Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:33]CC3C=CC(OC)=CC=3)([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH:8]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:33])([C:29]([F:31])([F:32])[F:30])[C:25]([F:26])([F:27])[F:28])[CH:19]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(OCCCOc2cccc(C(OCc3ccc(OC)cc3)(C(F)(F)F)C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(OCCCOc2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)c1
Yield: 80.9 %

Procedure:
100 mg (0.16 mmol) of 3-[3-(3-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-propoxy)-phenyl]-propionic acid ethyl ester in 10 mL of EtOAc were hydrogenated in the presence of 60 mg of 10% Pd/C. After removal of the catalyst and evaporation of the solvent, the residue was purified by column chromatography on silica gel with a gradient of EtOAc/n-heptane 1:5 to 1:3 to yield 64 mg (80%) of 3-(3-{3-[3-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenoxy]-propoxy}-phenyl)-propionic acid ethyl ester as a colorless oil, MS: 493 (M−H)−.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>C(O)C>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2nc(NCCN3CCOCC3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2nc(NCCN3CCOCC3)sc2c1
Yield: 77.6 %

Procedure:
A mixture of (2-morpholin-4-yl-ethyl)-(6-nitro-benzothiazol-2-yl)-amine (Example 26, 250 mg, 0.81 mmol) and tin(II) chloride dihydrate (914 mg, 5 eq.) in ethanol (30 mL) was heated at reflux for 6 hours. The reaction mixture was concentrated, treated with 1.0 N NaOH solution (50 mL), and extracted with ethyl acetate (2×100 mL). The organic layer was dried over MgSO4, concentrated and subjected to silica gel chromatography (10% 2M ammonia/methanol in CH2Cl2) to give the desired amine (175 mg, 77%). LCMS analysis (acetonitrile water, C18 silica) reveals 99.9% purity. MS (M+1, 279).
Reaction SMILES: [H-].[Na+].C(P([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(CC)=O)C.[CH:20](=O)[CH2:21][CH3:22].[Cl-].[NH4+]>O1CCCC1>[CH:9](/[C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1)=[CH:20]\[CH2:21][CH3:22]
Reactant: CCP(=O)(CC)Cc1ccc(C(=O)OC)cc1
Reactant: CCC=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC/C=C/c1ccc(C(=O)OC)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60%, 0.97 g) in tetrahydrofuran (80 mL) was added methyl 4-(diethylphosphorylmethyl)benzoate (5.8 g) at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added a solution of propionaldehyde (1.6 mL) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give methyl (E)-4-(but-1-en-1-yl)benzoate (2.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]3[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH2:17]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][C:19]4([O:20][CH2:21][CH2:22][O:23]4)[CH2:24][CH2:25]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=CCC(CCC3CCC4(CC3)OCCO4)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Clc1ccc([C@H]2CC[C@H](CCC3CCC4(CC3)OCCO4)CC2)cc1
Temperature: 0 °C

Procedure:
A solution of 35.0 g of 4-chloro-1-[4-(2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl)-1-cyclohexenyl]benzene in 1 l of toluene is treated with 2.6 g of palladium/carbon (10%) and hydrogenated at room temperature under normal pressure until the uptake of hydrogen comes to a standstill. Thereafter, the reaction mixture is filtered and the filtrate is concentrated, there being obtained crude 4-chloro-1-[4-(2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl)cyclohexyl]benzene. A suspension of 32.8 g of aluminium chloride in 215 ml of methylene chloride is treated at 18° C. while stirring and gassing with nitrogen within 10 minutes with a solution of the crude product obtained in 110 ml of methylene chloride and stirred at 0° C. for a further 30 minutes. Subsequently, the reaction mixture is poured on to 600 ml of ice/water, stirred for 10 minutes and then extracted three times with methylene chloride. The organic phases are washed in succession with water, with saturated sodium hydrogen carbonate solution and with water, then dried over sodium sulphate and filtered. Concentration of the filtrate gives 4-chloro-1-[trans-4-[2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl]cyclohexyl]benzene.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@H:9]([C:10]2[C:11]([O:30][CH3:31])=[CH:12][C:13]([O:28][CH3:29])=[C:14]3[C:19]=2[O:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[CH:16][C:15]3=[O:27])[CH2:8][CH2:7][N:6]1[CH3:32])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.N>C1COCC1.C(Cl)(Cl)Cl.CC(O)C>[NH2:1][CH2:4][C@H:5]1[C@H:9]([C:10]2[C:11]([O:30][CH3:31])=[CH:12][C:13]([O:28][CH3:29])=[C:14]3[C:19]=2[O:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[CH:16][C:15]3=[O:27])[CH2:8][CH2:7][N:6]1[CH3:32]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CN=[N+]=[N-]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CN

