Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.C([O-])([O-])=O.[K+].[K+].[CH2:35]([O:37][C:38](=[S:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH:43](Br)[CH2:44][CH2:45][CH3:46])[CH3:36]>O>[CH2:35]([O:37][C:38](=[S:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([S:3][C:1](=[O:4])[CH3:2])[CH2:44][CH2:45][CH3:46])[CH3:36]
Reactant: CCCC(Br)CCCCC(=S)OCC
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Solvent: O
Product: CCCC(CCCCC(=S)OCC)SC(C)=O
Reaction time: 10 h
Yield: 94 %

Procedure:
8.6 grams (0.113 mole) of thioacetic acid in 20 ml of water-free ethanol were neutralized to phenolphthalein with 81 ml of 10% ethanolic potash solution (0.113 mole potassium hydroxide) and 29.7 grams (0.1 mole) of 6-bromo-8-methylthiooctanoic acid ethyl ether added. The mixture was heated at reflux for 6 hours in a nitrogen atmosphere and allowed to stand for 10 hours at room temperature. The precipitated potassium bromide was filtered off, the filtrate concentrated in a vacuum, the residue taken up in 300 ml of diethyl ether and filtered, the filtrate was washed twice, each time with 100 ml of water, dried with sodium sulfate and concentrated in a vacuum. There were obtained 26 grams (89% of theory) of crude 6-acetylthio-8-methylthiooctanoic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:11][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[C:9]=2[CH3:10])=[CH:21][CH:22]=1)[CH3:28]
Reactant: Cc1c(O)ccc(C=O)c1O
Reactant: CCOc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(COc2ccc(C=O)c(O)c2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.9 %

Procedure:
To a solution of 2,4-dihydroxy-3-methylbenzaldehyde (1.00 g, 6.57 mmol) in DMF (20 mL) were added potassium carbonate (1.36 g, 9.86 mmol) and 1-(chloromethyl)-4-ethoxybenzene (1.23 g, 7.23 mmol), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 3:2) to give the title compound (336 mg, yield 18%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][S:23]([C:26]1[C:27]([CH3:32])=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[C:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].C(=O)(O)[O-].[Na+:37].O1CCOCC1>[Pd].O>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][S:23]([C:26]1[C:27]([CH3:32])=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:37]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)[O-])N2C(=O)C(C(C)O)C2C1
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (30 mg), 10% palladium on charcoal (30 mg), sodium bicarbonate (6 mg), dioxane (3 ml) and water (1 ml) is hydrogenated at 40 psi for 30 mins. The mixture is filtered to remove the catalyst which is washed with water (3×3 ml) The combined filtrate is extracted with ethylacetate (3×2 ml), concentrated in vacuo to ca. 2 ml, and lyophilized to give sodium 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]([CH3:35])[C@@H:8]([NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=1)[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[N:12][N:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:11]2[O:10][C:9]([C@H:8]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([C:31]([F:32])([F:34])[F:33])[CH:24]=3)[C@H:7]([OH:6])[CH3:35])=[N:13][N:12]=2)=[CH:19][CH:18]=1)#[N:21]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a pre-cooled (−55° C.) solution of 4-((1R,2R)-2-(tert-butyldimethyl-silyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-(trifluoromethyl)benzo-nitrile (790 mg, 1.50 mmol) in THF (100 mL) was added TBAF (1.80 mL, 1.80 mind, 1 M solution in THF) over 10 min. Upon complete addition the reaction mixture was allowed to warm to 0° C. over 1 h, then stirred at 0° C. for a further 30 min and quenched with sat. aq. NH4Cl (100 mL). The resulting mixture was partitioned between H2O (50 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (150 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (50-80% EtOAc in hexanes) to provided the title compound as a colourless amorphous solid (610 mg, 98%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.20 (dm, J=8.8 Hz, 2H), 8.00 (dm, J=8.8 Hz, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.17 (dd, J=2.5, 8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.17 (dd, J=5.7, 8.8 Hz, 1H), 4.45 (pentet, J=6.1 Hz, 1H), 1.42 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][OH:11])[C:5]([F:16])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:11][CH2:10][C@@H:9]([NH:8][C:6]1[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:12]([CH3:13])([CH3:15])[CH3:14])(=[O:27])=[O:26]
Reactant: CC(C)(C)[C@@H](CO)Nc1nc(Cl)ncc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol, 14a, (1.95 g, 7.87 mmol) and triethylamine (1.37 mL, 9.84 mmol) in dichloromethane (25 mL) was added methanesulfonyl chloride (0.76 mL, 9.84 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (50 mL) were added. The organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to afford 2.55 g of the desired product as a pale yellow foamy solid: LC/MS (10-90% ACN/water 5 min with 0.9% FA, C4) m/z 326.99 (M+H) RT=2.96 minutes.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=[O:25].O>CCCCCC.C1(C)C=CC=CC=1>[CH3:18][C:8]1[CH:9]=[C:10]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]2=[N:12][C:7]=1[CH:24]([C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)[OH:25]
Reactant: O=Cc1cccs1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(nc1C(O)c1cccs1)CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 ml) in toluene (20 ml) at -70° C., under nitrogen, was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyridine (6 g 0.025 m) and the mixture kept at -20° C. for 0.25 hours. This was blown over into a solution of 2-thiophenecarboxaldehyde (3.0 g) in toluene (30 ml) kept at -20° C., then allowed to warm to room temperature and water added. The organic phase was extracted with 2N hydrochloric acid, then basified with solid potassium carbonate and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and evaporated. The residue was recrystallised from n-hexane to give the title compound (4.42 g), m.p. 102°-4° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].[Cl:20]Cl.O>C(O)(=O)C>[Cl:1][CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4]
Reactant: O=C(CCl)N1CC(c2ccccc2)c2ccccc21
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCl)N1CC(c2ccccc2)c2cc(Cl)ccc21
Temperature: 15 °C

