Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CCOC(C)=O>CCOC(C)=O.CCOCC>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][NH:28][CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(C#N)c3)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(C#N)c2)n(-c2ccc3c(c2)CNCC3)n1
Temperature: 22.5 °C
Reaction time: 6.5 h
Yield: 50.3 %

Procedure:
To t-butyl 7-(3-t-butyl-5-(3-(3-cyanophenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.34 g, 0.66 mmol) in EtOAc (5.0 ml) was added 3M HCl/EtOAc (1.1 mL, 3.3 mmol). The resulting mixture was stirred at 20-25° C. for 6.5 h. The suspension was diluted with Et2O to fully precipitate the solids. These were collected by filtration, rinsed with Et2O and dried to yield 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(3-cyanophenyl)urea (0.1377 g, 46% yield) of as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 10.1 (s, 1H), 9.47 (brs, 2H), 8.97 (s, 1H), 7.94-7.93 (m, 1H), 7.63-7.60 (m, 1H), 7.49-7.33 (m, 5H), 6.37 (s, 1H), 4.36 (brs, 2H), 3.37 (brs, 2H), 3.06-3.03 (m, 2H), 1.28 (s, 9H); MS (ESI) m/z: 415.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]=1)(=[O:5])=[O:4].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[F:19][C:2]([F:1])([F:18])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OC1=CCCc2cc(F)ccc21)C(F)(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=S(=O)(Oc1cccc2cc(F)ccc12)C(F)(F)F

Procedure:
To a solution of 6-fluoro-3,4-dihydro-1-naphthalenyl trifluoromethane sulfonate (0.77 g, 2.8 mmol) in dioxan (15 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.95 g, 4.2 mmol) and the reaction mixture heated under reflux for 18 h. The solvent was removed in vacuo and the crude product purified by column chromatography on silica, eluting with hexane, to yield 6-fluoro-1-naphthyl trifluoromethanesulfonate as a white solid.
Reaction SMILES: C1COCC1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.CCOCC.[CH:20](=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23].C1(C)C=CC=CC=1>O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH:20]([OH:28])[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[OH:23])=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1O
Reactant: Cc1ccc([Mg]Br)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C(O)c2ccccc2O)cc1
Reaction time: 2 h
Yield: 112.3 %

Procedure:
To a 500 ml round bottom flask containing 100 mL of THF under Ar was added commercial 1 M p-methylphenyl magnesium bromide/Et2O (100 mL, 100 mmol). Subsequently, salicylaldehyde (4.9 g, 40.3 mmol) was added dropwise in four equal portions spaced over 2 hr. After 20 min, once HPLC analysis revealed the aldehyde to be consumed, the reaction was quenched by dropwise addition of 26 ml of sat'd NH4Cl/H2O to produce a white paste. To this suspension was added 200 mL of PhMe and sufficient H2O to permit stirring. The organic layer was decanted whereupon the white paste was triterated a second time with 1:1 THF/PhMe. After decanting, the combined organic layers were concentrated using a rotary evaporator to obtain 9.7 g of crude 4-methyl-2′-hydroxybenzhydrol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19].[OH-].[K+]>CO>[C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:19][C:18](=[O:20])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (364 mg, 1.56 mmol) was dissolved in MeOH (10 ml) and the solution was cooled to 0° C. Acetophenone (188 mg, 1.56 mmol) and 1.7M KOH (1.8 ml) were added. The reaction was stirred at 0° C. for 3 h. The resulting solid was filtered on a Buckner funnel to give 130 mg of 3-[5-(3-oxo-3-phenyl-propenyl)-pyridin-2-yl]-acrylic acid tert-butyl ester as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Fc1cc2nc(Cl)[nH]c2cc1F
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(F)c(F)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.943 g (5 mmole) of 12 in 25 mL of ClCH2CH2 Cl, was added 1.25 mL (5 mmole) of BSA at 75° C. The reaction mixture was stirred at 75° C. for 30 min. To this solution, was added 1.75 g (5.5 mmole) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.07 mL (5.5 mmole) of TMSOTf. Stirring was continued at 75° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with 100 mL of CHCl3, and extracted with sat. NaHCO3 solution (100 mL×2) and sat. NaCl solution (100 mL). The CHCl3 phase was dried (Na2SO4) and evaporated. The residue was chromatographed on a silica column (3×25 cm, eluted successively with 0.5%, 1% MeOH/CHCl3). Evaporation of the appropriate fractions and recrystallization of the residue from MeOH gave 1.257 g (3 crops, 56%) of 64 as crystalline needles. MP 90°-91° C.; MS m/e 446.0694 (5%, M+ =446.0692); 1H NMR (DMSO-d6) d 7.93 (dd, 1, 7-H, 3JF-H =10.5 Hz, 4JF-H =7.5 Hz), 7.82 (dd, 1, 4-H, 3JF-H =10.5 Hz, 4JF-H =7.5 Hz), 6.23 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.55 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.44 (m, 1, 3'-H, J3-4 =4.5 Hz), 4.45 (m, 3, 4'-H and 5'-H), 2.13, 2.10, 2.02 (3×s, 9, 3×Ac); 13C NMR (DMSO-d6) d 169.95, 169.50, 169.18 (3×OCOCH3), 148.76, 148.62, 146.10, 145.93 (C5 and C6, 1JF-C =242 Hz), 140.16 (C2), 137.01 (C3a, 3JF-C =12 Hz), 128.54 (C7a, 3JF-C =12 Hz), 107.31, 107.09 (C4, JF-C =20 Hz), 100.93, 100.66 (C7, JF-C =24 Hz), 86.89 (Cl'), 79.41 (C4'), 70.40 (C2'), 68.62 (C3'), 62.67 (C5'), 20.43, 20.28, 20.00 (3×OCOCH3).
Reaction SMILES: O[C:2]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:16])[C:3]=1[CH3:17].P(Cl)(Cl)([Cl:20])=O.CN(C)C1C=CC=CC=1>>[Cl:20][C:2]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:16])[C:3]=1[CH3:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c(C)c(=O)n2c1CCC2
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n2c1CCC2
Reaction time: 16 h
Yield: 62.9 %

