Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CC1COC1C=C2C(=CC=1)C(=O)C1C(O)=CC=CC=1O2.Cl.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH:24]1[NH:33]CC(O)COC1C=C2C(=CC=1)C(=O)C1C(O)=CC=CC=1O2>C(O)C>[NH2:33][CH:24]1[CH2:25][CH2:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23]1
Reactant: O=c1c2ccc(OCC(O)CNC3CCc4ccccc4C3)cc2oc2cccc(O)c12
Agent: Cl
Agent: O=c1c2ccc(OCC3CO3)cc2oc2cccc(O)c12
Solvent: CCO
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 6-(2,3-epoxypropoxy)-1-hydroxyxanthen-9-one (2.84 g), prepared as described in U.S. Pat. No. 3,912,733, and 2-aminotetralin (1.49 g) in absolute ethanol (40 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(1-hydroxy-9-oxoxanth-6-yloxy)propanamine hydrochloride is obtained ((i): R=H, Ar=radical 1, wherein Z is H, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (5 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (8.5 g), water (15 mL) and sodium bicarbonate (10.6 g). The mixture was heated to about 100° C. and maintained at the same temperature for about 20 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to 30° C. followed by addition of water (50 mL) and ethyl acetate (25 mL). The mixture was stirred for about 10 minutes and layers were separated. The aqueous layer was extracted with ethyl acetate (25 mL). Total organic layer was washed with water (50 mL). The organic layer was subjected to complete distillation under vacuum at 55° C. followed by addition of ethyl acetate (5 mL). The mixture was stirred for 20 minutes followed by addition of n-hexane (75 mL). The mixture was further stirred at room temperature for solid separation followed by isolation of solid by filtration and washing with n-hexane (10 mL). The solid isolated was subjected to drying under vacuum at 60° C. for 3 hours to afford the title compound in about 91% yield having HPLC purity of about 99.18%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:16](OCC)=[O:17]>>[CH:16]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: CCOC=O
Reactant: NCCCNC(=O)OCc1ccccc1
Product: O=CNCCCNC(=O)OCc1ccccc1
Yield: 99 %

Procedure:
Benzyl 3-aminopropylcarbamate 12 (8.00 g, 36.0 mmol) was dissolved in 250 mL of ethyl formate. The solution was refluxed for 4 h. Following complete conversion of the amine, the solution was concentrated to dryness in a rotary evaporator to obtain the formamide as a colorless oil (8.90 g, 99%).
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[CH:12]=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[CH:24](O)=O.Cl>CCOCC>[ClH:1].[ClH:1].[C:3]1([C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:24])[CH:12]=[N:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=CO
Reactant: c1ccc(-c2cncc(OC[C@H]3CCCN3)c2)cc1
Agent: C=O
Agent: Cl
Solvent: CCOCC
Product: CN1CCC[C@@H]1COc1cncc(-c2ccccc2)c1

Procedure:
To 5-phenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine from Example 52 (150 mg, 0.59 mmol) was added formalin (38%, 5.0 mL) and formic acid (88%, 2.5 mL), and the mixture was refluxed for 16 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3. The mixture was extracted with CHCl3, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3/MeOH 10:1.5 to afford the base. The salt was prepared by treatment with HCl in Et2O, as described above, to give the title compound. mp. 89-90° C. MS (CI/NH3) m/z 269 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.05-2.29 (m, 2H), 2.38-2.47 (m, 1H), 3.07 (s, 3H), 3.23-3.32 (m, 1H), 3.64-3.82 (m, 1H), 3.92-4.00 (m, 1H), 4.44 (dd, J=7.7, 11.0 (1H), 4.61 (dd, J=3.0, 11.2, 1H), 7.51-7.62 (m, 3H), 7.70-7.74 (m, 2H), 7.88 (s, 1H), 8.36 (br s, 1H), 8.56 (br s, 1H). Anal. Calcd for C17H20N2OCl.2 HCl.0.5 H2O: C, 58.29; H, 6.62; N, 8.00. Found: C, 58.16; H, 6.76; N, 8.18. [α]25D=+9.2° (c 0.39, MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.C(#N)C.CN(C)C=[O:17]>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:17])=[CH:6][CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Solvent: CC#N
Product: Nc1ccc(C=O)cc1

