Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][NH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[Cl:24])[C:20](=[O:25])[NH:19][CH:18]=[CH:17]3)[CH2:9][CH2:8]1)C>CO>[Cl:24][C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][NH:19][C:20]2=[O:25])=[CH:15][C:14]=1[O:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([NH:6][CH2:5][C:4]([OH:26])=[O:3])[CH2:12][CH2:11]1
Reactant: CCOC(=O)CN[C@H]1CC[C@@H](Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Solvent: CO
Product: O=C(O)CN[C@H]1CC[C@@H](Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
185 mg of [4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yloxy)-cis-cyclohexylamino]-acetic acid ethyl ester (23, crude product) were dissolved in 2 ml methanol. After adding 2 ml of 2 N NaCO3-solution, the solution was stirred at room temperature for 1.5 h. The solvent was evaporated in vacuo and the residue was purified by preparative HPLC, which delivers the title compound as trifluoro acetate. Rt=0.91 min (Method B). Detected mass: 351.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)(=[O:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:13])[CH3:12]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCCCn1ccc2ncnc(Cl)c21
Temperature: 40 °C
Reaction time: 96 h

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g), 5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) and N,N-dimethylformamide (5.0 mL) was stirred at 40° C. for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=1:3→6:4) to give the title compound (637 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27](OC)=[C:26]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:25]=[C:24](C)[N:23]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[C:54]1(C)C=CC=CC=1>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH3:54])=[C:26]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:34][CH2:35]2)[N:25]=[C:24]([O:50][CH3:49])[N:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)nc(C)nc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(NCC(NC(=O)OCc2ccccc2)C(=O)O)c(C)c(N2CCC(c3ccc4c(n3)NCCC4)CC2)n1

Procedure:
280 mg (0.443 mmole) of tert-butyl 2-benzyloxycarbonylamino-3-{5-methoxy-2-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in 15 ml of dichloromethane with 3 ml of trifluoroacetic acid is stirred at ambient temperature for 18 hours. Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane then poured into diisopropyl ether. 210 mg of expected product is obtained by filtration in the form of a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1.[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[Cl:41][C:42]1[C:43]([C:52]([F:54])([F:53])[F:55])=[N:44][N:45]([CH2:48][C:49]([N:36]2[CH2:37][CH2:38][N:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=3)[CH2:34][CH2:35]2)=[O:50])[C:46]=1[CH3:47]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Trifluoromethylphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.38 (m, 1H), 7.11 (m, 3H), 5.00 (s, 2H), 3.79 (m, 2H), 3.73 (m, 2H), 3.27 (m, 2H), 3.23 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+H expected=455.0, found 455.0.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: C[Mg]Br
Reactant: Cc1cc(C=O)ccc1Br
Solvent: C1CCOC1
Product: Cc1cc(C(C)O)ccc1Br
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 4-bromo-3-methylbenzaldehyde (4 g, 20 mmol) in dry tetrahydrofuran (40 mL) was cooled to 0° C. under nitrogen atmosphere, and then methyl magnesium bromide (20 mL, 1N in tetrahydrofuran) was added dropwise. The ice bath was removed, and the mixture was stirred for 2 hours. Ammonium chloride aqueous (40 mL) was added and the mixture was extracted with dichloromethane (20 mL*3). The organic phase was dried by sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 1-(4-bromo-3-methylphenyl)ethanol as a colorless oil (4.0 g, 93%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].Cl.Cl.[CH:36]1([NH2:42])[CH2:40][CH2:39][CH2:38][CH:37]1[NH2:41].C(N(C(C)C)CC)(C)C.C(OC(C)C)(C)C>O.CN1CCCC1=O>[NH2:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[NH:42][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Reactant: NC1CCCC1N
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1N[C@@H]1CCC[C@H]1N
Yield: 85.9 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), rac-(1R,2R)-cyclopentane-1,2-diamine dihydrochloride (230 mg), diisopropylethylamine (480 μL), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave device at 150° C. for 2 hours. Water and diisopropyl ether were added thereto, and the precipitated solid was filtered to obtain rac-5-{[(1R,2R)-2-aminocyclopentyl]amino}-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (195 mg).
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([O:18]C)=[CH:15][CH:16]=2)[C:11]([CH2:24][C:25]([OH:27])=[O:26])=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[C:1]([N:9]1[C:17]2[C:12](=[C:13]([C:20]([F:21])([F:22])[F:23])[C:14]([OH:18])=[CH:15][CH:16]=2)[C:11]([CH2:24][C:25]([OH:27])=[O:26])=[CH:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c(CC(=O)O)cn2C(=O)c2ccccc2)c1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)Cc1cn(C(=O)c2ccccc2)c2ccc(O)c(C(F)(F)F)c12

