Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C[Li].C([Li])(C)(C)C.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C>O1CCCC1.C(OCC)C.CCCCC>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[B:24]([OH:25])[OH:23]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(C(=O)O)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
3-Bromo-4-methoxybenzoic acid (2.00 g) is dissolved in tetrahydrofuran (50 ml), and the mixture is cooled to −78° C., and thereto is added dropwise a 1.1M methyllithium in diethyl ether (7.7 ml). The mixture is stirred at −78° C. for 5 minutes, and thereto is added dropwise a 1.6M tert-butyllithium in n-pentane (13.2 ml), and the mixture is stirred at −78° C. for 15 minutes, and the mixture is allowed to warm to −45° C., and the mixture is stirred for 45 minutes, and then again cooled to −78° C. Thereto is added dropwise triisopropylborate, and the mixture is stirred at −78° C. for 15 minutes, and the mixture is allowed to warm to room temperature. The mixture is stirred at room temperature for 1.5 hours, and the mixture is concentrated under reduced pressure, and thereto are added water and hexane. The aqueous layer is adjusted to pH 4 by addition of a 6N-hydrochloric acid and a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate and methanol twice. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To the resulting residue is added diethyl ether, and the resulting solids are collected by filtration to give 2-methoxy-5-carboxyphenylboronic acid (1.37 g) as a crude product.
Reaction SMILES: COC(=O)CCCOC1C=C(N)C=CC=1.COC(=O)C([C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[C:27]([O:34][CH2:35]C2C=CC=CC=2)[CH:26]=1)(C)C(OC)=O>>[O:34]1[C:27]2[CH:26]=[CH:25][CH:30]=[CH:29][C:28]=2[N:31]=[CH:35]1
Reactant: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: COC(=O)CCCOc1cccc(N)c1
Product: c1ccc2ocnc2c1

Procedure:
Methyl-4-(5-aminophenoxy)butyrate was made as described in example 7 above and coupled with dimethyl-2-(3-benzyloxy-4-nitrophenyl)-2-methylmalonate according to the method described in example 7 to produce the methyl ester of 2-Anilino-6-(2-(3-[3-carboxypropoxy]anilino carbonyl)prop-2-yl))benzoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([Mg]Cl)([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+]>C1COCC1>[CH3:19][C:18]([C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][C:6]3[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:15](=[O:16])[C:10]2=[N:11][CH:12]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cnc2c(c1)CCc1cc(Cl)ccc1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 20.05 grams (82.28 mmol) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 400 ml of dry THF at -72° C. and under an atmosphere of nitrogen was added dropwise over 40 minutes 66.0 ml of 2.7 M t-butyl magnesium chloride in THF. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was then poured into 10% aqueous ammonium chloride and extracted four times with CH2Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound, along with 8-chloro-11-(1,1-dimethyl-1-ethyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol. These compounds were separated via flash chromatography to give the title compound, which was recrystallized from isopropyl ether to give 4.37 grams (18%) of the title compound as a white solid.
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[SH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: CC(=O)SCc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(CS)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 3-(acetylthiomethyl)benzoic acid (16.4 g, 78.10 mmol, 1.00 equiv) in methanol (150 mL), and a solution of potassium carbonate (26.9 g, 194.93 mmol, 2.50 equiv) in water (70 mL). The resulting solution was stirred for 4 h at 60° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of water and adjusted to pH 3 with 10% hydrochloric acid. The resulting solution was extracted with 3× (100/20 mL) of ethyl acetate/tetrahydrofuran and the organic layers combined. The resulting mixture was washed with 1×100 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 12 g (91%) of 3-(mercaptomethyl)benzoic acid as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:32]2[S:36][C:35]([C:37]3([OH:41])[CH2:40][CH2:39][CH2:38]3)=[N:34][CH:33]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([O:19]CC)=[O:18])[CH:15]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>CO>[F:1][C:2]1[C:3]([C:32]2[S:36][C:35]([C:37]3([OH:41])[CH2:38][CH2:39][CH2:40]3)=[N:34][CH:33]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n2S(=O)(=O)c2ccc(C)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3[nH]2)cn1
Temperature: 25 °C