Procedure:
The procedure of Example 1 was followed except that 2.3 g (3.4 wt.% of the p-nitrotoluene) of acetonitrile were substituted for the N,N-dimethylformamide, to obtain 37.7 g (0.312 mol) of p-aminobenzaldehyde and then obtain 38.5 g (0.315 mol) of p-hydroxybenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[NH2:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([NH:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:30])[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)O)cc1Cl
Reactant: NCC(O)CO
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)CCC(=O)NCC(O)CO)cc1Cl

Procedure:
The reaction and work up was conducted as described in the preparation of compound 204. Starting compounds were N-(2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (100 mg, 0.46 mmol) (disclosed in WO 01/05746) and 3-aminopropane-1,2-diol (23 mg, 0.25 mmol). The crude product was purified by flash chromatography using DCM/MeOH/NH3(aq.) 90:10:0.5 as the eluent to afford the title compound as a yellow solid.
Reaction SMILES: [Mg].BrCCBr.CC1(C)C[O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)=N1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>O1CCCC1.O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:9][OH:10]
Reactant: CC1(C)COC(c2cccc(Br)c2)=N1
Reactant: Cc1ccccc1Br
Agent: [Mg]
Solvent: BrCCBr
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cccc(CO)c1
Reaction time: 16 h

Procedure:
3-(2-Methylphenyl)benzyl alcohol was prepared as follows: Under a nitrogen atmosphere a stirred mixture of magnesium turnings (3.0 g, 0.12 mole) and 10 ml of 1,2-dibromoethane in 100 ml of dry tetrahydrofuran was heated to 30°. To the stirred mixture was added dropwise 4,5-dihydro-4,4-dimethyl-2-(3-bromophenyl)oxazole (26.9 g, 0.11 mole) in 50 ml of dry tetrahydrofuran. Upon complete addition, the reaction mixture was heated at reflux for 1.5 hours. The so-prepared Grignard reagent was cooled, placed in a dropping funnel, and added dropwise at 0° to a stirred solution of 2-bromotoluene (18.1 g, 0.11 mole) and 0.5 g of bis(1,3-diphenylphosphino)propanenickel(II) chromate in 150 ml of dry tetrahydrofuran. The temperature of the reaction mixture was maintained at 0° throughout the addition. Upon complete addition, the temperature was allowed to rise to 15°, and the reaction mixture was stirred for 16 hours, then heated under reflux for approximately 24 hours. The reaction mixture was cooled and poured into 500 ml of water. The resultant emulsion was broken by pouring small amounts of the mixture into 1000 ml portions of water. Each portion was extracted with two 200 ml portions of toluene. The combined toluene extracts were evaporated under reduced pressure to afford 25 g of oily residue. The combined water layers were divided into three parts, and to each part was added 10 ml of 6 N hydrochloric acid. Each part was extracted with toluene. The combined extracts were evaporated under reduced pressure to give an additional 8.8 g of oily residue. The residues were combined and impurities removed by distillation using a Kugelrohr distilling system. The residue was purified by column chromatography on silica gel, producing 4,5-dihydro-4,4-dimethyl-2-[(2'-methyl[1,1'biphenyl]-3-yl)oxazole (7.2 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[CH:15]=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[Br:18]N1C(=O)CCC1=O>C1COCC1>[Br:18][C:11]1[NH:10][C:9]2[C:8](=[O:14])[N:7]3[CH:15]=[N:16][N:17]=[C:6]3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=2[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCn1c2nc[nH]c2c(=O)n2cnnc12
Solvent: C1CCOC1
Product: CCCCn1c2nc(Br)[nH]c2c(=O)n2cnnc12
Temperature: 70 °C
Yield: 5.5 %

