Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[C:39]([NH:41][CH:42]3[CH2:44][CH2:43]3)[N:38]=[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:36]=2)[CH:32]=[N:33][CH:34]=1>COCCOC.CCOC(C)=O>[CH:42]1([NH:41][C:39]2[N:38]=[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:36]=[C:35]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH:7]=4)[CH:30]=3)[CH:40]=2)[CH2:44][CH2:43]1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Reactant: CN(C)CCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CN(C)CCOc1cccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)c1

Procedure:
To a solution of Dimethyl-(2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl)-amine (2 eq, 0.272 mmol, 0.079 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (3 eq, 0.408 mmol, 0.204 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 50 mg) and PdCl2dppf (0.1 eq, 0.014 mmol, 11 mg). The reaction mixture is heated using microwave radiation at 90° C. for 90 minutes. The reaction mixture is dissolved in EtOAc and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 452.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH3:19])=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.C(OCC)C.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]([CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])[CH3:19])=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
A mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N′-(2-dimethylamino-ethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine (Intermediate 98, 553 mg, 1.08 mmol), iron (363 mg, 6.51 mmol) and NH4Cl (43.5 mg, 0.81 mmol) in ethanol (23 mL) and water (7.67 mL) were heated at reflux for 1.5 h. The mixture was then cooled and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (100 mL) and CH3OH (10 mL) and this mixture was stirred for 0.25 h and then filtered. The filter cake was washed with further CH2Cl2 and CH3OH and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 provided a solid. This solid was dissolved in diethyl ether and a small amount of brown precipitate was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (409 mg, 79%) as a brown glass; 1H NMR: (CDCl3) 2.26 (6H, s), 2.38-2.43 (2H, m), 2.68 (3H, s), 2.94-2.98 (2H, m), 3.84 (3H, s), 3.91 (3H, s), 6.71 (1H, s), 7.26-7.36 (2H, m), 7.40 (1H, d), 7.63 (1H, s), 8.09 (1H, s), 8.21 (1H, s), 8.33 (1H, s), 8.67 (1H, d); m/z: ES+ MH+ 480.32.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br)([O-:11])=[O:10].C(=O)([O-])O.[Na+]>C(O)C>[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNCc1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h

Procedure:
6.35 g (45.4 mmol) of glycine ethyl ester hydrochloride, 2.45 g (11.3 mmol) of 2-nitrobenzyl bromide and 4.75 g (56.5 mmol) of sodium hydrogencarbonate were dissolved in ethanol, and the obtained solution was stirred at 70° C. overnight. The reaction solution was filtered, and the obtained filtrate was treated with ethyl acetate as the extracting solvent by an ordinary method to obtain the crude product. After the purification by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].C[Si](C)(C)[C:11]1[C:12]([F:18])=[C:13]([Br:17])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:17][C:13]1[C:12]([F:18])=[C:11]([C:5](=[O:7])[CH3:6])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)c1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
Aluminium trichloride (1.51 g, 11.3 mmol) in dry methylene chloride (10 ml) was cooled to 0° C. and acetyl chloride (0.80 ml, 11.3 mmol) was added in one portion. The mixture was stirred for 15 min. after which a solution of 3-trimethylsilyl-2-fluorobromobenzene (2.33 g, 9.4 mmol) in dry methylene chloride (10 ml) was added dropwise. The mixture was warmed to ambient temperature and stirred for 2 h. The mixture was kept at ambient temperature in a water bath and aqueous sodium carbonate (10%, 50 ml) was added slowly. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phase was dried MgSO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/isooctane, 1:1) yielded the title compound (1.7 g). MS m/z (rel. intensity, 70 eV) 218 (M+, 32), 216 (M+, 34), 203 (bp), 201 (97), 94 (61).