Procedure:
Compound 8b (659 mg, 2.8 mmol) was stirred in phosphorous oxychloride (1.5 mL, 15.8 mmol) at RT. Dimethylaniline (0.07 mL, 0.56 mmol) was added and the reaction stirred for 16 h. The solution was concentrated in vacuo, quenched with ice, and made basic with sat. NaHCO3 solution. The aqueous solution was concentrated in vacuo. The residue was taken up in a 20% MeOH/CH2Cl2 and insoluble inorganic salts were removed by filtration. Organics were concentrated and purified by silica gel chromatography (75% EtOAc/CH2Cl2) to give 450 mg (63%) of compound 8c as a white solid. MS (ES) [m+H] calc'd for C12H14ClNO3, 256. found 256.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>O.ClC(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cccc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)c1C
Temperature: 190 °C
Yield: 30 %

Procedure:
A mixture of 3.9 parts of 3,6-dichloro-4,5-dimethylpyridazine, 4.2 parts of 1-(2,3-dimethylphenyl)piperazine and 2.94 parts of potassium carbonate was stirred and heated for 4 hours in an oil bath at 190° C. After cooling, the mixture was taken up in water and trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2 parts (30%) of 3-chloro-6-[4-(2,3-dimethylphenyl)-1-piperazinyl]-4,5-dimethylpyridazine; mp. 194.5° C. (compound 217).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH2:34]O)[CH:12]=2)[N:7]=1>ClCCl>[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[CH2:34][Cl:3])[CH:12]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CO)ccc2n1
Solvent: ClCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CCl)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
218 μl of thionyl chloride are added dropwise to 622 mg of [2-amino-6-(2-hydroxymethyl-5-fluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 50 ml of dichloromethane, and the mixture is stirred at 25° C. for 2 h. The mixture is evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, and the operation is repeated. The residue is employed in the subsequent reactions without further treatment.
Reaction SMILES: [C:1]1([NH:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][Cl:19]>C1(C)C(C)=CC=CC=1>[Cl:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][Cl:19])[S:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])=[O:9]
Reactant: ClCCNCCCl
Reactant: O=S(=O)(Cl)Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=S(=O)(Nc1ccccc1)N(CCCl)CCCl
Temperature: 100 °C

Procedure:
66 g of the product obtained in Step 1 above are added to a suspension of 38.6 g of N,N-bis(2-chloroethyl)amine hydrochloride in 265 ml of xylene heated to 100° C. The reaction mixture is heated at 140° C. for 12 hours and, after cooling, filtered over a frit. The filtrate is concentrated and then purified by flash chromatography (eluant CH2Cl2/AcOEt: 95/5) to yield the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[CH:10][NH:11][C:6]2=[CH:5][C:4]=1[O:12][CH3:13].Cl[C:15]1([C:21]([O:23][CH3:24])=[O:22])[C:19](=[O:20])[CH:18]=[CH:17][S:16]1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:17]3[S:16][C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([OH:20])[CH:18]=3)[CH:10]=[N:11][C:6]2=[CH:5][C:4]=1[O:12][CH3:13]
Reactant: COc1cc2[nH]cnc2nc1OC
Reactant: COC(=O)C1(Cl)SC=CC1=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)nc32)cc1O

