Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:15]=[N:16][CH:17]=3)[CH:10]=2)[N:5](C2CCCCO2)[N:4]=1)=O.[S].[N:30]1[CH:35]=[C:34]([NH2:36])[C:33]([NH2:37])=[C:32]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:31]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:32]2[C:33]3[N:37]=[C:1]([C:3]4[C:11]5[C:6](=[N:7][CH:8]=[C:9]([C:12]6[CH:13]=[C:14]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH:15]=[N:16][CH:17]=6)[CH:10]=5)[NH:5][N:4]=4)[NH:36][C:34]=3[CH:35]=[N:30][CH:31]=2)[CH:39]=1
Reactant: CCC(=O)Nc1cncc(-c2cnc3c(c2)c(C=O)nn3C2CCCCO2)c1
Reactant: Nc1cncc(-c2cccnc2)c1N
Agent: CC[SiH](CC)CC
Agent: [S]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Nc1cncc(-c2cnc3[nH]nc(-c4nc5c(-c6cccnc6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide (LX) (1 eq), sulfur (1 eq) and 3,3′-bipyridine-4,5-diamine (XLVIII) (1 eq) in DMF was heated overnight at 140° C. under argon. The solution was cooled and the DMF was distilled under vacuum. The residue was taken in DCM. Triethylsilane (2.5 eq) followed by TFA (30% by volume) was added to the solution and stirred for 2 h at room temperature until TLC showed disappearance of starting material. The solvent was removed under vacuum. Water was added to the residue, sonicated briefly and basified with 5 N NH4OH solution. The solids formed were filtered, washed with cold water and dried at room temperature. The solids were triturated with DCM followed by MeOH to get N-(5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide (47) as a brown solid (49% yield). 1H NMR (DMSO-d6, 400 MHz,): δ 1.67 (t, J=6 Hz, 3H), 2.45 (q, J=6 Hz, 2H), 7.62 (m, 1H), 8.50 (s, 1H), 8.62 (m, 1H), 8.72 (s, 1H), 8.77 (m, 3H), 8.91 (m, 1H), 8.99 (m, 2H), 9.41 (s, 1H), 10.31 (s, 1H), 13.95 (s, 1H), 14.62 (s, 1H). ESIMS found C25H19N9O m/z 462.50 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC(C)(CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of hydroxypivalic acid (3 g) and potassium carbonate (3.9 g) in N,N-dimethylformamide (25 mL) was added benzyl bromide (2.9 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.7 g).
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cccc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3.62 g of 3-methoxy-2-nitrobenzaldehyde was dissolved in 80 ml of methylene chloride and a boron tribromide-methylene chloride solution (15.03 g of boron tribromide, 40 ml of methylene chloride) was added dropwise under ice cooling, followed by stirring at 0° C. for one hour. The reaction solution was poured into ice, extracted with chloroform, dried and then concentrated to obtain 3.32 g of the desired compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:12]([CH3:14])[CH3:13])[CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([OH:23])[C:18]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:26][C:16]([F:15])([F:25])[C:17]1[N:21]([CH3:22])[N:20]=[C:19]([O:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][N:12]([CH3:14])[CH3:13])[CH:3]=2)[C:18]=1[Cl:24]
Reactant: CN(C)Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cn1nc(O)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)Nc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 97.4 %

Procedure:
1.98 g (0.01 mol) of the product of step (a) was mixed with 2.2 g (0.011 mol) of 5-trifluoromethyl-4- chloro-3-hydroxy-1-methylpyrazole and 1.65 g of potassium carbonate in 15 ml of DMSO and heated for 24 hours at 90° C. The mixture was poured into 400 ml of H2O and extracted with ether. The organic layer was separated, washed with H2O, brine, dried over MgSO4 and solvent removed to give 3.7 g of solid, m.p. 72°-76° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: OCC1CCNCC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCC(CO)CC1
