Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH3:12]OS(OC)(=O)=O.ClCCl.C(N(CC)CC)C>O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH3:12])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: COS(=O)(=O)OC
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a 3-neck 1-liter round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added 2-carboxybenzaldehyde (100.00 g, 0.659 moles), dimethylsulfate (162.8 g 1.291 moles) and 200 ml of dichloromethane under nitrogen. The mixture was heated to reflux and triethylamine (135.89 g, 1.343 moles) was added at such a rate to maintain a brisk reflux. After the addition was complete, the solution was allowed to cool to room temperature and stirred overnight. Water (400 ml) was then added and the layers separated. The aqueous layer was extracted with dichloromethane (1×200 ml) and the combined organic layers washed with saturated sodium bicarbonate solution (1×400 ml), dried over magnesium sulfate and concentrated in vacuo to give a golden oil. Vacuum distillation of this oil gave 88.7 g of the product as a pale yellow oil, bp 95°-98° C./0.4 mm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:29]CC3C=CC(OC)=CC=3)([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.C(#N)C.O.OS([O-])(=O)=O.[K+]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:21]([F:22])([F:23])[F:24])[C:25]([F:27])([F:28])[F:26])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OC(COc2ccc(C(OCc3ccc(OC)cc3)(C(F)(F)F)C(F)(F)F)cc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OC(COc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 48.6 %

Procedure:
76 mg (0.12 mmol) of rac 4-(1-phenyl-2-{4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-ethoxy)-benzoic acid methyl ester in 4 ml of a mixture of acetonitrile:water (9:1) were treated with 250 mg (0.46 mmol) of ceric ammonium nitrate at room temperature overnight. An additional 100 mg (0.18 mmol) of ceric ammonium nitrate were added and stirring was continued for 3 h. EtOAc and 1M KHSO4 were added and the phases were separated. The inorganic one was extracted with EtOAc, the combined organic phases were washed with brine and dried (Na2SO4) and evaporated. Column chromatography on ISOLUTE Flash NH2 with a gradient of EtOAc/n-heptane to EtOAc gave 30 mg (48%) of rac 4-{1-phenyl-2-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-ethoxy}-benzoic acid methyl ester as a colorless oil, MS: 513 (M−H)−.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].CC[O-:15].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>CO.CCCCCC.C1(C=CC(O)=CC=1)O>[C:10]([OH:11])(=[O:15])[CH:8]=[CH2:6].[C:17]([OH:20])(=[O:3])[CH:18]=[CH2:19].[CH2:10]([OH:11])[C@H:8]([C@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:12])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: CC[O-]
Reactant: C=CC(=O)Cl
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: C=CC(=O)O
Temperature: 17 °C
Reaction time: 10 h

Procedure:
9.1 g mannitol (D(-)-Mannitol, Merck, for determination of boric acid) is mixed to an emulsion in 120 ml methanol (Merck, dried for analysis purposes) in a round flask, and is subsequently dissolved through boiling in reflux. 18 g of sodium ethylate is then slowly added (Merck, 30% in methanol) and boiled in reflux for one hour. A felt of long needles is formed. Methanol is then evaporated off in a vacuum and the mixture is mixed to an emulsion four times in n-hexane and once again the solvent is removed and the mixture is dried in a desiccator. 11.5 g of a light yellow crystaline substance is obtained. This is mixed to an emulsion in 120 ml n-hexane in a 250 ml round flask and maintained at 17 degrees C. Under heavy agitation, 9.1 g acryloyl chloride is slowly added (Merck, stabilised for synthesis). After 5 hours of agitation and 10 hours standing, 0.1 g of hydroquinone is added and the mixture is dried in a vacuum. 21.3 g of a mannitol diacrylate and common salt mixture is formed. The mixture is dissolved in 200 ml deionised water and subsequently, by means of an ion exchanger, (Amberlite IR 120, acidic) separated from the common salt. 0.1 g hydroquinone is introduced into the eluate, the water is removed and drying in a desiccator is then undertaken. 15.3 g of a light yellow substance remains. This is completely soluble in water or in acrylic acid. It is hard to dissolve in acetone, methanol, ethanol or ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([F:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:14][CH2:12][C:11]1[C:2]([F:1])=[C:3]([C:8]([F:13])=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)ccc(C)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(F)ccc(CBr)c1F
Temperature: 25 °C
Yield: 107 %

