Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:29][C:30]1[CH:31]=[C:32]([NH2:38])[CH:33]=[C:34]([Cl:37])[C:35]=1[F:36]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:38][C:32]1[CH:31]=[C:30]([Cl:29])[C:35]([F:36])=[C:34]([Cl:37])[CH:33]=1)[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(Cl)c(F)c(Cl)c1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−20° C.) solution of (R)-2-tert-butoxycarbonylamino-propionic acid (57.2 g, 302 mmol) in anhydrous THF (582 mL) was added N-methyl-morpholine (34.9 mL, 317 mmol) at a rate to keep the internal temperature at −15° C. Isobutyl chloroformate (42.0 mL, 317 mmol) was then added over a 20 min period and the resulting mixture was stirred for 30 min. A solution of 3,5-dichloro-4-fluoro-phenylamine (54.4 g, 302 mmol) in THF (160 mL) was then added over 40 min. The reaction mixture was warmed to 20° C. and stirred for 20 h. The reaction mixture was filtered and concentrated in vacuo. To the resulting oil was added MeOH (200 mL) and the solution was concentrated to provide the title compound as a tan colored solid, m/z 295.3 [M−t-Bu]+. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=[C:12]([O:22]C)[CH:11]=2)[CH:3]=1.Br.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:14][NH:13][C:12](=[O:22])[CH:11]=2)[CH:3]=1
Reactant: COc1cc(-c2cc(Cl)ccc2C#N)c(OCC(F)(F)F)cn1
Agent: Br
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1OCC(F)(F)F

Procedure:
168 mg (0.47 mmol) of 4-chloro-2-[2-methoxy-5-(2,2,2-trifluoroethoxy)pyridin-4-yl]benzonitrile and pyridinium hydrobromide were reacted according to General Method 3A. Yield: 112 mg (purity 92%, 67% of theory)
Reaction SMILES: [Li].[S:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[CH:4]=[CH:3]1.[O:14]([C:21]1[S:25][C:24]([CH2:26][NH2:27])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[O:14]([C:21]1[S:25][C:24]([CH2:26][NH:27][C:11]([C:9]2[CH:10]=[C:5]3[CH:4]=[CH:3][S:2][C:6]3=[N:7][CH:8]=2)=[O:13])=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCc1ccc(Oc2ccccc2)s1
Reactant: O=C(O)c1cnc2sccc2c1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Oc2ccccc2)s1)c1cnc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Then, the lithium salt of the resulting thieno[2,3-b]pyridine-5-carboxylic acid, C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation Example 26 (4.7 mg, 23 μmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (14 mg, 32 μmol) and triethylamine (9 μl, 63 μmol) were dissolved in N,N-dimethylformamide (0.5 mL), and the solution was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution, the organic layer was partitioned, and washed with brine. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (3.0 mg, 8.2 μmol, 40%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.O.O.[F:23][C:24]([F:32])([F:31])[C:25]([C:27]([F:30])([F:29])[F:28])=[O:26]>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:25]([C:27]([F:30])([F:29])[F:28])([C:24]([F:32])([F:31])[F:23])[OH:26])[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(-c2cc[nH]c2-c2ccc(Cl)cc2)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: OC(c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1)(C(F)(F)F)C(F)(F)F
Yield: 83.7 %

Procedure:
A mixture of 2.9 g (0.01 mole) of 2,3-bis(4-chlorophenyl)-1H-pyrrole and 2.5 g (0.011 mole) of hexafluoroacetone trihydrate in 50 ml toluene was heated at reflux overnight. The mixture was concentrated on a rotary evaporation and the solid residue was chromatographed on 200 g silica gel (eluting with toluene), then recrystallized from hexane to give 3.8 g of product, m.p. 144°-145° C.
Reaction SMILES: [CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@:14]4([O:19][C@@H]5O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]5O[C@@H]5O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:43]([O-:45])=[O:44])([CH3:42])[CH2:5][CH2:4][CH2:3]2)=[CH2:17].[Na+].[K].P([O-])([O-])([O-])=O.SC[C@H]([C@@H](CS)O)O.O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>OP([O-])(O)=O.[K+].CC#N.C(Cl)(Cl)Cl.CO.O>[CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@:14]4([OH:19])[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:43]([OH:45])=[O:44])([CH3:42])[CH2:5][CH2:4][CH2:3]2)=[CH2:17]
Reactant: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)[O-])[C@@H]2CC[C@]1(O[C@@H]1O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]1O[C@@H]1O[C@@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)C3
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])[O-]
Agent: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: CO
Solvent: CC#N
Product: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]2CC[C@]1(O)C3