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][C:6](=[O:8])[N:7]=1.[N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH:40]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][N:59]=[C:60]=[O:61])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:19]=[O:20]>N1C=CC=CC=1>[CH2:30]([CH:29]([CH:40]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60]([NH:1][C:2]1[NH:3][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][C:6](=[O:8])[N:7]=1)=[O:61])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:18][C:19]([NH:1][C:2]1[NH:3][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][C:6](=[O:8])[N:7]=1)=[O:20])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCc1cc(=O)nc(N)[nH]1
Reactant: CCCCCCCCCCC(CCCCCCCCN=C=O)C(CCCCCCCCCC)CCCCCCCCN=C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCC(CCCCCCCCNC(=O)Nc1nc(=O)cc(CCCCCCCCC)[nH]1)C(CCCCCCCCCC)CCCCCCCCNC(=O)Nc1nc(=O)cc(CCCCCCCCC)[nH]1
Reaction time: 24 h
Yield: 97.2 %

Procedure:
In a 250 mL round-bottomed flask was added 2-amino-6-nonylpyrimidin-4(1H)-one (1.88 g, 7.92 mmol) in Pyridine 50 mL to give a white suspension. The mixture was heated to 50 deg/C. 11,12-bis(8-isocyanatooctyl)docosane (2.327 g, 3.77 mmol) was dissolved in 5-10 mL of pyridine and added all at once to the mixture. The reaction was heated to 75 deg/C. and stirred for 24 h. The pyridine was removed and the residue was taken up in chloroform and the viscous solution was dripped into a rapidly stirring solution (500 mL) of MeOH upon which a white solid formed. The solution was decanted off and the residue was taken up in MeOH (10 ml) and rapidly stirred for 1 h. The product was collected by vacuum filtration dried under vacuum to give 4 g of 1,1′-(9,10-didecyloctadecane-1,18-diyl)bis(3-(6-nonyl-4-oxo-1,4-dihydropyrimidin-2-yl)urea).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN.[CH2:14]([N:16](CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Br)cc1
Reaction time: 18 h
Yield: 78.1 %

Procedure:
Add a solution of 4-bromo-benzenesulfonyl chloride (5.0 g, 19.2 mmol) in 10 mL THF at r.t. to a solution of methylamine (9.6 ml, 2 M in THF, 19.2 mmol) and triethylamine (2.72 mL, 19.2 mmol) over a period of 60 min and stir for 18 h. Add further methylamine (9.6 ml, 2 M in THF, 19.2 mmol) and triethylamine (2.72 mL, 19.2 mmol) and stir for 18 h. Evaporate the solvent under vacuum and add dichloromethane. Wash the organic layer with saturated aqueous sodium bicarbonate solution, followed by saturated sodium chloride solution. Filter through a hydrophobic filter paper and remove the solvent under vacuum. Further purify this material via column chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in hexane to afford the title compound (3.75 g) as a white solid. MS (m/e): 251 (M+H).
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C@H:16]([NH:18][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OCCC1=CO
Reactant: C[C@@H](N)c1ccccc1
Agent: [Na]
Product: C[C@@H](NC=C1CCOC1=O)c1ccccc1
Yield: 70.9 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and (R)-1-phenylethylamine (55 mmol) and proceeding according to the abovementioned method A1, (R)-3-(1-phenylethylamino)methylenedihydrofuran-2-one (7.70 g, efficiency: 71%) is produced in the form of a white powder.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O>CN(C=O)C.O.CN(C=O)C.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]>[N+:9]([C:4]1[CH:3]=[C:2]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:11])=[O:10]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