Procedure:
To a mixture of 9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (65 mg, 0.28 mmol) in THF (2 mL) was added N-bromosuccinimide (49.8 mg, 0.280 mmol). The mixture was heated in a microwave reactor at 70° C. for 10 minutes. The mixture was purified with prep LCMS to give the desired product (4.8 mg, 6%). LCMS calculated for C10H12BrN6O (M+H): 311.0; found: 311.0, 313.0.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:18][C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:16]2[C:11]=1[C:12]([NH2:17])=[N:13][CH:14]=[N:15]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c(CN3CCOCC3)ccc12
Solvent: C1CCOC1
Product: Nc1ncnn2c(CN3CCOCC3)cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 160.2 %

Procedure:
To a solution of 7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (562 mg, 2.40 mmol) in THF (19 ml) at −20 C was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (344 mg, 1.2 mmol) in three portions. The reaction was stirred at −20 C for 3 h. Upon the completion, the reaction was quenched with aqueous saturated Na2SO3 and allowed to warm up to rt. The crude was extracted with ethyl acetate. The organic was washed with brine, dried over Na2SO4 and concentrated. The resulting crude was purified via column chromatography (95:5 v/v CH2Cl2—CH3OH) to afford 600 mg of the title compound as yellow solid (yield 79%). 1H-NMR (DMSO-d6) δ 7.84 (s, 1H), 6.71 (s, 1H), 3.74 (s, 2H), 3.51 (t, J=4 Hz, 4H), 2.37(t, J=4 Hz, 4H); MS [M+H]+=312; LCMS RT=1.04 min.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14].Cl[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32])=[O:24]>CCCCCC.O1CCCC1.O>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C:23]1([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH3:14])[CH2:22][O:24]1
Reactant: CCc1ccccn1
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(c1ccccn1)C1(c2ccc(F)cc2F)CO1
Reaction time: 0.17 h

Procedure:
n-Butyllithium (19.7 ml of a 1.6M solution in hexane) was added to a stirred solution of diisopropylamine (3.18 g) in dry tetrahydrofuran (50 ml) at -70° under an atmosphere of dry nitrogen. The solution was stirred at -70° for 0.17 hour, followed by 0.17 hour at 0° and then re-cooled to -70°. 2-Ethylpyridine (3.37 g) was added over 0.08 hour, the red solution resulting was stirred at -70° for 0.33 hour and then added via a syringe to a stirred solution of 2-chloro-2',4'-difluoroacetophenone (5.00 g) in dry tetrahydrofuran (50 ml) at -70°. The solution was stirred at -70° for 3 hours and then at room temperature for 18 hours. Water (4 ml) was added and the solution was evaporated. The residual oil was partitioned between water (80 ml) and dichloromethane (100 ml). The organic layer was separated, washed with water (80 ml) and then extracted with 2N hydrochloric acid (2×80 ml). The combined acidic extracts were basified to pH 12 with 2N sodium hydroxide solution and extracted with dichloromethane (3×75 ml). The combined organic layers were dried (Na2SO4), evaporated, and the residue was chromatographed on silica gel. Elution with ethyl acetate gave, after combination and evaporation of appropriate fractions, the title compound (2.25 g) as a yellow oil which was used directly in the next stage.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:16][C:17]1[C:18](=[O:36])[N:19]([C:23]2[CH:24]=[C:25]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:26]([NH:28][CH:29]2[CH2:31][CH2:30]2)=[O:27])[CH:20]=[CH:21][N:22]=1)([CH2:14][CH3:15])[CH2:12][CH3:13].[CH2:37]([NH2:39])[CH3:38]>O>[CH:29]1([NH:28][C:26](=[O:27])[C:25]2[CH:32]=[CH:33][C:34]([CH3:35])=[C:23]([N:19]3[CH:20]=[CH:21][N:22]=[C:17]([NH:16][C:11]([CH2:14][CH3:15])([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:39][CH2:37][CH3:38])[CH2:12][CH3:13])[C:18]3=[O:36])[CH:24]=2)[CH2:31][CH2:30]1
Reactant: CCC(CC)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O)c1ccccc1OCCCl
Reactant: CCN
Solvent: O
Product: CCNCCOc1ccccc1C(CC)(CC)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O