Procedure:
Steviolbioside, 3-sulfopropyl ester, potassium salt prepared in Part B. was incubated anaerobically for three days at 37° C. with 5 wt% fresh rat cecal contents, at concentrations of 0.25, 0.5, and 1.0 mg/ml in sterile Krebs-Ringer 0.25M phosphate buffer (pH 7.4) containing 0.25 mg/ml dithiothreitol and 0.25 mg/ml α-D-glucose. TLC [silica gel F-254; CHCl3 :CH3OH:H2O (15:10:2)] and HPLC [30 cm C-18 on μ-Bondapak; 15 min linear gradient of 10-40% CH3CN in 0.005M KH2PO4 (pH 3.45); 200 nm] analysis showed all the initial ester (Rf=0.42; tR =14.0 min) to have been consumed within 24 h to yield apparently only the sulfopropyl ester of steviol, (Rf =0.63; tR =16.3 min). No steviol (Rf =0.95; tR =31.3 min) was detected. After 3 days the bacterial cells were sedimented by centrifugation. The sediment was extracted (THF), as was the supernatant, after lyophilization. HPLC analysis for steviol of the two THF extracts showed none to be detectable. With a detection limit of 0.05 g, as little as 0.03 and 0.13 percent degradation to steviol could have been detected for the sediment and supernatant fractions, respectively.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: Cc1nc(Br)c([N+](=O)[O-])c(=O)[nH]1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1

Procedure:
In analogy to the procedure described in example 1, the 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one (as prepared in Eur. Pat. Appl. EP 1 074 549 A2) was treated with the 1-phenylpiperazine in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield the 2-methyl-5-nitro-6-(4-phenyl-piperazin-1-yl)-3H-pyrimidin-4-one as yellow solid; m.p.>250° C. (decomposition); MS: [M−H]−=314.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([OH:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.Cl[CH2:24][O:25][CH3:26]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([O:13][CH2:24][O:25][CH3:26])([CH3:11])[CH3:12]
Reactant: Cc1cc(F)c(C(C)(C)O)c(Br)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(C)(C)c1c(F)cc(C)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
To a solution of 2-(2-bromo-6-fluoro-4-methylphenyl)propan-2-ol (12 g, 48.56 mmol) in DCM (120 mL) and diisopropylethylamine (6.9 g, 53.42 mmol) in DCM (120 mL) was added dropwise chloromethylmethylether (4.3 g, 53.42 mmol) at 0° C. under argon and the mixture was then stirred at rt for 15 h. The reaction mixture was quenched with water and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (20:1) to give 1-bromo-3-fluoro-2-(2-(methoxymethoxy)propan-2-yl)-5-methylbenzene (10 g, 70.73% yield) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.22 (s, 1H), 6.71-6.75 (m, 1H), 4.54 (s, 2H), 3.33 (s, 3H), 2.20 (s, 3H), 1.72 (d, J=5.2 Hz, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:15]>C(O)C>[N:16]1([C:14]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[O:15])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2nccc(N)c2c1
Solvent: CCO
Product: COc1ccc2nccc(NC(=O)n3ccnc3)c2c1
Reaction time: 1 h

Procedure:
A suspension of 4-amino-6-methoxyquinoline (406a) (2.0 g, 11 mmol) in ethanol-free chloroform (60 ml) was treated with 4-N,N-dimethylaminopyridine (1.4 g, 11.4 mmol) and 1,1′-carbonyl diimidazole (2.6 g, 15.9 mmol). The suspension became clear over 1 hour then precipitation occurred. After a further 2 hours, filtration afforded the product as a white solid which was dried in vacuo (1.8 g, 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13](Br)[CH:12]2[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]1[O:22][CH:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Oc2ccc(OCc3ccccc3)cc2C(O)C1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(OCc3ccccc3)cc2C2OC21
Yield: 103.2 %