Yield: 15.6 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from Example 16C was reacted with 4-piperidinemethanol (135 mg, 1.17 mmol) according to the procedure described in Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (36 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (brs, 1H), 9.10 (brs, 1H), 8.55 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.37-7.43 (m, 2H), 7.27 (m, 1H), 6.97 (m, 1H), 6.48 (s, 1H), 4.20-4.50 (m, 3H), 3.99 (s, 3H), 3.23 (m, 2H), 2.96-3.00 (m, 2H), 2.74-2.78 (m, 2H), 2.01-2.05 (m, 2H), 1.61-1.65 (m, 2H), 1.27 (s, 9H), 1.00-1.15 (m, 2H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([O-:16])=[O:15]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc([N+](=O)[O-])c3)c2cn1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (127 mg, 0.66 mmol) (described in a previous experimental) and 3-nitroaniline (1.70 g, 12.3 mmol) is stirred under N2 at 200° C. for 1.5 h. The resulting product is chromatographed over alumina (5-20% EtOH/CHCl3) to give 7-amino-4-(3-nitroanilino)pyrido[4,3-d]pyrimidine (81 mg, 39%) as a brown solid. 1H NMR (DMSO) δ 10.17 (1H, brs), 9.37 (1H, s), 8.87 (1H, brs), 8.48 (1H, s), 8.33 (1H, brd, J=7.5 Hz), 7.95 (1H, ddd, J=8.2, 2.1, 1.0 Hz), 7.67 (1H, t, J=8.2 Hz), 6.70 (2H, brs), 6.47 (1H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:8]([CH:7]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(OC)c(OCCCCl)c1
Reactant: O=[N+]([O-])O
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
Methyl 3-(3-chloropropoxy)-4-methoxybenzoate (6.65 g, 25.7 mmol) was reacted with nitric acid as described in Example 16A Step 2 to give methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate (6.70 g, 22.1 mmol, 86%). 1H NMR (300 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.37 (s, 1H), 4.26 (t, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.76 (t, 2H), 2.26-2.18 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:16]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=2[C:14]#[N:15])[CH:3]=1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Cc1cc(CO)no1
Product: Cc1cc(COc2cccc([N+](=O)[O-])c2C#N)no1
Yield: 86 %

Procedure:
Prepared as in Example 172172c from (5-methylisoxazol-3-yl)methanol and 2,6-dinitrobenzonitrile in 86% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.43 (d, J=0.8 Hz, 3H), 5.50 (s, 2H), 6.38 (d, J=0.4 Hz, 1H), 7.83 (dd, J=1.2, 8.4 Hz, 1H), 7.91-7.98 (m, 2H). MS 260 (MH+).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Br
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
Into a solution of 4,5-difluoro-2-nitroaniline (3.7 g) in acetic acid (27 ml) was added bromine (6.8 g) dropwise at 50° l to 56° C. and stirred for 2.5 hours. The reaction mixture was poured into ice water (60 ml) and the resulting precipitate was collected by filtration and washed with water sufficiently to give the title compound (4.7 g) as yellow prisms, mp 105° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Li]CCCC.[B:23]([O:32]C(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1>[C:14]([S:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][C:8]=1[O:24][B:23]([OH:32])[OH:28])(=[O:13])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: CCCc1ccc(NS(=O)(=O)C(C)(C)C)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(NS(=O)(=O)C(C)(C)C)c(OB(O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-n-propylphenyl-t-butylsulfonamide (2.85 g, 11.2 mmoL) in anhydrous THF (20 mL) cooled to -40° C. under N2 was added 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to rt and stirred for 2 h. To the mixture, containing the bright red dianion at 0° C., was added B(OiPr)3 (3.9 mL, 1.5 equiv). The next day 2N HCl (3 mL) was added and the mixtue was stirred for 1 h. The solvent was removed under reduced pressure and the residue was extracted With EtOAc. The organic was washed with 2N HCl, H2O and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound. Rf=0.5 (1:1 EtOAc/Hex). The crude material was used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:16]=2[O:15]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(Cc3ccccc3)c2O1
Product: O=C(NCC1Cc2cccc(Cc3ccccc3)c2O1)OCc1ccccc1