Procedure:
A solution of ethyl 2-(4-(5-fluoro-4-(2-(1-hydroxycyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-1-yl)acetate (Example 65A) (734 mg, 1.232 mmol) in methanol (8.2 mL) and 2N aqueous sodium hydroxide solution (2.16 mL, 4.31 mmol) was heated by microwave irradiation (Biotage, Initiator) in a sealed vessel to 105° C. for 5 minutes. The reaction was cooled to room temperature and concentrated to a volume of 2 mL. The solution was diluted with 10% aqueous HCl. The solid was filtered and air-dried to give the title compound. MS ESI(+) m/z 413.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[NH:15][CH2:14][CH2:13][N:12]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:11]2)[CH:6]=[CH:5][N:4]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>[NH4+].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:33][C:32]([F:34])([F:35])[C:31]([C:28]1[CH:27]=[CH:26][C:25]([N:15]2[CH2:14][CH2:13][N:12]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH2:11][CH:10]2[CH2:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:30][CH:29]=1)([OH:40])[C:36]([F:37])([F:39])[F:38]
Reactant: COc1cc(CC2CN(S(=O)(=O)c3cccs3)CCN2)ccn1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(CC2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)ccn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
To a 50-mL round-bottomed flask was added 3-((2-methoxy-4-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (168 mg, 0.47 mmol), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (184 mg, 0.57 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (91 mg, 0.19 mmol, Strem, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (43 mg, 0.05 mmol, Strem, Newburyport, Mass.), sodium tert-butoxide (137 mg, 1.43 mmol, Aldrich, St. Louis, Mo.), and toluene (5 mL). The reaction mixture was stirred at 100° C. for 18 h and allowed to cool to room temperature. The reaction mixture was diluted with saturated NH4Cl (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude product was purified by silica gel chromatography, eluting with 40% EtOAc/hexanes to give 1,1,1,3,3,3-hexafluoro-2-(4-(2-((2-methoxy-4-pyridinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (121 mg) as a colorless oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([N:8]([C:10]1[C:11]([Cl:30])=[C:12]([C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([CH3:25])[CH:21]=[CH:20]2)[CH3:9])=[O:7])([OH:3])=O.[NH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([NH:37][CH3:38])=[O:36].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:30][C:11]1[C:10]([N:8]([C:6](=[O:7])[CH2:5][CH2:4][C:1](=[O:3])[NH:31][C:32]2[CH:41]=[CH:40][CH:39]=[C:34]([C:35](=[O:36])[NH:37][CH3:38])[CH:33]=2)[CH3:9])=[CH:28][CH:27]=[C:26]([Cl:29])[C:12]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([CH3:25])[CH:21]=[CH:20]2
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CCC(=O)O)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CNC(=O)c1cccc(NC(=O)CCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.2 %

Procedure:
to amixture of 8-[3-[N-(3-carboxypropionyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (139 mg), 3-amino-N-methylbenzamide (51.3 mg) and anhydrous dichloromethane (4 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71.5 mg) and 1-hydroxybenzotriazole (54.6 mg). The mixture was stirred for 12 hours at ambient temperature ans washed with water. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purifed by preparative thin-layer chromatography (chloroform-methanol) followed by pulverization with diethyl ether to give 8-[2,6-dichloro-3-[N-[3-[N-(3-methylcarbamoylphenyl)carbamoyl]propionyl]-N-methylamino]benzyloxy]-2-methylquinoline (103 mg) as an amorphous powder.
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]([CH:6]([C:8]1[CH:17]=[CH:16][C:11]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:10][CH:9]=1)[CH3:7])=[O:5].[Na]>O>[O-:5][C:4]([CH:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:16][CH:17]=1)[CH3:7])=[O:3].[Na+:2]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Temperature: 95 °C

Procedure:
The chloroester solution prepared in (c) was heated to reflux at 95°-100° C. and 13 kg of 50% sodium hydroxide in water was added over twenty minutes. The mixture was refluxed for forty minutes at 95±5° C. GLC analysis of an aliquot indicated complete reaction. 6.4 liters of water were slowly added to the mixture, keeping the temperature about 75° C. After water addition was complete, the mixture was cooled to 70° C. and was seeded with 30 g of good quality sodium ibuprofen. The resulting slurry was cooled to 0° C. over two hours. The slurry was stirred at 0° C. for thirty minutes and filtered. The sodium ibuprofen cake was washed wih 60 kg of heptane and dried.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([CH:27]=O)=[CH:23][CH:24]=[CH:25][CH:26]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:1]1[CH:2]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:9]
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccccc1-c1ccccc1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccccc1-c1ccccc1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available [1,1′-biphenyl]-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.98 min.; [M+H]+: 416.24 g/mol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[C:6]4[CH:16]=[CH:17][C:3]([Cl:2])=[CH:4][C:5]=4[O:9][N:8]=3)[CH2:15][CH2:14]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4cc(Cl)ccc34)CC2)CC1

