Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:15]=[C:14]([CH2:16]O)[O:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1(C)C=CC=CC=1>[Cl:3][CH2:16][C:14]1[O:13][N:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:15]=1
Reactant: OCc1cc(-c2ccccc2)no1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: ClCc1cc(-c2ccccc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Thionyl chloride (2.41 ml) was added to a solution of (3-phenyl-5-isoxazolyl)methanol (2.89 g) in toluene (10 ml) and stirred at 60° C. for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 5-(chloromethyl)-3-phenylisoxazole (2.75 g, yield 86%) as pale-brown crystals. m.p. 69-70° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[CH:5][N:6]=1.[CH:7]1[C:20]2[CH:19]([C:21](Cl)=[O:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:21]([CH:19]1[C:20]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[S:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:22]
Reactant: Nc1ncco1
Reactant: O=C(Cl)C1c2ccccc2Sc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1ncco1)C1c2ccccc2Sc2ccccc21
Reaction time: 16 h
Yield: 18.6 %

Procedure:
To a stirred solution of (0.048 g, 0.575 mmol) 2-amino-oxazole [Cockerill & al., Synthesis 591(1976)], and DMAP (0.003 g, 0.03 mmol) in pyridine (2 ml) was added at 0° C. (0.100 g, 0.384 mmol) 9H-thioxanthene-9-carbonyl chloride. Stirring was continued at RT for 16 h, the reaction mixture was evaporated and water (5 ml)/sat. NaHCO3 solution (2 ml) was added. The solid was filtered off, dissolved in dichloromethane, dried (MgSO4), and concentrated in vaccuo. The crude material was purified by column chromatobraphy on silica gel (methylene chloride/methanol 40:1) to give the product (0.022 g, 18%) as a white solid, m.p. 188-191° C. and MS: m/e=309.1 (M+H+).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][C@H:15]([CH2:17]N3C=C(C)N=N3)[O:14][C:13]2=[O:24])[CH:5]=[CH:6][C:7]=1[Sn:8]([CH3:11])([CH3:10])[CH3:9].[Si:25]([O:32]C[C@@H]1OC(=O)N(C2C=CC(I)=CC=2)C1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][CH2:17][C@@H:15]1[O:14][C:13](=[O:24])[N:12]([C:4]2[CH:3]=[CH:2][C:7]([Sn:8]([CH3:9])([CH3:10])[CH3:11])=[CH:6][CH:5]=2)[CH2:16]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: Cc1cn(C[C@H]2CN(c3ccc([Sn](C)(C)C)c(F)c3)C(=O)O2)nn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1

Procedure:
Using the procedure described for (5R)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (above), but starting from (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (2.45 g, 5.66 mM) gave the title compound as a white solid after chromatography, using hexanes then 20% ethyl acetate/hexanes (1.59 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH:22]([OH:24])=[O:23].[C]=O>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:22]([OH:24])=[O:23])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [C]=O
Solvent: O
Product: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3.5 h
Yield: 103.8 %

Procedure:
To 4,4′-difluorobenzhydrol (10.0 g, 45.4 mmol, 1 equiv) in H2SO4 (37 M; 200 mL, 7.4 mol, 160 equiv) in an ice bath was added formic acid (20 mL, 24 g, 0.53 mol, 12 equiv) with no stirring. After a few seconds, carbon monoxide evolution was observed. The reaction was allowed to stand without stirring for 3.5 h. The reaction mixture was carefully poured into H2O (1000 mL) (highly exothermic). The aqueous mixture was extracted with EtOAc (1×250 mL). The organic layer was dried (anh. Na2SO4) and rotary evaporated (75° C.) to yield 11.7 g of an orange oil. This oil was dissolved in Et2O (100 mL) and extracted with 2 M NaOH (1×50 mL). The aqueous layer was then acidified with 12 M HCl (8 mL) and extracted with EtOAc (1×50 mL). The organic layer was dried (anh. Na2SO4), rotary evaporated (75° C.), and put under high vacuum for 16 h. This provided 6.15 g (54.6%) of product as a yellow, crystalline solid.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:18][N:19](C=O)C>>[CH3:18][NH:19][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]=1[F:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Thionyl chloride (0.15 g, 1.30 mmol) was added slowly to a solution of 2-fluoro-4-nitrobenzoic acid (Formula 37) (0.20 g, 1.10 mmol) in DMF (5 mL) cooled at −5° C. The mixture was stirred for an additional 1 hour at −5° C. Excess methylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 hour. Ethyl acetate (50 mL) was added to the mixture, which was washed with brine (2×50 ml). The organic layer was dried over MgSO4, and concentrated to yield N-Methyl-2-fluoro-4-nitrobenzamide (Formula 38) (0.18 g, 85%) as a yellowish solid. 1H NMR (acetone-d6) δ 3.05 (d, 3H, J=4.3), 6.31 (dd, 1H, J=13.5 and 2.1), 6.40 (dd, 1H, J=8.6 and 2.1), 7.64 (dd, 1H, J=8.6 and 8.6).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].C1C2NC3C(=CC=CC=3)C=2C=CC=1>>[OH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Oc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: OCCCCCCCCBr
Agent: c1ccc2c(c1)[nH]c1ccccc12
Product: OCCCCCCCCOc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Yield: 84.3 %