4-Bromo-2-nitroaniline (1.0 eq) and Na2CO3 (2.0 eq) were dissolved in DMF/H2O (5:1) at room temperature. Nitrogen was bubbled through the reaction mixture for 5 minutes and PdCl2(dppf)2 (0.1 eq) was added. After stirring at 23° C. for approximately 10 minutes, 2-thiopeneboronic acid (1.1 eq) in DMF was added and the reaction was heated at 90° C. for 12 hours. After this time, the solution was concentrated and partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting black residue was purified by silica gel chromatography (0-20% EtOAc:hexanes) to yield an orange solid. LC/MS m/z 221.1 (MH+), Rf 2.67 minutes.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]1([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]4[C:26]5[C:21](=[N:22][C:23]([C:27]6[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=6[F:37])=[CH:24][CH:25]=5)[N:20](C5CCCCO5)[N:19]=4)[CH:15]=3)[C:10]2=[O:44])[CH2:8][CH2:7]1>C(Cl)Cl.CO>[Cl:4][C:32]1[C:31]([O:33][CH3:34])=[CH:30][C:29]([O:35][CH3:36])=[C:28]([F:37])[C:27]=1[C:23]1[N:22]=[C:21]2[NH:20][N:19]=[C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[C:10](=[O:44])[N:9]([CH:6]3[CH2:8][CH2:7]3)[CH2:17]4)[C:26]2=[CH:25][CH:24]=1
Reactant: COc1cc(OC)c(F)c(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)n[nH]c3n2)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sulfuryl chloride (10. μL, 0.12 mmol) was added to a stirring solution of 2-cyclopropyl-5-[6-(2-fluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one (65 mg, 0.12 mmol) in methylene chloride (1 mL). The mixture was stirred at r.t. for 30 min. It was concentrated to dryness. The solid was dissolved in methanol (0.3 mL). To the solution was added a solution of HCl previously prepared from acetyl chloride (0.15 mL) and methanol (0.15 mL). The mixture was stirred at r.t. for 1 h and then diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=479.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.CN.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([NH:34][CH3:33])=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with methylamine, HATU and DIPEA in THF to give 330 as a colorless solid after reverse phase HPLC. MS: (ESI+) 453.0
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([NH2:43])([CH3:42])([CH3:41])[CH3:40]>CO>[C:39]([NH:43][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:22])[CH:21]=[C:12]([C:11]3[CH:28]=[C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[O:13]2)=[CH:18][CH:17]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)oc2c1

Procedure:
A solution of 3′,5′-dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 28 (2.5 g, 4.9 mmol) and tert-butyl amine (1.05 mL, 9.8 mmol) in dry methanol (150 mL) was stirred at reflux for 6 h. Reaction mixture was concentrated on rotavapor and crude product purified by column chromatography to afford 34. Yield 2.6 g (93%); mp 170-171° C.; MS (FAB) 580 (M++1); IR (KBr) 3428, 1648; 1H NMR (200 MHz, CDCl3) δ 8.02 (d, J=8.8 Hz, 1H), 7.59-7.33 (m, 10H), 7.13 (d, J=1.9 Hz, 2H), 7.07 (s, 1H), 7.01 (dd, J=9.8 Hz, 2.0 Hz, 1H), 6.76 (s, 1H), 6.71 (s, 1H), 5.12 (s, 4H), 4.57-4.54 (m, 1H), 4.27-4.16 (m, 2H), 3.24 (d, J=10.5 Hz, 1H), 3.05 (t, J=10.6 Hz, 1H), 1.45 (s, 9H); 13C NMR δ 178.3, 163.5, 163.2, 160.7, 158.1, 136.8, 133.9, 129.0, 128.6, 127.9, 127.5, 118.3, 115.2, 108.0, 105.9, 101.5, 72.9, 70.8, 67.5, 54.0, 45.3, 28.1. Analysis Calcd for C36H37NO6: C, 74.59; H, 6.43; N, 2.42. Found: C, 74.44; H, 6.35; N, 2.51.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH:10]1([C:16]#[CH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.C1COCC1>C([O-])(O)=O.[Na+].CCOC(C)=O.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.[Cu]I>[CH:10]1([C:16]#[C:17][C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C#CC1CCCCC1
Reactant: N#Cc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C#CC2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
