Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[C:5]([CH3:17])=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[OH-].Cl>C(Cl)Cl.O.CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:25][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:6]2[C:5]([CH3:17])=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1nc(C)c2c(Cl)c3ccccc3nc21
Reactant: NCc1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCn1nc(C)c2c(NCc3ccccc3)c3ccccc3nc21
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A mixture of 1-ethyl-3-methyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and benzylamine (0.98 ml, 9 mmol) was heated at 80° C. overnight. The reaction mixture was poured into water (100 ml), then NH4OH (0.5 ml) was added. The mixture was extracted with CH2Cl2 (200 ml) and the CH2Cl2 was concentrated to about 20 ml and then this solution was purified by column chromatography on silica gel, followed by high pressure liquid chromatography eluting with 20% ethyl acetate/hexane to afford the product as the free base. The free base was dissolved in CH2Cl2 (20 ml) and treated with ethereal HCl. The mixture was evaporated and the residue was crystallized from ether to afford 0.9 g of 1-ethyl-3-methyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.HCl, as an off white solid, m.p. 228°-231° C.
Reaction SMILES: [OH-].[K+].[CH:3]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][CH2:17][C:18]([CH3:28])([CH3:27])[C:19](=[O:26])[CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[CH:14][CH:13]=1>O.CS(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]([CH3:27])([CH3:28])[C:19](=[O:26])[CH:20]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:9][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:29][CH:30]=1
Reactant: BrCC1CCCCC1
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)Cn1cncn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(CC1CCCCC1)n1cncn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.7 %

Procedure:
First 5.6 g of potassium hydroxide in 12 ml of water and then 17.7 g (0.1 mol) of cyclohexylmethylbromide in 5 ml of dimethylsulphoxide were added dropwise to 29.3 g (0.1 mol) of 1-(4-chlorophenoxy)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one (prepared as described in Example 3) in 100 ml of dimethylsulphoxide at 20° C. The reaction mixture was subsequently stirred at room temperature for 15 hours, poured into 200 ml of water and extracted with 200 ml of methylene chloride. The organic phase was washed three times with 100 ml of water each time, dried over sodium sulphate and concentrated by distilling off the solvent. The residue was taken up in 100 ml of ether, whereupon the product crystallized out. 18.6 g (47% of theory) of 1-(4-chlorophenoxy)-5-cyclohexyl-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 58°-60° C. were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]#[C:14][C:15]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([CH:29]=[O:30])[CH:10]=[C:9]1[C:31]([O:33]C)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([N:8]1[C:12]([C:13]#[C:14][C:15]([OH:28])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:11]([CH:29]=[O:30])[CH:10]=[C:9]1[C:31]([OH:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C=O)c(C#CC(O)(c2ccccc2)c2ccccc2)n1Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1cc(C(=O)O)n(Cc2ccccc2)c1C#CC(O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6 (0.49 g, 1.1 mmol) in MeOH (20 mL) and water (6 mL) was added KOH (0.18 g, 3.3 mmol) and stirred at 60° C. for 2 hours. The solvent was removed in vacuo. The residue obtained was acidified with 2N HCl to pH 2-3 and extracted with EtOAc (3×15 mL). The combined organic layer was dried over MgSO4, filtered and then concentrated in vacuo to give 7 as a light brown solid. The crude product was subjected to the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 7.50-7.52 (m, 4H), 7.45 (s, 1H), 7.21-7.26 (m, 7H), 7.02-7.03 (m, 2H), and 5.64 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[NH2:24]>>[CH3:20][O:21][C:22](=[O:27])[C:23]([NH:24][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccc(-c2cc[nH]n2)c(OCC2CC2)n1
Reactant: COC(=O)C(C)(C)N
Product: COC(=O)C(C)(C)NC(=O)c1ccc(-c2cc[nH]n2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 359.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]#[CH:19]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:18]#[CH:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 69 %

Procedure:
To a stirred suspension of 4-hydroxybenzaldehyde (425.8 g) and K2CO3 (807.6 g) in acetone (2,960 ml) at reflux temper-ature of about 60° C. under a nitrogen atmosphere, was added dropwise 3-bromo-propyne (502.4 g) over a period of 2 hours. The reaction was heated at reflux for 3 more hours. After cooling to room temperature the reaction mixture was filtered and the excess of K2CO3 removed and washed several times with acetone. The filtrate was washed with saturated aqueous solution of NaHCO3 and NaCl. The aqueous phase was extracted with diethyl ether. The combined organic extracts were dried over Na2SO4, filtered and concentrated to a volume of 1 liter. The solution was kept in the refrigerator overnight. The crystals were filtered out and washed with cold diethyl ether. The filtrate was kept in the refrigerator and some more crystals were formed and removed. This procedure was repeated 3 times resulting in 1,385.26 g of 4-(2-propynyloxy) benzaldehyde in 83% yield. The material was analysed by gas chromatography, and shown to be 99.9% pure. Infrared and mass spectroscopic analysis confirmed the structure.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:12][C:10]1[C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=[CH:2][CH:11]=1
Reactant: Cc1cc(Cl)nc2c(N)nc3ccccc3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccnc2c(N)nc3ccccc3c12