Procedure:
In a similar manner as described for example C6, 1.50 g of the above-synthesized 5,6-dimethoxy-1H-imidazo[4,5-b]pyridine and 0.81 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 40 ml chloroform yield the title compounds as an isomeric mixture which was used for the next step without further purification (example B4).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4]1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O.CCN(CC)CC>>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=CO
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4ccc(Cl)cc43)cc2)C1
Yield: 49.3 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine hydrochloride (158 mg, 1.2 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (100 mg, 0.51 mmol, 1 equiv.) with the addition of anhydrous Et3N (2.11 equiv.) are reacted to give the named compound as a yellow solid (100 mg, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].[OH-].[K+]>C(O)(=O)C>[N+:19]([C:15]1[CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([O:17][CH3:18])=[CH:11][C:12]=1[C:13]#[N:14])([O-:21])=[O:20]
Reactant: COc1cc(C#N)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-benzyloxy-3-methoxybenzonitrile (4.78 g, 20 mmol) in acetic acid (10 ml) was slowly added to nitric acid (25 ml) at 20° C. to 30° C. The mixture was stirred at room temperature for 6 hours, basified (pH 10-11) with cooling (KOH 10N), extracted with methylene chloride, dried over MgSO4 evaporated. The solid was recristallysed in hot EtOAc, a yellow solid of title compound was obtained (3.62 g, 64%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:22]Cl.[Na+]>CN(C=O)C.O.CCOC(C)=O>[CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([C@@:10]2([CH3:12])[CH2:11][O:22]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [O-]Cl
Reactant: C=C(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)[C@@]1(C)CO1
Reaction time: 2 h
Yield: 65 %

Procedure:
To (S)-tert-butyl (1-cyclohexyl-4-methyl-3-oxopent-4-en-2-yl)carbamate (5.36 g, 18.1 mmol) in DMF at −10° C. was added NaOCl (47.1 mL of a 9.5% w/w solution, 36.2 mmol). Addition of NaOCl was performed at a rate to maintain an internal temperature of ≦−10° C. After the addition was complete the reaction mixture was transferred to an ice bath and stirred for an additional 2 h at which time it was diluted with water and EtOAc, extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 heptane/EtOAc) provided tert-butyl ((S)-3-cyclohexyl-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)carbamate (3.68 g, 65%) as a colorless amorphous solid. MS (EI) for C17H29NO4, found 310.2 (MH−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Br[C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=1)[C:25]([C:27]1[CH:37]=[C:36]([CH3:38])[C:30]2[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=2[CH:28]=1)=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:24]3[CH:39]=[C:40]([N:15]4[CH2:14][CH2:13][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=6[NH:7][C:8]5=[O:18])[CH2:17][CH2:16]4)[CH:41]=[CH:22][CH:23]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: Cc1cc(C(=O)c2cccc(Br)c2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cccc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c3)CC1)C(=O)N2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Under an argon atmosphere 330 mg (1.20 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 350 mg (1.01 mmol) 6-(3-bromo-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one and 586 mg (1.80 mmol) caesium carbonate were stirred in 10 mL xylene, then combined with 56 mg (0.090 mmol) BINAP and 20 mg (0.089 mmol) palladium(II)acetate and stirred for 48 h at 100° C. The mixture was evaporated down i. vac., the residue was dissolved in DMF/MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and the acetonitrile was evaporated down. The aqueous residue was made basic with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered and washed with water and dried. The product was again purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[N:34][CH:33]=[C:32](Cl)[N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[N:31]=[C:32]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:33]=[N:34][CH:35]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cncc(Cl)n2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0499 g, 0.130 mmol) and 2,6-Dichloropyrazine (0.0311 g, 0.209 mmol) were combined then added dry N,N-Dimethylformamide (0.911 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.40 (s, 1H), 8.22 (d, J=8.8, 2H), 7.90 (s, 1H), 7.49 (d, J=8.8, 2H), 6.17 (t, J=5.5, 1H), 4.69 (d, J=16.4, 2H), 3.86 (t, J=5.1, 2H), 3.79-3.69 (m, 4 H), 3.49 (d, J=4.3, 4H), 3.18-3.06 (m, 2H), 2.80 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+
Reaction SMILES: [CH3:1][Si:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])OCC.[Mg].Br[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1>O1CCCC1>[CH3:1][SiH:2]([O:6][CH2:7][CH2:8][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]1[CH:11]=[CH:10][C:9]([SiH:2]([CH3:1])[O:6][CH2:7][CH2:8][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: CCO[Si](C)(OCC)c1ccccc1
Reactant: Brc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C[SiH](OCCc1ccccc1)c1ccc([SiH](C)OCCc2ccccc2)cc1
Reaction time: 3 h
Yield: 147.5 %