Procedure:
To a room temperature solution of methyl 2,6-difluoro-3-methylbenzoate (9.35 g, 50.2 mmol, 1.0 equiv) and N-bromosuccinimide (11.6 g, 65.3 mmol, 1.3 equiv) in carbon tetrachloride (230 mL) was added catalytic AIBN (˜200 mg) as a solid in one portion. The resulting reaction mixture was heated to reflux overnight. After the reaction mixture was allowed to cool to room temperature, it was washed with aq. satd. NaHCO3. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 14.24 g (>100% mass recovery) of unpurified bromide, which was taken on to the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:19][C:18](=O)[N:17]4[CH:21]=[CH:22][N:23]=[C:16]4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)([Cl:26])=O.C(N(CC)C1C=CC=CC=1)C.C(=O)(O)[O-].[Na+]>>[Cl:26][C:18]1[N:17]2[CH:21]=[CH:22][N:23]=[C:16]2[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[N:19]=1
Reactant: CN1CCC(c2ccc(-c3cc4nccn4c(=O)[nH]3)cc2)CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Product: CN1CCC(c2ccc(-c3cc4nccn4c(Cl)n3)cc2)CC1
Temperature: 50 °C
Yield: 71.2 %

Procedure:
To a suspension of 7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (0.728 g, 2.361 mmol) in phosphoryl trichloride (12 mL, 131.1 mmol) under nitrogen was added N,N-diethylaniline (0.9390 mL, 5.902 mmol). The reaction was then heated to 50° C. for 4 hours. The reaction was concentrated, and the residue obtained was treated with 15 mL of a 1:1 mixture of ice and saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (4×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was triturated with diethyl ether and the solid was collected by means of vacuum filtration. The solid was saved. The filtrate was concentrated and the resulting residue purified by silica gel column chromatography, eluting with 20% methanol in dichloromethane. The product-containing fractions were concentrated under reduced pressure and the material was combined with the triturated solid to afford 5-chloro-7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidine (550 mg, 1.68 mmol, 63% yield). MS (apci) m/z=327.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1>C1(=O)CCCCC1.C(O)C.[Pd]>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][CH:2]3[CH2:11][CH2:10][CH2:5][CH2:4][CH2:3]3)=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: O=C1CCCCC1
Product: CCCCC1OC(=O)c2cc(NC3CCCCC3)ccc21

Procedure:
Analogously to the method described in Example 14, 4.1 g (20.0 mmol) of compound obtained in Example 4 in 5 ml of cyclohexanone and 150 ml of 95% ethanol are added to 10% Pd—C catalyst and hydrogenated to give the title compound.
Reaction SMILES: C(C1C=CC(C(Cl)=O)=CC=1)CC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[NH2:17].[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH2:37][CH3:38].[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([CH2:36][CH2:37][CH3:38])=[CH:40][CH:41]=2)=[S:49])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCCc1ccc(C(=O)Cl)cc1
Agent: CCCc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
4-Propyl-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-propyl-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-propyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 58%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[NH:1]([C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:15]([CH3:16])=[O:17]
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c(cn1)[nH]c1ccccc12

Procedure:
2 g of 3-amino-β-carboline are suspended in 35 ml of pyridine and mixed with 4 ml of acetic anhydride. The aminocarboline dissolves during slight heating. After 20 minutes the solution is evaporated. The crystalline residue is washed with water and is recrystallized from ethyl acetate. Yield: 1.5 g of 3-acetamino-β-carboline with a 200°-203° C. melting point.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12]>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1cc(CO)ccc1Cl
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C=O)ccc1Cl
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to −78° C. under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to warm up to 0° C. After stirring for 1 h, the reaction was cooled to −78° C. and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][N:13]=1>ClCCl>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([NH:3][CH2:1][CH3:2])=[O:19])=[CH:14][N:13]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1
Reactant: CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cnc(Cl)nc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 72613.2 %

