Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.[CH2:39](I)[CH3:40].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:39]([N:13]([CH2:12][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH3:40]
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1OC)CC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a room temperature solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.41 g, 0.80 mmole) in 5 ml of anhydrous N,N-dimethylformamide were added ethyl iodide (120 μl, 1.5 mmoles) and potassium carbonate (120 mg, 0.87 mmole). This mixture was then heated to 50° C. and maintained at that temperature for about 4 hours after which it was stirred at room temperature for about 16 hours. The N,N-dimethylformamide was then removed under reduced pressure. The product was partitioned between ethyl acetate and water, and then washed with brine, before drying over sodium sulfate. The solvents were removed in vacuo. Preparative thin layer chromatography provided 360 mg of the title product as a yellow foam.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:28])[CH:10]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:2]=1.ClC(Cl)(Cl)C(=N)O[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>O1CCCC1.B(F)(F)F.CCOCC>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([O:28][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH:10]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])[C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(O)CCc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Boron trifluoride etherate (8.0 μL, 65 μmol) was added to a stirred solution of tert-butyl 5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-hydroxypentanoate (7.88 g, 16.3 mmol) and 4-methoxybenzyl 2,2,2-trichloroethanimidoate (6.88 g, 24.5 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature at which stirring was continued for 2 h. A further portion of boron trifluoride etherate (8.0 μL, 65 μmol) was then added and stirring was continued at room temperature for a further 2 h. Two further additions of boron trifluoride etherate (8.0 μL, 65 μmol) followed by stirring at room temperature for 2 h were carried out before evaporation of the solvent. The residue was chromatographed on silica gel (5% to 10% diethyl ether: cyclohexane) to give the title compound (3.39 g, 34%) as a pale yellow oil which was a mixture of diastereomers. LC/MS: 4.81 min; z/e 605, calcd (M+1) 605. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.45 (4H), 7.35-6.80 (7H), 4.50 (2H), 3.80 (3H), 3.60 (3H), 2.95 (1H), 2.80 (1H), 2.65 (1H), 1.85 (4H), 1.45 (9H), 0.85 (9H), 0.5 (6H).
Reaction SMILES: [ClH:1].[CH2:2]([C:11]1[CH:45]=[CH:44][C:14]([C:15]([NH:17][C:18]2[CH:19]=[C:20]([NH:25]/[C:26](/[NH:29][C:30](=[O:43])[C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)=[N:27]\[H])[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:16])=[CH:13][CH:12]=1)C=CC1C=CC=CC=1.Cl>CC(O)=O>[ClH:1].[CH2:2]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]2[CH:19]=[C:20]([NH:25][C:26]([NH:29][C:30](=[O:43])[C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)=[NH:27])[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:16])=[CH:44][CH:45]=1)[C:11]1[CH:45]=[CH:44][CH:14]=[CH:13][CH:12]=1
Reactant: [H]/N=C(/NC(=O)c1cc(OC)c(OC)c(OC)c1)Nc1ccc(C)c(NC(=O)c2ccc(CC=Cc3ccccc3)cc2)c1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(C(=O)NC(=N)Nc2ccc(C)c(NC(=O)c3ccc(Cc4ccccc4)cc3)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the compound Boc (7e) (103 mg, 0.15 mmol) in a mixture of AcOH (1.5 mL) and concentrated HCl (0.75 mL) is stirred at room temperature for 4 hours. The solvent is then evaporated and the residue is taken up in Et2O. The title compound is recovered in the form of white solid (7 g) (85 mg, 90%, Mp 112° C.).
