Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@@H:10]1[C@H:39]([O:40]C(=O)C2C=CC=CC=2)[C@@H:38]([O:49]CC2C=CC=CC=2)[C@H:37]([CH3:57])[O:36][C@H:11]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17](C(OCC1C=CC=CC=1)=O)[NH:18]CC1C=CC=CC=1)(=O)C1C=CC=CC=1>C1COCC1>[O:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[C@@H:11]1[O:36][C@@H:37]([CH3:57])[C@H:38]([OH:49])[C@@H:39]([OH:40])[C@H:10]1[OH:9]
Reactant: C[C@@H]1O[C@@H](OCCCCC(NCc2ccccc2)C(=O)OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OCc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1O[C@@H](OCCCCCN)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of protected rhamnoside 46 (145 mg, 0.19 mmol) in THF (4 ml) NaOMe (0.5 M in MeOH, 0.5 ml) was added and stirred for 4 h. The mixture was neutralized with Amberlite IR 120 (H+) ion exchange resin, filtered and concentrated. The crude product was dissolved in a mixture of THF (10 ml) MeOH (5 ml), H2O (4 ml) and AcOH (1 ml). The solution was purged with Ar, then 10% Pd/C (300 mg) was added and the solution purged with H2 for 30 min, then stirred under an H2 atmosphere for 12 h, filtered and concentrated. Purification by RP SPE (Waters Sep-Pak®, C18) afforded 39 (44 mg, 0.18 mmol, 94%). 1H-NMR (600 MHz, D2O) δ 4.85 (s, 1H, anomeric Rha), 4.01-3.96 (m, 1H), 3.81-3.70 (m, 3H), 3.62-3.57 (m, 1H), 3.50 (app. t, J=9.6, 1H), 3.11-3.03 (m, 2H), 1.78-1.67 (m, 4H, linker), 1.56-1.46 (m, 2H), 1.34 (d, J=6.3, 3H, Rha CH3)13C-NMR (150 MHz, D2O) δ 98.3 (anomeric), 70.6, 70.0, 68.8, 67.1, 66.1, 38.0, 26.6, 25.1, 21.0, 15.2 (Rha CH3); HRMS (MALDI-TOF): Calcd for C11H23NO5Na+ [M+Na]+ 272.1468. found 272.1433.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH2:17])[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[O:8][N:7]=1.CCN(C(C)C)C(C)C.[CH2:28]([C:30]1[C:35]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C:37]2=[O:42])=[CH:34][CH:33]=[CH:32][C:31]=1[S:43](Cl)(=[O:45])=[O:44])[CH3:29]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH:17][S:43]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][C:37]2=[O:42])[C:30]=1[CH2:28][CH3:29])(=[O:45])=[O:44])[CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[O:8][N:7]=1
Reactant: COC(=O)[C@@H](N)Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1c(N2CCOCC2=O)cccc1S(=O)(=O)N[C@@H](Cc1cc(-c2ccc(Cl)s2)on1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 2 (860 mg, 3 mmol) was dissolved in 15 ml DCM and DIPEA (2.041 ml, 12 mmol). 2-ethyl-3-(3-oxo-morpholin-4-yl)-benzenesulfonyl chloride, Intermediate 6 (911 mg, 3 mmol) in 10 ml DCM was slowly added and the reaction was stirred at RT overnight. After that 300 μl DIPEA were added and the reaction mixture was heated to 40° C. for 30 min. Then the solution was evaporated to dryness, dissolved in ethyl acetate, washed with 1 N HCl, sat. aq. NaHCO3 and brine. The combined organic layers were dried with MgSO4, filtered and evaporated to dryness. The crude product (1.5 g) was used without further purification in the next step.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3]O.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH2:7]([O:6][CH2:5][C@H:2]1[CH2:3][CH2:14][S:15](=[O:17])(=[O:16])[NH:1]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H](CO)COCc1ccccc1
Product: O=S1(=O)CC[C@H](COCc2ccccc2)N1