Procedure:
To a solution of 3-chloro-1-methylbenzo[f][1,7]naphthyridin-5-amine (from step 3) in ethyl acetate/methanol (1:2, 0.03 M) was added 10% wt palladium on carbon (0.2 eq.). The reaction vessel was shaken on a hydrogen Pan apparatus under 50 psi of hydrogen overnight. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 1-methylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (CDCl3): δ 8.63 (d, 1H), 8.44 (d, 1H), 7.71 (dd, 1H), 7.54 (m, 1H), 7.45 (d, 1H), 7.30 (m, 1H), 6.20 (bs, 2H), 3.01 (s, 3H). LRMS [M+H]=210.1.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CO.[CH3:22][C:23]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:36][O:37][CH3:38])[CH:34]=[O:35]>CCOCC>[CH3:38][O:37][N:36]=[C:33]([C:34]1[O:35][CH:12]=[N:11][CH:10]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:24]1[CH:39]=[C:40]([CH3:43])[CH:41]=[CH:42][C:23]=1[CH3:22]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CON=C(C=O)c1ccccc1COc1cc(C)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: CON=C(c1cnco1)c1ccccc1COc1cc(C)ccc1C
Yield: 44.6 %

Procedure:
p-Toluenesulfonylmethylisocyanide (0.23 g, 1.2 mmol), potassium carbonate (0.18 g, 1.3 mmol) and methanol (2 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetaldehyde (0.30 g, 1 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl oxazol-5-yl ketone O-methyloxime (0.15 g, 44.6%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[CH3:28][CH:29]([NH:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[CH3:30].[OH-].[Na+]>CS(C)=O.O>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:41][C:38]4[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][NH:31][CH:29]([CH3:30])[CH3:28])=[CH:40][CH:39]=4)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1
Reactant: CC(C)NCCOc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)NCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Product: Cl

Procedure:
Using the conditions essentially described in method A above, 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (10.6 g) was reacted with 4-[2-(1-methylethyl)aminoethoxy]phenol (4.88) in dimethylsulfoxide (125 ml) containing sodium hydroxide (1.0 g) in water (7 ml). The crude free base was extracted using ethyl acetate and the dried extract was treated with excess hydrogen chloride in ethyl acetate to furnish the crude trihydrochloride salt. Crystallization of the crude from methanol-isopropanol afforded 2.5 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2-[4-[2-(1-methylethyl)aminoethoxy]phenoxy]ethyl]piperazine trihydrochloride, mp 223°-235°.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH2:19][C@H:18]3[N:15]([C:16](=[O:30])[C@@H:17]3[C@H:20]([O:22][Si](CC)(CC)CC)[CH3:21])[C:14]=2[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH:10]=[CH:11][CH:12]=1)=[O:4].FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C1COCC1.O>[OH:22][C@@H:20]([C@H:17]1[C:16](=[O:30])[N:15]2[C@@H:18]1[CH2:19][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][O:5][C:3]([NH:2][CH3:1])=[O:4])[CH:8]=1)=[C:14]2[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH3:21]
Reactant: C=CCOC(=O)C1=C(c2cccc(COC(=O)NC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(c2cccc(COC(=O)NC)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.42 h
Yield: 62.9 %

