Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:27](=S)=[S:28]>CCO.O>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]3=[N:23][C:27](=[S:28])[N:24]=[C:19]3[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: Nc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: S=C1N=c2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2=N1
Yield: 68.4 %

Procedure:
A mixture of 4-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (326 mg, 1.0 mmol), KOH (66 mg, 1.1 mmol) and CS2 (66 μL, 1.1 mmol) in 95% EtOH (1.5 mL) and H2O (0.2 mL) was refluxed for 3 h, then evaporated, and the residue was purified by chromatography over silica gel (CHCl3 --MeOH, 4:1) to give 250 mg (68%) of the title compound as a foam solid. 1H NMR (DMSO-d6): 1.40-1.48 (m, 2H), 1.54-1.61 (m, 1H), 1.67-1.71 (m, 2H), 2.09-2.18 (m, 2H), 2.517 (d, 2H, J=6), 2.841 (t, 2H, J=5), 3.17-3.20 (m,2H), 4.139 (t, 2H, J=5), 6.551 (d, 1H, J=2), 6.605 (dd, 1H, J=8.5; 2), 6.950 (d, 1H, J=8.5), 7.11-7.28 (m, 5H). The hydrochloride, mp. 273-5° C. Analysis, Calcd. for C21H26ClN3OS: C 62.44, H 6.49, N 10.40; Found: C 62.28, H 6.42, N 10.21.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.FC(F)(F)OC1C=CC(B(O)O)=CC=1.[ClH:34]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:34].[F:1][C:2]([F:18])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: OB(O)c1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: NCc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
A solution of 4′-[(trifluoromethyl)oxy]-4-biphenylcarbonitrile (prepared from {4-[(trifluoromethyl)oxy]phenyl}boronic acid by a method analogous to that described for the 4′-trifluoromethyl analogue, Intermediate D6 of WO 02/30911) (66.6 g) in ethanol (2000 ml) and concentrated hydrochloric acid (100 ml) was hydrogenated over Pearlman's catalyst (10 g) at 25 psi until reduction was complete. The catalyst was removed by filtration through celite, then the solvent was removed in vacuo to obtain the desired product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6].Br[CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]2[C:19]([CH3:24])=[N:20][CH:21]=[C:22]([CH3:23])[C:11]=12>O1CCOCC1>[NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[S:6][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]2[C:19]([CH3:24])=[N:20][CH:21]=[C:22]([CH3:23])[C:11]=12
Reactant: S=C1NCCN1
Reactant: Cc1cnc(C)n2c1c(CCBr)c1ccccc12
Solvent: C1COCCO1
Product: Cc1cnc(C)n2c1c(CCSC1=NCCN1)c1ccccc12
Yield: 59.2 %

Procedure:
A mixture of 2-imidazolidinethione (3.1 g), 5-(2-bromoethyl)-1,4-dimethylpyrimido[1,6-a]indole (6 g, described in Example 13) and dry dioxane (400 ml) is refluxed for 6 hours. The resulting precipitate is collected by filtration and dissolved in water and the solution is neutralized with aqueous sodium bicarbonate. After adding a few drops of 10% sodium hydroxide, the aqueous mixture is extracted with chloroform. The combined extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from acetonitrile to obtain the title compound (3.8 g): mp 157°-159° C.; ir (CHCl3) 3400, 1610, 1595 and 1570 cm-1 ; uv(MeOH) λmax 250,299,311 and 325 nm; ε=35200, 4840, 8200, and 10870, respectively; and nmr (CDCl3) δ2.52(s), 2.99(s), 3.43(m), 3.60(s), 4.25(s) and 7.1-8.2(m).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C@H:15]2[CH2:24][N:19]3[CH2:20][CH2:21][NH:22][CH2:23][C@@H:18]3[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Cl>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@H:15]2[CH2:24][N:19]3[CH2:20][CH2:21][N:22]([C:2]4[N:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:23][C@@H:18]3[CH2:17][CH2:16]2)=[CH:25][CH:26]=1
Reactant: Clc1ncccn1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ncccn4)CCN3C2)cc1

Procedure:
The title compound was prepared according to Preparation 3 with 2-chloropyrimidine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 8). mp (.HCl) 283–285° C. HRMS calcd for C19H23FN4O: 342.1856; found: 342.1867.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[CH2:9][CH2:10]/[C:11](/[CH3:26])=[CH:12]/[CH2:13][CH2:14]/[C:15](/[CH3:25])=[CH:16]/[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:27])[CH2:9][CH2:10]/[C:11](/[CH3:26])=[CH:12]/[CH2:13][CH2:14]/[C:15](/[CH3:25])=[CH:16]/[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:6][CH:7]=1
Reactant: C/C(=C\COC1CCCCO1)CC/C=C(\C)CCC(O)c1ccc(Br)cc1
Agent: [Mn+4]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C/C(=C\COC1CCCCO1)CC/C=C(\C)CCC(=O)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A solution of 3.4 g of (4E,8E)-1-(4-bromo-phenyl)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dien-1-ol in 60 ml of methylene chloride is treated in succession with 0.29 g of sodium carbonate and 7.5 g of manganese(IV) oxide. After stirring for 3 hrs. the mixture is filtered and again treated in methylene chloride with 0.29 g of sodium carbonate and 7.5 g of manganese (IV) oxide. After filtration and silica gel chromatography with hexane/ethyl acetate (9:1) there are obtained 1.98 g of (4E,8E)-(RS)-1-(4-bromo-phenyl)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dien-1-one.