Procedure:
Demethylate 3-methoxy-9-phenylcarbazole (E-4) in the same manner as in Synthesis of Carbazole Derivative 1 to obtain 3-hydroxy-9-phenylcarbazole (E-5) having a colorless needle-like form with a yield of 91.8%; etherify the thus obtained 3-hydroxy-9-phenylcarbazole having a colorless needle-like form with 8-bromooctanol in the same manner as in Synthesis of Carbazole Derivative 2 to obtain 3-(8-hydroxyoctyloxy)-9-phenyl carbazole (E-6) having a colorless needle-like form with a yield of 84.3%; tosylate, thioacetylate, and hydlolyze the thus obtained 3-(8-hydroxyoctyloxy)-9-phenyl carbazole in the same manner as in Synthesis of Carbazole Derivative 2 to obtain 3-(8-meracaptooctyloxy)-9-phenyl carbazole (E-9) (hereinafter referred to as carbazole derivative 3) having a colorless needle-like form represented by the chemical structure 9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:25]1(O)OC2OC(O)C(O)OC2O[CH:26]1O>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[CH:26][CH:25]=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: OC1OC2OC(O)C(O)OC2OC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nccnc4c3O2)cc1
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (2.226 g, 5.258 mmole) in water (50 mL) was added a solution of glyoxal trimeric dihydrate (1.104 g, 5.258 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.135 g (58%) of the (R)-enantiomer of the title compound as a brown crystalline solid. Rf=0.27 (silica, ethyl acetate:hexanes 3:2); mp 124–127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:15].Br[CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:15][CH2:17][CH2:18][CH2:19][OH:20]
Reactant: OCCCBr
Reactant: Oc1ccc(Oc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCCOc1ccc(Oc2ccccc2)cc1Cl
Temperature: 70 °C
Yield: 95.4 %

Procedure:
To a 100 ml DMF solution of 2-chloro-4-phenoxyphenol (10 g, 45 mmol) were added 3-bromopropanol (8.2 ml, 91 mmol) and cesium carbonate (6.2 g, 50 mmol). The resulting suspension was heated to 70° C. for 7 hr. Solvent was removed under reduced pressure. The residue was diluted with AcOEt and water. The organic layer was separated. The aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 30% AcOEt/hexanes gave 3-(2-chloro-4-phenoxyphenoxy)-propanol 11.96 g (95%). This material was dissolved in acetonitrile 200 ml. To it was added triphenylphosphine (18.5 g, 55.8 mmol) and carbon tetrabromide (16.9 g, 64.4 mmol). After stirring at rt for 1 hr, the solvent was removed, and the residue was chromatographed on silica gel. Elution with 5% THF/hexanes gave the title compound as colorless oil 10.9 g (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:17]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Cl:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
To a solution of 5.00 g (26.8 mmol) of methyl 3-chloro-4-hydroxybenzoate dissolved in 40 mL of CH2Cl2 was added 6.55 g (53.6 mmol) of 4-dimethylaminopyridine, 4.85 g (32.2 mmol) of tert-butyldimethylchlorosilane and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was filtered, diluted with ethyl acetate, washed with 0.1N HCl, saturated NaHCO3, and brine. The product layer was then dried (MgSO4), filtered and evaporated in vacuo to afford 8.05 g (100%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.C([O:18][CH:19](OCC)[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)C.Cl>CO>[CH:19]([C:20]1[CH:21]=[CH:22][C:23]([CH2:26][N:27]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:24][CH:25]=1)=[O:18]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CCOC(OCC)c1ccc(CNc2ccc(C(C)C)cc2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(C=O)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 47.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and {[4-(diethoxymethyl)phenyl]-methyl}(4-isopropylphenyl)amine (0.65 g) as starting materials. The obtained residue was dissolved in a mixed solvent (15 mL) of methanol:1 mol/L-hydrochloric acid (1:2) and heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N-[(4-formylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:12]>>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:12])[N:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(O)c(Br)[n+]1[O-]
Product: OCc1ccc(O)c(Br)n1