Reaction SMILES: C([Li])CCC.CCCCCC.Cl[CH2:13][CH2:14][I:15].[CH3:16][O:17][C:18]1C=C[C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=1>C1COCC1>[I:15][C:14]1[C:18]([O:17][CH3:16])=[CH:23][N:22]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:13]=1
Reactant: COc1ccc(C(F)(F)F)nc1
Reactant: ClCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cnc(C(F)(F)F)cc1I
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 16 %

Procedure:
In an oven-dried flask, 5-methoxy-2-(trifluoromethyl)pyridine was dissolved in THF (20 mL). This mixture was cooled at −78° C., and then 2.5 M n-butyllithium in hexane (2.60 mL, 6.5 mmol) was added. After stirring at this same temperature for 40 minutes, 1-chloro-2-iodoethane (0.60 mL, 6.6 mmol) was added. The reaction was kept at −78° C. for an additional 30 minutes, and then quenched with saturated aqueous ammonium chloride. The mixture was warmed to room temperature, partitioned between ethyl acetate and water, and the organic layer dried with magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 40% ethyl acetate in heptanes) to yield 0.3128 g (16%) of 4-iodo-5-methoxy-2-(trifluoromethyl)pyridine. 1H NMR (400 MHz, DMSO-d6) δ: 8.38 (s, 1H), 8.29 (s, 1H), 4.05 (s, 3H).
Reaction SMILES: [CH:1]([Si:4]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:5][CH2:6][CH:7]([NH2:20])[CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]([C:31]1[S:32][C:33]([C:37]2[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][CH:38]=2)=[CH:34][C:35]=1Br)=[O:30].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>O1CCOCC1.C(Cl)Cl.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]>[CH3:27][O:28][C:29]([C:31]1[S:32][C:33]([C:37]2[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][CH:38]=2)=[CH:34][C:35]=1[NH:20][CH:7]([CH2:8][O:9][Si:10]([CH:11]([CH3:13])[CH3:12])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])=[O:30]
Reactant: CC(C)[Si](OCC(N)CO[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1NC(CO[Si](C(C)C)(C(C)C)C(C)C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Nitrogen was bubbled through a mixture of 2-triisopropylsilanyloxy-1-triisopropylsilanyloxymethyl-ethylamine (prepared from serinol using triisopropylsilyl chloride) (420 mg, 1.04 mmol) and 3-bromo-5-(4,4-dimethyl-cyclohex-1-enyl)-thiophene-2-carboxylic acid methyl ester (350 mg, 1.06 mmol) in dioxane (3.5 mL) containing CS2CO3 (1 g, 3.07 mmol) and Pd2(dba)3 (96 mg, 0.1 mmol) for 6 min. 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (105 mg, 0.17 mmol) was added and the mixture was stirred at 80° C. for 24 h. It was diluted with DCM, filtered through celite and evaporated. 5-(4,4-Dimethyl-cyclohex-1-enyl)-3-(2-triisopropylsilanyloxy-1-triisopropylsilanyloxymethyl-ethylamino)-thiophene-2-carboxylic acid methyl ester was obtained by chromatography over silica gel (hexane:EtOAc-95:5) (500 mg, 72%).
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[C:11]([CH2:15][O:16][C:17]([C:20]([C:23](Cl)=[O:24])([F:22])[F:21])([F:19])[F:18])([F:14])([F:13])[F:12]>[Pd]>[C:11]([CH2:15][O:16][C:17]([C:20]([CH:23]=[O:24])([F:22])[F:21])([F:19])[F:18])([F:14])([F:13])[F:12]
Reactant: O=C(Cl)C(F)(F)C(F)(F)OCC(F)(F)F
Agent: [Pd]
Agent: CC(C)[SiH](C(C)C)C(C)C
Product: O=CC(F)(F)C(F)(F)OCC(F)(F)F
Temperature: 0 °C
Yield: 54.3 %

Procedure:
