Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[OH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=2)[N:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:20]=1.C([O-])(O)=O.[Na+]>C(#N)C>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=3)[N:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:20]=2)[CH2:6][CH2:7]1
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)n1nc(OCCN2CCOCC2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 42.2 %

Procedure:
To a solution of 4-(2-chloroethyl)morpholine hydrochloride (390 mg, 2.10 mmol) in acetonitrile (25 mL) was added triethylamine (0.56 mL, 4.0 mmol) and ethyl 3-hydroxy-5-nitro-1H-indazole-1-carboxylate (563 mg, 1.91 mmol) and the mixture heated to reflux for 2 days. Additional portions of 4-(2-chloroethyl)morpholine hydrochloride (178 mg, 0.955 mmol) and triethylamine (130 μL, 0.95 mmol) were added and the reaction mixture was heated at reflux for a further 3 hr and then cooled to RT. Saturated aq. NaHCO3 (50 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, 0-100% EtOAc in isohexane, gradient elution) to afford ethyl 3-(2-morpholinoethoxy)-5-nitro-1H-indazole-1-carboxylate as a yellow solid (294 mg, 41%); Rt 1.26 min (Method 2, acidic); m/z 365 (M+H)+ (ES+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19](=[O:31])[C:20]1[C:21](=[C:26](I)[CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH3:25])=[O:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.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]>[CH3:25][O:24][C:22](=[O:23])[C:21]1[C:20](=[C:29]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:11]=2)[CH:28]=[CH:27][CH:26]=1)[C:19]([O:18][CH3:17])=[O:31]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2cccc(OCCN3CCOCC3)c2)c1C(=O)OC
Yield: 73 %

