Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13]1([Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([OH:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1
Reactant: COc1cc(O)c(C=O)cc1Cl
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(O)c(C(O)c2ccccc2)cc1Cl
Reaction time: 0.5 h

Procedure:
The above prepared 5-chloro-2-hydroxy-4-methoxy-benzaldehyde (example 36, step 1, 1.050 g, 5.63 mmol) was dissolved in 15 mL of abs. THF and treated at −15° C. with PhMgBr (15.5 mL of 1M [THF], 2.7 eq.) and the mixture kept at this temperature for 0.5 h. Careful pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3) yielded 1.39 g of the title compound as light brown oil.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[SH:24]>>[Cl:21][C:18]1[C:17]([F:22])=[C:16]([F:23])[C:15]([S:24][C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[C:14]([F:13])[C:19]=1[F:20]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Fc1c(F)c(Cl)c(F)c(F)c1S
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2c(F)c(F)c(Cl)c(F)c2F)s1
Yield: 58.2 %

Procedure:
Prepared by a similar procedure to that described for example 1 from the 1-(5-chloro-4-nitro-2-thienyl)ethanone (205 mg, 1.0 mmol) and 2,3,5,6-tetrafluoro-4-chloro-benzenethiol (216 mg, 0.98 mmol) to afford the title product as a solid (220 mg, 57% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.55 (1H, s), 3.37 (3H, s). MS m/z: 384.12, 386.12 [M+H]+.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:22]Br)=[C:15]([CH:21]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C(O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:22][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)=[C:15]([CH:21]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cc(F)ccc1CBr
Reactant: Oc1cccc(F)c1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(F)ccc1COc1cccc(F)c1
Yield: 105.1 %

Procedure:
To a solution of 1.5 g of sodium metal in 100 ml of ethanol are added 8 g of 3-fluorophenol and 17 g of ethyl 5-fluoro-2-bromomethylbenzoate [U.S. Pat. No. 4,082,850]and the mixture is refluxed with heating for 8 hours. After cooling, 300 ml of water is added and the mixture is extracted with toluene. The extract is washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 20 g of ethyl 5-fluoro-2-[(3-fluorophenyl oxy)methyl]benzoate (oil). Mass spectrum m/z: 292(M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC[C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: Cc1nc(CCl)cs1
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3csc(C)n3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 4-chloromethyl-2-methylthiazole as described for compound 78. Crystallized from ethyl acetate. M.p. 135°-137° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21]Cl>CN(C)C(=O)C>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[NH:2][CH3:1]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: CNc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 61.7 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.49 g of 6-methylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.92 g of 2,6-dichlorobenzyl chloride, there was obtained 1.9 g of 9-(2,6-dichlorobenzyl)-6-methylaminopurine as colorless needles (yield: 62%), m.p. 219°-220° C. NMR spectrum of this product is identical with that of the corresponding compound synthesized in Example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C-:12]#[N:13].[Na+]>[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([C:12]#[N:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(C#N)c([N+](=O)[O-])c1

Procedure:
11.75 g (77.2 mmol) of 4-methyl-2-nitroaniline underwent a Sandmeyer reaction in a conventional process by diazotization and substitution with NaCN and CuSO4 to give 9.6 g of crude 4-methyl-2-nitrobenzonitrile. 1H-NMR (DMSO-d6, δ in ppm): 8.25 (1H), 8.05 (1H), 7.80 (1H), 2.50 (3H)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH:11](NC)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:18]([N:20]([CH2:31][C:32]([OH:34])=O)[S:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH3:19].[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.OS([O-])(=O)=O.[K+]>ClCCl>[CH2:18]([N:20]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:31][C:32]([NH:36][CH2:35][CH:11]1[CH2:12][CH2:13][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)[CH2:10]1)=[O:34])[CH3:19]
Reactant: CCN(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNC1CCN(c2ccc(C(F)(F)F)cc2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC(=O)NCC1CCN(c2ccc(C(F)(F)F)cc2)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 15.4 %