Procedure:
Prepared as described for intermediate F (example 1) from a mixture 6-Chloro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride (0.942 g, 4 mmol), trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.06 g, 4 mmol) and sodium triacetoxyborohydride (1.51 g, 7 mmol) in 1,2 dichloroethane (9.8 mL) The product fractions were concentrated to give 1.2 g (2.6 mmol, 64.3% yield) of a light brown solid. MS (m/e): 462.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([F:14])=[C:12]2[C:7]([CH:8]=[C:9](/[CH:17]=[CH:18]/[C@H:19]3[CH2:24][CH2:23][C@H:22]([C@H:25]4[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[C:10]([F:16])=[C:11]2[F:15])=[CH:6][CH:5]=1)[CH3:2].[H][H]>[C].[Pd].O1CCCC1>[CH2:1]([O:3][C:4]1[C:13]([F:14])=[C:12]2[C:7]([CH:8]=[C:9]([C:17]3[CH:6]=[CH:5][CH:4]=[CH:13][C:18]=3[C@H:19]3[CH2:24][CH2:23][C@H:22]([C@H:25]4[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:10]([F:16])=[C:11]2[F:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccccc3-c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1

Procedure:
The crude production of (E)-7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]ethenyl]-1,2,8-trifluoronaphthalene (16.6 g), 5% palladium-carbon (with 10% moisture) (3.1 g), tetrahydrofuran (100 ml) were added in an autoclave and reacted for 4 hours at room temperature under 4 atm of hydrogen. The reaction solution was filtrated with celite, and the filtrate was concentrated. Then, 7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]phenyl]-1,2,8-trifluoronaphthalene (9 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:20][CH2:19][CH2:18][CH2:17][C:8]=2[S:9][C:10]=1[NH:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2]>C1(C)C=CC=CC=1.O=[Mn]=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[NH:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(NC(=O)C2CC2)sc2c1CCCC2
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(NC(=O)C2CC2)sc2ccccc12
Temperature: 60 °C
Yield: 72 %