Procedure:
Compound of example 107 (0.6 g, 1.32 mmol) and triphenylphosphine (0.414 g, 1.58 mmol) were dissolved in THF (10 mL) containing water (0.1 mL). The resultant solution was stirred for 12 h. It was concentrated and the residue obtained was subjected to flash column chromatography using 5% IPA+1% liquor NH3 in CHCl3 as eluant to obtain the title compound.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C1(C)C=CC=CC=1>[CH3:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COCCOCCOc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
In 110 g of dimethyl sulfoxide were dispersed 21.6 g (0.15 mol) of 1-naphthol, 27.4 g (0.1 mol) of 2-(2-methoxy-ethoxy)ethyl 4-toluenesulfonate, and 20.7 g (0.15 mol) of potassium carbonate. The dispersion was heated and stirred at 80° C. for 3 hours. After cooling, the solution was combined with 200 g of water and 200 g of toluene, from which an organic layer was separated. It was washed 2 times with 50 g of water, 5 times with 2.5 wt % sodium hydroxide aqueous solution and then 4 times with 100 g of water. The organic layer was concentrated, obtaining 21 g of oily matter. On vacuum distillation (120° C./0.06 Torr), 18.6 g of the target compound was recovered (yield 75%).
Reaction SMILES: [N+](C1C=C(C=CC=1Cl)C(C1C=CC(Cl)=C([N+]([O-])=O)C=1)=O)([O-])=O.ClC1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.[N+]([C:42]1[CH:43]=[CH:44][C:45]([Cl:60])=[C:46]([CH:59]=1)[C:47]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([N+]([O-])=O)[CH:50]=1)=[O:48])([O-])=O>>[Cl:60][C:45]1[CH:44]=[CH:43][CH:42]=[CH:59][C:46]=1[C:47]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)=[O:48]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: O=C(c1ccc(Cl)cc1)c1ccccc1Cl
Yield: 95 %

Procedure:
For example, 3,3'-dinitro-4,4'-dichlorobenzophenone can be prepared in a yield of 95 to 98% by nitrating 4,4'-dichlorobenzophenone [E. R. Kofanov et al., J. Org. Chem. USSR, 15, 98-100 (1979)]. 5,3'-Dinitro-2,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone [E. H. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)]. 3,3'-Dinitro-4-chlorobenzophenone can be prepared in a high yield by nitrating 4-chlorobenzophenone [G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538 (1972)]. 3,4'-Dinitro-4-chlorobenzophenone can be prepared by nitrating 4-halogeno-4'-nitrobenzophenone obtained by the condensation reaction between p-nitrobenzoyl chloride and chlorobenzene [P. T. Montagne et al., Ber., 49, 2267-2270 (1916); G. S. Mironov et al., J. Org. Chem. USSR, 8, 1538-1543 (1972)]. 3,3'-Dinitro-6,4'-dichlorobenzophenone can be prepared in a high yield by nitrating 2,4'-dichlorobenzophenone obtained by the condensation reaction between 2-chlorobenzoyl chloride and chlorobenzene [H. F. Faith et al., J. Am. Chem. Soc., 77, 543 (1955)].
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:40]2[CH:45]=[CH:44][C:43]([S:7]([CH3:1])(=[O:9])=[O:8])=[CH:42][CH:41]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 94.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 67, 0.5 g, 0.93 mmol), 4-(trifluoromethyl)phenylboronic acid (0.56 g, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.4 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.23 g, 47%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[F:21][CH:22]([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:1]1[CH:2]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: O=Cc1cccc(OC(F)F)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 3-(difluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 394.02 g/mol.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[NH2:10][CH2:11][C:12](O)=O.[ClH:15]>>[ClH:15].[ClH:15].[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[C:12]1[CH2:11][NH2:10]
Reactant: CNc1ccccc1N
Reactant: NCC(=O)O
Agent: Cl
Product: Cn1c(CN)nc2ccccc21
Temperature: -15 °C