Procedure:
A solution of crude [1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-methylamine (28.0 mg, 0.12 mmol, crude) and [ethyl-(4-fluoro-benzenesulfonyl)-amino]-acetic acid (30.0 mg, 0.12 mmol) in dichloromethane (5 mL) at 25° C. was treated with HATU (43.7 mg, 0.12 mmol). N,N-Diisopropylethylamine (29.7 mg, 0.23 mmol) was added to the solution. The reaction mixture was stirred for 2 h. The reaction mixture was then poured into 0.2 M aqueous KHSO4 and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (50/50 hexanes/ethyl acetate) afforded 2-[ethyl-(4-fluoro-benzenesulfonyl)-amino]-N-[1-(4-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-acetamide (9.0 mg, 16%) as a white solid. [MH]+=488.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[C:11]([Cl:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.O=[Mn]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[C:11]([Cl:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1Cl
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc(OCc2ccccc2)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of (4-Benzyloxy-2-chloro-phenyl)-methanol in dichloromethane, MnO2 (10 eq) were added and the mixture reaction stirred overnight. Filtered through a pad of celite and purified by chromatography in silica gel to give the title product.
Reaction SMILES: [OH:1][CH:2]1[C:17](=[O:18])[N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:4]2[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:26]1[CH:31]=[N:30][C:29]([CH:32]2[CH2:34][CH2:33]2)=[CH:28][N:27]=1>C(#N)C>[CH:32]1([C:29]2[N:30]=[CH:31][C:26]([O:1][CH:2]3[C:17](=[O:18])[N:5]4[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:9][CH:4]4[CH2:3]3)=[N:27][CH:28]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)C(O)CC2C1
Reactant: Brc1cnc(C2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 63.1 %

Procedure:
To a solution of the product from Example 205B (89 mg, 0.347 mmol) in anhydrous acetonitrile (3.5 mL) was added cesium carbonate (226 mg, 0.695 mmol) and 2-bromo-5-cyclopropylpyrazine (104 mg, 0.521 mmol). The resulting mixture was stirred under N2 at 50° C. for 48 hours. The mixture was allowed to cool to room temperature, and then it was partitioned between water and ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane to give the title compound (82 mg, 63%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH2:11][C@@H:10]2[C@@H:6]([CH2:7][C:8]3(OCC[O:12]3)[CH2:9]2)[CH:5]=1>CC(C)=O.O.Cl.[Cl-].[Na+]>[OH:1][CH2:2][CH2:3][C:4]1[CH2:11][C@@H:10]2[C@@H:6]([CH2:7][C:8](=[O:12])[CH2:9]2)[CH:5]=1
Reactant: OCCC1=C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1C[C@@H]2CC(CCO)=C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
3.00 g of 3-(2-hydroxyethyl)-7,7-ethylenedioxy-cis-bicyclo[3,3,0]oct-2-ene (prepared as described in Preparation 43) were dissolved in a mixture of 30 ml of acetone and 12 ml of water, and 0.5 ml of concentrated hydrochloric acid was added to the solution. The mixture was stirred for 1 hour at room temperature, after which it was diluted with a saturated aqueous solution of sodium chloride, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting residue (2.61 g) was purified by silica gel column chromatography. 1.97 g of the title compound was obtained in the form of an oil from the fractions eluted with hexane containing from 35 to 45% by volume of ethyl acetate.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([Si:8]([CH3:41])([CH3:40])[O:9][CH2:10][C@@H:11]([O:13][C:14]1[CH:15]=[C:16]([O:29][C:30]2[N:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][CH:31]=2)[CH:17]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:19]=1)[CH3:12])([CH3:7])[CH3:6]>O.C1COCC1>[CH3:4][C:5]([Si:8]([CH3:41])([CH3:40])[O:9][CH2:10][C@@H:11]([O:13][C:14]1[CH:15]=[C:16]([O:29][C:30]2[N:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)[CH:17]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:19]=1)[CH3:12])([CH3:6])[CH3:7]
Reactant: COC(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of lithium hydroxide monohydrate (0.10 g, 4.17 mmol) in water (15 mL) was added to a solution of methyl 6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate (0.90 g, 1.67 mmol) in THF (30 mL). The mixture was allowed to stir at RT overnight. The THF was removed in vaccuo and the resulting solution was partitioned between water (50 mL) and ethyl acetate (75 mL), then the ethyl acetate layer separated, washed with brine and dried (MgSO4). The aqueous layer was then taken to pH 7 by addition of 1N hydrochloric acid (5.2 mL) and extracted with ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The ethyl acetate layers were combined and evaporated to give the required product (0.84 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[S:9]1C[C:13](=[O:14])[NH:12][C:10]1=[S:11].C([O-])(=O)C.[Na+].O>C(O)(=O)C.CCOCC>[CH3:1][C:2]1[O:6][C:5](=[C:7]2[S:11][C:10](=[S:9])[NH:12][C:13]2=[O:14])[CH2:4][CH:3]=1
Reactant: Cc1ccc(C=O)o1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC1=CCC(=C2SC(=S)NC2=O)O1
Yield: 94.2 %

