)OCc3ccccc3)cc2)nc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A solution containing the product from Example 128B (0.50 g, 0.78 mmol) in DMF (8 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (0.165 g, 0.235 mmol), and the product from Example 74A (0.60 g, 1.63 mmol), stirred at 100° C. for 6 hours, cooled to 25° C., filtered through celite®, and partitioned between ethyl acetate and water. The organic was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-15% ethyl acetate in chloroform to give the product (0.322 g, 63% yield).
Reaction SMILES: CC(C)=[O:3].[CH2:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][CH:18]2[C:21]([NH2:23])=[O:22])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[C:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][CH:18]2[C:21]([NH2:23])=[O:22])=[CH:14][CH:13]=1)(=[O:3])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C1CCc2ccc(Cc3ccccc3)cc21
Reactant: CC(C)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1CCc2ccc(C(=O)c3ccccc3)cc21
Reaction time: 8 h

Procedure:
To 150 ml. of acetone is added 12.5 g. of 6-benzylindan-1-carboxamide, followed by the dropwise addition of a solution of 5 g. of sodium dichromate in 24 ml. of 6N sulfuric acid. After the addition has been completed, the mixture is stirred overnight. Then 200 ml. of water is added and the acetone is distilled off under reduced pressure. The residue is extracted with ethyl acetate. The extract is washed with water and dried, followed by removal of the solvent by distillation under reduced pressure. The residue is purified by column chromatography (500 g. of silica gel; eluted with a 7:3 solvent mixture of chloroform and acetone) and the resultant crude crystals are recrystallized from benzene. The procedure gives 6-benzoylindan-1-carboxamide as crystals melting at 195°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.[OH:32][C@H:33]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[N:6]=[C:5]2[N:19]1[CH2:20][CH2:21][N:22]([C:34](=[O:35])[C@H:33]([OH:32])[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:23][CH2:24]1
Reactant: CC(C)(C)C[C@@H](O)C(=O)O
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2cc(F)ccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)CC1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200 mg, 0.61 mmol) in CH2Cl2 (5 mL) was added triethylamine (170 μL, 1.22 mmol) followed by the addition of (R)-2-hydroxy-4,4-dimethylpentanoic acid (116 mg, 0.79 mmol), then HATU (301 mg, 0.79 mmol). An additional 3 mL of CH2Cl2 were added, and the reaction was stirred for 3 h. After quenching with water, the mixture was extracted twice with CH2Cl2. The organic phase was dried over MgSO4 and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes yielded (R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one (240 mg, 86%). m/z: M+1 obs=453.5; tR=3.19 minutes 1H NMR (400 MHz, DMSO-d6) δ 8.46 (m, 1H), 8.01 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.96 (m, 2H), 4.89 (d, J=7.1 Hz, 1H), 4.45 (m, 1H), 3.97 (m, 4H), 3.76 (m, 4H), 1.56 (m, 1H), 1.42 (m, 1H), 0.97 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:19]O.[OH-].[Na+].O>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([OH:14])[O:13][N:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cc(O)on2)cc1

Procedure:
According to method of U.S. Pat. No. 3,781,438, 2 g of ethyl 3-(4-nitrophenyl)-3-oxopropanoate was dissolved in methanol, slightly excessive hydroxylamine hydrochloride and equivalent amount of sodium hydroxide were added, the mixture was heated to reflux. 3 hr later, the reaction was traced by Thin-Layer Chromatography, water was added to the reaction mixture, extracted with ethyl acetate, dried and concentrated to obtain 3-(4-nitrophenyl)isoxazol-5-ol as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13]C(C(F)(F)F)=CC=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC(C(C2C=C([N+]([O-])=O)C=CC=2C)=O)=C(Cl)C=1.[F:51][C:52]1C=C[C:55](N)=[C:54](C)[CH:53]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:52]([F:51])=[CH:53][C:54]=2[CH3:55])[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1cc(F)ccc1N
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.56 mmol) and 4-fluoro-2-methyl-phenylamine (0.56 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:8][C:9]1[C:10](=[O:26])[N:11]([CH2:15][C:16](=[O:25])[NH:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cn1cccc(OCc2ccccc2)c1=O)NOc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(Cn1cccc(O)c1=O)NOc1ccccc1
Yield: 57 %