Procedure:
A mixture of 3-(2-morpholin-4-yl-ethoxy)-phenylamine (1.4 g, 6.1 mmol), 3-iodophthalic acid dimethyl ester (2.0 g, 6.2 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), rac-BINAP (0.12 g, 0.19 mmol), and cesium carbonate (2.8 g, 8.6 mmol), in 12 mL toluene was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, diluted with CH2Cl2 (20 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (60 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 1.9 g of the product at 95:5 methylene chloride-methanol, in 73% yield; 1H NMR (CDCl3) δ 2.57 (t, J=4.6 Hz, 4H), 2.79 (t, J=5.7 Hz, 2H), 3.73 (t, J=4.6 Hz, 4H), 3.87 (s, 3H), 3.89 (s, 3H), 4.09 (t, J=5.7 Hz, 2H), 6.60 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 6.70 (t, J=2.1 Hz, 1H), 6.74 (dd, J=7.8 Hz, J=1.8 Hz, 1H), 7.11 (dd, J=7.4 Hz, J=1.0 Hz, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.43 (dd, J=8.4 Hz, J=0.9 Hz, 1H), 7.98 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[N:17]=[N:18][N:19]([CH2:21][Si](C)(C)C)[CH:20]=2)[NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[N:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)N[C@@H](c1ccc(Br)cc1)c1cn(C[Si](C)(C)C)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc([C@@H](NS(=O)C(C)(C)C)c2ccc(Br)cc2)nn1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 1.0 g (2.3 mmol) N-((S)-(4-bromophenyl){1-[(trimethylsilyl)-methyl]-1H-1,2,3-triazol-4-yl}methyl)-2-methylpropane-2-sulfinamide in 5.0 ml THF was added 2.5 mL (2.5 mmol) 1.0M solution TBAF. After 30 min at room temperature, the reaction mixture was concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-10% MeOH:Methylene chloride) afforded 0.80 g (95%) N-[(S)-(4-bromophenyl)(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-2-methylpropane-2-sulfinamide. 1H NMR (CDCl3, 400 MHz) 7.51-7.49 (m, 2H); 7.31 (m, 2H); 7.21 (s, 1H); 5.70 (d, 1H, J=2.96 Hz); 4.49 (d, 1H, J=2.75 Hz); 4.04 (s, 3H); 1.24 (s, 9H). ESMS [M+1]+=373.0.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(OCC)c3)nc12
Reactant: Nc1ccc(Br)cn1
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(N)nc4)c3n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.19) (627 g, 2.0 mmol) and commercially available 2-amino-5-bromopyridine (450 mg, 2.6 mmol) according to general procedure II. Obtained as a yellow solid (93 mg, 12%). MS (ISP) 406.2 [(M+H)+]; mp 162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:34]1[CH2:38][C:37](=[O:39])[NH:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:31])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:34]4[CH2:38][C:37](=[O:39])[NH:36][CH2:35]4)=[O:22])=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reactant: O=C1CNCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (100 mg, 0.20 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), imidazolidin-4-one (34 mg, 0.39 mmol, 2.00 equiv), HATU (150 mg, 0.39 mmol, 2.00 equiv), DIEA (51 mg, 0.39 mmol, 2.00 equiv). The resulting solution was stirred for 1 h at rt. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:0). This resulted in 100 mg (88%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]imidazolidin-4-one as yellow oil.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([O:17][C:18](=[O:35])[NH:19][CH2:20][CH:21]([OH:34])[CH2:22][NH:23][CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])([CH3:16])[CH3:15]>C(O)C>[CH3:13][C:14]([O:17][C:18](=[O:35])[NH:19][CH2:20][CH:21]([OH:34])[CH2:22][N:23]([CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:15])[CH3:16]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCOP(=O)(CCNCC(O)CNC(=O)OC(C)(C)C)OCC
Solvent: CCO
Product: CCOc1c(N(CCP(=O)(OCC)OCC)CC(O)CNC(=O)OC(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.0 mL, 34 mmol) in absolute ethanol (180 mL) prepared under nitrogen, was added a solution of [3-[[2-(diethoxyphosphinyl)ethyl]amino]-2-hydroxypropyl]carbamic acid 1,1-dimethylethyl ester (12.11 g, 34 mmol) in ethanol (60 mL) over 1 hour. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in chloroform (150 mL), preadsorbed onto silica gel, and purified by flash chromatography (7 cm diameter, gradient elution with 2.5-15% methanol in dichloromethane) to yield [3-[[2-(diethoxyphosphinyl)ethyl](2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]-2-hydroxypropyl]carbamic acid 1,1-dimethylethyl ester as a clear viscous oil (11.34 g, 70%; IR (neat, cm-1):3350, 1800, 1700: 1H NMR (CDCl3 400 MHz): δ 5.37, 5.19 (br s, NH), 4.82-4.72 (m, 3H), 4.16-3.11 (m, 11H), 2.24-2.14 (m, 2H), 1.47-1.43 (m, 12H), 1.32 (t, J=7 Hz, 6H).
Reaction SMILES: O[PH2]=O.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([CH:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=C[CH:20]=[CH:19]4)O)=[CH:12][N:13]=2)[N:10]=1.II>C(O)(=O)C>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]3[CH:16]=[CH:17][C:18]4[C:23](=[CH:24][CH:25]=[CH:20][CH:19]=4)[N:22]=3)=[CH:12][N:13]=2)[N:10]=1
Reactant: OC(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: Clc1ccc2ncc(-c3ccc4ccccc4n3)n2n1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
H3PO2 (28.8 mL of a 50% aqueous solution, 263 mmol) was added to a solution of (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanol (Stage 1.1, 10.89 g, 35.0 mmol) in acetic acid (272 mL) at 80° C. Iodine (13.34 g, 52.6 mmol) was then added and the RM was stirred at 110° C. for 90 min. The RM was cooled down to rt and acetic acid was removed. The residue was taken up in water and DCM. A 2 N NaOH solution was then added until pH=11. The organic layer was then separated and washed with water (2×). The aqueous layer was further extracted with DCM (3×). The combined organic layer was then dried, filtered and concentrated. The residue crystallized in EtOAc. The resulting solid was purified by flash chromatography (Flashmaster, with a 50 g silica gel column, TBME/MeOH: 97:3→84:16). The solid crystallized again in EtOAc/Et2O. It was filtered and dried under vacuum to afford the title compound as a white solid (tR 4.72 min (conditions 4), MH+=295.0, 1H-NMR in DMSO-d6: 8.86 (m, 1H); 8.30 (m, 1H); 8.23 (d, 1H); 7.98 (d, 1H); 7.82 (m, 1H); 7.72 (m, 2H); 7.50 (dd, 1H); 7.35 (d, 1H); 4.52 (s, 2H)).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:27]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:27])[C:3](=[O:2])[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(OC)cc2)c1C
Temperature: 25 °C
Yield: 60.9 %