Procedure:
A mixture of 5-methylfuran-2-carboxaldehyde (5.51 g, 50 mmol, purchased from Wako Junyaku Kogyo), rhodanine (6.66 g, 50 mmol, purchased from Tokyo Kase), and anhydrous sodium acetate (2.3 g, 150 mmol, purchased from Kokusan Kagaku) in 35 ml of acetic acid (purchased from Wako Junyaku Kogyo) was refluxed for 30 minutes. After being cooled, the reaction mixture was poured into 500 ml of water. The precipitate was collected and washed with water, with ethanol, and then with ether to give 10.04 g (yield: 89.1%) of (5-methylfurylidene) rhodanine as an orange-brown color crystalline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([F:19])[CH:18]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:20][C:9]1[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Oc1cc(F)cc(F)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2cc(F)cc(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3,5-difluorophenol.
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][C:17]2[CH2:18][NH:19][C:20]3[N:21]=[C:22]([NH:24][C:25]([C:27]=3[N:28]=2)=[O:26])[NH2:23])=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6].CN(C1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)CC1C=NC2N=C(N)N=C(N)C=2N=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>>[C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][C:17]2[N:28]=[C:27]3[C:20]([N:21]=[C:22]([NH:24][C:25]3=[O:26])[NH2:23])=[N:19][CH:18]=2)=[CH:29][CH:30]=1)=[O:10])[C:5]([OH:7])=[O:6]
Reactant: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Agent: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Product: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1

