Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]([O-:17])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[K+].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:19][C:15]([C:12]1[CH:13]=[N:14][C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]2)=[CH:10][CH:11]=1)=[O:17]
Reactant: NCCCCCCCCCCCCO
Reactant: CCN1CCN(c2ccc(C(=O)[O-])cn2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To 4.07 g of potassium 6-(4-ethyl-1-piperazinyl)-pyridine-3-carboxylate and 3.00 g of 12-aminododecanol was added 50 ml of chloroform and then 2.01 g of 1-hydroxybenzotriazole (HOBt) and 3.07 g of 1,3-dicyclohexylcarbodiimide (DCC) were added thereto while stirring at room temperature and then the mixture was stirred at room temperature for 17 hours. A further 50 ml of chloroform was added, the mixture was stirred and then insolubles were filtered off. After the residue on a filter paper was washed with chloroform, the washing and the chloroform solution were combined and washed with a 10% aqueous solution of sodium hydroxide and dried over anhydrous magnesium sulfate. After the chloroform solution was concentrated, diisopropyl ether was added and the crystal thus separated out was recovered by filtration and dried under reduced pressure to afford 5.10 g of the title compound as a crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1ccc2ncc([N+](=O)[O-])c(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1
Temperature: 25 °C

Procedure:
6-Methyl-3-nitroquinolin-4-ol (Compound of step 2, 610 mg) in POCl3 (5 mL) was stirred for 45 min at 120° C. The mixture was cooled to RT and poured slowly into ice-water. The precipitate was filtered, washed with ice-cold water and dissolved in CH2Cl2. The organic phase was washed with cold brine, and the aqueous phase was discarded. After drying over Na2SO4, the organic solvent was evaporated to dryness to obtain the title compound. Yield: 600 mg (90%); 1HNMR (DMSO-d6, 300 MHz: δ 9.299 (s, 1H), 8.192 (s, 1H,), 8.096-8.124 (d, 1H, J=8.4 Hz), 7.893-7.927 (dd, 1H, J=8.4 Hz, 1.8 Hz), 2.604 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)CCC>[CH3:18][O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(Cl)ncn1
Reactant: COCCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COCCN1CCN(c2cc(N)ncn2)CC1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.3 g, 2.32 mmol) and diisopropylethylamine (0.30 g, 2.32 mmol) were suspended in n-butanol and then 1-(2-methoxyethyl)piperazine 5-2 (0.334 g, 2.32 mmol) was added. The reaction was stirred at 125° C. for 18 hours. The butanol was removed under reduced pressure, diluted with DCM and loaded onto a silica column eluted with DCM (100 mL), DCM:MeOH (99:4) and then DCM:MeOH:NH4OH (9:1:0.1). The product 5-3 was isolated after evaporation. 1H-NMR (DMSO): 7.95 ppm (s, 1H); 6.23 ppm (s, 2H); 5.59 ppm (s, 1H); 3.43 ppm (m, 4H); 3.33 ppm (m, 2H); 3.25 ppm (s, 3H); 2.59 ppm (m, 2H); 2.54 ppm (m, 4H).
Reaction SMILES: [I:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[OH-].[Na+].[ClH:14]>O1CCCC1>[ClH:14].[I:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cccc(F)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc(F)c1I

Procedure:
A solution of 2-iodo-3-fluoronitrobenzene (27.0 g, 0.101 mol) in tetrahydrofuran (200 mL) was added dropwise over a 10 minute period to a stirring solution of stannous chloride dihydrate (68.0 g, 0.302 mol) in concentrated hydrochloric acid (200 mL). After 3 hours at room temperature the reaction was poured onto ice, made alkaline (pH 11) with 50% NaOH, and extracted with diethyl ether. The combined organic phases were washed with water, brine, dried (MgSO4), filtered, and concentrated to almost dryness. Ethereal HCl was added pH 1-2), and the resulting precipitate filtered and dried to afford 25.0 g of the title compound, m.p. 197°-198° C. (dec.).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH3:26])[C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[OH:18].[CH:27]([C:30]1[CH:31]=[C:32]([C:40]2[CH:45]=[C:44]([CH3:46])[C:43]([O:47][CH2:48][C:49](=O)[CH3:50])=[C:42]([CH3:52])[CH:41]=2)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37])([CH3:29])[CH3:28].C(O)(=O)C>O1CCCC1>[OH:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C@@H:16]([NH:15][CH:49]([CH3:50])[CH2:48][O:47][C:43]1[C:42]([CH3:52])=[CH:41][C:40]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:30]([CH:27]([CH3:28])[CH3:29])[CH:31]=2)=[CH:45][C:44]=1[CH3:46])[CH3:26]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: COC(=O)c1ccc(-c2cc(C)c(OCC(C)=O)c(C)c2)cc1C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cc(C)c(OCC(C)N[C@@H](C)[C@H](O)c3ccc(O)cc3)c(C)c2)cc1C(C)C
Temperature: 25 °C
Yield: 30.5 %

