Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([N:11]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:13][C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>CO>[CH:1]([N:4]([CH2:35][CH3:36])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)=[CH:13][C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH:32]([CH3:34])[CH3:33])(=[O:30])=[O:31])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)N[C@H]1CC[C@@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(C(C)C)[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 1-[(1R,2R,4S)-4-isopropylamino-2-(propane-2-sulfonylmethyl)cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one (43 mg) in methanol (1 mL) was treated with acetaldehyde (0.025 mL) and stirred at room temperature. After 35 min, sodium cyanoborohydride (8 mg) was added, and the mixture was stirred at room temperature for 22.5 h. The mixture was concentrated and partitioned between water and ethyl acetate. The aqueous phase was extracted with additional ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide 1-((1S,2R,4R)-4-(isopropyl(ethyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-4-(3-(trifluoromethyl)phenyl)-5,6-dihydropyridin-2(1H)-one (41 mg) as a white glassy solid. MS found: (M+H)+=529.39.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O)([O-:11])=[O:10]>C(O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccc(N=Cc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
The mixture of p-toluidine (10 g) and 2-nitrobenzaldehyde (14.1 g) in anhydrous ethanol was heated to reflux for 3 h. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was washed with diethyl ether and petro ether to give 4-methyl-N-(2-nitrobenzylidene)aniline as yellow solid (17.3 g, yield 77.2%). LC/MS m/e obsd. (ESI+) [(M+H)+] 241.2.
Reaction SMILES: [CH3:1][C:2]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[OH:12].Cl.O>CO>[CH3:1][C:2]1([CH2:13][CH2:14][CH2:15][CH:16]([CH3:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][CH2:4][C:5]2[C:6](=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=2)[O:12]1
Reactant: CC(=CCc1cccc(O)c1O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)CCCC(C)CCCC(C)CCCC1(C)CCc2cccc(O)c2O1
Yield: 79 %

Procedure:
3-(3,7,11,15-Tetramethyl-2-hexadecenyl)-1,2-benzenediol (1.00 g; 2.57 mmole) and conc. hydrochloric acid (2.0 ml) in 10 ml of methanol were heated under reflux for 4 hours, then the reaction solution was poured into 100 ml of water and was extracted twice with 50 ml of isopropyl ether. The extract was washed twice with 100 ml of water and once with 100 ml of saturated aqueous solution of sodium chloride, followed by drying it over anhydrous magnesium sulfate, distilling off the solvent and subjecting the resulting residue to silica gel column chromatography. Thus, 790 mg of the title compound was recovered from the fractions eluted through the column with hexane-ethyl acetate (30:1). Yield=79%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:20](=[O:21])[NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(Br)c1)Oc1ccc2ncccc2c1

Procedure:
A mixture of quinolin-6-ol (0.29 g, 2 mmol), 3-bromo-phenyl isocyanate (0.47 g., 2.4 mmol), potassium carbonate 0.28 g. (0.28 g. 2 mmol) and potassium iodide (0.32 g.) in dry dimethylformamide (2 ml) was heated at 80° C. for 20 hours. The reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined ethyl acetate fractions were concentrated under vaccum. The residue was washed with methanol (2×3 ml) to give 1d, yield: 0.34 g. (49.5%).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.[Li+].[OH-]>C1COCC1.O>[Cl:12][C:9]1[N:8]=[CH:7][C:6]([CH:5]=[CH:4][C:3]([OH:13])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C=Cc1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
3-(6-Chloro-pyridin-3-yl)-acrylic acid methyl ester (107 mg, 0.541 mmol) in THF was added to a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 3 hrs at room temperature. The resulting residue was dissolved in H2O and then washed three times with Et2O, neutralized with 1N HCl to pH 5˜7. The resulting solid filtered and washed with H2O and then dried in vacuo to give 3-(6-chloro-pyridin-3-yl)-acrylic acid (80 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:12]([OH:14])=O)=[CH:5][C:6]2[N:10]=[N:9][NH:8][C:7]=2[CH:11]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH:28]1[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>>[N:30]12[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31]1)[CH:28]([NH:27][C:12]([C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:7]3[NH:8][N:9]=[N:10][C:6]=3[CH:5]=1)=[O:14])[CH2:29]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1cc2[nH]nnc2cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1cc2[nH]nnc2cc1C(=O)NC1CN2CCC1CC2