Procedure:
Each assay sample contained 12 μL of protein stock solution (2 mg/mL), 4.8 uL of either dihydrofolic acid (FAH2) or methotrexate stock solution (1 mM), and 31.2 μL of a solution of 154 μM Dapoxyl™ 12800 in Buffer A. Each sample contained 12 μL of protein stock solution (2 mgs/mL), 4.8 uL of NADP stock solution (50 mM), and 31.2 μL of a solution of 154 μM Dapoxyl™ 12800 in Buffer A.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)([OH:42])=[O:41]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:46]3[CH:47]=[CH:48][C:43]([C:40]([OH:42])=[O:41])=[CH:44][CH:45]=3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3ccc(C(=O)O)cc3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 4-carboxyphenylboronic acid replacing phenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:37](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:48][CH3:49].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:37][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:26][CH2:25]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:48][CH3:49]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNCC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3[nH]1)cn2C
Yield: 53.1 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k), starting with 0.340 g of tert-butyl 4-({[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}methyl)piperidine-1-carboxylate instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 1.13 cm3 of 5N potassium hydroxide. 0.140 g of tert-butyl 4-({[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-amino}methyl)piperidine-1-carboxylate is obtained with the following characteristics:
Reaction SMILES: S(Cl)(=O)(=O)[OH:2].F[C:7](F)=[CH:8][C:9]([F:12])([F:11])[F:10].[CH2:14]([OH:16])[CH3:15]>>[C:9]([CH2:8][C:7]([O:16][CH2:14][CH3:15])=[O:2])([F:12])([F:11])[F:10]
Reactant: FC(F)=CC(F)(F)F
Reactant: CCO
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)CC(F)(F)F
Temperature: 20 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
A 100 mL Hastelloy shaker tube was loaded with 26.5 g (0.227 mole) chlorosulfuric acid, cooled in liquid nitrogen, evacuated and loaded with 30 g (0.225 mole) of 1,1,3,3,3-pentafluoropropene. The reaction vessel was allowed to warm and kept on a shaker at 40° C. at autogenous pressure for 6 hours. The pressure tube was unloaded, and the reaction mixture was added drop by drop into the flask containing 60 ml of ethanol at −10° C. over a 15 minute period. The reaction mixture was stirred overnight at 20° C. and then was poured into 200 ml of ice water. The organic layer was separated, washed with sodium bicarbonate, water, and dried under MgSO4. Distillation gave 31 g of CF3CH2COOEt (87%), bp 108-109° C.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.[F:35][C@@H:36]1[CH2:40]CN[CH2:37]1>>[F:24][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:31]4[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[C@@:13]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:12]=2[CH:11]=[C:10]([O:22][CH2:23][C:36]([F:35])([CH3:40])[CH3:37])[CH:9]=1
Reactant: F[C@@H]1CCNC1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1F
Product: CC(C)(F)COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(-c3cccnc3F)ccc1O2

Procedure:
The title compound was synthesized by steps analogous to those described in method A6 above, but using intermediate 20B, 2-fluoropyridin-3-ylboronic acid and (R)-3-fluoropyrrolidine. MS m/z=467.0 [M+H]+. Calculated for C25H21F3N4O2: 466.16
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=O)[O:28]CC)[CH:21]=3)[C:12]2=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:28])[N:34]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH3:33])[CH:21]=3)[C:12]2=[O:32])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Reactant: CNC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1)C1CCCC1
Temperature: 130 °C

Procedure:
To a solution of 0.16 g of ethyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-carbamate obtained in stage a) below in 2 mL of tetrahydrofuran are added successively 0.368 mL of N-methylcyclopentylamine and 0.512 mL of triethylamine. The reaction mixture is heated by microwave at 130° C. for 3 hours and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 0.048 g of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-1-cyclopentyl-1-methylurea, the characteristics of which are as follows:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:33][N:34]1[C:38]([CH3:39])=[C:37](B2OC(C)(C)C(C)(C)O2)[C:36]([CH3:49])=[N:35]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH2:24]([N:17]([C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:37]2[C:36]([CH3:49])=[N:35][N:34]([CH3:33])[C:38]=2[CH3:39])[CH2:12]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)C(=O)N(Cc1ccccc1)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)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: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(Cc1ccccc1)C(=O)C(C)(C)C)C2
Reaction time: 2 h
Yield: 86 %

Procedure:
(6S)-6-[Benzyl(tert-butylcarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (0.5 g, 1.028 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (0.350 g, 1.482 mmol) and Pd(PPh3)4 (0.170 g, 0.147 mmol) were added to a solution of K2CO3 (0.30 g, 2.17 mmol) in a mixture of 1,2,-dimethoxyethane (30 mL) and H2O (4 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 2 h. It was allowed to reach room temperature, diluted with AcOEt (300 mL) and filtered through Celite (washing with AcOEt). The organic layer was washed with brine (1×200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (80-100% AcOEt/Hexane) to afford 0.38 g of the coupling product (Rf=0.1 (30% AcOEt/Hexane), viscous yellow oil, 83% yield).