Procedure:
Sodium triacetoxyborohydride (0.23 g) was added to a mixture of 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.082 g), methyl 3-isopropyl-3′,5′-dimethyl-4′-(2-oxo-propoxy)biphenyl-4-carboxylate (0.17 g) and acetic acid (0.03 mL) in tetrahydrofuran (2.5 mL) at room temperature with stirring, and the mixture was stirred at 50° C. for 4 hrs. After being cooled to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:methylene chloride/methanol=9/1) followed by aminopropyl silica gel column chromatography (eluent:hexane/ethyl acetate=4/1) to afford methyl 4′-{(2RS)-2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)1-methylethylamino]propoxy}-3-isopropyl-3′,5′-dimethylbiphenyl-4-carboxylate (0.074 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](I)=[C:9]([CH2:11][CH3:12])[N:10]=[C:4]2[CH:3]=1.[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH:33]=[O:34])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]>>[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH:33]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]4=[N:10][C:9]=3[CH2:11][CH3:12])[OH:34])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]
Reactant: CCc1nc2cc(Cl)ccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: CCc1nc2cc(Cl)ccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 88.8 %

Procedure:
[step 3] Using 7-chloro-2-ethyl-3-iodoimidazo[1,2-a]pyridine (700 mg, 2.28 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (335 mg, 1.14 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[(7-chloro-2-ethylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (480 mg, 89%) was obtained.
Reaction SMILES: C(O)C.Cl.O1CCCCC1[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[CH:16]=[CH:15]2.C(=O)([O-])O.[Na+]>C(O)C>[F:33][C:31]([F:32])([F:34])[O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([OH:11])[CH:13]=3)[N:18]=2)=[CH:25][CH:26]=1
Reactant: FC(F)(F)Oc1ccc(COc2ccc3cc(OC4CCCCO4)ccc3n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2nc(OCc3ccc(OC(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A 1 N hydrochloric acid ethanol solution (40 ml) was added to an ethanol (10 ml) solution of 6-(Tetrahydro-2H-pyran-2-yloxy)-2-[4-(trifluoromethoxy)benzyloxy]quinoline (3.5 g, 8.3 mmol) and then stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure, and the resulting crude crystal was washed with hexane-diethylether to afford the title compound as a white powder (2.52 g, yield 90%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[O:10])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](N)CC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](N)CC4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-4-aminocyclohexyl)amide (85 mg, 0.153 mmol) was dissolved in dichloromethane (8 mL). Trifluoroacetic acid (2.5 mL, 32.4 mmol) was added and the orange reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (8 mL) and ethylenediamine (1 mL, 14.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was sequentially washed with water, dichloromethane, ethyl acetate, and hexanes to afford 61 mg (93%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-4-aminocyclohexyl)-amide as a light yellow solid. MS: [M+H]+=424; 1H NMR (300 MHz, DMSO-d6) δ: 9.05 (d, J=1.0 Hz, 1H), 8.47 (d, J=9.1 Hz, 1H), 8.42 (d, J=1.0 Hz, 1H), 8.08 (d, J=7.1 Hz, 1H), 7.98 (s, 1H), 7.40 (d, J=9.1 Hz, 1H), 4.17 (d, J=1.0 Hz, 3H), 4.00 (br. s., 1H), 2.96 (br. s., 1H), 1.87-2.02 (m, 2H), 1.66-1.76 (m, 2H), 1.55-1.66 (m, 2H), 1.44-1.54 (m, 2H).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C@H:12]([CH3:26])[N:11]1[C:27](=[O:38])[CH2:28][C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:37])(C(C)(C)C)(C)C.C(O)(=O)C.O>C1COCC1>[Cl:37][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:29]=1[CH2:28][C:27]([N:11]1[C@@H:10]([CH2:9][OH:8])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])[C@@H:12]1[CH3:26])=[O:38]
Reactant: COc1cccc(Cl)c1CC(=O)N1[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc2[C@@H]1C
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(Cl)c1CC(=O)N1[C@@H](CO)Cc2c(CCC(C)(C)O)cccc2[C@@H]1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
Dissolve 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-chloro-6-methoxy-phenyl)ethanone (0.58 g, 1.04 mmol) in THF (5.3 mL). Add acetic acid (16 mL, 279 mmol) and water (5.3 mL). Stir at 50° C. for 1.5 hours. Concentrate under reduced pressure. Dissolve the residue in ethyl acetate and wash with saturated sodium bicarbonate solution, water, and brine. Dry over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with acetone: hexanes (gradient, 0-30%) to give the title compound as a white foam (0.34 g, 0.76 mmol). MS (m/z): 446.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:33])[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[N:12]=2)=[C:6]([F:34])[CH:5]=1)[CH3:2].ClCC1N=C(N(C2C=CC(OCC)=CC=2F)C)C2C(=CC=CC=2)N=1.C1(=O)NC(=O)C2=CC=CC=C12.[K]>CN(C)C=O>[NH2:22][CH2:21][C:13]1[N:12]=[C:11]([N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=2[F:34])[CH3:33])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CCOc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)c(F)c1
Agent: CCOc1ccc(N(C)c2nc(CCl)nc3ccccc23)c(F)c1
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCOc1ccc(N(C)c2nc(CN)nc3ccccc23)c(F)c1
Temperature: 70 °C
Yield: 90 %