Procedure:
8.00 g MnO2 (Activated, Fluka) was added to the suspension of 10 millimol VI in 60 milliliter toluene, and the suspension was stirred at reflux temperature for 5 days. The reaction mixture cooled down to 60° C., filtrated, and evaporated to give the desired compound VII as solid crystal.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][N:16]=2.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]=1F.[K].O>CN(C)C(=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]=1[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[CH:17][N:16]=2
Reactant: CS(=O)(=O)c1cccc(F)c1F
Reactant: Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CS(=O)(=O)c1cccc(F)c1Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
(6-Hydroxy-quinazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine (100 mg; 0.34 mmol) and 116 mg (0.61 mmol) of 1,2-difluoro-3-methanesulfonylbenzene were added to a solution of 120 mg (0.61 mmol) of tert-buxoty potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a thin layer silica gel chromatography (chloroform:methanol=10:1) to give 81 mg (yield: 51%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol) in DMF (11.7 mL) at 0° C. was added 1 M solution of NaHMDS in THF (7.48 mL, 7.48 mmol) slowly over 2 min. The reaction mixture was stirred for 10 min and then the cooling bath was removed. After 30 min a solution of methyl 3-(bromomethyl)benzoate (1.71 g, 7.48 mmol) in DMF (1.9 mL) was added slowly, and the resulting mixture was stirred at room temperature overnight. At the conclusion of this period, the reaction mixture was quenched with saturated aq ammonium chloride (˜1 mL), and partitioned between diethyl ether and water. The resulting mixture was stirred vigorously for 15 min. After this time, the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-60% ethyl acetate:hexanes) to afford the title compound (1.59 g, 79%). LCMS, [M+H]+=295.0. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=7.1 Hz, 1H), 7.94 (s, 1H), 7.50 (s, 1H), 7.47-7.36 (m, 3H), 5.31 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[CH:25]=[C:26]([C:33](O)=[O:34])[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=12>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]3=[N:24][CH:25]=2)=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnc3ccccn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Imidazo[1,2-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=472.3.
Reaction SMILES: C(O[CH2:5][O:6][CH:7]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.[I:26][C:27]1[C:28](=[O:34])[NH:29][C:30](=[O:33])[NH:31][CH:32]=1.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:19]([O:18][CH2:17][CH:7]([O:6][CH2:5][N:31]1[CH:32]=[C:27]([I:26])[C:28](=[O:34])[NH:29][C:30]1=[O:33])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)OCOC(COCc1ccccc1)COCc1ccccc1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(=O)n(COC(COCc2ccccc2)COCc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a suspension of 2-O-(acetoxymethyl)-1,3-di-O-benzylglycerol (44; prepared according to Martin J. C., Dvorak C. A., Smee D. F., Matthews T. R., Verheyden J. P. H. (1983) 9-[(1,3-Dihydroxy-2-propoxy)methyl]quanine: a new potent and selective antiherpes agent, J. Med. Chem. 26, 759-761) (2.038 g, 5.9 mmol) and 5-iodouracil (2.106 g, 8.85 mmol) in anhydrous CH2Cl2 (25 mL) at room temperature was added N,O-bis-(trimethylsilyl)acetamide (BSA, 5.46 mL, 22.13 mmol), and the mixture was stirred at room temperature under nitrogen for 2 h. The resulting clear solution was cooled to 0° C., and SnCl4 (1 M solution in CH2Cl2, 5.9 mL, 5.9 mmol) was added. The mixture was stirred at room temperature overnight, and then poured into a mixture of saturated aqueous NaHCO3 and CHCl3. The aqueous layer was extracted with CHCl3, and the combined organic phase was evaporated. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (97:3) to give the title compound 45 as a yellow oil (2.935 g, 95%). 1H NMR (CDCl3) δ 8.59 (s, 1H, NH), 7.82 (s, 1H, H-6), 7.36-7.26 (m, 10H, arom.), 5.28 (s, 2H, CH2N), 4.50 (s, 4H, 2 CH2), 3.99 (m, 1H, CHO), 3.52 (m, 4H, 2 CH2O).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]([NH2:30])=[NH:29].[OH-].[Na+]>COCCO>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]1[N:30]=[C:8]([C:3]2[S:4][C:5]([CH3:7])=[N:6][C:2]=2[CH3:1])[CH:9]=[CH:10][N:29]=1
Reactant: N=C(N)Nc1ccc(F)cc1F
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(F)cc3F)n2)s1
Yield: 78.5 %

Procedure:
A mixture of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (1.0 mmol, 0.21 g) and N-(2,4-difluoro-phenyl)-guanidine nitrate (2 mmol, 0.47 g) in 2-methoxyethanol (5 mL) was treated with NaOH (40 mg). After 24 h refluxing under N2 the solvent was evaporated to dryness and the residue was purified by flash chromatography (EtOAc/PE, 2:1) and recrystallisation from EtOAc/PE to afford the title compound as a brown powder (250 mg, 79%). 1H-NMR (300 MHz, CDCl3) δ 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 6.93 (d, 1H, J=5.3 Hz, pyrimidinyl-H), 7.01 (m, 2H, Ph-H), 7.58 (m, 2H, Ph-H), 8.40 (d, 1H, J=5.3 Hz, pyrimidinyl-H).
Reaction SMILES: [NH:1]1[CH:5]([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][C:2]1=[O:14].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:22]1[CH2:23][CH2:24][N:19]([C:17]([CH2:16][N:11]2[CH2:10][CH2:9][N:8]([C:6]([CH:5]3[NH:1][C:2](=[O:14])[CH2:3][CH2:4]3)=[O:7])[CH2:13][CH2:12]2)=[O:18])[CH2:20][CH2:21]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C1CCC(C(=O)N2CCNCC2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)N1
Yield: 93.7 %

Procedure:
1-(2-Pyrrolidone-5-carbonyl)piperazine (3.7 g), 3.7 g of 4-chloroacetylmorpholine, 4.4 g of anhydrous potassium carbonate, and 20 ml of N,N-dimethylformamide were stirred at 70°-75° C. for 1 hour. The insoluble matter was removed by filtering the reaction mixture, the solvent was removed by evaporating the filtrate, and the residue was purified by a silica gel column chromatography to give 5.7 g of the product. This was recrystallized from a mixture of ethanol, ethyl acetate and diethyl ether to give 4.2 g of desired product, m.p. 167°-169° C.