Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[N:19](S(C5C=CC(C)=CC=5)(=O)=O)[N:20]=[CH:21][CH:22]=4)=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)O1.Br[C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50]([NH2:52])=[O:51].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[N:20]1[NH:19][C:18]([C:17]2[C:11]3[C:12](=[N:13][CH:14]=[C:9]([C:45]4[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=4)[C:50]([NH2:52])=[O:51])[CH:10]=3)[NH:15][CH:16]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2nccc2-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)cc1
Reactant: NC(=O)c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)c1cncc(-c2cnc3[nH]cc(-c4ccn[nH]4)c3c2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
To a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-3-[2-(toluene-4-sulfonyl)-2H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (56 mg, 0.09 mmol) in a 1:1 acetonitrile/saturated aqueous NaHCO3 solution (2 mL total) in a microwave vial was added 5-bromonicotinamide (20 mg, 0.10 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (3.7 mg, 0.004 mmol). The vial was capped, flushed with N2, evacuated under vacuum, and heated in a microwave at 90° C. for 1800 seconds. The product was extracted into ethyl acetate and the organic layer was dried, over Na2SO4. The solution was filtered and concentrated under vacuum. The residue was redissolved in a 1:1 MeOH/acetone solution (2 mL, total) and treated with 200 uL of 50% KOH (aq) solution and stirred at ambient temperature for 1 hour. Citric acid (1M) was added dropwise until pH=7 and the product was extracted into ethyl acetate. The organic layer was dried over Na2SO4, filtered, and adsorbed onto silica gel. The material was purified by flash chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexane then concentrated under vacuum. The residue was titrated with diethyl ether to afford the title compound as a beige solid (0.8 mg, 3% yield). 1H NMR (500 MHz, d6-DMSO) δ 12.6 (s, 1H), 11.8 (s, 1H), 8.95 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.25 (s; 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.41 (d. J=7.5 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H). MS: m/z 305.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](C)Nc1ccc(F)c(F)c1F

Procedure:
(2S)-2-(2,3,4-trifluoroanilino)propionic acid (219 mg; 99% ee) was dissolved in ethanol (2 ml) and hydrochloric acid (5 mol/l; 0.2 ml) was added thereto at room temperature. The liquid reaction mixture was heated under reflux for 6 hours and then the solvent was evaporated. To the obtained residue was added chloroform. Next, the organic layer was washed with a saturated aqueous solution of sodium chloride and water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to give the title compound (246 mg) as a pale yellow oily substance. The optical purity of the product was 99% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 7.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:21][CH2:22]1
Reactant: ICC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CC4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and iodomethylcyclopentane.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:37][N:38]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]1>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: Cn1cc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(-c2c(-c3cnn(C)c3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 80 °C
Yield: 35.1 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (50 mg, 0.095 mmol), tetrakis(triphenylphosphine)palladium(0) (5.51 mg, 4.77 μmol), sodium carbonate (20.23 mg, 0.191 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (12.02 mg, 0.095 mmol) in acetonitrile (1 mL) and water (0.250 mL) was heated at 80° C. under nitrogen, overnight (ca. 18 h). The reaction mixture was then cooled to RT and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in DCM, to give the title compound (17.5 mg). LCMS (A) m/z: 525 [M+1]+, Rt 1.34 min (acidic).
Reaction SMILES: ClCCl.C[C:5]1([CH3:13])[O:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])O1.CN(C1C=CC=CN=1)C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])C(Cl)=O>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]([C:7](=[O:12])[CH2:8][C:9]([O:10][CH2:5][CH3:13])=[O:11])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: Cc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
To a dichloromethane solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10 g) and dimethylaminopyridine (17 g), a dichloromethane solution of 3-methyl-4-nitro-benzoyl chloride (14 g) was added dropwise under ice cooling. After stirring at room temperature for 3 hours and then adding 100 ml of ethanol, the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off under the reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain ethyl 3-(3-methyl-4-nitro-phenyl)-3-oxo-propionate (12.4 g). mp; 207-211° C.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was refluxed overnight in 400 ml of toluene containing 3.5 g of morpholine and 3.4 g of 4-methoxybenzaldehyde. At the end of this time, an additional 1.7 g of aldehyde was added and heating was continued for six (6) more hours. The reaction mixture was then concentrated and purified by flash chromatography (CH2Cl2, then 10% EtOAc/CH2Cl2). Fractions containing the product were concentrated and recrystallized from benzene/pentane to give 3.37 g of analytically pure material, m.p. 160°-162° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19]C(C)C)=[O:18])[CH:3]=1.[OH-].[K+]>O1CCCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1
Reactant: COc1ccc(-c2nc(C(=O)OC(C)C)cc(Cl)c2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C(=O)O)cc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a mixture of isopropyl 4,5-dichloro-6-(4-methoxyphenyl)picolinate (5.25 g, 15.4 mmol) in tetrahydrofuran (40 mL) and water (10 mL) was added potassium hydroxide (1.26 g, 22.4 mmol). The reaction mixture was allowed to stir at room temperature for 12 h. After 1 hour of stirring, solids precipitated from the mixture. HCl (aq) (2N, 25 mL) was added to the reaction mixture, and it formed a clear biphasic mixture. The mixture was added to water (75 mL) in a reparatory funnel and extracted with EtOAc (2×75 mL). The combined organic layers were washed with water (25 mL) and saturated NaCl (50 mL) and then concentrated under reduced pressure to provide 4.57 g (99% yield) of 4,5-dichloro-6-(4-methoxyphenyl)picolinic acid as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.72-7.64 (m, 2H), 7.07-6.99 (m, 2H), 3.89 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.78, 161.05, 157.26, 146.30, 143.76, 133.54, 130.98, 128.72, 123.45, 113.77, 55.48; mp=164-181° C.