Procedure:
2-{4-[(4-Ethoxy-2-fluoro-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione: To (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-2-fluoro-phenyl)-methyl-amine (341 mg 0.94 mmol) in N,N-dimethylformamide (3 mL) was added potassium phthalimide (381 mg, 2.1 mmol). The reaction was heated to 70° C. for 2.5 hours. The reaction was quenched with H2O and diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO4), concentrated and purified by gradient MPLC (0-100%, EtOAc/Hexane, SiO2) to give 380 mg (90%) of the title compound as a solid. 1H NMR (MeOH-d4) δ 7.95-7.93 (dd, 2H), 7.86-7.84 (dd, 2H), 7.68-7.62 (m, 2H), 7.23-7.18 (t, 1H), 7.11-7.05 (m, 2, H), 6.77 (d, 2H), 5.04 (s, 2H), 4.03 (q, 2H), 3.20 (s, 3H), 1.39 (t, 3H); LC-MS (ESI+; 457 ([M+H]+)).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][CH3:31])=[O:4].C([O-])(O)=O.[Na+].O>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:29]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][CH3:31])=[O:4]
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OC(C)=O)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
(3S,8S)-3-(4-Acetoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (120 mg) was dissolved in methanol (5 mL). To this solution was added NaHCO3 (400 mg). The mixture was stirred at rt for 2-3 h. After completion of the reaction, the mixture was poured into water (10 mL) and was extracted with EtOAc (30 mL). The organic layer was washed with water, brine, dried and concentrated to get the desired product as a white solid (110 mg) LCMS (m/z): 461.
Reaction SMILES: [O:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])S(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18](=[O:25])[C:19](CO)([CH3:22])[CH2:20][OH:21]>ClCCl.N1C(C)=CC=CC=1C>[CH3:16][O:17][C:18](=[O:25])[C:19]([CH3:22])([O:1][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[CH2:20][O:21][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:1]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C(C)(CO)CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(C)(COS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
Add Tf2O (80 mL) dropwise to a cool solution (−78° C.) of 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid methyl ester (Preparation 5, 32.5 g) in dichloromethane (400 mL) and 2,6-lutidine (80 mL). Allow the reaction to reach room temperature. and stir for about 2 hours. Dilute with dichloromethane (400 mL) and wash with HCl (3% aqueous solution). Dry the organic layer over MgSO4, filter and concentrate. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate 5%, to give 2-methyl-2,3-bis-trifluoromethanesulfonyloxy-propionic acid methyl ester as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ ppm 4.7 (d, 2H, J=10.3 Hz), 4.5 (d, 2H, J=10.3 Hz), 3.8 (s, 3H), 1.4 (s, 3H).
Reaction SMILES: ClC(Cl)(Cl)C(O)=O.S([O-])([O-])(=O)=O.[Mg+2].N(OC(C)C)=O.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1N.[CH:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cu]>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccc(F)cc1F
Reactant: c1ccccc1
Agent: [Cu]
Agent: CC(C)ON=O
Agent: O=C(O)C(Cl)(Cl)Cl
Product: Fc1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a stirred solution of 25.0 g. of trichloroacetic acid in 250 ml. of benzene was added 2.0 g. of copper powder and 20 g. of anhydrous magnesiumsulfate, and the mixture cooled to +5° C. At this temperature, 14 g.of isopropyl nitrite was quickly added, immediately followed by the dropwise addition of a solution of 12.9 g. of 2,4-difluoroaniline in 100 ml. of benzene over about 20 min. The temperature was kept at 10°-15° C. throughout the addition, then gradually let warm to 25° C. After 1 to 11/2 hours the nitrogen gas evolution subsided, the solids were filtered off, and the filtrate washed with water5 × 500 ml. to neutrality. The organic layer was dried over 20 g. of magnesium sulfate, treated with 3 g. of charcoal, filtered and concentraedunder vacuum to an oil. This oil was dissolved in 150 ml. of hexane and stirred with 5 g. of silica gel, which removed most of the color. Upon filtration, the pale yellow filtrate was concentrated under reduced pressure to give 17.5 g (91%) of off-white crystalline 2,4-difluorobiphenyl (II), m.p. 59.5°-63°., quant. vpc showing 95% purity. All physical data obtained confirmed the structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:44])=[C:41]([Pb+3])[CH:42]=1>ClCCl.Cl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:44])=[C:39]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:38]=1
Reactant: Cc1ccc(Br)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.3 %

