Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[ClH:28]>O>[ClH:1].[ClH:28].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:24][CH2:23]1
Reactant: OCCN1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: O
Product: OCCN1CCN(c2cc(-c3ccc(F)cc3)c3ccccc3n2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of 16 g of 2-chloro-4-(4-fluorophenyl)quinoline and 25.4 g of 1-(2-hydroxyethyl)piperazine is stirred at 130° C. for 3 hours. After cooling, water is added and the resulting mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (150 g) with chloroform - methanol (100 : 1). The eluates pooled are concentrated to give an oily residue, which is treated with ethanolic hydrogen chloride to afford the hydrochloride. Recrystallization from ethanol - ethyl acetate gives 16.7 g of the title compound, m.p. 210°-218° C.
Reaction SMILES: [ClH:1].C([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=2)[CH2:11]1)C1C=CC=CC=1.O>C(O)C.[Pd]>[ClH:1].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCCC(Oc1ccc2c(c1)CC(NCc1ccccc1)CC2)C(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCC(Oc1ccc2c(c1)CC(N)CC2)C(=O)OCC

Procedure:
A solution of 2-benzylamino-7-(ethoxycarbonylbutan-4-yloxy)tetralin hydrochloride (10.7 g), prepared as described in Example 5, in 95% ethanol (250 ml) and water (25 ml) is hydrogenated at 60° C. and atmospheric pressure using 10% Pd/C (1.2 g) as the hydrogenation catalyst. After 6 hours the catalyst is filtered off, the filtrate is concentrated and the residue is taken up in absolute ethanol and concentrated to dryness a few times. The obtained product is then triturated with ethyl ether and filtered. The residue is crystallized from isopropanol yielding 8 g of the compound indicated in the title. M.p. 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=2)[CH2:19][CH2:18]1)=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:14][C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=4)[CH2:21][CH2:22]3)=[O:16])[C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: Cn1c(=O)[nH]c2ccc(Cl)cc21
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)n(C)c4cc(Cl)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one (61) (75 mg, 0.41 mmol, 1 eq), 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (125 mg, 0.41 mmol, 1 eq), cesium carbonate (401 mg, 1.23 mmol, 3 eq) in DMF (2 ml) was stirred at rt overnight. The reaction solution was diluted with ethyl acetate, washed with water. The organic layer was evaporated to dryness and the crude residue was purified by flash chromatography to provide the desired product 5-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (62): LCMS observed for (M+H)+: 449.2.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:25]([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH2:25][CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: CCc1ncc[nH]1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2C)o1
Temperature: 125 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 2-ethylimidazole (960 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(2-ethyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole as pale yellow prisms (438 mg, 38%). Melting point 91-92° C.
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-:13].[K+]>C(O)C>[CH3:2][C:1]([CH3:11])([CH2:10][OH:13])[CH:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[OH:12]
Reactant: [OH-]
Reactant: O=Cc1cccc2ccccc12
Agent: [K+]
Solvent: CCO
Product: CC(C)(CO)C(O)c1cccc2ccccc12
Reaction time: 0.25 h
Yield: 196.3 %

Procedure:
1-Naphthoaldehyde (57.72 g, 0.37 mol) and isobutylaldehyde (55.0 g, 0.76 mol) was mixed and 85% potassium hydroxide (24.5 g, 0.37 mol) dissolved in ethanol (340 ml) was added dropwise thereto with stirring. Exothermic reaction started immediately, and the temperature reached to 65° C. and then decreased. After dropping for about 15 min, the mixture was stirred at 55° C. for 4.5 hr. The reaction solution was concentrated, and water (300 ml) was added thereto. The mixture was extracted with chloroform (200 ml) twice. The extract was washed with saturated brine, dehydrated with anhydrous sodium sulfate and concentrated to give the title compound as a brown oil (83.62 g, yield 98.1%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/B(O)O>C([O-])([O-])=O.[K+].[K+].COCCOC.O>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](/[CH:33]=[CH:32]/[CH2:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])[CH:20]=2)[N:3]=1
Reactant: COCCCC/C=C/B(O)O
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(Br)c2)N=C1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COCCCC/C=C/c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Temperature: 95 °C
Yield: 56 %

Procedure:
A degassed solution of 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (200 mg, 0.488 mmol) and (E)-6-methoxy-hex-1-enylboronic acid (0.537 mmol) in 1 ml of 2 M K2CO3 and 2.5 ml of DME is treated with Pd(CH3CN)2Cl2 (20 mg, 5%), the mixture heated at 95° C. under a nitrogen atmosphere for 16 h, diluted with water and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified on a silica gel cartridge and then by preparative HPLC to afford the title compound, 121 mg (56% yield), identified by NMR and mass spectral analyses. (1H-NMR 300 MHz, CDCl3): 7.49 (d, 2H); 7.42 (s br, 1H); 7.27 (m, 5H); 7.06 (d, 2H); 6.49 (dd, 1H); 6.36 (d, 1H); 6.20 (dt, 1H); 3.41 (t, 2H); 3.35 (s, 3H); 3.12 (s, 3H); 2.22 (dt, 2H); 1.69-1.47 (m, 4H). MS [M+H]+ 444.4
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 26.3 %