Yield: 94.8 %

Procedure:
Treatment of (±)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (2.0 g, 8.36 mmol) with disopropylethylamine (1.62 g, 12.56 mmol) and benzyl chloroformate (1.64 g, 9.61 mmol) generally according to the procedure described for Intermediate 12 provided 2.96 g (95%) of (±)-benzyl(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C24H23NO3 C, 77.19; H, 6.21; N, 3.75. Found C, 75.58; H, 6.42; N, 3.55. Chiral HPLC eparation of (±)-benzyl(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel OD, methanol) provided two fractions. Fraction 1 (Rt=12.085 min, Chiralcel OD, methanol); Fraction 2 (Rt=17.945 min, Chiralcel OD, methanol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:14](=[O:17])(=[O:16])[NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([Cl:28])[CH:23]=[CH:24][C:25]=1[CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([N:15]2[CH:19]=[C:20]3[C:25]([CH:24]=[CH:23][C:22]([Cl:28])=[CH:21]3)=[CH:26]2)(=[O:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)c(CBr)c1
Reactant: NS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=S(=O)(N1CCN(Cc2ccccc2)CC1)n1cc2ccc(Cl)cc2c1

Procedure:
In ethanol (5 ml), 1-benzyl-4-sulfamoylpiperazine (251 mg) was dissolved. To the resulting solution, 3,4-bis(bromomethyl)-1-chlorobenzene (293 mg) and potassium carbonate (204 mg) were added, followed by heating under reflux for 3.5 hours. After cooling, the precipitate was filtered off. The filtrate was then distilled under reduced pressure and the residue was purified by chromatography on a silica gel column (dichloromethane˜ethanol:dichloromethane=1:100), whereby the title compound (222 mg, 58%) was obtained.
Reaction SMILES: C(O[C:4](=[O:17])[C:5]([N:7]([CH3:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6])C.[F:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:12]([O:11][C:9]([CH:8]1[N:7]([CH3:16])[C:5](=[O:6])[C:4]([OH:17])=[C:26]2[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:32][CH:31]=1)[C:25]2=[O:30])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C(=O)N(C)CC(=O)OC(C)(C)C
Reactant: O=C1C=CCCN1Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of tert-butyl N-[ethoxy(oxo)acetyl]-N-methylglycinate (1.43 g, 5.85 mmol) and 1-(4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one from Step 3 of Example 1 (1 g, 5 mmol) in anhydrous THF (10 mL) was added LiHMDS (1 M in THF) (1.02 g, 6.09 mmol) dropwise. The reaction mixture was stirred for 10 min. at −78° C., warmed to room temperature for 2.5 hours, then heated to 40° C. After heating for 24 hours, the reaction mixture was quenched with cold diluted HCl, then diluted with methanol, and concentrated under vacuum. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to give the title compound as a mixture of diastereomers. The appropriate fractions were collected for the first-eluting diastereomer, diastereomer 1, and this material was purified further using reverse phase HPLC on a C18 stationary phase eluting with 15%-85% acetonitrile (0.1% TFA) in H2O (0.1% TFA). For the second eluting diastereomer, diastereomer 2, the appropriate fractions were collected and the material was purified further using reverse phase HPLC on a C18 stationary phase eluting with 10%-60% methanol (0.1% TFA) in H2O (0.1% TFA). Diastercomer 1, the hydrogens at positions 4a and 5 have a trans relationship to one another: 1H NMR (400 MHz, CDCl3) δ 6.84 (m, 2H), 6.62 (t, J=8.7 Hz, 2H), 4.31 (d, J=14.7 Hz, 1H), 4.05 (d, J=14.7 Hz, 1H), 3.43 (d, J=6.5 Hz, 1H), 2.91 (m, 2H), 2.69 (m, 1H), 2.57 (s, 3H), 1.42 (m, 1H), 1.21 (m, 1H), 1.15 (s, 9H) ppm. ES MS M+1=405. Diastereomer 2, the hydrogens at positions 4a and 5 have a cis relationship to one another: 1H NMR (400 MHz, CDCl3) δ 13.07 (s, 1H), 7.22 (m, 2H), 7.02 (t, J=8.7 Hz, 2H), 4.67 (d, J=14.7 Hz, 1H), 4.51 (d, J=14.7 Hz, 1H), 3.82 (d, J=6.5 Hz, 1H), 3.33 (m, 1H), 2.99 (s, 3H), 2.02 (m, 3H), 1.68 (m, 1H), 1.44 (s, 9H) ppm. ES MS M+1=405.