Reaction SMILES: FC(F)=C(C1C=CC(OC)=CC=1)C(F)(F)F.[F:17][C:18](F)([F:34])[CH:19]([C:24]1[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[CH:29]=[O:30])[C:20]([F:23])([F:22])[F:21]>>[F:17][C:18]([F:34])=[C:19]([C:24]1[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=1)[CH:29]=[O:30])[C:20]([F:21])([F:22])[F:23]
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Agent: COc1ccc(C(=C(F)F)C(F)(F)F)cc1
Product: COc1ccc(C(=C(F)F)C(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 74 in the same manner of Compound 9.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14](O)[CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C([O:54][C:55](=[O:74])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59](B2OC(C)(C)C(C)(C)O2)[CH:58]=1)C.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl.C1(C)C=CC=CC=1.CCO.O.C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:59]3[CH:58]=[C:57]([CH2:56][C:55]([OH:74])=[O:54])[CH:62]=[CH:61][C:60]=3[O:63][CH3:64])[CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(OCc1ccccc1)N1CCc2cccc(O)c2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)O)cc1-c1cccc2c1CN(C(=O)OCc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled solution of 8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (113 mg, 0.40 mmol, 1.00 eq.) in DCM (1 mL), NEt3 (0.17 mL, 1.20 mmol, 3.00 eq.) and trifluoromethanesulfonic anhydride (0.10 mL, 0.60 mmol, 1.50 eq.) were added in sequence. The reaction mixture was stirred at 0° C. for 30 min and further at r.t. for 45 min. The mixture was diluted with DCM (50 mL) and washed with sat. aq. NaHCO3 soln. (2×25 mL). The org. layer was dried over MgSO4 and concentrated in vacuo. To a mixture under N2 of the triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (128 mg, 0.40 mmol, 1.00 eq.), and sodium carbonate (170 mg, 1.60 mmol, 4.00 eq.) in toluene/EtOH/water 20:4:1 (2.5 mL), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol, 0.05 eq.) was added. The mixture was stirred at 100° C. for 17 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was partitioned between AcOEt (20 mL) and water (10 mL). The layers were separated. The org. phase was washed with sat. aq. NaCl soln. (1×10 mL), dried over MgSO4, and concentrated in vacuo. The residue was partially purified by CC (SiO2, Hept/AcOEt 8:2 to 7:3) to give an yellow oil. The residue was dissolved in THF (3 mL) and 1M aq. NaOH (0.6 mL) was added. The resulting solution was stirred at r.t. for 68 hours. The org. solvent was removed in vacuo. The residue was diluted with water (10 mL) and acidified with 1M aq. HCl. The mixture was extracted with DCM/THF 3:1 (3×5 mL). The comb. org. phases were concentrated in vacuo. The crude product was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.
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.[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH2:19])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:15])([CH3:14])[CH3:13]
Reactant: Brc1cnc2ccccc2c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C=Cc1cnc2ccccc2c1

Procedure:
A mixture of 3-bromoquinoline 3-1(25 g, 120 mmol), acrylic acid tert-butyl ester (100 mL, 672 mmol), triethylamine (50 mL, 300 mmol) and Pd(OAc)2 (1.61 g, 7.2 mmol) in acetonitrile (100 mL) was refluxed for 18 hr. It is then cooled, diluted with 500 mL CH2Cl2 and filtered. The solution was washed with 10% NaHCO3, dried and concentrated. The residue was dissolved in 50 ml hot CH2Cl2 and diluted with 300 mL hexane. After standing, the desired product 3-2 was obtained as a crystalline compound.
