Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C1C=CC=CN=1)C.[CH3:27][C:28]1([CH3:36])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]1[NH2:35]>C(Cl)Cl>[CH3:27][C:28]1([CH3:36])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]1[NH:35][C:15]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:13][CH2:14]1)=[O:17]
Reactant: CC1(C)CCC(C)(C)C1N
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
To a stirred solution of N-Cbz-1-aminocyclopropanecarboxylic acid in dry CH2Cl2 containing dicyclohexycarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethyl-1-cyclopentyl amine dissolved in CH2Cl2. After stirring for 48 hours, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (1×50 ml). The organic layer is separated, dried over MgSO4 and evaporated to yield N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14]OC)[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1>[NH2:14][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: CON=C(CCC(=O)O)c1ccc(Cl)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: NC(CCCO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
4-(4-Chlorophenyl)-4-(methoxyimino)butanoic acid (Intermediate 15) (6.28 g, 26.00 mmol) in tetrahydrofuran (8 ml) was cooled, under an atmosphere of N2, in an ice-methanol bath then treated dropwise with borane-tetrahydrofuran complex (1.0M in THF) (26 ml, 26.00 mmol) over a period of 20 minutes. The resulting solution was allowed to warm to room temperature, stirred for 1 hour then heated at reflux for a further 6 hours. After cooling in ice-water the mixture was treated with water (6 ml) dropwise with stirring over 10 minutes. The mixture was again allowed to warm to room temperature and stirred for 2 hours before evaporating the bulk of the solvent. The residue was then cooled in ice-water and 50% NaOH(aq.) (6 ml) added dropwise with stirring. The resulting mixture was stirred and heated at 90° C. for 4 hours then cooled to room temperature and extracted with Et2O (3×). The combined extracts were washed with water followed by brine, dried over MgSO4 and evaporated to give 4-amino-4-(4-chlorophenyl)butan-1-ol (1.100 g, 21.2%) as a colourless, viscous oil which was used without further purification.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=O.C(=O)(O)[O-].[Na+]>O>[Cl:7][CH2:8][C:9]1[N:6]=[C:1]([CH2:2][CH2:3][CH3:4])[O:5][CH:11]=1
Reactant: CCCC(N)=O
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1nc(CCl)co1
Temperature: 130 °C

Procedure:
A mixture of butyramide (19.88 g) and 1.3-dichloroacetone (24.14 g) was heated at 130° C. for 1.5 hours. After cooling, the mixture was diluted with water, neutralized with aqueous sodium bicarbonate solution and extracted with ethyl ether. The extract was washed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel with acetone-hexane (1:9) to yield 4-chloromethyl-2-propyloxazole as an oil (10.70 g 35.3%). NMR (CDCl3)δ: 0.97 (3H, t, J=7.5 Hz), 1.79 (2H, sext, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz), 4.47 (2H, s), 7.53 (1H, s).
Reaction SMILES: [O:1]=[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[CH2:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O>N1C=CC=CC=1>[O:5]=[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:3](=[CH:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])=[O:1]
Reactant: O=C(CC(=O)Nc1ccccc1C(=O)O)Nc1ccccc1C(=O)O
Reactant: O=Cc1cccs1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(=O)O)C(=Cc1cccs1)C(=O)Nc1ccccc1C(=O)O
Yield: 57.3 %

Procedure:
2,2'-[(1,3-Dioxo-1,3-propanediyl)diimino]bisbenzoic acid (1.0 g, 2.92 mmol) and 2-thiophenealdehyde (0.49 g, 4.38 mmol) were heated under reflux in dry pyridine (8 ml) for 16 hours. After removing pyridine, the mixture was treated with water, made alkaline with 10% aqueous ammonia under ice cooling, and washed with ether. The aqueous layer was made acidic with 1N.HCl under ice cooling, and the precipitated crystals were collected on filter and washed with water. The resulting solid was purified by silica gel column chromatography and the effluent containing the desired compound was collected. After removing solvent, the residue was crystallized by treating water, collected by filtration, washed with water, and dried to give the title compound (0.730 g, yield, 57%), which was recrystallized from the mixed solvent of CH3OH--H2O to give the pale yellow crystals (0.602 g). m.p.: 213°-215° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][O:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][O:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)C(C)C
Yield: 32.8 %