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.Cl[Si:11]([CH2:19][Cl:20])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[Cl:20][CH2:19][Si:11]([O:2][CH3:1])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](Cl)(CCl)c1ccccc1
Reactant: CO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CO[Si](C)(CCl)c1ccccc1
Yield: 79.7 %

Procedure:
A solution of 1.6 ml (1.3 g, 0.040 mol) of methanol and 3.0 ml (2.2 g, 0.022 mol) of triethylamine in 100 ml of ether was stirred while a solution of 4.1 g (0.020 mol) of chloro(chloromethyl)methyl(phenyl)silane in 10 ml of ether was added dropwise. The resulting slurry was refluxed for 2 hours, cooled, washed with water, 0.1N aqueous HCl, saturated aqueous NaHCO3, water, and brine, dried over magnesium sulfate, and evaporated to leave 3.2 g of a pale yellow liquid. Distillation provided 1.7 g (42%) of the title compound as a colorless liquid: bp 46°-49° (0.05 mm); nD22 1.5207; nmr (CDCl3): 0.5 (3H, s), 3.0 (2H, s), 3.5 (3H, s) and 7.3-7.8 (5H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][NH:20][C:21](=[O:22])[C:11]3=[CH:10]2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].ClCCl>CS(C)=O>[CH2:27]([N:20]1[C:21](=[O:22])[C:11]2=[CH:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(Br)cn3)cc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCn1nc2c3ccccc3n(Cc3ccc(Br)cn3)cc-2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-[(5-Bromopyridin-2-yl)methyl]-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (250 mg, 0.704 mmol) was dissolved in dimethylsulfoxide (3 mL) and treated with sodium hydride (70.4 mg, 1.76 mmol, 2.5 equiv) and allyl bromide (170 mg, 1.41 mmol, 2.0 equiv). The mixture was stirred at ambient temperature for 18 hours, poured into dichloromethane (50 mL) and washed with sodium bicarbonate (2×50 mL, aqueous saturated) and brine (1×50 mL). The organic extract was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (eluting 80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the title compound: 1H-NMR (400 MHz, CD3OD) δ 8.90 (1H, s), 8.56 (1H, s), 8.34 (1H, d, J=9.0 Hz), 7.99 (1H, d, J=6.2 Hz), 7.74 (1H, d, J=8.2 Hz), 7.63-7.55 (2H, m), 7.42 (1H, d, J=8.4 Hz), 6.07-5.98 (1H, m), 5.81 (2H, s), 5.24-5.16 (2H, m), 4.86 (2H, s), ppm; low resolution mass spectrometry (ES+) m/z 396.8 (81Br) [(M+H)+; calculated for C19H15BrN4O: 397.0].