Procedure:
Using (R)-2-amino-3-benzyloxy-1-propanol (2.0 g) and methanesulfonyl chloride (1.8 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (370 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:11]([OH:13])=O)=[N:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([CH2:22][C:23]([O:25]CC)=[O:24])=[C:17]([F:28])[CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.Cl.C1COCC1>[Cl:21][C:20]1[C:15]([NH:14][C:11]([C:8]2[C:7]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:10][N:9]=2)=[O:13])=[CH:16][C:17]([F:28])=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=1
Reactant: O=C(O)c1nsc2cccc(F)c12
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Cl)c(NC(=O)c2nsc3cccc(F)c23)cc1F
Temperature: 25 °C
Reaction time: 96 h
Yield: 22.5 %

Procedure:
In DMF (10 ml) were dissolved 4-fluorobenzo(d)isothiazole-3-carboxylic acid (240 mg, 1.22 mmol), ethyl 4-amino-5-chloro-2-fluorophenylacetate (282 mg, 1.22 mmol), HOBt (313 mg, 2.32 mmol), EDC HCl (351 mg, 1.83 mmol) and DMAP (catalytic amount). The resulting solution was stirred for 4 days at room temperature. The reaction mixture was poured in 1M HCl, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure chromatography system from Yamazen, chloroform, 8 ml/min, φ 15 mm×300 mm). To the resulting ester were added THF (12 ml) and 0.25M NaOH (7.32 ml, 1.83 mmol), followed by stirring at room temperature for 4 hours. The reaction mixture was poured in 1M HCl to acidify the mixture. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (5-chloro-2-fluoro-4-((4-fluoro-3-benzo(d)isothiazolylcarbonyl)amino)phenyl)acetic acid (105 mg, 22%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([N:20]3[CH2:29][CH2:28][C:23]4(OCC[O:24]4)[CH2:22][CH2:21]3)=[O:19])[CH2:11][C@H:10]2[O:30][CH3:31])=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18](=[O:19])[N:20]3[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]3)[CH2:11][C@H:10]2[O:30][CH3:31])=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)N2CCC3(CC2)OCCO3)C[C@H]1OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)N2CCC(=O)CC2)C[C@H]1OC
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A mixture of 2.1 parts of cis-4-amino-5-chloro-N-[1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-oxobutyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide, 0.74 parts of sulfuric acid and 40 parts of water was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was made alkaline with sodium carbonate while cooling. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 1 part (51.9%) cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(4-oxo-1-piperidinyl)butyl]-4-piperidinyl]benzamide; mp. 156.9° C. (compound 109).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34]C)=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:17](=[O:31])[CH2:16][CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl>>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([OH:34])=[O:33])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:17](=[O:31])[CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC(=O)N(CCN(C)C)c1ccccc1-3
Solvent: ClCCl
Product: CN(C)CCN1C(=O)CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of methyl 14-cyclohexyl-5-[2-(dimethylamino)ethyl]-6-oxo-5,6,7,8-tetrahydroindolo[1,2-e][1,5]benzodiazocine-11-carboxylate in DCM (0.1M) 7 eq BBr3 (1M solution in DCM) were added. The solution stirred at RT for 20 mins. The volatiles were evaporated in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×150 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (40% over two steps).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:34][CH2:35][CH3:36])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([O:26]C(OC(C)(C)C)=O)C(=O)C(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[ClH:37].O1CCOCC1>ClCCl>[ClH:37].[OH:26][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-[(tert-butoxycarbonyl)oxy]-2,2-dimethylpropanamide (3.35 g, 6.52 mmol), dichloromethane (50 mL), and 4 M HCl in dioxane (13.0 mL, 52.2 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was concentrated twice from dichloromethane (2×25 mL) to provide 1-[4-(hydroxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:20](Cl)(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:20]([C@@:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(O)ncnc32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 50 mL flask was added inosine (1.0 g, 3.73 mmol) and N,N-dimethyl-4-aminopyridine (0.017 g, 0.074 mmol). N,N-dimethylformamide (16 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (8 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and palmitoyl chloride (1.3 mL, 4.1 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was quenched with a small chunk of ice and the solvents were evaporated leaving a white gum. Toluene (20 mL) was evaporated from the gum, which was then thoroughly triturated with 1:1 ethyl acetate-diethyl ether. The supernatant was isolated by suction filtration and the solvents evaporated leaving a syrup which turned into a soft, amorphous solid after 24 h in a vacuum desiccator.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3]Cl.[Br-].[C:7]1([N:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[NH:17][C:16](=[O:25])[CH2:15][C:14]2=[O:26])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([CH2:3][C:2]([CH3:5])=[CH2:1])[C:16](=[O:25])[CH2:15][C:14]2=[O:26])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(C)CCl
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: [Br-]
Product: C=C(C)CN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
In the same manner, by acting (2'-methylallyl) chloride or bromide in the presence of a metallation agent, starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, there is obtained 1-phenyl 5-(2'-methylallyl) 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine (R1 = H, R2 = Cl, R3 = ##STR20## R4 = C6H5) melting at 149°-151° C. upon recrystallisation in 50% ethanol.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:18]#[N:19])[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[I:22]Cl>>[I:22][C:15]1[N:13]2[CH:14]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=[C:11]([C:18]#[N:19])[C:12]2=[N:17][CH:16]=1
Reactant: ClI
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Yield: 99 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine (example C.23 step 3) (900 mg, 4 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as a light yellow solid (1.3 g, 99%). MS (ISP) 414.1 [(M+H)+].
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[CH3:17][C:15]1[N:16]=[C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[S:13][C:14]=1[CH3:18]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(C)s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc([C@H]2CC[C@H](C(=O)O)CC2)sc1C