Procedure:
Following the procedure of Example 22, 6-methoxy-1H-benzotriazole-5-carboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2>C(O)(=O)C>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[NH:19][CH:20]=[N:21]4)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CC(=O)O
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncnc4nc[nH]c34)cc12
Temperature: 116 °C
Yield: 66 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 6-chloropurine were used. No base was used, acetic acid was used as solvent, and the reaction was heated at reflux (116° C.) for 15 hours. Chromatography afforded the title compound (66%) as a white foam: mp, decomposes 175° C.; 13C NMR (CD3OD) δ153.7, 153.4, 141.5, 136.0, 131.5, 128.3, 125.6, 119.2, 113.3, 113.0, 109.9, 59.1, 43.6, 21.9. Anal. calcd for C17H19N7.HCl.2H2O: C, 51.84; H, 6.14; N, 24.89. Found: C, 52.14; H, 6.22; N, 25.03.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[C:14](OCC)=[O:15])=[N:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][OH:15])=[N:3]1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc2c([C@@H]3C[C@H]3CO)cccc2n1
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
Under nitrogen atmosphere, to a solution of trans-ethyl 2-(2-methyl-2H-indazol-4-yl)cyclopropanecarboxylate (3.89 g, 15.9 mmol) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (0.540 g, 15.9 mmol) at 0° C., and the mixture was stirred for 10 min. To the reaction mixture were added ethyl acetate, water and 10% aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with 2 N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (ethyl acetate) to give the title compound (3.00 g, yield 93%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][C:12]=2[CH2:24][CH2:25][CH2:26][CH3:27])=[O:10])=[CH:7][CH:6]=1.[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]2([C:11]3[C:15]4[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=4[O:13][C:12]=3[CH2:24][CH2:25][CH2:26][CH3:27])[O:32][CH2:31][CH2:30][O:10]2)=[CH:28][CH:29]=1
Reactant: CCCCc1oc2ccc(C(=O)OC)cc2c1C(=O)c1ccc(OCCBr)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCc1oc2ccc(C(=O)OC)cc2c1C1(c2ccc(OCCBr)cc2)OCCO1
Yield: 45.1 %

Procedure:
10.0 g (0.022 mol) of methyl 3-[4-(2-bromoethoxy)benzoyl]-2-butylbenzofuran-5-carboxylate, 3.39 g (0.055 mol) of ethylene glycol, 890 mg of para-toluenesulfonic acid (pTsA) and 100 ml of benzene are brought to reflux for 3 days, eliminating the water formed using a Dean-Stark apparatus. The mixture is evaporated to dryness and the residue is chromatographed on a column of silica, eluting with DCM (dichloromethane) and then a DCM/ethyl acetate (99/1) mixture. 5 g of the pure desired compound are thus isolated.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O.C(OCC)(=O)C>[N:21]1([CH2:20][CH2:19][N:14]2[CH:15]=[C:11]([B:6]3[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]3)[CH:12]=[N:13]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.272 g, 11.34 mmol) in N,N-dimethylformamide (13 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol) and 2-chloroethylpyrrolidine HCl salt (0.964 g, 5.67 mmol) as solutions in N,N-dimethylformamide (2 mL each). The reaction was stirred at room temperature for 0.5 hours and then heated to 65° C. for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). Water (50 mL) was added, and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2×30 mL). The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 292.2 [M+H]+;
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[N:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][N:11]=2)[C:3]1=[O:22].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=1>>[F:23][C:24]1[CH:25]=[C:26]([C:17]#[C:16][C:13]2[CH:14]=[CH:15][C:10]([N:4]3[CH:5]4[CH2:9][CH2:8][CH2:7][CH:6]4[N:2]([CH3:1])[C:3]3=[O:22])=[N:11][CH:12]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1cccc(I)c1
Reactant: CN1C(=O)N(c2ccc(C#C[Si](C)(C)C)cn2)C2CCCC21
Product: CN1C(=O)N(c2ccc(C#Cc3cccc(F)c3)cn2)C2CCCC21