Procedure:
Combine N-methyl-o-phenylenediamine (12.2 g, 100 mmol) and glycine (11.3 g, 150 mmol) in 6 N HCl (100 mL). Heat at reflux 90 hours, allow to cool, and concentrate in vacuo to 60 g. Add EtOH (50 mL) and chill at −15° C. Filter the solid and wash with cold 90% EtOH. Dissolve the blue solid in water (30 mL), add EtOH (100 mL) and treat with decolorizing charcoal. Wash the solid with 2:1 EtOH-water and concentrate filtrates in vacuo to 33 g. Add water (15 mL) and warm while adding EtOH (150 mL). Allow to cool, filter, and wash with 90% EtOH to obtain the product as blue flakes. Process the filtrate to obtain a second crop.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[Li+].[OH-].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2cncc(Cl)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCc2cncc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
Compound 27b (1.22 mmol, 340 mg) was combined with LiOH (4.9 mmol, 118 mg) in 3 mL of THF, 3 mL of MeOH, and 3 mL of water. The mixture was stirred at room temperature for 4 h and was then combined with 15% aqueous citric acid and extracted with EtOAc. The extracts were washed with water and brine, dried over Na2SO4, and concentrated under vacuum to give 288 mg of 27c.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34]Br.P([O-])([O-])([O-])=O>CN(C=O)C>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4c(Cl)cccc4Cl)C(=O)O3)ccc2O1
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(2-hydroxyethoxy)hexyl]-1,3-oxazolidin-2-one (200 mg) in DMF (4 ml) under nitrogen was treated with sodium hydride (26 mg, 60% in oil) and the mixture was stirred at 200 for 10 min. 2,6-Dichlorobenzyl bromide (122 mg) was added and the mixture was stirred at 200 for 3 h. Phosphate buffer solution (20 ml, pH6.5) was added and the mixture was extracted with EtOAc (30 ml). The extract was washed with water (2×20 ml), dried (NaSO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel 20 mm diameter column. Elution with EtOAc-cyclohexane (1:1) gave the title compound (155 mg). LCMS RT=3.97 min.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)#[CH:12].N>>[N:6]1[CH:5]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[O:1][N:2]=2)[CH:9]=[N:8][CH:7]=1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cncnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 4-ethynylbenzonitrile (Aldrich, 64 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ7.99 (s, 1H), 8.10 (s, 4H), 9.34 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: O.[C:2](=[O:5])([O-])[O-:3].[Ce+3:6].[C:7](=[O:10])([O-])[O-:8].[C:11](=[O:14])([O-])[O-:12].[Ce+3]>C(O)(=O)C>[C:2]([O-:3])(=[O:5])[CH3:7].[Ce+3:6].[C:7]([O-:8])(=[O:10])[CH3:11].[C:11]([O-:12])(=[O:14])[CH3:2]
Reactant: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)[O-]

Procedure:
1147 g of water and 136 g of acetic acid were mixed and 236 g of cerium carbonate was added to form a clear solution of cerium acetate. The mixture was stirred for 48 hours to completely dissolve the carbonate. To the cerium acetate was added 512 g of zirconium acetate (20 wt % ZrO2) and stirred to make a homogeneous solution. The solution was spray dried at 110° C. to form a white powder of mixed acetates. The powder was calcined in a muffle furnace to a temperature of 500° C. for 1 hour to form the finished mixed oxide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:21]([F:20])[CH:22]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cccc(F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-fluoroaniline were reacted to yield N4-(3,4-ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.76 (d, 1H, J=5.6 Hz), 7.39 (m, 2H), 7.14 (d, 1H, J=2.4 Hz), 6.94-6.85 (m, 3H), 6.75 (d, 1H, J=9 Hz), 4.21 (s; 4H); LCMS: ret. time: 22.60 min.; purity: 100%; MS (m/e): 357 (MH+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[K+].[I:18]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.O>[I:18][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:8]=2)[NH:13][CH:14]=1
Reactant: II
Reactant: c1cc2cc(N3CCOCC3)cnc2[nH]1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1c[nH]c2ncc(N3CCOCC3)cc12
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a stirred solution of 53 (0.096 g, 0.47 mmol) in DMF (2 mL) was added solid KOH (85%, 0.112 g, 1.69 mmol). After 20 min iodine (0.132 g, 0.52 mmol) was added in one portion. After stirring for 1 hour the mixture was cooled with ice-water bath, and water (10 mL) followed by saturated aqueous Na2S2O3 solution (2 mL) were added. The precipitate was filtered off, washed with water and dried to afford 54 (0.102 g, 66%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 3.11-3.15 (m, 4H), 3.85-3.89 (m, 4H), 7.19 (d, J=0.26 Hz, 1H), 7.33 (d, J=0.24 Hz, 1H), 8.08 (d, J=0.26 Hz, 1H), 9.81 (bs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]([CH3:15])[CH3:14]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 55.1 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-2-methyl-propane (115 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-iso-butyl-1H-pyrazole (83 mg, 46%) as a white powder.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.CN(C=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:41])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:30][C:31]([OH:33])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccccc3n2)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)O)c3ccccc3n2)CC1
Reaction time: 3 h

Procedure:
To a solution of 5.2 g 4-{2-[(4-Benzyloxycarbonylmethoxy-quinoline-2-carbonyl)-amino]acetyl}-piperazine-1-carboxylic acid butyl ester in 120 ml ethyl acetate and 16 ml DMF were added under argon 530 mg Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (5 bar) for 3 h. The suspension was filtered over a plug of Celite® and washed with DMF. The crude product was obtained after evaporation of the solvent and used in the next reaction step without further purification. Yield: 4.4 g.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=1.CN([CH:22]=[O:23])C>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[C:9]([O:17][CH3:18])[C:8]=1[CH:22]=[O:23]
Reactant: COc1cc(Cl)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)cc(Cl)c1C=O
Temperature: 0 °C

Procedure:
A 2M n-BuLi solution (2.07 mL, 4.3 mmol) was added to a −78° C. THF solution (20 mL) of 1-chloro-3-methoxy-5-(trifluoromethyl)benzene (870 mg, 4.1 mmol). After 45 min neat DMF (0.39 mL, 5.0 mmol) was added, and the resulting solution was allowed to warm to 0° C. gradually, quenched with NH4Cl solution, and extracted with diethyl ether. The combined extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.