Reaction SMILES: [H-].[Na+].O([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])C1C=CC=CC=1.[CH3:20][NH:21][CH2:22][C:23]1[N:24]=[C:25]([CH:28]([CH3:30])[CH3:29])[S:26][CH:27]=1>C1COCC1>[CH3:20][N:21]([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:22][C:23]1[N:24]=[C:25]([CH:28]([CH3:30])[CH3:29])[S:26][CH:27]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
To a stirred slurry of 60% oil dispersion NaH (200 mg, 5 mmol) at <5° C. in 10 mL of THF was added N-phenoxycarbonyl-L-Valine (1.0 g, 4.2 mmol) followed by a 10 mL THF rinse and keeping the temperature <5° C. using an ice-water bath. In another flask, N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (851 mg, 5 mmol) was added to a <5° C. slurry of 60% oil dispersion NaH (220 mg, 5.5 mmol) in 10 mL of THF maintaining the temperature <5° C. Both solutions were stirred for 15 minutes, and then the acid salt solution was added to the amine salt solution in one portion. The reaction was allowed to proceed at <10° C. for 1 hour and then at ambient temperature for 30 minutes. The reaction was quenched by the addition of 10 mL of MeOH, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in a minimum of EtOAc and flash chromatographed on silica gel eluting with 1:1 ethyl acetate in isopropanol. The residue obtained was further purified by preparative thin layer chromatography eluting with 33.6% CHCl3, 7.7% H2O, 3.5% HOAc, 25.2% MeOH and 30% EtOAc to afford the title compound (310 mg, 24%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (50 mL) was added 5-(3-aminophenoxy)pyridin-2-amine dihydrochloride (3.5 g, 12.7 mmol), and the mixture was stirred at room temperature for 18 hr. 5% Aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate and hexane to give the title compound (3.44 g, 66%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH:42]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 100 mg, 0.193 mmol), 3-(methanesulfonyl)phenylboronic acid (58.1 mg, 0.290 mmol), K2CO3 (80.2 mg, 0.580 mmol) and Pd(PPh3)4 (22.4 mg, 0.0193 mmol) were diluted with dioxane (2 mL) and water (1 mL). The reaction was purged three times with nitrogen and stirred at 60° C. overnight. The reaction was cooled and loaded directly onto a silica gel column eluting with hexanes:ethyl acetate (2:1) to yield ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 69.8% yield).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([Cl:26])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[C:13]([F:21])[C:14]([F:20])=[C:15]([F:19])[C:16]=2[F:18])[C:11]([CH3:30])([CH2:22][CH2:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])[CH:10]=1)([OH:3])=[O:2].C(O[C:35](=O)[CH3:36])(=O)C>C(O)(=O)C>[F:21][C:13]1[C:14]([F:20])=[C:15]([F:19])[C:16]([F:18])=[C:17]2[C:12]=1[C:11]([CH3:30])([CH2:22][CH2:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])/[C:10](=[CH:1]\[CH:4]=[CH:5]\[CH:6]=[CH:7]\[CH:8]=[N:9]\[C:35]1[CH:36]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[N:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: CC1(CCCCS(=O)(=O)O)C=[N+](CCCCCC(=O)O)c2c(F)c(F)c(F)c(F)c21
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(CCCCS(=O)(=O)O)/C(=C\C=C\C=C\C=N\c2ccccc2)N(CCCCCC(=O)O)c2c(F)c(F)c(F)c(F)c21
Temperature: 120 °C

Procedure:
To 1-(5-carboxypentyl)-4,5,6,7-tetrafluoro-3-methyl-3-(4-sulfobutyl)-3H-indolium (24 mg) was added N-[5-(phenylamino)-2,4-pentadienylidene monohydrochloride (13 mg), acetic anhydride (4 ml) and acetic acid (2 ml). This mixture was heated to 120° C. for 1 hour 45 minutes after which time it was cooled to room temperature. This crude reaction mixture (ca. 5 mg/ml product) was used without purification as further described.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3][CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][C:24]([Cl:28])=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:28][C:24]1[N:25]=[C:26]([O:8][CH2:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[C:21]([NH:20][S:17]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=2[Cl:9])(=[O:19])=[O:18])=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1cncnc1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cncnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyrimidine-5-methanol (0.035 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (0.07 g). Yield 0.015 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:30]=2[CH3:31])=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)#[N:2].