Procedure:
The title compound was prepared from 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-ethylpropyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 266e) using the method described in Example 167f but using 70% ethylamine in water.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>ClCCl>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][CH2:8][O:9][S:21]([CH3:20])(=[O:23])=[O:22])[C:4]([CH3:11])([CH3:10])[O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H](CCO)C(C)(C)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)O[C@@H](CCOS(C)(=O)=O)C(C)(C)O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 41.3 %

Procedure:
Step G To a solution of 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethanol (2.7 g, 15.8 mol) and triethylamine (4.6 g, 45 mmol) in dichloromethane (100 mL) at 0° C. was added methanesulfonyl chloride (2.7 g, 24 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1.5 h, then water was added. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give methanesulfonic acid 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethyl ester as a yellow oil (2.5 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[C:25]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=O)(=[O:27])[CH3:26].CCN=C=NCCCN(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.CS(O)(=O)=O>[C:25]([NH:28][C:29]1[CH:30]=[C:31]([C:32]2[N:17]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:13]3[CH:12]=[CH:11][C:10]([C:8]4[O:9][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=5[N:7]=4)=[CH:16][C:14]=3[N:15]=2)[CH:35]=[CH:36][CH:37]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-c2nc3cc(-c4nc5cc(Cl)ccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 14.3 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in dimethylformamide (5 mL) was added 3-acetamidobenzoic acid (130 mg, 0.727 mmol) and WSC (167 mg, 0.872 mmol), and this was stirred at room temperature for 23 hours. Saturated aqueous sodium hydrogen carbonate solution was added, the precipitated crystals were filtered, washed with water and then dried. To a solution of the residue obtained in dioxane (5 mL) was added methanesulfonic acid (2 drops), and this was heated to reflux for 3 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, the precipitated crystals were filtered, washed with water and then dried. The residue obtained was purified by silica gel column chromatography to yield the title compound (50.5 mg, 14%) as white crystals.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)OC.[CH3:17][C:18]1[S:19][C:20]([CH:33]=O)=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[N:22]=1.C(CCCCCCC1N=CSC=1/C=C/C(=O)CCCCC)(OC)=O>COCCOC.O>[CH3:17][C:18]1[S:19][C:20](/[CH:33]=[CH:9]/[C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[N:22]=1
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCCc1nc(C)sc1C=O
Agent: CCCCCC(=O)/C=C/c1scnc1CCCCCCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCCCC(=O)/C=C/c1sc(C)nc1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 0.45 g of sodium hydride in 5 ml of anhydrous 1,2-dimethoxy-ethane a solution of 4.12 g of 2-oxoheptylphosphonic acid dimethyl ester in 20 ml of 1,2-dimethoxy-ethane was added under stirring at room temperature. The reaction mixture was stirred for an hour, then a solution of 1 g of 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carbaldehyde (XIII, R1 = CH3) prepared according to point (e) of Example 2, in 10 ml of 1,2-dimethoxy-ethane was added dropwise, and stirring was continued for 5 hours. After adding dropwise 30 ml of water under ice-cooling to the reaction mixture, it was extracted with 3 × 20 ml of diethyl ether. The extract was dried on over sodium sulphate and evaporated in vacuo. The evaporation residue was purified by preparative thin layer chromatography, using a silica gel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent. The yield was 0.81 g of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, R1 = CH3) of chromatographic purity.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([O:15][CH2:16][CH3:17])[NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:18]>CO>[CH2:16]([O:15][C:13]1[NH:14][C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:18])[C:11]=2[N:12]=1)[CH3:17]
Reactant: CCOc1nc2c(Cl)nc3ccccc3c2[nH]1
Reactant: N
Solvent: CO
Product: CCOc1nc2c(N)nc3ccccc3c2[nH]1
Temperature: 150 °C