Under a nitrogen atmosphere, add 5-bromo-2-cyano-pyridine (1.5 g, 8.2 mmol), cyclohexylacetylene (0.887 g, 8.2 mmol), dichlorobis(triphenylphosphine)palladium (575 mg, 0.82 mmol), copper(I) iodide (234 mg, 1.23 mmol) and triethylamine (11.4 mL, 82 mmol) to THF (50 mL). Heat the mixture to reflux and stir for 4 h. Cool the mixture to room temperature and dilute with saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL). Separate the layers and extract the aqueous layer with EtOAc (4×30 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 9:1 gradient over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (1.28 g, 74%). MS (APCI+) m/z: 211 (M H)+.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.S(Cl)([Cl:37])=O>C(Cl)Cl>[Cl:37][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1cccc2nc(CO)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cccc2nc(CCl)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of ethyl 2-hydroxymethyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in CH2Cl2 (3 ml) was added thionyl chloride (0.3 ml) dropwise and the mixture was refluxed for 3 hours. The reaction solution was poured into ice-water and the organic layer was washed with water, dried and evaporated to dryness to give a pale yellow amorphous powder (0.2 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([CH3:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1.C1C(=O)N([Br:37])C(=O)C1>ClCCl>[Br:37][C:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:8]([CH3:24])=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A mixture of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (0.41 g, 0.001 mol, from Step 3) and NBS (0.2 g, 0.0011 mol) in dichloromethane (5.0 mL) is stirred at room temperature for 1.5 h under argon atmosphere. The reaction mixture is purified by flash chromatography using 30% EtOAc in hexanes to furnish the title compound (0.37 g, 75%) as a white amorphous powder: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.89 (d, 1H, J=1.6 Hz), 7.62 (m, 2H), 7.01 (m, 2H), 5.56 (s, 2H), 3.89 (s, 3H), 2.15 (s, 3H), and 2.133 (s, 3H); ES-HRMS m/z 479.0412 (M+H calcd for C21H18N2O4F2Br requires 479.0413). 19F NMR(CD3OD/400 MHz) −111.870 (m) and −115.95 (m).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][CH:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[CH:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:36])=[N:4][CH:5]=1)[CH2:25][C:26]([F:28])([F:29])[F:27]
Reactant: CC(=O)O
Reactant: N#Cc1ncc(NC(CC(F)(F)F)C(N)=O)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(NC(CC(F)(F)F)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4,4,4-trifluorobutanamide (5 mg, 0.012 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (4 mg). MS 420.3 (M+H); UV 204.7, 263.3, 297.7 nm; t 0.417 min.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C:33]3[CH:41]=[C:40]4[C:36]([C:37]([NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])=[N:38][N:39]4COCC[Si](C)(C)C)=[CH:35][CH:34]=3)[CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1.C(OCC)(=O)C>[C:19]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C:33]3[CH:41]=[C:40]4[C:36]([C:37]([NH:50][C:51](=[O:55])[CH2:52][CH2:53][CH3:54])=[N:38][NH:39]4)=[CH:35][CH:34]=3)[CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cccc(OCc4ccccc4)c3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3cccc(OCc4ccccc4)c3)ccc12
Yield: 57.5 %

Procedure:
2.9 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[6-[3-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours. The reaction medium is diluted with 100 cm3 of ethyl acetate and the organic phase is washed successively with 50 cm3 of saturated sodium hydrogen carbonate solution, with 2×50 cm3 of water and with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2 kPa; 50° C.). The crude product obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate gradient (70/30 to 40/60 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 0.43 g of N-[6-[3-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide is obtained in the form of a white powder.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]1([CH2:26][OH:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[OH:27][CH2:26][C:20]1([NH:19][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: NC1(CO)CCCCC1
Agent: Cl
Product: O=C(NC1(CO)CCCCC1)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.214 mmol) and (1-amino-cyclohexyl)-methanol hydrochloride (CAN 5460-68-4, 22.8 mg, 0.17 mmol) as starting materials and isolated (46 mg, 62.32%) as white solid; LC-MS (UV peak area, ESI) 96.49%, 346.0 (M+H)+.