Procedure:
MeOH (120 mL) was added to a flask containing 4-[1-(4-methoxy-benzylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (5 g, 15.7 mmol). NaOMe solution (3.6 mL, 15.7 mmol, 4.375 M in MeOH) and N-bromosuccinimide (3.35 g, 18.8 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl and CH2Cl2. The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-50% EtOAc/hexanes) to give 3.5 g of the title compound. MS: (+) m/z 388.14, 390.15 (M+Na, 79/81Br).
Reaction SMILES: [CH2:1]1[O:16][C:4]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[NH:6][CH2:5]2)[O:3][CH2:2]1.[H-].[Na+].Cl[CH2:20][CH:21]([OH:29])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>COCCOC>[CH2:1]1[O:16][C:4]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7](=[O:15])(=[O:14])[N:6]([CH2:20][CH:21]([OH:29])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:5]2)[O:3][CH2:2]1
Reactant: OC(CCl)CN1CCOCC1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=S1(=O)c2ccccc2C2(CN1CC(O)CN1CCOCC1)OCCO2
Yield: 70.2 %

Procedure:
A suspension of 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal (0.48 g, 2 mmol) and 60% sodium hydride (0.08 g, 2 mmol.) in 1,2-dimethoxyethane (20 mL) was heated for one hour under refluxing. The resulting reaction liquid was further heated for 16 hours under refluxing, after addition of 1-chloro-3-morpholino-2-propanol (0.36 g, 2 mmol.). The reaction liquid was placed under reduced pressure to distill the solvent off. The residue was treated with 1N hydrochloric acid and ethyl acetate, and the aqueous layer was taken out. The aquous solution was made basic by addition of potassium carbonate, and the precipitated oil was extracted with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried solution was placed under reduced pressure to distill the solvent off. The resulting residue was treated by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the desired compound (0.54 g, yield 70%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:12][C:13]3[C:22]([CH:23]=2)=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=3)[CH:7]=[CH:8][CH:9]=1.C[Si](C)(C)[Cl:30].O>CC(C)=O>[ClH:30].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:23]3[C:22](=[N:21][C:20]4[C:15]([CH:14]=3)=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:13][CH2:12][C:11]=2[CH2:24][N:25]([CH3:26])[CH3:27])[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1cccc(C2=Cc3nc4ccccc4cc3CC2CN(C)C)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(C2=C(CN(C)C)CCc3nc4ccccc4cc32)c1
Yield: 22.9 %