Procedure:
17 (350 mg, 0.8 mmol) was suspended in 175 mL of EtOH. 10% (w/w, 38 mg) of 10% Pd/C catalyst was added to the hydrogenation flask (500 mL Pyrex® Parr reaction bottle tested to 120 psi, max. working pressure of 60 psi). The hydrogen pressure was set to 35 psi with agitation, and the process went on for 41 h. The catalyst was removed by vacuum filtration and separated from the product by dissolving the white precipitate in 125 mL hot CH2Cl2 and MeOH and THF. The clear solution was concentrated by rotary evaporation to yield a white solid. The solid was washed with MeOH to remove residual DCU to yield a white, feathery microcrystalline solid. Yield: 57%. 1H NMR (d6-DMSO, 400 MHz, 25° C.): δ 4.75 (s, 2H, —CH2—), 6.11 (t, J=7.0 Hz, 1H, Ar—H), 6.72 (d, J=7.2 Hz, 1H, Ar—H), 6.97 (m, 4H, Phenoxy-H), 7.11 (m, 2H, Ar—H, Phenoxy-H), 7.36 (t, J=7.2 Hz, 2H, Phenoxy-H), 7.58 (d, J=6.8 Hz, 2H, Phenoxy-H), 9.03 (s, 1H, —OH), 10.36 (s, 1H, —NH—). APCI-MS: m/z 336.9 [M+H]+. Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.75; H, 5.07; N, 8.49.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][NH:18][C:17](=[O:20])[NH:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>CC#N>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][NH:18][C:17](=[O:20])[NH:16][CH2:15]2)=[CH:12][C:13]=1[Br:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CNC(=O)NC2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(C2CNC(=O)NC2)cc1Br
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of [4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 29 mg, 0.10 mmol) in CH3CN (1 mL), NBS (19.5 mg, 0.100 mmol) was added. The resulting mixture was stirred overnight and concentrated to half the volume. The resulting precipitate was collected by filtration to obtain the title compound (12 mg, 32%): Mass spectrum (ESI, m/z): Calcd. for C15H20BrN3O3, 370.0 and 372.0 (M+H). found 370.1 and 372.1.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:19][CH2:20][OH:21])[C:12]([CH2:23][CH3:24])([CH3:22])[CH:11]1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:19][CH2:20][O:21][C:33](=[O:35])[CH3:34])[C:12]([CH2:23][CH3:24])([CH3:22])[CH:11]1[CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1CCOC(C)=O
Yield: 42.8 %

Procedure:
To a solution of 2.5 g of 2,6-diethyl-1-(2-hydroxyethyl)-2,3,6-trimethyl-4-piperidyl benzoate (Compound 45 - prepared following the procedure described in Preparation 9) in 50 ml of dimethylformamide were added 2.0 g of triethylamine and 1 g of acetic anhydride; the mixture was then heated at 80°-90° C. for 5 hours. When the reaction was complete, the reaction mixture was concentrated and 50 ml of benzene were added. The mixture was then washed with, in turn, an aqueous solution of sodium carbonate and water, and was dried over anhydrous sodium sulphate. After removing the solvent, the residue was subjected to distillation under reduced pressure, giving 1.2 g of Compound 50 as a colourless oil (bp 195° C./0.0008 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[N:32][C:33]([N:36]([CH3:47])[CH:37]3[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]3)=[CH:34][CH:35]=2)=[C:26]([OH:48])[CH:25]=1)(=O)=O.C(=O)(O)[O-].[Na+].O1CCOCC1>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.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:31]=[N:32][C:33]([N:36]([CH3:47])[CH:37]4[CH2:42][C:41]([CH3:43])([CH3:44])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]4)=[CH:34][CH:35]=3)=[C:26]([OH:48])[CH:25]=2)[CH:6]=[N:5][CH:4]=1
Reactant: CN(c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
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: O
Solvent: C1COCCO1
Product: COc1cncc(-c2ccc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(O)c2)c1
Temperature: 100 °C
Yield: 60 %