Procedure:
0.001 mole of 1-benzoyl-5-methoxy-4-trifluoromethyl-3-indolyl acetic acid is added portionwise, with stirring, to 1.5 g. of pyridine hydrochloride at 160°-220°. On cooling, the residue is extracted with saturated sodium bicarbonate solution and made neutral with 1.0N HCl. The solution is then extracted with ether, and the ether extracts washed well with water and dried over sodium sulfate. The ether solution is concentrated to give 1-benzoyl-5-hydroxy-4-trifluoromethyl-3-indolyl acetic acid.
Reaction SMILES: O[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:37]I.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[I:37][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(I)C1
Temperature: 100 °C
Yield: 93.8 %

Procedure:
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (3.5 g, 0.020 mol) in toluene (200 mL) was treated with imidazole (4.08 g, 0.060 mol), triphenylphosphine (0.60 g, 0.040 mol), and iodine (7.62 g, 0.030 mol). The mixture was heated at 100° C. for 1 h. It was then cooled to room temperature and poured into saturated NaHCO3 solution (30 mL). Excess triphenylphosphine was destroyed by addition of iodine until iodine coloration persisted in organic layer. The mixture was washed with 5% Na2SO3 solution, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica-gel column chromatography to afford 206a (5.31 g, 93%). MS-ESI: [M+H]+ 284.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:11].BrBr.C([O-])=O.[Na+].C(OC)(=O)NN>CO.O.O.CO>[OH:11][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: BrBr
Agent: COC(=O)NN
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: O=C(CO)c1ccccc1
Temperature: 20 °C