Procedure:
18 g of the product from Step 1 were dissolved in 200 ml methanol under dry nitrogen. The reaction mixture was treated with 7.7 g 2-aminobenzaldehyde as the hydrochloride and was subsequently heated to 80° C. After adding 400 ml 1 N hydrochloric acid, the reaction solution was stirred for eight days at 80° C. After cooling to room temperature, the reaction mixture was diluted with 200 ml ethyl acetate and was made alkaline with concentrated sodium hydroxide solution while being cooled in ice. The aqueous phase was extracted three times with 100 ml portions of ethyl acetate each time, and the combined organic phases were dried over magnesium sulfate and evaporated to dryness under vacuum. The residue was eluted and purified by column chromatography on silica gel using ethyl acetate/methanol in a ratio of 4/1. The first product fraction contained 5.4 g [3-(3-methoxy-phenyl)-1,2-dihydro-acridin-2-yl-methyl]-dimethylamine base in the form of beige crystals. In order to prepare the hydrochloride, the solid was dissolved with heating in 200 ml acetone and was treated with trimethylchlorosilane and water in equimolar amounts. 5.2 g (28.3% theoretical) [3-(3-methoxy-phenyl)-1,2-dihydro-acridin-2-yl-methyl]-dimethyl-amine hydrochloride were obtained (light yellow crystals, m.p.: 201° C. to 204° C.). 4.4 g [1-(3-methoxy-phenyl)-3,4-dihydro-acridin-2-yl-methyl]-dimethylamine base in the form of a beige, amorphous solid was obtained as the second fraction. To release the hydrochloride, the solid was dissolved with heating in 200 ml acetone and was treated with trimethylchlorosilane and water in equimolar amounts. 4.2 g (22.90% theoretical) [1-(3-methoxy-phenyl)-3,4-di-hydro-acridin-2-yl-methyl]-dimethylamine hydrochloride were obtained in the form of light yellow crystals, m.p.: 195° C. to 198° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][C@@H:24]2[CH2:28][CH2:27][N:26]([C:29]3[N:37]=[C:36]4[C:32]([N:33]=[CH:34][N:35]4[C@@H:38]4[CH2:42][C@H:41]([NH:43][C:44](=[O:47])[CH2:45][CH3:46])[C@@H:40]([OH:48])[C@H:39]4[OH:49])=[C:31]([NH:50][CH2:51][CH:52]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:30]=3)[CH2:25]2)[N:3]=1.[N:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH:71][C:72]([NH:74][C@@H:75]2[CH2:79][CH2:78][NH:77][CH2:76]2)=[O:73])[CH:66]=1>CCO>[N:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH:71][C:72](=[O:73])[NH:74][C@@H:75]2[CH2:79][CH2:78][N:77]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[CH:7][N:8]4[C@@H:11]4[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]4[OH:22])=[C:4]([NH:23][C@@H:24]4[CH2:28][CH2:27][N:26]([C:29]5[N:37]=[C:36]6[C:32]([N:33]=[CH:34][N:35]6[C@@H:38]6[CH2:42][C@H:41]([NH:43][C:44](=[O:47])[CH2:45][CH3:46])[C@@H:40]([OH:48])[C@H:39]6[OH:49])=[C:31]([NH:50][CH2:51][CH:52]([C:53]6[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=6)[C:59]6[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=6)[N:30]=5)[CH2:25]4)[N:3]=3)[CH2:76]2)[CH:66]=1
Reactant: O=C(Nc1cccnc1)N[C@@H]1CCNC1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5nc(Cl)nc6c5ncn6[C@@H]5C[C@H](NC(=O)CC)[C@@H](O)[C@H]5O)C4)nc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5nc(N6CC[C@@H](NC(=O)Nc7cccnc7)C6)nc6c5ncn6[C@@H]5C[C@H](NC(=O)CC)[C@@H](O)[C@H]5O)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
N-{(1S,2R,3S,4R)-4-[2-{(R)-3-[2-Chloro-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-6-ylamino]-pyrrolidin-1-yl}-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (1 eq.) and 1-pyridin-3-yl-3-(R)-pyrrolidin-3-yl-urea (3 eq.) are dissolved in EtOH. The reaction mixture is refluxed at room temperature for 48 hours. The reaction mixture is reduced in vacuo and purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA) to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:27][CH:26]([N:28]([CH3:30])[CH3:29])[CH2:25]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH2:20][CH:21]([N:24]4[CH2:25][CH:26]([N:28]([CH3:30])[CH3:29])[CH2:27]4)[CH2:22][CH2:23]3)=[O:17])[CH:10]=2)=[CH:31][CH:32]=1
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccn3)CC2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.7 %

Procedure:
After adding 20% palladium hydroxide-carbon (50 mg) to a solution of 4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (112 mg) in tetrahydrofuran (5.0 ml), the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered. The filtrate was concentrated to provide the title compound (91.5 mg, 87.8%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:16](O)[CH3:17]>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1N
Yield: 78 %