Procedure:
2.7 G of N-chloracetyl-3-phenylindoline was added with vigorous stirring to a solution of 0.77 g of chlorine in 10 ml of glacial acetic acid which had been cooled to 15° C. The temperature of the mixture which rose to 33° C. was cooled down to room temperature and the mixture stirred for a further hour. The resulting solution was poured into 100 ml of cold water. The liquid was decanted from the gummy residue, which was subsequently crystallized from ethanol to give 1.9 g of crystalline N-chloracetyl-3-phenyl-5-chloroindoline having a melting point of 107°-9° C.
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)=[C:9]([C:21]3[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[S:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:27][C:24]1[N:23]=[CH:22][C:21]([C:9]2[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH:16]2[CH2:20][CH2:19][N:18]([C:34]([C:32]3[S:33][C:29]([CH3:28])=[CH:30][CH:31]=3)=[O:35])[CH2:17]2)=[CH:26][N:25]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)nc3c2ncn3C2CCNC2)cn1
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC(n3cnc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)C2)s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 36.6 %

Procedure:
To a solution of 5-(2-morpholin-4-yl-9-pyrrolidin-3-yl-9H-purin-6-yl)-pyrimidin-2-ylamine (37 mg, 0.08 mmol) in DMF was added 5-methyl-thiophene-2-carboxylic acid (15 mg, 0.104 mmol, 1.3 eq), EDC (20 mg, 0.104 mmol, 1.3 eq), HOBt (14 mg, 0.104 mmol, 1.3 eq) and diisopropylethylamine (32 μL, 0.184 mmol, 2.3 eq). The mixture was stirred at 50° C. for 16 hrs. Then NaHCO3 was added and the mixture extracted twice with ethyl acetate. The combined organic layers were further washed with brine before drying over Na2SO4. The crude product was purified by chromatography to afford the title compound as yellow solid (14.4 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[C:7]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:6]=2.[CH2:33]([O:35][CH2:36][C:37](Cl)=O)[CH3:34].C(N(CC)CC)C>ClCCl.C(O)C>[CH2:26]([O:25][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:34]([CH2:33][O:35][CH2:36][CH3:37])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
tert-Butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (28.1 g, 64.3 mmol) was dissolved in dichloromethane (319 mL). Ethoxyacetyl chloride (7.87 g, 64.5 mmol) was added dropwise via an addition funnel and the mixture was stirred for 1 hour. The dichloromethane was removed under reduced pressure and the resulting residue was dissolved in a solution of triethylamine (35.84 mL, 0.26 mol) and ethanol (319 mL). The reaction was heated at reflux for 4 hours, and then allowed to cool overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic fraction was washed sequentially with water and saturated aqueous sodium chloride; dried over anhydrous sodium sulfate; filtered; and concentrated under reduced pressure. The oily residue was dissolved in acetonitrile. The acetonitrile was subsequently removed under reduced pressure to provide 30 g of tert-butyl [4-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)cc1C
Yield: 47.1 %