Procedure:
A 100-gallon glass lined kettle equipped with a cooling jacket was charged with 90.5 lbs. of acetophenone, 123 lbs. of methanol and 340 mls. of 98% sulfuric acid. The reactor was cooled to 20° C and the mixture was stirred during the addition of 119 lbs. of bromine that was added incrementally by a gravity fed system at a rate so that the temperature was maintained at between 20°-25° C over a 3-hour period. After the bromination was complete, 37 lbs. of methanol, 240 lbs of water and 112 lbs. of sodium formate were added. The mixture was stirred with agitation overnight at 60° C and after cooling to 40° C a solution of 68 lbs. methyl carbazate in 45 lbs. of a 54:46 methanol-water mixture was added. The reaction mixture was stirred for 2-hours at 40° C to form the carbomethoxy nydrazone of α-hydroxy acetophenone. Thereafter the reaction mixture was allowed to cool to 20° C, was centrifuged, and washed with water on the centrifuge.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18]1[CH:41]=[CH:40][C:21]([CH2:22][O:23][C@H:24]2[C@@H:36]([OH:37])[C@@H:35](O)[C@H:34]([CH3:39])[O:33][C@@H:25]2[S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:11][C:10]([F:13])([F:12])[S:7]([O:37][C@H:36]1[C@@H:35]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C@H:34]([CH3:39])[O:33][C@H:25]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:24]1[O:23][CH2:22][C:21]1[CH:40]=[CH:41][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)(=[O:8])=[O:6]
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](O)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CO[C@H]2[C@@H](OS(=O)(=O)C(F)(F)F)[C@@H](OS(=O)(=O)C(F)(F)F)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Trifluoromethanesulfonic anhydride (1.8 mL, 10.8 mmol) is added at 0° C. to a solution of phenyl 6-deoxy-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-14) (1.01 g, 2.69 mmol) and pyridine (2.2 mL, 26.9 mmol) in 30 mL of CH2Cl2. The solution is stirred at 0° C. for 1 h and allowed to warm at room temperature over 3 h. The reaction mixture is cooled to 0° C. before quenching with TEA (1.0 mL, 7.2 mmol). The reaction mixture is diluted with 30 mL of CH2Cl2, washed with saturated NaHCO3 (30 mL), 1N HCl (30 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (8% EtOAc/petroleum ether) to give 1.36 g (79%) of phenyl 6-deoxy-3,4-di-O-(trifluoromethanesulfonyl)-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-15): Rf 0.49 (20% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.48 (d, 2H, ArH), 7.33-7.21 (m, SH, ArH), 6.91 (d, 2H, ArH), 5.34 (t, J=2.0 Hz, 1H, H-3), 4.93 (d, J=9.2 Hz, 1H, H-1), 4.77 (d, J=11.2 Hz, 1H, CH2), 4.65 (d, J=11.2 Hz, 1H, CH2), 4.55 (dd, J=2.0, 8.8 Hz, 1H, H-4), 4.19-3.96 (m, 1H, H-5), 3.90 (s, 3H, OCH3), 3.47 (dd, J=2.0, 9.2 Hz, 1H, H-2), 1.36 (d, J=5.8 Hz, 3H, H-6).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[CH:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[CH:24]([C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:11]4([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)c1cccc(-c2ccc3c(c2)C2(CC(C4CCCOC4)O3)N=C(N)N(C)O2)c1
Temperature: 120 °C
Yield: 16.9 %

Procedure:
Pd(PPh3)2Cl2 (5 mg) in a 10 mL flask under Ar was treated sequentially with the 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (40 mg, 0.105 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.2 mL) and 3-isopropylphenylboronic acid (25.8 mg, 144 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give 6-(3-isopropylphenyl)-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (7.5 mg, 18%). 1H NMR (MeOD): 1.31 (d, 6H), 1.68 (m, 2H), 1.92-2.07 (m, 3H), 2.43-2.72 (m, 1H), 2.96 (m, 1H), 3.34 (s, 3H), 3.45-3.58 (m, 2H), 3.83-4.01 (m, 2H), 4.12-4.23 (m, 2H), 6.98 (m, 1H), 7.21 (m, 1H), 7.38 (m, 3H), 7.63 (m, 1H), 7.79 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:29][O:30]CC=C)[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:28])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2([CH2:29][OH:30])[C:13](=[O:14])[N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:11](=[O:27])[N:10]2[CH3:28])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C=CCOCC1(c2cccc(C#N)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
328 μL of trifluoroborane-dimethylsulfide complex are added to a solution of 354 mg of 4-[4-(3-cyanophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile (in DCM (5 mL. The mixture is stirred 6 hours at room temperature, diluted with DCM, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:12]([CH3:23])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.O>COCCOC.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>[CH3:23][C:12]1[CH:11]=[C:10]([CH:9]=[CH:8][C:4]2[CH:3]=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:7]=[CH:6][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)COc1ccc(C=Cc2cccc(Br)c2)cc1C
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: COCCOC
Product: Cc1cc(C=Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 57 %