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (6.00 g, 35.29 mmol) and N,N-dimethylaminopyridine (21.62 g, 177.21 mmol) is added anhydrous chloroform (200 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (55 ml), followed by 5-bromo-2-methylphenyllead triacetate (21.60 g, 38.99 mmol) in one portion and the reaction mixture is heated at 80° C. for 2 hours. The mixture is allowed to cool to room temperature, then diluted with dichloromethane (300 ml) and aqueous hydrochloric acid (300 ml), and the mixture is swirled for 5 minutes and filtered to remove inorganic residues. The filter cake is washed with dichloromethane, and all organic fractions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo to afford a crude solid which is recrystallised from dichloromethane/hexanes. This material is then further purified by flash column chromatography (hexane/ethyl acetate 5:1 ratio). The lead residues are removed by dissolving the resulting solid (approximately 6.50 g) in chloroform (100 ml) and stirring with 3-mercaptopropyl-functionalized silica gel (6.50 g, 1.20 mmol/g loading) overnight. The mixture is filtered and the filtrate concentrated in vacuo to afford 4-(5-bromo-2-methyl-phenyl)-2,2,6,6-tetramethylpyran-3,5-dione (6.50 g) as a cream powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[C:16](O)(=[O:19])[C:17]#[CH:18]>C1CCCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:16](=[O:19])[C:17]#[CH:18])=[C:10]([F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1F
Reactant: C#CC(=O)O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1F

Procedure:
Prepared analogously to Example 1.1.b. from 4′-chloro-3-fluorobiphenyl-4-ylamine and propynoic acid. Yield: 0.16 g (43.7% of theory); C15H9ClFNO (M=273.69); calc.: molecular ion peak (M+H)+: 274/276; found: molecular ion peak (M+H)+: 274/276; Rf value: 0.3 (silica gel, cyclohexane/ethyl acetate (3:1)).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH3:18])[CH2:13][CH2:12]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[CH:3]=2)[CH2:13][CH2:12]1
Reactant: CNC1CCN(C)CC1
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCC(NCc2cc(F)cc(Br)c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
Combine 1,3-dibromo-5-fluorobenzene (5.0 g, 19.7 mmol), 1-methyl-4-(methylamino)piperidine (2.58 mL, 17.7 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.49 g, 0.79 mmol), sodium t-butoxide (2.57 g, 27.58 mmole) and toluene (100 mL), stir and heat at 80° C. After 10 minutes, add Pd2(dba)3 (0.49 g, 0.79 mmol). After 3 hr. at 80° C., cool to ambient temperature. Dilute with ethyl acetate (100 mL) and wash with water (50 mL). Dry the organic layer over sodium sulfate, filter, and concentrate to an oil. Purify the residue by silica gel flash chromatography eluting with 10% (2M NH3-methanol) in CH2Cl2 to obtain 2.95 g (55%)of the title intermediate: 1H NMR (CDCl3): 6.6 (s, 1H), 6.5 (m, 1H), 6.3 (m, 1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.7 (s, 3H), 2.3 (s, 3H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H).