Procedure:
A solution of 2-bromo-3-hydroxy-6-methylpyridine 1-oxide 29 (15 g, 0.075 mol) in TFAA (50 mL, 0.375 mol) and was stirred at 40° C. for 24 h. The solvent was removed under vacuum. The residue was purified by column chromatography (silica gel: EA:Hex, 2:1). Yield: 4.5 g, 30%. 1H NMR (CDCl3): δ 7.32 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 4.56 (s, 2H).
Reaction SMILES: CC([O:4][CH:5]1[CH2:18][C:17]2[C:8]([CH3:24])([CH:9]3[CH:14]([CH2:15][CH:16]=2)[CH:13]2[CH2:19][CH2:20][C:21](=[O:22])[C:12]2([CH3:23])[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(=O)([O-])[O-].[K+].[K+].C>CO>[CH3:23][C@@:12]12[C:21](=[O:22])[CH2:20][CH2:19][C@H:13]1[C@@H:14]1[CH2:15][CH:16]=[C:17]3[CH2:18][C@@H:5]([OH:4])[CH2:6][CH2:7][C@:8]3([CH3:24])[C@H:9]1[CH2:10][CH2:11]2
Reactant: CC(=O)OC1CCC2(C)C(=CCC3C4CCC(=O)C4(C)CCC32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 15 °C

Procedure:
DHEA was prepared from DHEA acetate (obtained from Diosynth, Chicago, Ill. or Berlichem, Montville, N.J.) by saponification using potassium carbonate in methanol. The product was dissolved in 6 parts methanol at reflux, and charcoal was added and removed by filtration. The methanol was evaporated until a volume of 3 parts remained, and the solution was cooled to 15° C., maintained at this temperature for 1 hour, and filtered. The wet product was refluxed with 8.5 parts of water to remove the methanol, filtered, and dried under vacuum at 90° C. The loss on drying specification for the final product was ≦0.5%, and the specification for residual methanol was ≦0.01%.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[NH2:6].[NH3:16]>CO>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([C:4]([NH2:16])=[O:3])[NH2:6])=[CH:9][CH:10]=1
Reactant: N
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: NC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Reaction time: 96 h

Procedure:
0.1 mole (25 grams) of 4-chlorophenylalanine methyl ester hydrochloride were dissolved in 250 ml of methanol. Then ammonia was led in at 0° C. several times, each time up to saturation. The reaction was finished after 4 days. The solvent was drawn off and the white residue dried. The product was employed in this form in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Br)cc2C)n1

Procedure:
The tide compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromo-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (48.2 mg) with purity >90%. MS (pos) m/z 419.2, 421.2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[CH3:17]N(C=O)C.[H-].[Na+].CI>>[CH3:1][CH:2]1[CH2:7][N:6]([CH3:17])[CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CC1CNCCN1c1ccncc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC1CN(C)CCN1c1ccncc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
To 2-methyl-1-(3-nitro-4-pyridyl)piperazine in DMF (1.5 mL of 0.3 M, 0.4500 mmol) at 0° C. was added NaH (18.00 mg, 0.4500 mmol). The reaction was stirred for 10 mins then MeI (60.68 mg, 26.61 μL, 0.4275 mmol) was added. The reaction mixture was stirred for 4 hours at RT and quenched by the addition of water. The crude was loaded onto a MeOH pre-washed SCX column, rinsed with MeOH and the product was released with methanolic ammonia. The ammonia extracts were concentrated under reduced pressure. The residue was purified by column chromatography eluting with 1-15% MeOH:DCM to yield 2,4-dimethyl-1-(3-nitropyridin-4-yl)piperazine. MS (ES+) 237.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:22]=[N:23][N:24]([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH:25]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:28]1[C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N:24]1[CH:25]=[C:21]([CH3:20])[CH:22]=[N:23]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: Cc1cnn(-c2ccccc2C=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnn(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Yield: 35.4 %