Procedure:
Ethyl ({4-[2-(3-bromophenyl)ethenyl]-2-methylphenyl}oxy)acetate (150 mg, 0.40 mmol), Na2CO3 (106 mg, 1.00 mmol), 4-(triflouromethyl)benzeneboronic acid (83.5 mg, 0.44 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) was dissolved in DME and water (2:1, 6 mL) and the mixture heated at reflux for 4 hours. The mixture was allowed to cool to rt, was concentrated under reduced pressure and the residue partitioned between EtOAc (15 mL) and water (15 mL). The aqueous layer was then acidified with aqueous HCl (1N) and extracted with EtOAc and the combined organic layers dried (MgSO4), filtered and reduced to give the title compound (94 mg).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:35](O)=[O:36])[CH2:13][CH2:12]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:27]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:35]([NH:11][C:17]2[CH:18]=[CH:19][C:20]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:30][CH2:29][O:28][CH2:25][CH2:24]3)=[CH:21][CH:16]=2)=[O:36])[CH2:13][CH2:12]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(2-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (190 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (139 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (104 mg) and triethylamine (476 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 51) (169 mg) as yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]3[O:32][CH:31]=[CH:30][C:13]=3[C:14](S(C(F)(F)F)(=O)=O)=[C:15]3[C:20]=2[O:19][C:18]([CH3:21])=[CH:17][C:16]3=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.C([NH+](CC)CC)C.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][C:18]1[O:19][C:20]2[C:15]([C:16](=[O:22])[CH:17]=1)=[CH:14][C:13]1[CH:30]=[CH:31][O:32][C:12]=1[C:11]=2[O:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(=O)c2c(S(=O)(=O)C(F)(F)F)c3ccoc3c(OCCCc3ccccc3)c2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(=O)c2cc3ccoc3c(OCCCc3ccccc3)c2o1
Temperature: 65 °C
Yield: 75 %

Procedure:
9-(3-Phenylpropoxy)-7-methyl-4-trifluoromethanesulfonyl-5H-furo[3,2-g]chromen-5-one (1.5 g, 3.11 mmol, 0.2M, prepared from the corresponding 4-hydroxy system according to General Procedure G, Step 1) was dissolved in anhydrous dimethylformamide and treated with triethylammonium formate (1.8 g, 12.4 mmol.). The reaction flask was evacuated and back-filled with N2 three times. Anhydrous triethylamine (0.63 g, 6.20 mmol), Pd(OAc)2 (70 mg, 0.31 mmol) and triphenylphosphine (0.16 mg, 0.62 mmol) were added to the reaction mixture and the flask was again evacuated and back-filled with N2. The reaction mixture was heated to 60-70° C. for 24 hours under a N2 atmosphere. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with saturated aqueous NH4Cl solution. The organic layer was dried over MgSO4, concentrated under vacuum and the crude residue was purified by silica gel chromatography, eluting with diethyl ether:dichloromethane (0:1, then 1:3) to afford the title compound as a pale yellow solid (75%). 1H NMR (300 MHz, CDCl3) δ: 2.06-2.16 (m, 2H), 2.41 (s, 3H, CH3), 2.92 (t, J=7.5 Hz, 2H), 4.49 (t, J=6.6 Hz, 2H), 6.15 (s, 1H), 6.85 (d, J=2.1 Hz, 1H), 7.16-7.30 (m, 5H), 7.69 (d, J=2.1 Hz, 1H), 8.09 (s, 1H). MS (ES+) m/z: 335 (M+H+).
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O.Br>ClCCl>[CH3:1][C@H:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: OCCBr
Reactant: C[C@H](N)c1ccccc1
Agent: Br
Solvent: ClCCl
Product: C[C@@H]1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 50 h
Yield: 143.7 %

Procedure:
176.20 g(1449 mmole) of (S)-(-)-α-methylbenzylamine was dissolved in 185 ml of dichloromethane and 218.04 g(1748 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 658 ml(5750 mmole) of 48% aqueous hydrobromic acid solution was added thereto and the solution thereby obtained was allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was distilled for 2 hours under normal pressure at constant temperature to remove 580 ml of water as the by-product and aqueous hydrobromic acid solution. The residue was dissolved in 760 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 150 ml of ethyl acetate and then dried to obtain 306.5 g of the title compound.