Procedure:
7.0 g of 1-(2-chloroethyl)-3-isobutyl-3-D-galactopyranosylurea are dissolved in 15 ml of formic acid, and 5.0 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 2.0 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-D-galactopyranosylurea are thereby obtained as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:26])/[CH:21]=[CH:22]\[C:23]([OH:25])=[O:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccncc1
Product: O=C(O)/C=C\C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
A 15 ml portion of pyridine was added to 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine and 0.6 g of maleic anhydride. After stirring overnight, the solvents were removed on the rotary evaporator. The solid was taken up in about 400 ml of hot ethanol and the insoluble material filtered to give 0.33 g of 4-[[4-[(3-Bromophenyl)amino]-6-quinazolinyl]amino]-4-oxo-(Z)-2-butenoic acid: mass spectrum (m/e): M+H 413, 415.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:10]=[C:9]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:8]([F:17])=[C:7]([NH:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:18][C:7]1[C:8]([F:17])=[C:9]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[N:10]=[C:5]([CH:4]=[O:3])[CH:6]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(Cc2nccs2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: Nc1cc(C=O)nc(Cc2nccs2)c1F
Yield: 71.9 %

Procedure:
Following the procedure of Example 12, 6-(diethoxymethyl)-3-fluoro-2-(thiazol-2-ylmethyl)-N-tritylpyridin-4-amine (471 mg, 0.85 mmol), conc H2SO4 (0.5 mL), CH3CN (10 mL) and H2O (10 mL) gave the title compound (0.145 g, 71%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.72 (d, J=3.3 Hz, 1H), 7.28 (d, J=6.7 Hz, 1H), 7.26 (d, J=3.4 Hz, 1H), 4.59 (d, J=2.8 Hz, 2H), 4.56 (br s, 2H); 19F NMR (376 MHz, DMSO-d6) δ −142.44; HRMS-ESI (m/z) [M+H]+ calcd for C10H8FN3OS, 237.0372. found, 237.0363.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([CH2:17]OS(C)(=O)=O)[CH2:3]1.[CH3:23][N:24](C=O)C.[C-]#N.[Na+]>O>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([CH2:17][C:23]#[N:24])[CH2:3]1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)OCC1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCC1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Temperature: 52.5 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
A mixture of methanesulfonic acid 5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl ester (prepared as given in Example B1)(0.9 g, 2.66 mmol), DMF (5 ml) and sodium cyanide (0.19 g, 4.0 mol) were heated to 50-55° C. and stirred for 20 hrs. To this reaction mixture water (50 ml) was added and extracted with ethyl acetate (3×20 ml), organic layer was washed with saturated brine solution (20 ml). The organic layer was dried over Na2SO4 and evaporated to obtain [5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-acetonitrile (0.65 g, 91%) as brownish sticky mass.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:16][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[C:2]=1[Cl:1])=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2c(c1Cl)Sc1ccccc1N2
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.8 g of 4-chloro-3-hydroxy-10H-phenothiazine (see Example 3) in 20 ml of acetic anhydride was added 1.2 ml of pyridine. The reaction mixture was then stirred at ambient temperature for 12 hours and then poured in water (75 ml). The resulting precipitate was filtered, washed with water and dried under vacuum to give 1.65 g of 3-acetoxy-4-chloro-10H-phenothiazine (m.p.: 173° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:14][N:15]=[C:16]=[S:17]>ClCCl>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:16]([NH:15][CH3:14])=[S:17])[CH2:9][CH2:10]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)Nc1ccccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 4-(2-aminophenyl)morpholine (5.3 g) in dichloromethane (25 ml) was treated with methyl isothiocyanate (3.2 g) and the mixture stirred at room temperature for 36 hours to yield 1-(2-morpholinophenyl)-3-methylthiourea (m.p. 115°-116° C.) which was recrystallised from a 4:1 mixture of ethyl acetate and hexane.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[CH:4][CH:3]=1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:10]=1[C:11](Cl)=[O:12]>C1(C)C=CC=CC=1>[CH3:9][C:10]([C:4]1[CH:3]=[C:2]([NH:1][C:11](=[O:12])[C:10]2[C:9]([O:8][CH3:7])=[CH:17][CH:16]=[CH:15][C:14]=2[O:18][CH3:19])[S:6][N:5]=1)([CH3:14])[CH3:11]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: Nc1ccns1
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1cc(C(C)(C)C)ns1
Yield: 30 %