Procedure:
A solution of 9.5 g (28.5 mmol) of 6-benzyloxy-3-bromo-2,2-dimethyl-chroman-4-ol in 100 ml of THF was stirred overnight with 4.6 g (82 mmol) of potassium hydroxide powder. The batch was subsequently filtered through Celite and the filtrate was concentrated using a rotary evaporator, giving 8.3 g of 6-benzyloxy-2,2-dimethyl-3,4-epoxychroman, m.p. 70-72° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[CH3:17][N:18]1[CH2:25][CH:24]2[C:26](=O)[CH:20]([C@H:21]([CH3:29])[CH2:22][C@H:23]2[CH3:28])[CH2:19]1.C(OCC)(=O)C>O1CCCC1>[CH3:17][N:18]1[CH2:25][CH:24]2[C:26](=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:20]([C@H:21]([CH3:29])[CH2:22][C@H:23]2[CH3:28])[CH2:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: C[C@@H]1C[C@@H](C)C2CN(C)CC1C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C2CN(C)CC1[C@H](C)C[C@H]2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
To a solution of 130 g of triethyl phosphono acetate in tetrahydrofuran (600 ml) was added 25 g of sodium hydride (oily: 60% or above) under ice-cooling and the resulting mixture was stirred at room temperature for 10 minutes. Then a solution of 70 g of the crude (6R*,8R*)-3,6,8-trimethyl-3-azabicyclo[3.3.1]nonan-9-one in tetrahydrofuran (300 ml) was added thereto and the reaction mixture was heated under reflux for 2 hours. After adding ethyl acetate, the reaction mixture was washed twice with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 31.5 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12][C:13](=N)N)[N:6]=1.BrC[CH2:18][CH2:19][Cl:20]>O>[Cl:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:7]1[N:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: N=C(N)SCc1cccnn1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1cccnn1
Temperature: 75 °C
Reaction time: 15 h
Yield: 67.5 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (84 cc) is added dropwise, in the course of 10 minutes and whilst keeping the temperature below 18° C., to a solution of 2-(pyridazin-3-ylmethyl)-isothiourea dihydrochloride (106 g) in distilled water (220 cc). After heating for 20 minutes at 75° C. and then cooling to 10° C., a 10 N aqueous solution of sodium hydroxide (50 cc) and then 1-bromo-3-chloropropane (69 g) are added, whilst stirring, and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (340 cc in total). The organic extracts are combined, washed with distilled water (250 cc) and dried over anhydrous sodium sulphate. After filtration, the solution obtained is poured onto neutral silica gel (80 g) contained in a column of diameter 2.7 cm; the column is then eluted with methylene chloride (700 cc). The first fraction (200 cc) is discarded. The second fraction (500 cc) is collected and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Pyridazin-3-ylmethyl 3-chloropropyl sulphide (60 g) is thus obtained in the form of a red oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:12].N([O-])=O.[Na+].[BrH:18]>O.[Cu]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:18])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Reactant: Br
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(Cl)cc(Br)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
4-Amino-2,6-dichlorobenzoic acid methyl ester (1.00 g) was suspended in 40% aq. HBr and the mixture was cooled lto 0-5° C. After NaNO2 (376 mg) was added in small portions, the mixture was stirred for about 5 min. Copper (100 mg) was added and the mixture was warmed up to 100° C. The mixture was then stirred at 100° C. for 30 min, diluted with water and extracted with AcOEt. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane and AcOEt 50:1) to give 4-bromo-2,6-dichlorobenzoic acid methyl ester (1.07 g).
Reaction SMILES: CCCCCC.C([Li])CCC.C([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)C1C=CC=CC=1.[F:27][CH:28]([F:38])[O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.Cl>C1COCC1.CO.[OH-].[Pd+2].[OH-].O>[F:27][CH:28]([F:38])[O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[OH:19])=[CH:32][CH:31]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccccc1Cc1ccc(OC(F)F)cc1
Reaction time: 0.5 h
Yield: 221.3 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.71 M, 3.8 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.5 g, 9.5 mmol) in THF (90 mL) at −78° C. and the mixture solution was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-difluoromethoxybenzaldehyde (1.23 mL, 1.86 mmol) in THF (30 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure and the obtained residue was treated by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain a crude product. To a solution of the obtained crude product in methanol (26.8 mL), a 20% palladium hydroxide catalyst (147 mg) was added and furthermore concentrated hydrochloric acid (0.4 mL) was added thereto. The mixture solution was stirred under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (1.03 g, 42%).
Reaction SMILES: O.C([O-])(=O)C.[K+].[F:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1>CC#N>[F:7][C:8]1[C:13]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Nc1cc(-c2cccnc2F)ccn1
Temperature: 85 °C