Procedure:
To a solution of allyl (5R,6S)-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (284 mg) in THF (4 ml) was added a solution of anhydrous trifluoromethanesulfonic acid (0.6 ml) in water (2 ml) at 0° C., and the solution was stirred for 25 minutes. Thereto was added a cold aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (139 mg).
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3[CH:20]=[C:21]4[C@:26]([C:28](=[O:39])[C:29]5[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=5)([CH2:27][C:18]=3[CH:17]=[N:16]2)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.[CH3:56][N:57]1[CH:61]=[C:60]([S:62](Cl)(=[O:64])=[O:63])[CH:59]=[N:58]1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3[CH:20]=[C:21]4[C@:26]([C:28]([C:29]5[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=5)=[O:39])([CH2:27][C:18]=3[CH:17]=[N:16]2)[CH2:25][N:24]([S:62]([C:60]2[CH:59]=[N:58][N:57]([CH3:56])[CH:61]=2)(=[O:64])=[O:63])[CH2:23][CH2:22]4)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2cc(C(F)(F)F)ccn2)C1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3cc(C(F)(F)F)ccn3)C2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
HCl/Dioxane (4M) (25.3 ml, 101 mmol) was added to (R)-tert-butyl 1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (2.75 g, 5.07 mmol) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo to give an orange gum. This was dissolved in dichloromethane (75 mL) and Hunig's base (4.43 ml, 25.3 mmol) was added followed by 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.099 g, 6.08 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to give an orange oil. The crude product was purified twice by chromatography on silica gel (gradient: 0-70% ethyl acetate in isohexane, followed by 0-60% ethyl acetate in dichloromethane), to give (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (1.89 g) as a pale yellow solid. LCMS (Method F, ES-API): RT 2.39 min, m+H=587.2; 1H NMR (400 MHz, CDCl3): δ 8.87 (1H, d, J=5.0 Hz), 8.16-8.15 (1H, m), 7.72-7.70 (1H, m), 7.69-7.66 (2H, m), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.21-7.14 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.44 (1H, dd, J=12.0, 2.1 Hz), 4.21 (1H, d, J=16.9 Hz), 3.93 (3H, s), 3.80-3.76 (1H, m), 2.94 (1H, J=16.9 Hz), 2.88-2.79 (1H, m), 2.66 (1H, d, J=12.1 Hz), 2.53-2.48 (1H, m), 2.43 (1H, ddd, J=12.6, 10.5, 3.5 Hz).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>>[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: CC(C)c1ccc(NN)cc1
Product: CC(C)c1ccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (4-isopropyl-phenyl)-hydrazine according to example 85 gave the desired product. MS: M=435.3 (M+H)+
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([NH2:6])=[O:5])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCC[C@@H](O)CC(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC[C@H](CC(N)=O)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-hydroxyhexadecanamide (100 mg) and pyridine (210 μl) in dichloromethane (10 ml) was added methanesulfonyl chloride (144 μl). This mixture was stirred at room temperature overnight, and the resulting precipitate was filtered off. The filtrate was concentrated, and dissolved in ethyl acetate (20 ml). This solution was washed with 1N-hydrochloric acid (20 ml×3), saturated sodium carbonate (20 ml×2), and brine (20 ml). After drying over MgSO4 and concentration, the residue was chromatographed on a silica gel, eluting with a mixture of dichloromethane and methanol (50:1) to give (R)-3-methanesulfonyloxyhexadecanamide (40 mg).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[N:13][N:12]=2)[CH2:7][CH2:6]1.N1C=CC=C[CH:26]=1.Cl[C:32](=O)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl>[Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:17]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[O:19][N:18]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: c1ccncc1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: NC(=NO)c1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Solvent: ClCCl
Product: CCOC(=O)CCc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-[4-(2-Bromo-5-fluorophenoxy)piperidin-1-yl]-N′-hydroxy-1,3,4-thiadiazole-2-carboximidamide (500 mg, 1.2 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. in an ice-water bath. To this solution was added pyridine (0.155 mL, 1.92 mmol) followed by ethyl 3-chloro-3-oxopropanoate (270 mg, 1.8 mmol). After stirring for 1 h, the solvent was removed in vacuo. The residue was dissolved in pyridine (8 mL) and stirred at 90° C. overnight. The solvent was removed and the residue was partitioned between EtOAc and water. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude product was purified by preparative TLC to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].C(N(CC)CC)C.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)C(C)C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.00 g, 3.18 mmol) in 25 mL of CH2Cl2 was placed under an atmosphere of nitrogen and then chilled in an ice water bath. The solution was treated with triethylamine (0.89 mL, 6.7 mmol) and then slowly with isobutyryl chloride (0.35 mL, 3.3 mmol). The reaction was stirred and allowed to slowly come to ambient temperature. After 16 h, the reaction was diluted with 15 mL of CHCl3 and 15 mL of 10% Na2CO3 solution and the layers were separated. The organic portion was washed with H2O (15 mL). The combined aqueous washes were back-extracted with CHCl3 (10 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light yellow foam. The foam was purified by chromatography (SiO2, 10–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a white foam. The foam was triturated with hexanes and filtered to yield N-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-2-methylpropanamide (0.821 g) as a white solid. mp 108–110° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, J=7.5 Hz, 1H), 7.72 (t, J=5.4 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.46–7.41 (m, 1H), 7.26–7.21 (m, 1H), 6.97 (t, J=5.5 Hz, 1H), 6.62 (s, 2H), 4.75 (s, 2H), 3.61 (q, J=7.0 Hz, 2H), 3.17–3.13 (m, 4H), 2.29 (h, J=6.9 Hz, 1H), 1.71 (p, J=7.1 Hz, 2H), 1.17 (t, J=7.0 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.4, 152.3, 149.5, 145.3, 132.4, 127.4, 126.1, 124.2, 121.2, 114.7, 65.8, 63.1, 50.2, 36.6, 34.4, 28.0, 19.9, 15.3; MS (APCI) m/z 385 (M+H)+; Anal. Calcd for C20H28N6O2•0.25H2O: C, 61.76; H, 7.38; N, 21.61; Found: C, 61.67; H, 7.55; N, 21.72.
Reaction SMILES: Br[C:2]1[C:3]([Cl:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:10][C:3]1[C:2]([C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: COc1ccc(Br)c(Cl)n1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(OC)nc2Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Under an argon atmosphere, to a solution of 3-bromo-2-chloro-6-methoxypyridine (4.61 g) in toluene (60 mL) were added (2-fluoro-5-methoxyphenyl)boronic acid (3.52 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichlorome thane adduct (1.69 g) and 2.0 M aqueous sodium carbonate solution (31.1 mL), and the mixture was stirred at 80° C. for 1 hr. Water was added at room temperature, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.06 g) as a white amorphous solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][O:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: COc1ccccc1C(=O)c1ccc(C(=O)O)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.308 g (1.2 mmol) of 4-(2-methoxybenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.