Procedure:
A solution of the 5-amino-isothiazole and 1.1 g of 2,6-dimethoxybenzoyl chloride in 50 ml of toluene was heated at reflux for two hours, during which time a precipitate formed. The precipitate was collected by filtration and dried to give 340 mg of N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2,6-dimethoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:19][CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCNCC4)[nH]c3cc2Cl)CC1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(C(=O)C5CC5)CC4)[nH]c3cc2Cl)CC1
Yield: 46 %

Procedure:
To a mixture of [6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone (example 36, 150 mg, 1.0 eq.) and cesium carbonate (243 mg, 2.0 eq.) in acetonitrile (8 mL) was added cyclopropane carbonylchloride. The reaction mixture was refluxed 4 h. The reaction mixture was concentrated in vacuo and the residue partitioned between tert-butylmethylether and water. The aqueous layer was extracted with tert-butylmethylether and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel with a 98:2 to 95:5:0.25 gradient of dichloromethane/methanol/ammonia as eluant, to afford 59 mg (46%) of the title compound as a light-yellow solid.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH2:33])[CH3:32])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:32])[CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-c1nnn[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1-c1nnn[nH]1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (30 mg, 0.15 mmol), 1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanamine (45 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.047 mL, 0.27 mmol) in isopropyl alcohol (0.5 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H18ClFN9 (M+H)+: m/z=450.1. found: 450.1.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[O-].[Na+].[CH2:18](I)[CH3:19]>C1COCC1.CO>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][O:4][CH2:18][CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.94 g BocSer in 66 mL THF was added a solution of 1.47 g NaOMe in 2.6 mL MeOH, followed by 11.7 g EtI. After 15 minutes, more NaOMe (0.49 g) and EtI (2 mL) were added and the reaction was stirred at RT overnight. More NaOMe and EtI were added and the reaction was stirred for an additional 6 hours. The mixture was concentrated in vacuo, dissolved in 25 mL H2O and washed 2×25 mL ether. The aqueous phase was acidified with concentrated HCl and extracted 4×25 mL CH2Cl2. The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to 0.34 g crude product which carried on. NMR (300 MHz, CDCl3), delta 1.19 (t, J=7 Hz, 3H), 1.46 (s, 9H), 3.53 (q, J=7 Hz, 2H), 4.43 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:33][CH2:34][CH2:35][CH3:36])[N:14]([CH2:15][CH2:16][NH:17][C:18]([CH:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:33][CH2:34][CH2:35][CH3:36])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:19])[CH:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C(CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C(N)CC(C)C

Procedure:
1,1-Dimethylethyl N-[1-({[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamate (0.35 g, 0.7 mmol) was combined with 1 N hydrochloric acid (40 mL) and heated on a steam bath for 30 minutes. The reaction mixture was allowed to cool and then it was made basic with 10% sodium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0.15 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-amino-4-methylpentamide as a white solid, m.p. 60-65° C. Analysis: Calculated for C21H31N7O: %C, 63.27; %H, 7.86; %N, 24.66; Found: %C, 62.27; %H, 7.67; %N, 24.77. HRMS (EI) calcd for C21H31N7O (M+) 397.2590 found 397.2582.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:49][CH:48]=1)[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)=[O:24]>>[C:54]([O:53][C:50]1[CH:49]=[CH:48][C:47]([CH2:46][C@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:20])[C:23]([N:25]([C@@H:37]([CH3:45])[CH:38]([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])[CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:52][CH:51]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 81 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O-])(O)=O.[Na+].[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>CO>[CH2:1]([NH:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1cccc(O)c1
Reactant: CCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCNc1cccc(O)c1

Procedure:
0.11 mol of n-heptyl bromide and 0.1 mol of NaHCO3 are added to 0.1 mol of m-aminophenol in 150 ml of methanol and the mixture is refluxed for 5 h. After cooling, the mixture is filtered and the solvent is removed in vacuo. The oil which remains is fractionated in vacuo, to give 3-(n-heptylamino)phenol; b.p. 130-140° C. (8·10−5 torr), m.p. 27-30° C., yld. 62%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:30][CH:31]1OCC[O:32]1)[C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[CH:13][CH:12]=1.Cl>C1COCC1>[CH:31]([CH2:30][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:10](=[O:29])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])=[CH:15][CH:16]=1)=[O:32]
Reactant: COc1ccccc1N(CC1OCCO1)C(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1N(CC=O)C(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
N-(2-Methoxyphenyl)-N-(1,3-dioxolan-2-yl)methyl-4-phthalimidomethylbenzamide (450 mg, 0.953 mmol) was dissolved in THF (6 ml) to which was subsequently added 10% hydrochloric acid (4 ml) at room temperature. After 2 hours of stirring at 60° C., the resulting reaction solution was extracted with chloroform and washed with saturated brine. The resulting organic layer was dried on anhydrous magnesium sulfate, the solvent was removed by evaporation and then the resulting residue was mixed with 5 ml of chloroform to remove insoluble materials by filtration, thereby obtaining 300 mg (73.5%) of the title compound in the form of yellow oil which was used in the subsequent reaction without further purification.