Procedure:
1-(2-Aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.00 mL, 7.20 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372-376. The crude product was recrystallized from 93:7 acetonitrile:water and then from isopropanol (7.3 mL/g) and dried for two hours in a drying oven to provide 0.78 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 213-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:4][CH:5]=[N:6][C:7]=1[SH:8].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](O)=O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]2[S:8][C:7]3[N:6]=[CH:5][N:4]=[C:3]([N:9]4[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]4)[C:2]=3[N:1]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(S)c2N)CC1
Reactant: O=C(O)CCc1ccc(F)cc1
Product: Fc1ccc(CCc2nc3c(N4CCNCC4)ncnc3s2)cc1
Yield: 80 %

Procedure:
This compound was synthesized from tert-butyl 4-(5-amino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using 3-(4-fluorophenyl)propionic acid, yielding the title compound in 80% yield.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=2)[C:20]([CH:21]=[O:22])=[C:19]([Cl:23])[N:18]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
Intermediate (2b) was dissolved into 60 mL of 1:1 DCM:TFA and heated to 40° C. for 16 hours. The mixture was concentrated under reduced pressure to yield intermediate (2c) as a yellow oil in a quantitative yield. MS m/z: [M+H+] calcd for C15H18ClN3O3S 356.1. found 356.3.
Reaction SMILES: I[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].Cl[C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[N:10]=1>C1(C)C=CC=CC=1.CN(C)C(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:11]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:9]([CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[N:10]=1
Reactant: COC(=O)CCI
Reactant: Cc1cc(C)nc(Cl)n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)CCc1nc(C)cc(C)n1
Temperature: 110 °C
Yield: 9.1 %

Procedure:
A suspension of Zn—Cu couple (3.45 g) in toluene/N,N-dimethylacetamide (14:1, 30 mL) was degassed by bubbling N2 through the suspension for 15 min. Then methyl 3-iodopropanoate (1.96 g, 9.14 mmol) was added to the suspension, and the resulting mixture was heated at 110° C. for 6 h. The reaction mixture was allowed to cool to 70° C., and 2-chloro-4,6-dimethylpyrimidine (961 mg, 6.77 mmol) and tetrakis(triphenylphosphine) palladium (235 mg, 0.203 mmol) were added. The reaction mixture was maintained at 70° C. for 22 h. Upon cooling to r.t., the mixture was filtered, and the filter cake was rinsed with ether (10 mL×3). The filtrate was extracted with 1 M hydrochloric acid (75 mL×2). The acidic extracts were basified with the addition of sodium bicarbonate, and the resulting solution was extracted with ether (75 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and the solution was concentrated to give a residue, which was purified by prep-TLC to afford methyl 3-(4,6-dimethylpyrimidin-2-yl)propanoate as a pale-yellow solid (120 mg). MS (ESI): m/z 195 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[OH:19])/[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:26]1([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)/[C:15]([OH:17])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/O)C(=O)O)cs1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.6 %

Procedure:
To a solution of (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-hydroxyiminoacetic acid (86.3 g: 0.30 Mol.) in dimethylformamide (600 ml) are added potassium carbonate (92 g: 0.67 Mol.) and triphenylmethyl chloride (100 g: 0.36 Mol.), and the mixture is stirred at room temperature for 3 days. The reaction mixture is poured into a mixture of concentrated hydrochloric acid (111 ml) and ice water (1500 ml) and extracted with ethyl acetate. The extract is washed with water, aqueous 5% sodium hydrogen carbonate, 2% hydrochloric acid and brine, dried over sodium sulfate, and concentrated. The residue is crystallized from dichloromethane to give (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (144 g) as colorless crystals. Yield: 91%. mp. 157° to 158° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:19]([C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl)=[CH:23][CH:22]=1)#[N:20]>CN(C)C=O>[C:19]([C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]2[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:10])[CH3:11])=[O:7])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Reactant: CC(C)N(C(=O)c1ccc(O)cc1)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4-hydroxy-N,N-bis(1-methylethyl)benzamide (2.47 g, 11.2 mmol) in 50 mL of N,N-dimethylformamide is treated with 60% sodium hydride (500 mg, 12.5 mmol). After stirring at 0° C. for 10 minutes, the reaction is treated with 5-(4-cyanophenoxy)pentyl chloride (3.25 g, 14.5 mmol) and stirred at 70° C. for 2 hours. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The resulting material is purified by chromatography on silica gel (60 g) with 70-80% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]N,N-bis(1-methylethyl)benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:5])[CH3:2].[CH2:17]([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:24][C:7]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])=[O:16]
Reactant: OCCCCCCO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OCCCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-ethoxycarbonylphthalimide with 1,6-hexanediol under conditions shown in Table 19, ethyl N-{2-(6-hydroxyhexyloxycarbonyl)benzoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].I[CH3:29].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[N:16]([CH3:29])[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reaction time: 0.17 h