Reaction SMILES: [C:1]([O:4][CH:5]([C:7]1[C:8]([CH2:31][O:32][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]=2)[CH3:6])(=[O:3])[CH3:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][CH:5]([C:7]1[C:8]([CH2:31][OH:32])=[CH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:11]=2)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)c1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)OC(C)c1c(CO)cc2cc(OCc3ccccc3)ccc2c1-c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of the crude ether from Step 5 in THF (10 mL) at 0° C. was added HOAC (4 drops) followed by n-Bu4NF (1M, THF, 1.4 mL). The reaction mixture was stirred 2 hr. at 0° C. then quenched with a saturated solution of NH4Cl and diluted with Et2O. The organic phase was washed with H2O, brine, dried over MgSO4, and the solvent evaporated. The residue was purified by chromatography on silica gel using hexane/EtOAc, 7:3, to give the title product.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[NH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[C:24]#[N:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCCCCC.C(OCC)(=O)C>[F:30][C:26]1[C:23]([C:24]#[N:25])=[C:22]([NH:21][C@H:2]2[CH2:11][CH2:10][C@@H:9]3[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]3)[CH2:3]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Reactant: N#Cc1c(N)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](Nc3cccc(F)c3C#N)CC[C@H]2CN1C(=O)OC
Yield: 1.2 %

Procedure:
Following the procedures from Example 3A, and using 5.38 g (19.0 mmol) of ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate, 1.36 g (10.0 mmol) of 2-amino-6-fluorobenzonitrile, 3.6 mL (60 mmol) of glacial acetic acid, 5.7 g (27.0 mmol) of sodium triacetoxyborohydride, flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 50 mg (1% yield) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=O)=[CH:14][C:13]=1[C:22]([O:24]C)=O.Cl>O1CCCC1>[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:18])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:14][C:13]=1[C:22](=[O:24])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(OC)c(C(=O)OC)c1
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(=O)C(C)(C)C)cc1C(=O)CC(=O)C(C)(C)C
Yield: 66.3 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 1.5 gm (38 mmol) of 60% sodium hydride, 3.6 gm (36 mmol) of pinacolone, 3.0 gm (13.4 mmol) of dimethyl 4-methoxyisophthalate, and 30 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream and refluxed with heating for 5 hours. After cooling the reaction mixture, 10 ml of 2N aqueous hydrochloric acid was added, and the product was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The crude product was recrystallized using hexane to obtain 3.2 gm of the target compound as colorless crystals (yield: 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(O[N:41]1[N:49]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O.NN>CN(C=O)C.O>[NH:41]([C:28]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[C:17]([O:16][C:15]3[CH:31]=[CH:32][C:12]([NH:11][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[O:10])=[CH:13][CH:14]=3)[CH:22]=[CH:21][N:20]=2)[NH:27][CH:26]=1)=[O:30])[NH2:49]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NN)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.23 mmol) in 10 ml of anhydrous DMF were added HATU (105 mg, 0.28 mmol) and N,N-diisopropylethylamine (89 mg, 0.69 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of hydrazine monohydrate (0.25 ml, 5.2 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 1-[4-({2-[4-(hydrazinocarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(3-methylphenyl)urea as white solid. Yield: 98 mg, 95%.