Procedure:
4-Chloro-2-ethoxy-1H-imidazo[4,5-c]quinoline (500 mg) was added to a high-pressure vessel with ammonia (40 mL of a 7 N solution in methanol), and the vessel was sealed and heated at 150° C. overnight. An analysis by LC/MS indicated the presence of starting material, and the reaction was heated at 150° C. for an additional four hours, allowed to cool, and concentrated under reduced pressure. The crude product was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.4:7.6:92) to provide 52 mg of 2-ethoxy-1H-imidazo[4,5-c]quinolin-4-amine as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[Cl:11][C:12]1[C:13]([NH:45]S(C)(=O)=O)=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH3:21])[N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH:33][S:34]([C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)(=[O:36])=[O:35])=[O:32])=[CH:24][CH:23]=3)[C:16]=2[CH:44]=1>C1COCC1>[Cl:11][C:12]1[C:13]([NH:45][CH3:1])=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH3:21])[N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH:33][S:34]([C:37]4[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=4)(=[O:36])=[O:35])=[O:32])=[CH:24][CH:23]=3)[C:16]=2[CH:44]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nc2cc(NS(C)(=O)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: CCc1nc2cc(NC)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of acetic anhydride (0.14 ml) in THF (5 ml) was added formic acid (0.06 ml, 1.65 mmol) at 0° C. under nitrogen and the mixture was stirred at 60° C. for 2 h. Then the mixture was recooled to 0° C. and was added 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (Example 110, step 6, 100 mg, 0.3 mmol) in THF (2 ml). The mixture was stirred at room temperature for 2 h. The volatile component was removed under reduced pressure, and the residue was dissolved with ethyl acetate (100 ml). The organic layer was washed with 2N aqueous NaOH (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:10) to afford 68 mg (67%) of the title compound as pale yellow solids.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([CH2:20]Br)[CH:17]=[CH:16][C:15]=12.C([O-])([O-])=O.[K+].[K+]>>[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([CH2:20][N:10]([CH2:20][C:18]3[CH:17]=[CH:16][C:15]4=[N:11][S:12][N:13]=[C:14]4[CH:19]=3)[C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[CH:17]=[CH:16][C:15]=12
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrCc1ccc2nsnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1nc2cc(N(Cc3ccc4nsnc4c3)Cc3ccc4nsnc4c3)ccc2[nH]1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), benzo[c][1,2,5]thiadiazol-5-yl-methylbromide (504 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.128 mg (29.8%); MS m/z: 430.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 5.01 (s, 4H); 6.78 (br s, 1H); 6.82-6.84 (m, 1H); 7.39-7.41 (m, 1H); 7.71-7.73 (m, 2H); 7.88 (s, 1H); 7.90 (s, 2H); 8.06-8.08 (m, 2H); 11.85 (br s, 1H); HPLC (METHOD [A]): rt 14.11 min (98.9%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[NH:12][C:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][O:33][CH2:34][CH2:35][NH:36][CH2:37][CH3:38])=[C:10]1[C:39]([O:41][CH3:42])=[O:40].[C:43](=O)([O:49]C(C)(C)C)[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(N(CC)CC)C>ClCCl>[CH3:42][O:41][C:39]([C:10]1[CH:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[NH:12][C:11]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][O:33][CH2:34][CH2:35][N:36]([C:43]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:49])[CH2:37][CH3:38])=[O:40]
Reactant: CCNCCOCc1ccccc1CCC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CC(=O)OC)N1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCOCc1ccccc1CCC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CC(=O)OC)N1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice-cooled stirred solution of dimethyl 4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methyl}phenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate (700 mg/1.13 mmol) in dichloromethane (50 ml) was added di-t-butyl carbonate (297 mg/1.36 mmol) and triethylamine (172 mg/1.70 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with water. The separated organic layer was washed with water, dried over MgSO4, filtered and concentrated to give a crude mixture. This crude was purified by column chromatography on silica gel (CH2Cl2:MeOH=40:1) to afford a yellow amorphous (813 mg/quant.).