Procedure:
Methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (F) (0.44 g) was added to a stirred suspension of oil-free sodium hydride (0.31 g) in dry tetrahydrofuran (10 ml), under an atmosphere of nitrogen. The dark-red solution was stirred for 10 minutes, and iodomethane (0.18 g) was added. The mixture was stirred for 30 minutes, and was poured into 1M hydrochloric acid (30 ml). The mixture obtained was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with brine (25 ml), then dried (MgSO4), and evaporated. The yellow oil obtained was purified by flash chromatography on silica gel (50 ml), eluting with 50:45:5 v/v/v hexane:dichloromethane:ethyl acetate, to give methyl 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl)benzoate (F') (0.33 g, 72%) as a yellow oil, which was crystallized from dichloromethane/hexane to give a yellow solid, mp 144°-146° C.; NMR: 3.81(s, 3H, NCH3), 3.83(s, 3H, COOCH3), 3.92(s, 3H, OCH3), 4.11(s, 2H, CH2Ar), 7.27(d, 1H), 7.37(s, 1H, H2 -indole), 7.49 (m, 2H), 7.60(d, 1H), 8.01(dd, 1H, H6 -indole), 8.50(d, 1H, H4 -indole).
Reaction SMILES: [C:1]([O:20][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][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ON1C2C=CC=CC=2N=N1.[OH:60][CH2:61][C@@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[NH2:63].C(N=C=NC(C)C)(C)C>O1CCCC1>[C:1]([O:20][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][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:63][C@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[CH2:61][OH:60])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 27-stearoyloxyheptacosanoic acid (8.88 g, 12.8 mmoles), tetrahydrofuran (120 ml), dried 1-hydroxybenzotriazole (4 g, 34.1 mmoles), phytosphingosine (3.91 g, 12.33 mmoles) and N,N'-diisopropylcarbodiimide (2.55 ml, 16.3 mmoles) was stirred under nitrogen for 2 hours at 40° C. and for another 4 hours at 50° C. After filtration and recrystallisation from hot chloroform 8.84 g of the title compound was obtained.
Reaction SMILES: [CH:1]1([C:9](=O)[CH2:10][CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C([OH:15])C>[Pd]>[CH:1]1([CH2:9][C:10](=[O:15])[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=O)C1CC=CCCCC1
Reactant: CCO
Agent: [Pd]
Product: CC(=O)CC1CCCCCCC1
Reaction time: 0.67 h
Yield: 52 %

Procedure:
A solution of 1-cyclooct-3-enylpropan-1-one (1.5 g, 9 mmol) in ethanol (20 ml) was treated with 10% palladium on charcoal (0.09 g) at room temperature and the resulting suspension was hydrogenated during 40 min. at 20 bars. After filtration through Celitee ® and concentration under vacuum, the crude product was purified by flash chromatography (hexane/Et2O 19:1) to give 0.78 g of 1-cyclooctylpropanone (52%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[C:17]([C:21]2[N:22]([CH2:38][CH3:39])[C:23]3[C:28]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[CH:32]=O)=[CH:27][N:26]=[CH:25][C:24]=3[N:37]=2)=[N:18][O:19][N:20]=1>>[NH2:15][C:16]1[C:17]([C:21]2[N:22]([CH2:38][CH3:39])[C:23]3[C:28]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[CH2:32][NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:27][N:26]=[CH:25][C:24]=3[N:37]=2)=[N:18][O:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(-c3cccc(C=O)c3)c21
Product: CCn1c(-c2nonc2N)nc2cncc(-c3cccc(CNC4CCNCC4)c3)c21

Procedure:
The title compound was prepared from 4-amino-piperidine-1-carboxylic acid tert-butyl ester and the product of Example 153 Step 1 using the method of Example 149, followed by the method described in Example 21. MS (ES+) m/e 419 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].[Br:8][C:9]1[C:14]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:13][C:12]([NH:28][C:29](=O)[O:30]C(C)=C)=[C:11]([F:35])[CH:10]=1.CN1CCCC1>O1CCOCC1>[Br:8][C:9]1[C:14]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:13][C:12]([NH:28][C:29]([NH:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])=[O:30])=[C:11]([F:35])[CH:10]=1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(Br)cc1F
Reactant: CC(C)(C)CCN
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3Br)c(C)nc2n1
Temperature: 65 °C
Yield: 97.4 %