Procedure:
A mixture of cis/trans-4-(4,5-dimethyl-thiazol-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:7) (170 mg, 0.636 mmol) in 1,4-dioxane (6.4 ml) and 2 M aqueous sodium hydroxide solution (3.2 ml, 6.4 mmol) was stirred for 24 h at room temperature. The reaction mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). The aqueous layer was acidified to pH 4-5 by addition of 2 M aqueous hydrogen chloride solution (3.2 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were washed with one 20-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (136 mg, 89%) as white solid. MS m/e: 240 ([M−H]−)
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>O1CCOCC1>[O:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8]3[N:23]=[C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)[S:21][C:9]=3[N:10]=[C:11]([N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:20][C:35]3=[O:36])[N:12]=2)[CH2:2][CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Solvent: C1COCCO1
Product: O=c1[nH]c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)sc2n1
Temperature: 110 °C
Yield: 55.3 %

Procedure:
A mixture of N-[7-morpholin-4-yl-2-(3-morpholin-4-ylazetidin-1-ylmethyl)thiazolo[5,4-d]pyrimidin-5-yl]benzene-1,2-diamine (75 mg, 0.16 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in 1,4-dioxane (1 mL) was heated at 110° C. for 3 h. After cooling to ambient temperature, the mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 99:1 to 98:2) to afford 183 as a cream solid (45 mg, 57%). LCMS (Method G): RT=6.72 min, M+H+=509. 1H NMR (CDCl3, 400 MHz) δ 8.71 (s, 1 H); 7.77 (m, 1 H); 7.15-7.05 (m, 3 H); 4.42 (m, 4 H); 4.01 (s, 2 H); 3.86 (m, 4 H); 3.71 (m, 6 H); 3.15 (s, 3 H) and 2.36 (m, 4 H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1N1CCc2cnc3c(C)cccc3c21
Yield: 8.3 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (1.5 g) in ethanol (100 ml) was hydrogenated over 10% palladium on charcoal (0 25 g) at an initial pressure of 3 bar. After 7 hours the mixture was filtered through celite and evaporated. Conversion to free base and recrystallisation from ethyl acetate/petroleum ether yielded 1-(2-methylphenyl)-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (0.11 g, 31%), m.p. 109°-110°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:28]=[C:27]([C:35](O)=O)[N:26]=2)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[CH3:13]>>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[N:28]=[C:27]([C:35]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=4)[N:7]=3)[N:26]=2)[CH:18]=[CH:19][C:20]=1[C:21]([F:22])([F:23])[F:24])[CH3:13]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccc(N)nc1
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4ccc(N)nc4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.15 g, 1.0 mmol) and 4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.4) (0.19 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.076 g, 31%). MS (ISP) 497.3 [(M+H)+]; mp 216° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:36]=[CH:37][CH:38]=1)[CH2:14][C:15]1[C:16](=[O:35])[O:17][C:18]2[CH:28]=[C:27]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:19]=2[C:20]=1[CH2:21][C:22]([OH:24])=[O:23])([O-:10])=[O:9].ClCCl.C(O)(=O)C>CO>[CH3:1][O:23][C:22](=[O:24])[CH2:21][C:20]1[C:19]2[CH:25]=[CH:26][C:27]([O:29][C:30](=[O:34])[N:31]([CH3:32])[CH3:33])=[CH:28][C:18]=2[O:17][C:16](=[O:35])[C:15]=1[CH2:14][C:13]1[CH:36]=[CH:37][CH:38]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1
Reactant: CN(C)C(=O)Oc1ccc2c(CC(=O)O)c(Cc3cccc([N+](=O)[O-])c3)c(=O)oc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Trimethylsilyl diazomethane (0.82 mL, 2.0 M in hexane) was added to a solution of {3-(3-nitrobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}acetic acid (compound 7f-1-1COOH) (350 mg, 0.82 mmol) in methanol (5.0 mL)/dichloromethane (8.0 mL), and the mixture was stirred at room temperature for 10 minutes. Acetic acid (2.0 mL) was added to the reaction mixture, and the title compound (338 mg, 94%) was obtained by vacuum concentration as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[CH:4][C:3]=1[OH:18].[CH:19]#[C:20][CH:21](O)[CH2:22][CH2:23][CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:20]([CH:21]([O:18][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:12])[C:2]=1[F:1])[O:9][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:6]2)[CH2:22][CH2:23][CH3:24])#[CH:19]
Reactant: C#CC(O)CCC
Reactant: CCCCCC1CCc2cc(O)c(F)c(F)c2O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CCC)Oc1cc2c(c(F)c1F)OC(CCCCC)CC2
Reaction time: 18 h