Procedure:
Following GENERAL METHOD 1-3 for Suzuki Coupling, to a 25 mL microwave vial, was added 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (94 mg, 0.400 mmol), 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (Intermediate 9-2, 105 mg, 0.2 mmol), sodium bicarbonate (50.4 mg, 0.600 mmol) and Pd(PPh3)4 (11.56 mg, 10.00 μmol), followed by dioxane (2 mL) and water (0.5 mL). The reaction mixture was purged with N2 for 10 minutes, and heated in a microwave at 100° C. for 1 h, then diluted with EtOAc and filtered through celite. The filtrate was acidified to pH ˜3 with 1N HCl, and loaded onto an SCX column. The column was washed with MeOH, and eluted with 2N NH3 in MeOH. After concentration, the residue was purified by preparative HPLC to provide 5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (55 mg, 0.120 mmol, 60% yield), LCMS: Rt=0.50 min [Method Q]; MS (M+1)=448.4; 1H NMR (METHANOL-d4) δ 8.17 (d, J=5.1 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.22-7.33 (m, 4H), 7.06 (s, 1H), 5.10 (m, 1H), 3.97 (s, 3H), 3.03 (s, 3H), 1.74 (dd, J=12.6, 3.0 Hz, 2H), 1.59 (t, J=12.4 Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(C(F)(F)F)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(C(F)(F)F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 18 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36][OH:37].[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=1>N1C=CC=CC=1.CCCCCC>[C:47]([O:37][CH2:36][CH:35]=[C:34]([CH3:38])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:39])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:40])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:41])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:42])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:43])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:44])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:45])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH3:1])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of solanesol were dissolved in 50 ml of pyridine and the solution was added with a solution of 4.5 g of nicotinic acid chloride in pyridine dropwise over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for two hours to complete the reaction. The reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 80 g of silica gel in n-hexane/ether solvent mixture as elution solvent to obtain a white yellow waxy final product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][N:25]=1.C(N(CC)CC)C.Cl.C([O-])(O)=O.[Na+]>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([C:23]([F:34])([F:22])[F:33])=[N:25][CH:26]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(C(F)(F)F)nc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 6-trifluoromethylnicotinoyl chloride (0.65 g, 3.10 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The mixture was neutralized with sat. aq. NaHCO3. The product was isolated by filtration, washed with water (50 mL) and dried overnight in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-6-trifluoromethyl-nicotinamide as a white solid (0.73 g, 51% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.39 min (97.69%); mp: 240-242° C.; 1H NMR (DMSO-d6) δ 1.92-2.12 (m, 1H), 2.29-2.44 (m, 1H), 2.54-2.70 (m, 1H), 2.81-3.09 (m, 1H), 4.32 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.6 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 5.11 (dd, J=5.0, 13.1 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.59 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 8.40-8.60 (m, 1H), 9.22 (s, 1H), 9.56 (t, J=5.8 Hz, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.49, 31.21, 42.87, 47.14, 51.60, 120.60 (q, J=2.9 Hz), 121.41 (q, J=272 Hz), 122.23, 123.00, 127.20, 130.54, 132.78, 137.49, 142.45, 143.13, 148.1 (q, J=34 Hz), 149.02, 163.74, 167.89, 170.98, 172.85; LCMS: MH=447; Anal Calcd for C21H17N4O4F3+0.25H2O: C, 55.94; H, 3.91; N, 12.43. Found: C, 55.97; H, 3.49; N, 12.28.