Procedure:
To a solution of 2-aminobenzoic acid (7.29 mmol, 1.0 g) in ethanol (20 ml), H2SO4 (45 mmol, 2.5 ml) was added and the mixture was refluxed for 20 hours. The solvent was evaporated and the crude residue was dissolved in water. The solution neutralised with 6N NaOH aqueous solution and extracted with CHCl3. The organic phase was evaporated affording 0.939 g (yield 78%) of the expected product.
Reaction SMILES: [N:1]1([CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.Br[C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1[CH3:28].[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.O>[N:1]1([CH:14]([CH2:17][CH3:18])[CH2:15][O:16][CH2:28][C:21]2[CH:20]=[CH:25][C:24]([C:26]#[N:27])=[CH:23][CH:22]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccc(C#N)cc1Br
Reactant: CCC(CO)n1cnc2cnc3ccccc3c21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(COCc1ccc(C#N)cc1)n1cnc2cnc3ccccc3c21
Yield: 60.2 %

Procedure:
2-(1H-imidazo[4,5-c]quinolin-1-yl)-1-butanol (3.0 g, 12.4 mmol) was added to a stirring mixture of cc-bromo-p-tolunitrile (3.0 g, 15.3 mmol), sodium hydroxide (40 ml, 50%), dichloromethane (40 ml), and benzyltrimethylammonium chloride (0.02 g, 0.11 mmol). The reaction was maintained for 72 hours and then diluted with dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted with additional dichloromethane (100 ml). The organic fractions were combined, washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9/1 dichloromethane/methanol, Rf0.48) to provide 2.66 g of 4-{[2-(1H-imidazo[4,5-c]quinolin-1-yl)butoxy]methyl}benzonitrile.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH2:5])=[O:4].[Cl:6][C:7](=[CH2:10])[C:8]#[N:9]>N1C=CC=CC=1>[Cl:6][CH:7]([C:8]#[N:9])[CH2:10][S:1][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: C=C(Cl)C#N
Reactant: NC(=O)CS
Solvent: c1ccncc1
Product: N#CC(Cl)CSCC(N)=O
Reaction time: 0.75 h

Procedure:
A solution of 2-mercaptoacetamide (20 g) in dry pyridine (80 ml) was stirred whilst 2-chloroacrylonitrile (18 ml) was added slowly with ice-bath cooling. After the addition was complete, the ice-bath was removed, and the mixture was stirred for 45 minutes. The resultant mixture contained the title compound. A portion of the mixture was shaken repeatedly with petroleum ether (b.p. 60° to 80° C.) to leave the title compound as a syrup. 'H nmr δ (CD3COCD3) 5.50 (1H,t,J=7HZ, CH2CH), 3.40 (2H, d,J=7HZ, CH2CH), 3.50(2H, s, CH2CN).
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>Cl(O)(=O)(=O)=O>[C:19]([O:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])(=[O:21])[CH3:20]
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)OC1C(N2CCCC2=O)c2sccc2OC1(C)C
Temperature: 0 °C

Procedure:
A solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (2.0 g, 7.48 mmol) and perchloric acid (70%, 10 drops) in acetic anhydride (20 mL) were stirred for 1 h at 0°-5° C. The solution was poured into ice water (100 mL). The product was extracted into dichloromethane, washed with water (4x), and evaporated in vacuo. The resultant oil was purified by flash chromatography, using 1% methanol in dichloromethane as the eluant, then crystallized from hexanes to give the product, 2.12 g (92%), as a colorless solid: mp 92°-93° C.; IR(KBr): 1745 and 1684 cm-1 ; MS: 310 (MH+); 1 1H NMR (CDCl3): w 1.37 (s, 3H), 1.38 (s, 3H), 1.98 (m, 2H), 2.10 (s, 3H), 2.37 (m, 2H), 3.24 (m, 1H), 3.40 (m, 1H), 5.15 (d, J=9.1 Hz, 1H), 5.44 (d, J=9.1 Hz, 1H), 6.58 (d, J=5.4 Hz, 1H) and 7.13 (d, J=5.4 Hz, 1H).