Procedure:
The title compound, a light yellow oil, MS: m/e=336.2 (M+H+), was prepared in accordance with the general method of Example 37, step 3 starting from (3aRS,6aSR)-1-methyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-hexahydro-cyclopenta-imidazol-2-one (Example 109, step 1) and 1-fluoro-3-iodobenzene.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4]O.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CCO)CC>C1COCC1>[O:3]1[CH2:1][C@H:2]1[CH2:4][N:10]1[C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]2[C:6]1=[O:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC[C@@H]1CO1
Agent: CCN(CC)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CO1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To THF solution (400 ml) of (R)-(+)-glycidol 2.47 g (32 mmol), phthalimide 7 g (47.6 mmol), triphenyl phosphine 14.3 g (54.5 mmol) and molecular shieve 4 Å 30 g were added at room temperature and then DEAE 8.7 g (50 mmol) was added dropwise under cooling on ice-bath. The reaction mixture was allowed to stand at room temperature overnight. Molecular shieve was removed by filtration and filtrate was evaporated to dryness in vacuo. The desired product was further purified by silica gel chromatography. 4.9 g of desired product was obtained as an oil. The NMR spectra were consistent with the desired title intermediate.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.B([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(O)O.C(=O)([O-])[O-].[K+].[K+]>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].C(#N)C.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)O)cc3)n2n1
Temperature: 145 °C
Yield: 226.6 %

Procedure:
To the mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (340 mg, 1.26 mmol), 4-boronobenzoic acid (210 mg, 1.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 0.063 mmol) and potassium carbonate (261 mg, 1.89 mmol) was added 3:1 acetonitrile/water (3 mL). The resulting mixture was heated at 145° C. (microwave) for 800 s. The reaction was then filtered and concentrated to afford 4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzoic acid (886 mg, >100% yield) as a crude off-white solid: LRMS (ESI) m/e 311.2 [(M+H)+, calcd for C17H19N4O2 311.2].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:27])[CH3:26]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:31]5[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]5)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc2cc(Br)ccc2c1
Product: CC(C)N1CCN(c2ccc3cc(C(=O)Nc4ccc5cccnc5c4)ccc3c2)CC1

Procedure:
This material was prepared analogous to the procedure described for Example 33. 6-Bromo-naphthalene-2-carboxylic acid quinolin-7-ylamide, Example 32(b), (116 mg, 0.31 mmol) reacted with 1-isopropylpiperazine (315 mg, 2.46 mmol, Aldrich) to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[F:20].[C:21](=[O:28])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:22].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C(O[Pd]OC(=O)C)(=O)C.O1CCOCC1>[C:24]([O:23][C:21]([NH:22][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[F:20])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(N)=O
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc(Cl)c(F)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1Oc1cnc(NC(=O)OC(C)(C)C)c(F)c1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
Methyl 2-(6-chloro-5-fluoropyridin-3-yloxy)-4-fluorobenzoate (0.875 g), tert-butyl carbamate (0.410 g), cesium carbonate (1.427 g), diacetoxypalladium (0.033 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.169 g) were added to dioxane (10 mL). The reaction was degassed with nitrogen then sealed. The reaction was then heated to 85° C. After stirring for 16 hours the reaction was cooled, diluted with water (25 mL) and the product was extracted into dichloromethane (2×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 40 g) eluting with a gradient of 5% to 25% ethyl acetate/hexanes gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]=[CH2:20])=[CH:12][CH:11]=2)[CH:3]=1.[Zn](CC)[CH2:22]C.ICI>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]3[CH2:22][CH2:20]3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: CC[Zn]CC
Reactant: C=COCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Solvent: ICI
Solvent: CCOCC
Product: Clc1ccc(Br)cc1Cc1ccc(CCOC2CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-bromo-1-chloro-2-(4-(2-(vinyloxy)ethyl)benzyl)benzene (100 mg, 0.27 mmol) and Et2Zn (0.68 mL, 0.68 mmol, 1.0 M in hexane) in dry ethyl ether (2 mL) was added diiodomethane (0.06 mL, 0.68 mmol) dropwise during 20 min at room temperature under argon. After stirring overnight, the reaction mixture was poured slowly into ice cold dilute hydrochloride solution with stirring. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) and then with brine (10 mL), and then dried over sodium sulfate. The residue was concentrated and purified by preparative TLC (eluent EA:PE=1:25) to obtain intermediate CR (86 mg) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 7.32˜7.24 (m, 3H), 7.18 (d, 2H), 7.12 (d, 2H), 4.05 (s, 2H), 3.73 (t, J=7.2 Hz, 2H), 3.32˜3.29 (m, 1H), 2.88 (t, J=7.2 Hz, 2H), 0.57˜0.44 (m, 4H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12].[OH-:14].[Na+].O>CN1CCCC1=O>[CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12]
Reactant: [OH-]
Reactant: CC=CC=CCCCCCCCBr
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC=CC=CCCCCCCCO
Temperature: 95 °C
Yield: 65.5 %