Reaction SMILES: CN(C)C=O.[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[NH:11]([CH2:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[C:12]([NH2:14])=[NH:13].[CH3:24][S:25]([O:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:41])[NH2:40])[CH:35]=2)[CH:30]=1)(=[O:27])=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].[NH:11]([CH2:15][C:16]1[O:20][C:19]([C:21]([O:23][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:40])[NH2:41])[CH:35]=3)[CH:30]=2)=[O:22])=[CH:18][CH:17]=1)[C:12]([NH2:14])=[NH:13]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: N=C(N)NCc1ccc(C(=O)O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Reaction time: 0.5 h

Procedure:
##STR50## In a solvent mixture of 8 ml of dry N,N-dimethylformamide (DMF) and dry pyridine, were dissolved 2.0 g of 5-guanidinomethyl-furan-2-carboxylic acid methanesulfonate and 1.8 g of 6-amidino-2-naphthol methanesulfonate. To the resulting solution, while being cooled in ice, were added 1.8 g of DCC and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 30 minutes with cooling in ice and then overnight at 30° C. The insolubles were removed by filtration and ethyl ether was added to the filtrate. The supernatant was removed by decantation. The residue was dissolved in a small amount of methanol and the methanol solution was added dropwise to ethyl ether. After precipitation the supernatant was removed by decantation. These procedures were repeated twice. Finally, the precipitate was collected by filtration and dried to obtain 1.2 g of a pale yellow substance of 6-amidino-2-naphthyl 5-guanidinomethyl-furan-2-carboxylate dimethanesulfonate.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[CH:13]1([N:18]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[N:33]=[N:32][C:31](Cl)=[CH:30][CH:29]=4)[N:25]=[CH:26][C:21]=3[C:20]3[CH:35]=[CH:36][N:37]=[CH:38][C:19]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH:13]1([N:18]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[N:33]=[N:32][C:31]([N:9]5[CH2:8][CH2:7][C:6]6([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]6)[CH2:11][CH2:10]5)=[CH:30][CH:29]=4)[N:25]=[CH:26][C:21]=3[C:20]3[CH:35]=[CH:36][N:37]=[CH:38][C:19]2=3)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Clc1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nn1
Reactant: O=C1COC2(CCNCC2)CN1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1COC2(CCN(c3ccc(Nc4ncc5c6ccncc6n(C6CCCC6)c5n4)nn3)CC2)CN1
Temperature: 160 °C
Yield: 4.6 %

Procedure:
To a mixture of compound 400 (110.0 mg, 646 μmol) and compound 140 (40.0 mg, 109 μmol) in N-methylpyrrolidinone (1.50 mL) was added N,N-diisopropylethylamine (DIEA) (0.100 mL, 575 μmol). The resulting mixture was heated at 160° C. under microwave irradiation for 6 h. The crude material was purified by reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each, 25 min from 10 to 40%). The isolated material was further purified by prep-TLC (10% methanol in DCM with 1% NH4OH) to give compound 396 as a yellow solid (2.5 mg, 5%). 1H NMR (500 MHz, CD3OD) δ 9.21 (s, 1 H) 8.91 (s, 1 H) 8.37-8.46 (m, 2 H) 8.08 (d, J=5.38 Hz, 1 H) 7.46 (d, J=10.03 Hz, 1 H) 5.43 (quin, 1 H) 4.21 (s, 2 H) 4.06 (ddd, J=13.27, 3.48, 3.30 Hz, 2 H) 3.37-3.42 (m, 4 H) 2.44 (dd, J=12.96, 8.31 Hz, 2 H) 2.08-2.24 (m, 4 H) 2.03 (d, J=13.45 Hz, 2 H) 1.84-1.93 (m, 2 H) 1.74-1.83 (m, 2 H) ppm; LCMS-ESI (POS), M/Z, M+1: Found 500.2, Calculated 500.2.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(F)cc3)cc2)C1

Procedure:
The procedure is the same as for Example 1 (Stage 1.2) starting from 1.50 g (7.45 mmol) of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (commercial), 2.15 g (11.18 mmol) of 4′-fluorobiphenyl-4-ol, 2.93 g (11.18 mmol) of triphenylphosphine and 2.26 g (11.18 mmol) of diisopropyl azodicarboxylate. After purification by chromatography on a column of silica gel, elution being carried out with dichloromethane, 1.55 g of the expected product are obtained in the form of an oil.