Procedure:
A solution of ethylamine (4.26 g, 0.0946 mol) and triethylamine (28.7 g, 0.284 mol) in dichloromethane (75 mL), pre-cooled to −15 to −10° C., was added dropwise to a solution of 2-chloropyrimidine-5-carbonyl chloride (16.64 g, 0.0946 mmol) in dry dichloromethane (250 mL) at −15° C., then the reaction mixture was stirred at −15° C. for 1 hour. The reaction was quenched by the addition of a solution of concentrated hydrochloric acid (32.3 mL) in water (300 mL). The resulting mixture was stirred at room temperature for 1 hour. The layers were separated, and the aqueous phase was further extracted with dichloromethane (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via column chromatography to provide 2-chloro-N-ethylpyrimidine-5-carboxamide (12.75 g, 72%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]4[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=4)=[CH:18][CH:17]=3)=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1csc(COc2ccc(-c3ccc4c(c3)OCO4)cc2)n1

Procedure:
A solution of 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 75 mg, 0.2 mmol) in dioxane (4 mL) was added to a reaction tube containing 3,4-methylenedioxybenzeneboronic acid (ASDI Incorporated, Newark, Del.; 100 mg, 0.6 mmol). A solution of potassium carbonate (80 mg, 0.6 mmol) in water (0.4 mL) was added and the mixture was degassed. A solution of bis(tricyclohexylphosphine)-palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) in dioxane (0.5 mL) was added and the tube was heated in a microwave oven at 170 degrees for 25 min. The solution was acidified, filtered through silica gel, evaporated, and triturated with aqueous methanol to give 2-(4-benzo[1,3]dioxol-5-yl-phenoxymethyl)-thiazole-4-carboxylic acid. Mass spectrum MH+=356.
Reaction SMILES: O1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].O1CCCC1.CC(C)([O-])C.[K+]>O>[F:17][C:12]([F:18])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:21][F:22])([CH2:19][F:20])[CH:2]=[C:7]([N:23]3[CH2:27][CH2:26][CH2:25][C:24]3=[O:28])[C:6]=2[CH:8]=1)[C:13]([F:15])([F:16])[F:14]
Reactant: O=C1CCCN1
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Yield: 16.2 %

Procedure:
To a mixture of 0.41 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.18 g of 2-pyrrolidinone and 8 ml of tetrahydrofuran was added 0.22 g of potassium tert-butoxide with stirring under ice-cooling and the mixture was stirred for 3.5 hours under ice-cooling and then stirred at room temperature for 4 days. Water was added and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.08 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 104°-105° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]3=[N:13][O:14][N:15]=[C:11]3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[C@@H:29]1[CH2:31][O:30]1>>[N:13]1[O:14][N:15]=[C:11]2[CH:10]=[C:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][N:4]([CH2:31][C@@H:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:24](=[O:28])[O:25][CH2:26][C:27]=5[C:19]=4[CH3:18])[OH:30])[CH2:3][CH2:2]3)[CH:17]=[CH:16][C:12]=12
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: c1cc2nonc2cc1CCN1CCNCC1
Product: Cc1c([C@@H](O)CN2CCN(CCc3ccc4nonc4c3)CC2)ccc2c1COC2=O