A 3-necked round bottom flask was charged with 10% Pd/C (400 mg) and cooled to 0° C. Triisopropylsilane (6.44 g, 40.7 mmol) was added, and CF3CH2OCF2CF2COCl (9.15 g, 34.9 mmol) was added dropwise. The mixture was warmed to room temperature, and the exotherm was then controlled by a room temperature water bath. The mixture was stirred an additional 22 hr over which time an additional 0.2 g of catalyst was added. The product was removed by vacuum transfer at 27 Pa. After isolation of the lower layer and washing several times with petroleum ether at -25° C. there was obtained 4.32 g of colorless liquid. 19F NMR (glyme-d10): -74.4 (t of t'2, J=8.2, 21.7), -87.35 (m, OCF2), -128.27 (apparent quartet, J-4 Hz, CF2CHO). GC/MS showed the major product with a fragment ion of m/z=209.0023. Calcd. for CSH3F6O2 (M-F): 209.0037.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17].C([O-])(=O)C.[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([N:14]2[CH2:15][CH2:16][O:12][C:13]2=[O:17])[CH:3]=1
Reactant: O=C1NCCO1
Reactant: Brc1cnc2ccccc2c1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=C1OCCN1c1cnc2ccccc2c1

Procedure:
26,0 g of 3-bromoquinoline and 4.35 g of 2-oxazolidinone in 200 ml of xylene are heated under reflux in the presence of 7.4 g of potassium acetate and 4.8 g of copper powder for 9 h, analogously to the process of B.Renger in Synthesis (1985) 856. After the mixture has been worked up, the crude product is purified over silica gel with a 500:10:1 mixture of methylene chloride, methanol and concentrated ammonia as the mobile phase, to give 3-(quinolin-3-yl)-2-oxazolidinone as a crystalline solid: Rf (500:10:1 mixture of methylene chloride, methanol and concentrated ammonia)=0.39; FAB-MS: (M+H)+ =215. Hydrogenation of 0.67 g of the resulting product in 10 ml of ethanol in the presence of 0.1 g of palladium-on-charcoal (10% of palladium) at 50° C. in the course of 20 h and FC over 80 g of silica get (mobile phase N) gives 3(R,S)-(2-oxo-oxazolidin-3-yl)-1,2,3,4-tetrahydroquinoline as a white solid: Rf (N)=0.61; MS: M+ =218.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([N:29]1[C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[C:31]([CH2:38]O)=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)(Cl)Cl>[CH2:22]([N:29]1[C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[C:31]([CH2:38][Br:20])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: OCc1nn(Cc2ccccc2)c2c1CCCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nn(Cc2ccccc2)c2c1CCCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
To a stirring solution of 752 mg (2.87 mmol, 1.3 equiv) of triphenylphosphine in 10 mL of CCl4 at 0° C. is added 135 μL (2.63 mmol, 1.2 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 580 mg (2.39 mmol) of (4,5,6,7-Tetrahydro-1-benzyl-1H-indazol-3-yl) methanol in 3 mL of CCl4 is added over 2 min. The resulting solution is stirred 2.5 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 76 mg of the title compound as a clear oil: 1H NMR (CDCl3, 300 MHz) δ7.32-7.24 (m, 3H), 7.10 (m, 2H), 5.17 (s, 2H), 4.49 (s, 2H), 2.48 (m, 4H), 1.74 (m, 4H); low resolution MS (FAB)m/e 305 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[C:46]1[CH:55]=[C:54]2[C:49]([CH:50]=[C:51]([C:57]3[CH:58]=[N:59][CH:60]=[C:61]([F:64])[C:62]=3[CH3:63])[N+:52]([O-:56])=[CH:53]2)=[CH:48][N:47]=1.[CH:65]1([C:68]([NH2:70])=[O:69])[CH2:67][CH2:66]1>O1CCOCC1.ClCCl.CO>[CH:65]1([C:68]([NH:70][C:46]2[CH:55]=[C:54]3[C:49]([CH:50]=[C:51]([C:57]4[CH:58]=[N:59][CH:60]=[C:61]([F:64])[C:62]=4[CH3:63])[N+:52]([O-:56])=[CH:53]3)=[CH:48][N:47]=2)=[O:69])[CH2:67][CH2:66]1
Reactant: Cc1c(F)cncc1-c1cc2cnc(Cl)cc2c[n+]1[O-]
Reactant: NC(=O)C1CC1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(F)cncc1-c1cc2cnc(NC(=O)C3CC3)cc2c[n+]1[O-]
Temperature: 100 °C

Procedure:
A mixture of chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (28 mg, 0.035 mmol), cesium carbonate (227 mg, 0.69 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (19 mg, 0.035 mmol), 7-chloro-3-(5-fluoro-4-methylpyridin-3-yl)-2,6-naphthyridine 2-oxide (100 mg, 0.35 mmol), and cyclopropanecarboxamide (59 mg, 0.69 mmol) in dioxane (2 mL) was heated at 100° C. for 8 hours in a vial sealed with a Teflon cap. The reaction mixture was diluted with dichloromethane (50 mL) and methanol (5 mL), filtered over Celite, and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC purification (5-85% ACN in water w/0.1% NH4OH, 14 min) Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.14 (s, 2H), 8.63 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 2.12 (d, J=1.5 Hz, 3H), 2.08 (m, 1H), 0.86 (m, 4H). LCMS (Method E): RT=3.626 min, M+H+=339.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][S:16][C:10]=2[CH:9]1[C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C)C(=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.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)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][S:16][C:10]=2[CH:9]1[C:17]1[CH:22]=[C:21]([C:31]#[N:32])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C1c2scnc2CCN1C(=O)OC(C)(C)C
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C#N)cc1C1c2scnc2CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-4-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (375 mg, 0.75 mmol, 1.00 eq.) in N,N-dimethylacetamide (1.5 mL), zinc cyanide (44 mg, 0.37 mmol, 0.50 eq.), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 16 μmol, 0.02 eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (11 mg, 20 μmol, 0.03 eq.) and poly(methylhydrosiloxane) (15 μL) were added in sequence. The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. To the previous mixture, zinc cyanide (44 mg, 0.37 mmol, 0.50 eq.), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 16 μmol, 0.02 eq.), 1,1′-bis-(diphenylphosphino)-ferrocene (11 mg, 20 μmol, 0.03 eq.) and poly(methylhydrosiloxane) (15 μL) were added. The resulting mixture was stirred at 150° C. under microwave irradiation for 30 min. The reaction mixture was diluted with AcOEt and water was added. The layers were separated and the org. layer was dried over MgSO4, filtered over celite, and concentrated in vacuo. The residue, redissolved in DMF (4 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a brown oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:16][CH2:15]1.[CH:28](=[O:37])[C:29]1[C:30]([O:35][CH3:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.Cl>C1COCC1.C(O)(C)C.O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[C:27]([CH:28]([OH:37])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:16][CH2:15]1
Reactant: COc1ccccc1C=O
Reactant: COc1ccccc1N1CCN(CCc2ccccn2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(O)c1cccnc1CCN1CCN(c2ccccc2OC)CC1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
n-Butyl-lithium (1.6M solution in hexane) (7.0 ml, 11.2 mmol, 1.1 equiv.) was added dropwise at below -60° C. to a solution of 1-(2-methoxyphenyl)-4-(2-pyridylethyl)piperazine base (3.00 g, 10.1 mmol) in anhydrous THF (20 ml). The resulting orange-red solution was stirred for a further 0.25 h at -70° C. then quenched with a solution of ortho-anisaldehyde (1.5 g, 11.0 mmol) in anhydrous THF (2 ml). The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (2×75 ml). The organic extract was washed (brine), dried (Na2SO4) and concentrated in vacuo. The residue was subjected to chromatography (SiO2 :Et2O) to give the first Rf diastereoisomer as a white foam which was dissolved in isopropanol (20 ml) and acidified with ethanolic hydrogen chloride to afford the first diastereoisomer of the title compound as the trihydrochloride (227 mg), m.p. 140°-145° C. (Found: C,57.7;H,6.5;N,7.8 C26H31N3O3.3HCl requires C,57.5;H,6.3;N,7.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[Br:8].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([Br:8])=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