[H-].[Na+].Br[CH2:42][C:43]([O:45]CC)=[O:44].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:23]([C:24]([C:26]2[CH:27]=[N:28][N:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:30]=2[CH3:31])=[O:25])[CH2:42][C:43]([OH:45])=[O:44])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(C(=O)Nc2ccc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)N(CC(=O)O)c2ccc(N3CCC(O)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 10.2 %

Procedure:
N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl) phenyl)-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide (3.3 g) and sodium hydride (60% content, 0.3 g) were reacted in dimethylformamide (30 ml) under ice-cooling for 1 h. Dimethylformamide solution (10 ml) containing ethyl bromoacetate (1.4 g) was added and the mixture was stirred under ice-cooling for 1 h and, after allowed to warm to roan temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Tetrabutylammonium fluoride (3.0 g), tetrahydrofuran (20 ml) and acetonitrile (20 ml) were added to the residue and the mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure. To the residue was added dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of toluene-ethyl acetate was added to the residue to allow crystallization. The crystals were recrystallized from hydrous isopropanol to give the title compound (0.3 g), melting point: 155–158° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([O:8][C:15](=[O:18])[CH2:16][CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Oc1cccc(F)c1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of 3-fluorophenol (22.4 g, 0.2 mol), pyridine (24 ml, 0.3 mol) and dichloromethane (200 ml) at room temperature was added 20 ml (0.225 mol) propionyl chloride over a period of 5 min. The reaction was exothermic. The solution was stirred for another 30 min. After addition of dichloromethane, the organic phase was washed with sat. NaHCO3 solution and water, dried over MgSO4 and concentrated in vacuo. 33.8 g (100%) of 3-fluoro-1-propionyloxybenzene was obtained. This compound was reacted with 33.3 g (0.25 mol) AlCl3 at 150° C. for a period of 10 min. After careful quenching with water, the reaction mixture was extracted three times with ether. The ether phase was dried (MgSO4) and evaporated to give 29.5 g (0.176 mol, 88%) rearranged product. This intermediate was dissolved in 200 ml of acetone and K2CO3 (42, 0.3 mol) and MeI (25 ml, 0.4 mol) were added. The reaction mixture was heated at 40° C. for a period of 12 h. The reaction mixture was filtered and the acetone was evaporated. The residue was dissolved in ether and the ether phase washed with a 0.5 M NaOH solution and water. Drying (MgSO4) and evaporation gave 31.2 g (0.17 mol, 86% yield for three steps) of 4-fluoro-2-methoxypropiophenone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:23]([CH3:24])[CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNC
Product: CN(C)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and Dimethylamine were converted to yield [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-dimethyl-amine as white semisolid, MS: 391 (MH+, 1Br).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:8]=1)[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)NCc1cccc(-c2ccnc(Cl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(C)(C)C
Yield: 61 %

Procedure:
tert-Butyl-[3-(2-chloro-pyrimidin-4-yl)-benzyl]-amine from the above reaction (1.33 g, 4.84 mmol) was treated with allyl chloroformate (0.77 mL) in methylene chloride (15 mL) with diisopropyl ethylamine (1.7 mL) at room temperature for 3 hours. The mixture was diluted with methylene chloride (50 mL), washed with water (2×), brine, dried over Na2SO4, filtered. Removal of the solvent followed by chromatography on silica gel (1:4 ethyl acetate:hexane eluent) afforded product in 61% yield. LC-MS showed the product had the expected M+H+ of 360. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) 8.6 (d, 1H) 7.9 (d, 2H) 7.6 (d, 1H) 7.4 (m, 2H) 5.9 (m, 1H) 5.2 (m, 2H) 4.7 (s, 2H) 4.6 (d, 2H) 1.4 (s, 9H).