Procedure:
5-[(1R)-2-{4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one was prepared in a similar fashion as to the synthesis described in EXAMPLE 12 starting from 5-[2-(piperazin-1-yl)ethyl]-2,1,3-benzoxadiazole and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one. LC/MS: [(M+1)]+=423.
Reaction SMILES: C(C1C=NC(C2C=CC(O)=CC=2)=NC=1)CCCCCCCCCC.FC1C=C(C(O)=O)SC=1CCC.[CH2:37]([C:40]1[S:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][CH:41]=1)[CH2:38][CH3:39].[N+:49]([O-])([OH:51])=[O:50].OS(O)(=O)=O>>[N+:49]([C:41]1[CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[S:44][C:40]=1[CH2:37][CH2:38][CH3:39])([O-:51])=[O:50]
Reactant: CCCc1ccc(C(=O)OC)s1
Reactant: O=[N+]([O-])O
Agent: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCCc1sc(C(=O)O)cc1F
Agent: O=S(=O)(O)O
Product: CCCc1sc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 2.0 g of 4-fluoro-5-propyl-thiophene-2-carboxylic acid (prepared in accordance with Scheme 1 by nitrating methyl 5-propyl-thiophene-2-carboxylate in HNO3/H2SO4 to form methyl 4-nitro-5-propyl-thiophene-2-carboxylate, followed by reduction of the latter by means of Sn/HCl to give the corresponding amino compound, conversion of the latter into the diazonium tetrafluoroborate, thermolysis and, finally, hydrolysis) and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:32]C(=O)OC(C)(C)C)([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:40].C(OC(C)C)(C)C>ClCCl.C(OCC)(=O)C>[ClH:40].[NH2:32][C:29]([C:26]1[CH:27]=[CH:28][C:23]([N:22]2[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:24][CH:25]=1)([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-n2c(-c3cccnc3N)nc3ccc(-c4ccccc4)nc32)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CC(C)(N)c1ccc(-n2c(-c3cccnc3N)nc3ccc(-c4ccccc4)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}-1-methylethyl)carbamate (27 mg) in dichloromethane (1 mL) was added a solution of hydrogen chloride in ethyl acetate (80 ul). The reaction was allowed to stir at room temperature for 1 h. Upon completion of the reaction, diisopropylether was added to the suspension and the solid was filtered to give the product (19 mg, 71%). 400 M Hz 1H-NMR (DMSO-d6) δ: 8.90-8.70 (m, 3H), 8.37 (d, J=8.3 Hz, 2H), 8.15 (dd, J=6.0 Hz and 1.8 Hz, 1H), 8.08-8.03 (m, 3H), 7.86 (dd, J=7.3 Hz and 1.4 Hz, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.52-7.47 (m, 2H), 7.46-7.41 (m, 1H), 6.89 (dd, J=7.3 Hz and 6.4 Hz, 1H), 1.70 (s, 6H); LCMS: 421 [M+H].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2S[C:12]3[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:21]=1)(=[O:3])C.Cl[O-:23].[Na+].[OH-].[Na+].[S:27](S([O-])=O)([O-:30])(=O)=[O:28].[Na+].[Na+].Cl>>[CH:17]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:21]=[C:4]([C:1]([OH:3])=[O:23])[CH:5]=[CH:6][C:7]=3[S:27](=[O:30])(=[O:28])[C:12]=2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=1
Reactant: [O-]Cl
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2(=O)=O
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Add 1.85 g. of 8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid to a stirred mixture of 370 ml. of 50% aqueous sodium hypochlorite and 13 ml. of 20% aqueous sodium hydroxide at 60° C. Raise the temperature to 85° C. and stir for 30 minutes. Pour the mixture over ice and add sodium metabisulfite Acidify with 6N hydrochloric acid. Separate the solids by filtration wash with water and dry to obtain the title product. (m.p. 350°-352° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:48]([NH:47][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:49])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(N)nc3)n2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)Nc4ccccc4)nc3)n2)cc1
Yield: 38.5 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)pyridine-2,5-diamine (0.150 g, 0.281 mmol) and phenyl isocyanate (Fluka) (0.077 mL, 0.70 mmol) in THF (3 mL) was stirred at rt for 5 h. The resulting solid was collected by filtration to give 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-phenylurea (0.0707 g) as a yellow solid. The filtrate and wash were concentrated and purified by silica gel chromatography (25 g, eluent: EtOAc in hexanes 0%-30%) to give a second batch of the product (0.0924 g). The total yield was 0.1631 g, 89%. 1H NMR (300 MHz, CDCl3) δ 11.83 (s, 1H); 11.66 (br. s., 1H); 8.80-8.89 (m, 1H); 8.41 (br. s., 1H); 8.27-8.36 (m, 1H); 7.88-7.99 (m, 1H); 7.62 (d, J=8.18 Hz, 2H); 7.31-7.41 (m, 3H); 7.15-7.24 (m, 4H); 7.03-7.12 (m, 1H); 6.75-6.93 (m, 5H); 6.64-6.73 (m, 1H); 4.85 (br. s., 4H); 3.79 (d, J=10.96 Hz, 6H); 2.61 (s, 3H). m/z (ESI, +ve ion) 654.0 (M+H)+.