Procedure:
Treat a solution of 3,3-dimethylbutan-1-amine (0.080 g, 0.790 mmol) and prop-1-en-2-yl (4-bromo-2-fluoro-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (0.244 g, 0.527 mmol) in dioxane (5 mL) with 1-methylpyrrolidine (4.48 mg, 0.053 mmol), heat at 65° C. for 3 h, then cool to RT overnight. Collect the resulting solid via filtration; concentrate the filtrate to dryness and purify via silica gel chromatography (10-30% EtOAc/DCM). Combine the two solids to afford the title compound (260 mg, 97% yield). MS (m/z): 506.1/508.1 (M+1).
Reaction SMILES: [NH:1]([C:5]1[CH:15]=[C:14]2[C:8]([CH:9]=[C:10]([O:16][CH3:17])[O:11][C:12]2=[O:13])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].[Cl:18]N1C(=O)CCC1=O>CN(C=O)C>[NH:1]([C:5]1[CH:15]=[C:14]2[C:8]([C:9]([Cl:18])=[C:10]([O:16][CH3:17])[O:11][C:12]2=[O:13])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc2ccc(NC(=N)N)cc2c(=O)o1
Solvent: CN(C)C=O
Product: COc1oc(=O)c2cc(NC(=N)N)ccc2c1Cl
Yield: 37.4 %

Procedure:
0.27 g of 7-guanidino-3-methoxyisocoumarin (1 mmole) was chlorinated with 0.15 g of N-chlorosuccinimide (1.1 mmole) in 5 ml DMF at r.t. overnight. The reaction mixture was evaporated to dryness, and purified by silica gel column chromatography which is eluted with methylene chloride and methanol (5:1) to give 0.1 g of 7-guanidino-3-methoxy-4-chloroisocoumarin (yield 34%). One spot on TLC, Rf =0.75 (Butanol:acetic acid:pyridine:water=4:1:1:2); NMR spectrum is similar to 7-guanidino-3-methoxyisocoumarin except no peak at 6.1 ppm; mass spectrum (FAB+), m/e=268 (M+ -Cl). Anal. Calc. for C11H11N3O3Cl2.1/2H2O: C, 42.17; H, 3.83; N, 13.41; Cl, 22.68. Found: C, 42.65; H, 3.72; N, 13,28; Cl, 22.32.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:33]1[C:46]2[C:37](=[N:38][C:39]3[C:44]([C:45]=2[NH:47][C:48]2[CH:49]=[C:50]([CH2:55][OH:56])[CH:51]=[C:52]([NH2:54])[CH:53]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1>>[CH:33]1[C:46]2[C:37](=[N:38][C:39]3[C:44]([C:45]=2[NH:47][C:48]2[CH:53]=[C:52]([NH:54][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH:51]=[C:50]([CH2:55][OH:56])[CH:49]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)O
Reactant: Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 70.2 %

Procedure:
The same reaction procedure to the example 18 were carried out using 2-ethyl-5-{[4-(3,5-dimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxynicotinic acid and [3-(acridine-9-yl-amino)-5-aminophenyl]-methanol to give the titled compound.
Reaction SMILES: Cl[C@H:2]([C@H:7]([OH:11])[CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH3:6])=[O:4].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C>[CH2:8]([C@H:7]1[O:11][C@@H:2]1[C:3]([O:5][CH3:6])=[O:4])[CH2:9][CH3:10]
Reactant: CCC[C@@H](O)[C@@H](Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CCO
Product: CCC[C@H]1O[C@@H]1C(=O)OC
Temperature: 15 °C
Reaction time: 14 h
Yield: 104 %

Procedure:
Methyl (2R,3R)-2-chloro-3-hydroxyhexanoate (0.9 g, 5 mmol), ethanol (10 ml) and potassium carbonate (2.1 g, 15 mmol) were mixed, and the mixture was stirred at 15° C. for 14 hours. Methyl tert-butyl ether (20 ml) was added. The mixture was washed with water (10 ml) three times. The organic layer was concentrated under reduced pressure to obtain the title compound (0.75 g, yield: 100%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(I)ccc1O
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(I)ccc1OC1CCOCC1
Yield: 84.6 %

Procedure:
In a manner similar to the method described in example 4a, 5-iodosalicylaldehyde (3 g, 12.1 mmol) (Aldrich) reacted with methanesulfonic acid tetrahydropyran-4-yl ester (4 g, 22 mmol) and K2CO3 in N,N-dimethylformamide to give 5-Iodo-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 3.4 g, 85%).