Procedure:
A pressure vessel was charged with 6.35 mL of water and degassed with nitrogen for 0.5 h. To this vessel was added potassium acetate (2.31 g, 23.5 mmol), 2-fluoropyridine-3-boronic acid (2.48 g, 17.6 mmol), 4-chloropyridin-2-amine (1.51 g, 11.7 mmol), dichloro-bis(di-tert-butylphenylphosphino)Pd(II) (0.146 g, 0.235 mmol) and 58.5 mL CH3CN. The mixture was purged under nitrogen for several additional minutes, and the pressure bottle was sealed. The reaction mixture was heated to 85° C. for 15 h. Upon cooling the layers were separated, and the organic portion was dried with Na2SO4 and concentrated. The resulting solid was triturated with ethyl acetate/diethyl ether to provide 4-(2-fluoropyridin-3-yl)pyridin-2-amine as a tan solid. MS m/z=190 [M+H]+. Calc'd for C10H8FN3: 189.19.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[C:28]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (0.7 g) and triethylamine (1 ml), and benzoyl chloride (0.3 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[CH2:21]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[C:11]([S:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:29])=[O:2])=[C:12]1[CH3:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Br)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Br)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1-Benzyl-6-bromo-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.040 g, 0.086 mmol) was dissolved in THF:MeOH (1:1) then LiOH (1M aq.) was added and the reaction stirred at room temperature overnight. Acid-base extraction afforded the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH2:16][C:15]([C:21]([OH:23])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:21]([C:15]3[CH2:16][O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([Cl:10])=[CH:20][CH:19]=4)=[O:23])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2OC1
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)C1=Cc2cc(Cl)ccc2OC1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
DIEA (45.5 μL, 0.26 mmol) was added to 6-chloro-2H-chromene-3-carboxylic acid (50.0 mg, 0.24 mmol) and HATU (99.3 mg, 0.26 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (49.7 mg, 0.24 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 66.6 mg of product in 69% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CS(C)=O.[Cu]I>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Nc1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccccc3)nc12
Temperature: 90 °C
Reaction time: 120 h
Yield: 48 %

Procedure:
A mixture of 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.206 g, 0.50 mmol), potassium carbonate (0.152 g, 1.10 mmol), copper (I) iodide (0.014 g, 0.075 mmol), proline (0.017 g, 0.15 mmol) and aniline (0.46 mL, 5 mmol) in 1 mL of dimethylsulfoxide was stirred at 90° C. for 5 d, then allowed to cool. The mixture was partitioned between 50 mL of ethyl acetate and 30 mL of water, and the organic layer was washed with 30 mL of a sat. aq. NaCl solution, dried over MgSO4, and concentrated to a residue. Column chromatography (0→45% EtOAc/hexanes) afforded 0.102 g (48%) of 2,2-dimethyl-1-[2-phenylamino-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a pale orange solid.
Reaction SMILES: ClC1N=CC=C[C:3]=1[C:4]([O:6][CH3:7])=O.[C:12](=[O:15])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:7]1[O:6][CH2:4][CH2:3][O:15][CH2:12][CH2:7][O:6][CH2:4][CH2:3][O:15][CH2:12][CH2:7][O:6][CH2:4][CH2:3][O:15][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccnc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: C1COCCOCCOCCOCCOCCO1

Procedure:
3.4 g of methyl 2-chloronicotinate were reacted with 3.4 g of 4-piperidinopideridine in 75 ml of DMF in the presence of 5.5 g of potassium carbonate and a spatula tipful of 18-crown-6 analogously to Example 1a, 5.9 g (97%) of the product being obtained.