Procedure:
8,10-dodecadienyl bromide (1.0 g, 4.08 mmol), prepared as described above, was dissolved in N-methylpyrrolidinone (0.96 mL) under Ar-atmosphere, and 50% NaOH (0.22 mL, 4.18 mmol) was added via syringe. The reaction mixture was heated to 95° C. for 4 hrs. A colourless precipitate was observed. After cooling to room temperature, water (10 mL) was added and the resulting mixture was extracted with heptane (3×6 mL). The resulting organic phase was washed with water (10 mL) and dried (Na2SO4). Evaporation of the solvent from the organic phase gave the 8,10-dodecadienol product as a yellow liquid (487 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1.BrC(C1C=CC=CC=1)C(Cl)=O.C(Cl)(=O)C(Cl)=O>C(OCC)(=O)C.C(Cl)Cl.O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:11]([CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: COc1cccc(CCNc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C(Br)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc(CCN(C(=O)Cc2ccc(Br)cc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of {2-(3-methoxyphenyl)ethyl}phenylamine (1.06 g, 4.65 mmol) in ethyl acetate (80 mL) under nitrogen was added a solution of 4-bromophenylacetyl chloride (1.06 g, 4.65 mmol) in ethyl acetate (20 mL), the bromophenylacetyl chloride being prepared from the corresponding carboxylic acid (1 g, 4.65 mmol) and oxalyl chloride (0.61 mL, 6.98 mmol) in CH2Cl2 (20 mL). After 1 hour, the reaction was poured into water (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (1.92 g, 98% yield): EI−MS (m/z) 423.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH:44][C:45]3[S:49][N:48]=[CH:47][N:46]=3)(=[O:43])=[O:42])=[CH:37][C:36]=2[C:50]#[N:51])=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:16]=2)[CH:14]=1.C(Cl)Cl>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH:44][C:45]3[S:49][N:48]=[CH:47][N:46]=3)(=[O:42])=[O:43])=[CH:37][C:36]=2[C:50]#[N:51])=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:16]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3Oc3ccc(S(=O)(=O)Nc4ncns4)cc3C#N)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccc(Cl)cc1-c1ccnc(N2CCNCC2)n1
Reaction time: 1 h
Yield: 42.1 %

Procedure:
3-Cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 43.6 mg, 0.154 mmol), tert-butyl 4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate (Preparation 873, 50.0 mg, 0.128 mmol) and potassium carbonate (53 mg, 0.38 mmol) in dimethyl sulfoxide (1 mL, 10 mmol) was stirred at 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature and poured into saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude intermediate, tert-butyl 4-[4-(5-chloro-2-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate, as a yellow solid. Trifluoroacetic acid (300 uL, 4 mmol) was added to a solution of tert-butyl 4-[4-(5-chloro-2-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate (83 mg, 0.154 mmol) in methylene chloride (2.9 mL, 46 mmol). After 1 hour, the reaction mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the product as a white solid (trifluoroacetic acid salt, 36 mg, 51%).