Procedure:
21.0 g of methylphenyldiethoxysilane, 2.43 g of magnesium and 100 ml of tetrahydrofuran were charged into a 500-ml, three-necked flask provided with a stirrer, a cooler, and a dropping furnel and stirred in a nitrogen gas stream, while 100 ml of a tetrahydrofuran solution containing 11.8 g of p-dibromobenzene was dropwise added thereto from the dropping furnnal over about 3 hours. After the dropwise addition, the mixture was further stirred and refluxed for about 5 hours. After the refluxing, the resulting polymer was separated by filtration, and the solvent was removed therefrom by distillation. The residues were subjected to distillation under reduced pressure, whereby 15 g of p-bis(methylphenylethoxysilyl)benzene was obtained (yield: 78%, boiling point: 213°-215° C./3 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH2:28])[CH:23]=[CH:22]2.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH:28][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:16])[CH:23]=[CH:22]2
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Reactant: Nn1ccc2cc(F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1 mmol) and K2CO3 (1 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt, then stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is crystallized from EtOAc/heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (62 mg, 17%) as a solid. MS: 365 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.82 (s, H), 6.55 (s, H) 6.90-7.41 (m, 4H), 7.49 (m, H), 8.26 (d, 2H), 8.57 (br, H), 8.96 (br, H). IC50=19 nM.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[NH:11][C:10]([CH2:12][O:13][CH3:14])=[N:9][C:8]=1[C:15]([O:18][CH3:19])([CH3:17])[CH3:16])=O.Cl.[NH2:22][C:23]([NH2:25])=[NH:24].C[O-].[Na+]>C(O)CCC>[NH2:24][C:23]1[N:25]=[C:5]([C:7]2[NH:11][C:10]([CH2:12][O:13][CH3:14])=[N:9][C:8]=2[C:15]([O:18][CH3:19])([CH3:17])[CH3:16])[CH:4]=[CH:3][N:22]=1
Reactant: N=C(N)N
Reactant: COCc1nc(C(C)(C)OC)c(C(=O)C=CN(C)C)[nH]1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: COCc1nc(C(C)(C)OC)c(-c2ccnc(N)n2)[nH]1
Yield: 60.4 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-methoxyisopropyl-2-methoxymethylimidazole (Method 56; 3.13, 11.1 mmol) and guanidine hydrochloride (2.65 g, 27.8 mmol) were suspended in 1-butanol (20 ml). Sodium methoxide (2.4 g, 44 mmol) was added in one portion and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The volatiles were removed by evaporation. Water (50 ml) was added and extracted EtOAc (3×50 ml). The organic layers were combined and dried with Chemelut CE1010 and the solvent evaporated in vacuo. The residue was purified by flash silica chromatography eluting with DCM:MeOH (100:0 increasing in polarity to 95:5) to give the title compound as an orange solid (1.86 g, 60%). NMR: 1.43 (d, 3H), 3.16 (s, 3H), 3.24 (s, 3H), 3.63 (m, 1H), 3.89 (m, 1H), 4.50 (q, 2H), 5.26 (m, 1H), 6.57 (s, 2H), 6.80 (d, 1H), 7.40 (s, 1H), 8.21 (d, 1H); m/z 278.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[CH:24]=2)=[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[CH:14]4)[O:8][C:7]=12.[ClH:38]>CCOC(C)=O>[ClH:38].[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:9]3[O:8][C:7]4=[C:2]([NH2:1])[N:3]=[CH:4][C:5]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]6)[CH:24]=5)=[C:6]4[CH:10]=3)=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5ccc6[nH]ncc6c5)cc34)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3ccc4[nH]ncc4c3)oc12
Yield: 60 %

Procedure:
A solution of crude tert-butyl 4-{4-[7-amino-2-(1H-indazol-5-yl)furo[2,3-c]pyridine-4-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (from Step A) in EtOAc was treated with HCl (4 M in EtOAc, 5 mL, 5 mmol) for 60 min. The reaction was filtered to afford 24 mg (60%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 8.89 (s, 1 H), 8.41 (s, 1 H), 8.08 (s, 1 H), 8.04 (d, J=7.07 Hz, 1 H), 7.89 (s, 1 H), 7.86 (s, 1 H), 7.78 (d, J=8.59 Hz, 1 H), 7.57-7.63 (m, 1 H), 4.67-4.77 (m, 1 H), 3.57-3.65 (m, 2 H), 3.22-3.29 (m, 2 H), 2.37-2.46 (m, 4 H); MS (ESI): 400.09 [M+H]+; HPLC tR=1.81 min.