Procedure:
A solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (180 mg, 0.70 mmol) and 2-(4-methyl-pyrazol-1-yl)-benzaldehyde (130 mg, 0.70 mmol) in acetic acid (5 mL) is warmed to 100° C. for 16 hours then cooled to room temperature and neutralized with NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (105 mg, 35%). LCMS (ESMS): m/z 424.20 (M++1)
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:9]=[N:8][CH:7]=1)CCC.Br[C:28]1[N:33]=[C:32]([C:34]([NH:36][CH3:37])=[O:35])[C:31](=[O:38])[N:30]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=2)[C:29]=1[CH3:49]>COCCOC>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([N:10]2[C:6]([C:28]3[N:33]=[C:32]([C:34]([NH:36][CH3:37])=[O:35])[C:31](=[O:38])[N:30]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:46])([F:47])[F:48])[CH:40]=4)[C:29]=3[CH3:49])=[CH:7][N:8]=[N:9]2)=[CH:18][CH:17]=1)#[N:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1-c1ccc(C#N)cc1
Reactant: CNC(=O)c1nc(Br)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: COCCOC
Product: CNC(=O)c1nc(-c2cnnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 100 °C
Yield: 40.2 %

Procedure:
4-(5-Tributylstannanyl-[1,2,3]triazol-1-yl)-benzonitrile (0.15 g, 0.32 mmol), 6-bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (SM2, 0.054 g, 0.14 mmol), Pd(PBut3)2 (10 mg) and DME (2 ml) were placed in a tube for microwave synthesis. The mixture was degassed with argon and heated in a synthesis microwave heater (CEM) at 100° C. (max 150 W) for 10 minutes. The solvent was removed in vacuo giving a crude product which was purified on silica and then further purified on preparative HPLC. The pure fractions were freeze-dried giving 27 mg (41%) of the title compound.
Reaction SMILES: C(C1C=CC(C2SC=CC=2CO)=CC=1)C.OC1C(F)=CC(CCC(OCC)=O)=CC=1F.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[CH2:45][O:46][C:47]2[C:52]([F:53])=[CH:51][C:50]([CH2:54][CH2:55][C:56]([O:58]CC)=[O:57])=[CH:49][C:48]=2[F:61])=[CH:36][CH:35]=1)[CH3:33]>>[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[CH2:45][O:46][C:47]2[C:52]([F:53])=[CH:51][C:50]([CH2:54][CH2:55][C:56]([OH:58])=[O:57])=[CH:49][C:48]=2[F:61])=[CH:36][CH:35]=1)[CH3:33]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2ccsc2-c2ccc(CC)cc2)c(F)c1
Agent: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: CCc1ccc(-c2sccc2CO)cc1
Product: CCc1ccc(-c2sccc2COc2c(F)cc(CCC(=O)O)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 207 by coupling of (2-(4-ethylphenyl)thiophen-3-yl)methanol and ethyl 3-(4-hydroxy-3,5-difluoro phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((2-(4-ethylphenyl)thiophen-3-yl)methoxy)-3,5-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=6.5 Hz, 2H), 7.28 (m, 3H), 7.20 (m, 1H), 6.76 (d, J=6.5 Hz, 2H), 5.05 (s, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.70 (m, 2H), 2.62 (t, J=6.0 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=O.[CH3:14][N:15]([CH3:19])[C:16]([NH2:18])=[S:17]>C(O)(C)C.CCOC(C)=O>[CH3:14][N:15]([CH3:19])[C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[N:18]=1
Reactant: CN(C)C(N)=S
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CN(C)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Yield: 64.7 %

Procedure:
A solution of 2-bromo-4′-nitroacetophenone (4.42 g, 18.1 mmol), N,N,-dimethylthiourea (3.77 g, 36.2 mmol) in isopropanol (60 mL) was heated at reflux for 45 min. The cooled reaction mixture was diluted with EtOAc. The solution was washed with saturated aqueous NaHCO3, H2O and brine, dried (MgSO4) and concentrated under reduced pressure to give N,N-dimethyl-4-(4-nitrophenyl)-2-thiazolamine (2.92 g, 65% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ8.24 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 3.11 (s, 6H); MS (FAB) m/z 250 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]([NH2:10])=[O:9]>CN(C)C1C=CN=CC=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].C(#N)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:8]([NH2:10])=[O:9]
Reactant: Clc1ccccn1
Reactant: NC=O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: NC(=O)c1ccccn1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.255 g of bis(tricyclohexylphosphine)-palladium(II) dichloride, 5.458 g of 2-chloropyridine, 3.12 g of formamide, 4.64 g of 4-dimethylamino-pyridine and 25 ml of acetonitrile are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, and the suspension is mixed with ethyl acetate and water, and extracted. The aqueous phase is extracted by shaking 3 times with ethyl acetate, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated. The oil obtained is chromatographed over silica gel. The yield of title compound is 36% (part of the product remains in the water phase).