Procedure:
A solution of 24 g of 2-methylanisole, 35 g of N-bromosuccinimide and 1.24 g of dibenzoyl peroxide in 150 ml of carbon tetrachloride was heated to boiling under reflux for 12 hours. After cooling the solution was filtered and the filtrate is evaporated. The residue was recrystallized from hexane. There were obtained 18.6 g (47%) of 4-bromo-2-methylanisole as a colorless solid; m.p. 66°-68°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([CH:13]=[CH2:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[CH3:19][N:20]1[CH:26]2[CH2:27][CH2:28][CH:21]1[CH2:22][NH:23][CH2:24][CH2:25]2>>[CH:13]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:23]3[CH2:24][CH2:25][CH:26]4[N:20]([CH3:19])[CH:21]([CH2:28][CH2:27]4)[CH2:22]3)[CH:10]=2)[C:5](=[O:18])[C:6]([C:15]([OH:17])=[O:16])=[CH:7]1)=[CH2:14]
Reactant: CN1C2CCNCC1CC2
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4CCC(C3)N4C)cc21
Yield: 44.7 %

Procedure:
The title compound was prepared in 44.7% yield according to example 8 by reacting 6,7-difluoro-1-vinyl-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with 9-methyl-3,9-diazabicyclo[4.2.1 ]nonane, m.p. 214°-215° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(=O)[C:47](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:46]([C:61]3C=CC(S(C)(=O)=O)=CC=3)[CH:45]=N2)C=CC=1.N>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:45][CH:46]([CH3:61])[CH3:47])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Agent: N
Solvent: O
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (prepared as an intermediate in Example 375) in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (yield: 0.486 g, 100%). mp 121-128° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=7 Hz, 6H), 1.84 (m, 1H), 3.30 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.92 (m, 2H), 8.07 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 417 (M+H)+, 434 (M+NH4)+. Anal. calc. for C21H21FN2O4S.0.50 H2O: C, 59.28; H, 5.21; N, 6.58. Found: C, 59.49; H, 4.97; N, 6.34.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:27]3([CH3:31])[C:28]([CH3:30])([CH3:29])[CH:23]([N:24]([C:32]([C:34]4[CH:42]=[CH:41][C:37]5[N:38]=[CH:39][NH:40][C:36]=5[CH:35]=4)=[O:33])[CH2:25][CH2:26]3)[CH2:22][C:21]=2[CH:43]=1.N>C(#N)C.CO>[N:38]1[C:37]2[CH:41]=[CH:42][C:34]([C:32]([N:24]3[CH2:25][CH2:26][C:27]4([CH3:31])[C:28]([CH3:30])([CH3:29])[CH:23]3[CH2:22][C:21]3[CH:43]=[C:17]([CH2:16][NH:15][C:12](=[O:14])[CH3:13])[CH:18]=[CH:19][C:20]=34)=[O:33])=[CH:35][C:36]=2[NH:40][CH:39]=1
Reactant: CC12CCN(C(=O)c3ccc4nc[nH]c4c3)C(Cc3cc(CN)ccc31)C2(C)C
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: CC(=O)NCc1ccc2c(c1)CC1N(C(=O)c3ccc4nc[nH]c4c3)CCC2(C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (38 μL) and acetic anhydride (26 μL) are added to a suspension of (9-aminomethyl-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-(3H-benzoimidazol-5-yl)-methanone (0.10 g) in acetonitrile (2 mL). The resulting mixture is stirred at ambient temperature for 1 h. Then, methanol (1 mL) and concentrated aqueous ammonia solution (0.5 mL) are added and the resulting solution is stirred for another 30 min. The solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (water/MeCN) to give the title compound as a white foam-like solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27]#[N:28])[N:25]=1>>[C:27]([CH2:26][C:24]1[N:25]=[C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[S:22][CH:23]=1)#[N:28]
Reactant: N#CCc1csc(N)n1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2nc(CC#N)cs2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using (2-Amino-thiazol-4-yl)-acetonitrile instead of 3-Chloroaniline to yield the final compound as a light yellow solid, MS (ISP): m/e=354.1 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)[CH3:15])[N:13]=1)([C:3]([O:5]CC)=O)=[O:2].O.[NH3:30]>C(O)C>[C:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([F:28])[CH:17]=2)[CH3:15])[N:13]=1)(=[O:2])[C:3]([NH2:30])=[O:5]
Reactant: CCOC(=O)C(=O)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Reactant: N
Solvent: CCO
Solvent: O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=O)C(N)=O)n1
Yield: 26 %