A mixture of 4.90 g (10.9 mmol) of 4-[(3,4-dibromophenyl)amino]-6-nitro-quinoline-3-carbonitrile and 12.4 g (54.7 mmol) of SnCl2 dihydrate in 200 mL of ethanol was refluxed under N2 for 1.5 h. After cooling to 25° C., the reaction was diluted with ice water, neutralized with sodium bicarbonate and stirred for 2 h. This solution was then extracted with chloroform, treated with Darco, dried (magnesium sulfate) and evaporated. After drying in vacuo (40° C.), there was obtained 1.25 g of brown solid: mass spectrum (electrospray, m/e): M+H 417, 419, 421.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:34]=[N:33][C:10]3[O:11][C:12]4[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[N:16][C:15]([C:24]5[CH:32]=[CH:31][CH:30]=[C:29]6[C:25]=5[CH:26]=[CH:27][NH:28]6)=[N:14][C:13]=4[C:9]=3[CH:8]=2)[CH3:5])C[CH2:2]1.Cl.N1CCC1.CC([O-])=O.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH3-]C#N.[Na+]>[Cl-].[Na+].O.CCOC(C)=O.CO.C(Cl)Cl.CN(C=O)C>[N:4]1([CH2:6][C:7]2[CH:34]=[N:33][C:10]3[O:11][C:12]4[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[N:16][C:15]([C:24]5[CH:32]=[CH:31][CH:30]=[C:29]6[C:25]=5[CH:26]=[CH:27][NH:28]6)=[N:14][C:13]=4[C:9]=3[CH:8]=2)[CH2:1][CH2:2][CH2:5]1
Reactant: CN(Cc1cnc2oc3c(N4CCOCC4)nc(-c4cccc5[nH]ccc45)nc3c2c1)C1CC1
Agent: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: c1cc(-c2nc(N3CCOCC3)c3oc4ncc(CN5CCC5)cc4c3n2)c2cc[nH]c2c1
Reaction time: 16 h

Procedure:
To compound 23 (as per Example S above) (17 mg, 0.04 mmol) in a mixture of dry DMF (2 mL), CH2Cl2 (0.5 mL) and MeOH (0.2 mL) was added azetidine hydrochloride (16 mg, 0.17 mmol) and NaOAc (14 mg, 0.17 mnnol) under Ar(g). After 5 minutes NaBH(OAc)3 (27 m0, 0.13 mmol) and NaBH3CN (5.4 mg, 0.09 mmol) were added and the reaction mixture was stirred for 16 h. EtOAc (45 mL) was added along with 50% saturated brine (5 mL); the layers were separated, extracted with EtOAc (3×10 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 2-8% MeOH/CH2Cl2) furnished U (5.4 mg, 0.012 mmol, 28%) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: COC(=O)Cc1ccc(F)c(C#N)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(F)c(C#N)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of compound methyl (3-cyano-4-fluorophenyl)acetate (200 mg, 1.03 mmol) in 15 mL of anhydrous THF was cooled to −78° C. NaHMDS (1.11 mmol) was added to the reaction dropwise at −78° C. After the addition, the mixture was stirred at −78° C. for 1 h and then CH3I (160 mg, 1.33 mmol) was added to the reaction dropwise at −78° C. The reaction was warmed to room temperature slowly and stirred at ambient temperature over night. The reaction was quenched with NH4Cl solution, extracted with EtOAc. The orgianic layer was washed with saturated chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified via preparative TLC to afford methyl 2-(3-cyano-4-fluorophenyl)propanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH:13]([C:16]1[N:17]=[C:18]([C:21](Cl)=[O:22])[S:19][CH:20]=1)([CH3:15])[CH3:14]>O1CCOCC1>[C:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:21]([C:18]1[S:19][CH:20]=[C:16]([CH:13]([CH3:15])[CH3:14])[N:17]=1)=[O:22])(=[O:12])[CH3:11]
Reactant: CC(C)c1csc(C(=O)Cl)n1
Reactant: COc1ccc(C(C)=O)c(N)c1
Solvent: C1COCCO1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Under nitrogen, a solution of compound 201a (3 g, 1 eq.) in 1,4-dioxane (30 mL) was added at 0° C. to a solution of compound 214 (4.1 g, 1.2 eq.) in 1,4-dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel to yield compound as a beige solid 217a in 75% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) (ppm) 1.43 (d, J=6.98 Hz, 6H), 2.65 (s, 3H), 3.26 (hep, J=6.98 Hz, 1H), 3.92 (s, 3H), 6.69 (dd, J=2.59 and 8.80 Hz, 1H), 7.2 (d, J=0.84, 1H), 7.87 (d, J=8.9 Hz, 1H), 8.58 (d, J=2.59 Hz, 1H), 13.5 (br s, 1H); MS (ESI, EI+): m/z=319 (MH+).