Reaction SMILES: I[C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])(C)(C)C.[C:22](=[O:24])=[O:23].[OH-].[Na+]>C1COCC1.CCOCC>[C:11]1([C:3]2[C:2]([C:22]([OH:24])=[O:23])=[C:7]3[CH2:8][CH2:9][O:10][C:6]3=[CH:5][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=O
Reactant: Ic1c(-c2ccccc2)ccc2c1CCO2
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccccc2)ccc2c1CCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A magnetically stirred solution of 2,3-dihydro-4-iodo-5-phenylbenzofuran (1.60 g, 4.97 mmol) in anhydrous THF (40 mL) under nitrogen at -78° C. was treated with tert-butyllithium (1.73 M in pentane, 6.10 mL, 10.6 mmol), keeping the temperature less than -65° C., throughout. The solution was stirred for 0.5 h and treated with anhydrous carbon dioxide over 1 h at such a rate as to keep the temperature below -60° C. during addition. The solution was stirred for 2 h, allowed to warm to room temperature, and treated with Et2O, ice (100 g), and 1 N NaOH (200 mL). The layers were separated and the organic portion was further extracted with fresh 1 N NaOH (2×200 mL). The combined organic extracts were acidified with concentrated HCl, extracted with CH2Cl2 (3×150 mL), and the extracts washed with brine (200 mL), dried (MgSO4), filtered, and concentrated in vacuo to give 0.795 g (67%) of the title compound: 1H NMR (300 MHz, CDCl3)δ 3.45 (t, J=8.5 Hz, 2H), 4.65 (t, J=8.5 Hz, 2H), 6.93 (d, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 7.29-7.42 (m, 5H), 11.2 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C1COCC1>C(OCC)(=O)C>[CH2:14]([N:18]=[CH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[Cl:1])[CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc2nccc(Cl)c2c1
Reactant: CCCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN=Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a suspension of 4-chloro-quinoline-6-carbaldehyde (3.59 g, 18.73 mmol) in heptanes (36 mL) was added n-butylamine(1.51 g, 20.60 mmol, 1.1 equiv.) at room temperature. The reaction mixture was stirred for 5 h at room temperature by this time all solids were dissolved and gave a light brown solution containing a little oily stuff on the wall of flask. Then, 4 mL of THF was added and the clear solution was stirred for another 15 h. This solution was diluted with ethyl acetate (50 mL) and washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvents were removed under the vacuum and the remaining residue was dried under high vacuum to afford 4.62 g (˜100% yield) of butyl (4-chloro-quinolin-6-ylmethylene)-amine as a brown oil which was used directly for the next substitution reaction. LRMS(+) m/e calcd for C14H15ClN2 (M+H)+247.7, found 247.2.
Reaction SMILES: [P:1](=[O:93])([S:84][CH2:85][O:86][C:87](=[O:92])[C:88]([CH3:91])([CH3:90])[CH3:89])([O:43][CH:44]([OH:83])[C@H:45]1[O:49][C@@H:48]([N:50]2[CH:58]=[C:56]([CH3:57])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[O:59]C(C1C=CC=CC=1)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[O:2][C@@:3]1([OH:42])[C@@H:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[O:6][C@@H:5]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:4]1>C(O)(=O)C.O.CO>[P:1](=[O:93])([S:84][CH2:85][O:86][C:87](=[O:92])[C:88]([CH3:91])([CH3:90])[CH3:89])([O:43][CH:44]([OH:83])[C@H:45]1[O:49][C@@H:48]([N:50]2[CH:58]=[C:56]([CH3:57])[C:54](=[O:55])[NH:53][C:51]2=[O:52])[CH2:47][C@@H:46]1[OH:59])[O:2][C@@:3]1([OH:42])[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[O:38])[NH:36][C:34]2=[O:35])[CH2:4]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)OP(=O)(OC(O)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)SCOC(=O)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](C(O)OP(=O)(O[C@]3(O)C[C@H](n4cc(C)c(=O)[nH]c4=O)O[C@@H]3CO)SCOC(=O)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The totally protected dimeric phosphorothioate triester (3a) is dissolved in a mixture of acetic acid/water/methanol (8:1:1, v:v:v) (10 ml). The reaction is left with stirring at ambient temperature for 5 hours. The reaction medium is then evaporated and the residue is coevaporated several times with water and toluene. The residue is then chromatographed on a silica gel column using a gradient of methanol (0 to 10%) in dichloro-methane as eluent. The fractions containing the product (4a) are collected, concentrated under reduced pressure, and then the residue is coevaporated several times with dioxane and lyophilized in dioxane. (4a) is obtained in the form of a white powder (98 mg, 85%).
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:3]([OH:5])=O.[CH:13]1([NH:20][C:21]([NH2:23])=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:20][C:21]2[S:22][CH:2]([CH2:6][C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[C:3](=[O:5])[N:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: N[C@@H](Cc1cccnc1)C(=O)O
Product: O=C1N=C(NC2CCCCCC2)SC1Cc1cccnc1

Procedure:
Synthesis was performed from (2S)-2-amino-3-pyridin-3-ylpropanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:5][N:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH2:39])=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH:39][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][CH2:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1cc(CNc2ccccc2C(=O)O)ccn1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-benzoic acid (Step A, 516 mg, 2.0 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol), TBTU (0.706 g, 2.2 mmol), and DIEA (0.7 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h. The mixture was diluted with more CH2Cl2. The organic layer was washed with water, brine, and dried with MgSO4. The solution was filtered, condensed, and the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2) to obtain the titled compound as oil. MS (ES+): 517.2 (M+H)+. Calc'd for C30H36N4O4-516.27.