Procedure:
To 2-ethoxalylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g, 1.29 mmol) in ethanol (10 ml) was added ammonia water (2 ml). After the addition, the mixture was refluxed for 2 h, evaporated under reduced pressure to a residue, which was extracted with chloroform. The extracts were dried over and evaporated under reduced pressure to residue, which was chromatographed to afford 2-oxamoylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.121 g, 26% yield) as crystalline material: mp 179.0°-180.0° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([C:13]3[N:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:10]3[N:19]=[C:20]([NH2:22])[N:21]=[C:9]3[CH:8]=2)[CH:2]=1.S([N:33]=[C:34]=[O:35])(C1C=CC(C)=CC=1)(=O)=O.[CH2:36](N)[CH3:37]>CN(C=O)C.C1COCC1>[CH2:36]([NH:33][C:34]([NH:22][C:20]1[N:21]=[C:9]2[CH:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:12]=[C:11]([C:13]3[N:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:10]2[N:19]=1)=[O:35])[CH3:37]
Reactant: Nc1nc2cc(-c3cccnc3)cc(-c3ncccn3)n2n1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ncccn3)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A warmed suspension of the product of Step 1 (330 mg, 1.14 mmol) in DMF (10 mL) was treated with TosNCO (0.43 mL, 2.9 mmol). The mixture was stirred at room temperature for 1 h. EtNH2 (14 mL of a 2 M solution in THF) was added all at once and the suspension was heated in the microwave at 100° C. for 12 min. On cooling to 0° C. for 1 h, the precipitated solid 1-ethyl-3-(7-pyridin-3-yl-5-pyrimidin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-urea was collected by filtration, washed with MeOH and dried in vacuo at 80° C. for 2 h. MS m/z 361 (M+H+).
Reaction SMILES: C([Li])CCC.CCCCCC.[S:12]1[CH:16]=[CH:15][N:14]2[CH:17]=[N:18][CH:19]=[C:13]12.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:20][Si:21]([CH3:23])([CH3:22])[C:16]1[S:12][C:13]2=[CH:19][N:18]=[CH:17][N:14]2[CH:15]=1
Reactant: c1cn2cncc2s1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cn2cncc2s1
Reaction time: 0.5 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (16.7 ml) was added in an argon atmosphere at −50° C. to a solution of 3.17 g of imidazo[5,1-b]thiazole in 120 ml of dry THF. The mixture was stirred at the same temperature for 30 min. Trimethylsilyl chloride (3.54 ml) was added thereto, and the mixture was stirred for 20 min. A 1.6 N n-butyllithium/n-hexane solution (8.0 ml) was added thereto, and the mixture was stirred for 20 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was then added thereto, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 4.53 g of 2-(trimethylsilyl)imidazo[5,1-b]thiazole.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[N+:5]([C:8]1[CH:9]=[C:10]([Br:15])[CH:11]=[CH:12][C:13]=1[F:14])([O-])=O>C1COCC1>[Br:15][C:10]1[CH:11]=[CH:12][C:13]([F:14])=[C:8]2[C:9]=1[CH:1]=[CH:2][NH:5]2
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2cc[nH]c12
Reaction time: 1 h
Yield: 23.4 %

Procedure:
At −40° C., vinylmagnesium bromide (300 mL of 1.0M solution in THF, 300 mmol) was added dropwise to a solution of 3-nitro-4-fluoro-bromobenzene (22 g, 100 mmol) in THF (700 mL). After 1 h at −40° C., the mixture was quenched by aqueous NH4Cl solution and extracted by EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column chromatography affording 4-bromo-7-fluoro-1H-indole (5 g, 23.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[B:13]1(B2OC(C)(C)C(C)(C)O2)[O:17]C(C)(C)C(C)(C)[O:14]1.C([O-])(=O)C.[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([B:13]([OH:17])[OH:14])=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1ncc(Br)cc1C(F)(F)F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncc(B(O)O)cc1C(F)(F)F

Procedure:
5-bromo-3-(trifluoromethyl)pyridin-2-amine (9.85 mmol, commercially available), Bis(pinacolato)diboron (11.82 mmol), potassium acetate (1.4 g) and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) complex with DCM (200 mg, commercially available) was dissolved in dioxane (75 mL) under argon atmosphere. The reaction mixture was refluxed for 8 h. The reaction mixture was cooled, diluted with ethyl acetate (75 mL) and filtered. The filtrate was concentrated. The crude product was purified over silica gel using 0-10% ethyl acetate in petroleum ether to obtain the titled boronic acid derivative.