Procedure:
10.0 g (39.0 mmol) of 7,8-difluoro-2-pentylchroman-6-ol are initially introduced in 140 ml of THF together with 4.0 g (41.0 mmol) of 1-hexyn-3-ol and 11.3 g (42.9 mmol) of triphenylphosphine, and 9.1 ml (46.8 mmol) of DIAD are added over the course of 20 min with ice-cooling. After 18 h at RT, water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride soln., and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1), giving 6-(1-ethynylbutoxy)-7,8-difluoro-2-pentylchroman as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-])=[CH:7][C:6]=2[N:16]=1)[CH3:2].[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:30][C:7]1[C:6]2[N:16]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (14.3 g, 35.8 mmol) in 90 mL of CH2Cl2 was treated with 90 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature. After 30 min, the reaction was treated with 90 mL of CH2Cl2 and 90 mL of water. The organic portion was then washed with 1% Na2CO3 solution (2×), water, brine, dried over Na2SO4 and concentrated. The resulting solid was triturated in ether and filtered to yield 9.35 g of tert-butyl 2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light tan solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]([NH:19][NH2:20])=[CH:17][C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH3:23])[C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]=[C:26]=S.CO>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:18]2[NH:19][N:20]=[C:24]([NH:25][CH3:26])[C:17]=2[C:15](=[O:16])[N:14]([CH2:21][CH2:22][CH3:23])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(CCOCc2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(CCOCc2ccccc2)c1=O
Reaction time: 20 h

Procedure:
A solution of 1-(2-benzyloxyethyl)-6-hydrazino-3-propyluracil (2.0 g, 6.3 mM) and methyl isothiocyanate (1.2 ml, 18 mM) in DMF (20 ml) was stirred at 60° C. for 1 hour and then at 100° C. for 20 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol afforded colorless prisms (1.39 g, 62%), m.p. 224°-226° C.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:17]([CH3:19])[CH3:18])[NH:9][C:10]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)=[O:11])=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>COCCOC>[F:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][CH2:5][C:6]([N:8]([CH:17]([CH3:19])[CH3:18])[NH:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[O:11])=[O:7])=[C:2]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]([F:31])([F:44])[F:43])[CH:23]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)N(NC(=O)c1ccsc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccsc1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 63.1 %

Procedure:
A solution of thiophene-3-carboxylic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (251 mg, 0.60 mmol) in DME (5 ml)/2M Na2CO3 (1.05 ml, 2.12 mmol) was with 2-trifluoromethoxyphenylboronic acid (187 mg, 0.91 mmol) and Pd[PPh3]4 (140 mg, 0.12 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the product as a solid (188 mg, 63%). MS m/e 497.41 (M+H+)