Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[CH3:2][NH+:3]1[C:19]2[C:11]([N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:10][C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2>C([O-])([O-])=O.[Na+].[Na+]>[CH3:2][N:3]1[C:19]2[C:11]([N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:10][C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: C[NH+]1C2=c3ccccc3=NC2=Cc2ccccc21
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1c2c3ccccc3nc-2cc2ccccc21
Yield: 51.3 %

Procedure:
5-Methylquindolinium hydroiodide (1.5 g, 4.2 mmol) from Example 3 was shaken with a 5% solution of Na2CO3 (100 mL) and extracted with chloroform (2×200 mL). The extract of the free base was purified on a basic alumina column using chloroform to elute the quindoline impurity; elution with 1-2% methanol in chloroform gave 0.5 g of the title compound as a purple solid, mp 178-180° C. [lit 166-169° C. (Gellert, E.; Raymond-Hamet; Schlittler, E. Helv. Chim. Acta 1951, 34, 642-651)]; 1H NMR (DMSO-d6) δ 8.92 (s, H11), 8.50 (d, J=9.2, 1H, H4), 8.47 (d, J=8.4, 1H, H6), 8.38 (d, J=8.4, 1H, H1), 7.89 (t, J=7.6, 1H, H3), 7.69-7.64 (m, 2H, H2 and H9), 7.52 (t, J=8.4, 1H, H8), 7.02 (t, J=8.4, 1H, H7), 4.90 (s, 3H, NCH3); 13C NMR (DMSO-d6) δ 160.46, 144.76, 138.96, 132.56, 130.13, 129.47, 128.66, 126.15, 124.97, 124.26, 123.60, 119.30, 116.36, 116.23, 113.64, 38.73.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:18]=1[CH3:36].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:21]1[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:18]([CH3:36])=[C:17]([Cl:16])[N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: NC[C@@H]1COCCN1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nc(NC[C@@H]2COCCN2Cc2ccccc2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 32.9 %

Procedure:
A solution of [(3R)-4-benzylmorpholinyl]methylamine (preparation 95) (4.2 g, 20.4 mmol), benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (1 g, 3.06 mmol), and triethylamine (0.7 ml, 5.0 mmol) in ethyl acetate (25 ml) was heated under reflux for 18 hrs. The cooled reaction mixture was diluted with ethyl acetate, washed with water, then brine, dried over MgSO4 and concentrated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 100:0) to give the title compound as a white solid, (500 mg, 32%).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC[O-].[Na+].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:16]1[N:17]([CH2:27][C:28](OC(C)(C)C)=[O:29])[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=1>CO>[NH2:4][C:3](=[NH:5])[NH:2][C:28](=[O:29])[CH2:27][N:17]1[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:19][CH:20]=[C:16]1[CH2:15][C:11]1[O:10][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(N)N
Reactant: CC(C)(C)OC(=O)Cn1c(Cc2ccco2)ccc1-c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)NC(=O)Cn1c(Cc2ccco2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of guanidine hydrochloride in anhydrous MeOH (1.5 ml) was added powder NaOEt (80 mg. 1.17 mmol). After 10 min stirring at room temperature, the reaction mixture was treated with tert-butyl [2-(2-furylmethyl)-5-phenyl-1H-pyrrol-1-yl]acetate. After 5 h stirring at 55° C., the reaction mixture was cooled and quenched with H2O (5 ml), diluted with EtOAc (15 ml). The organic layer was separated and the aqueous was extracted with EtOAc (2×15 ml). The combined organic extracts were washed with H2O (15 ml), brine (15 ml), dried (Na2SO4) and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/2M NH3 in MeOH: 97/3) to give the titled compound (73 mg, 57%) as a solid: mp 80-82° C.; MS (−) ES, 321 (M−H)−.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13].[CH3:34][CH2:35][C:36](=[O:39])[CH2:37][CH3:38]>O1CCCC1>[CH2:12]([C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:36]([CH2:37][CH3:38])([OH:39])[CH2:35][CH3:34])=[C:19]([CH3:25])[CH:18]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCC(=O)CC
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C)CC
Reaction time: 3 h
Yield: 65.8 %

Procedure:
A 2.5 M solution of n-butyllithium in hexane (14.7 mL, 36.73 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 4.28 g, 14.69 mmol) in tetrahydrofuran (92 mL) at −78° C. Pentan-3-one (4.85 mL, 44.07 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for three hours and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and a 1 N hydrochloric acid aqueous solution was added to adjust the pH to about 7. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=6/1) to give the title compound (3.66 g, 62%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[N:12]=[C:11](Cl)[N:10]=[C:9]([CH3:14])[N:8]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:6][C:7]1[N:8]=[C:9]([CH3:14])[N:10]=[C:11]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: COCCN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1nc(C)nc(Cl)n1
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
2-methoxyethanamine (Aldrich, 0.350 g, 4.66 mmol) was added to a solution of 2,4-dichloro-6-methyl-1,3,5-triazine (0.80 g, 4.88 mmol) in dioxane (10 mL). Heat was generated. Hünig's base (1.0 mL, 5.73 mmol) was added and the mixture was stirred for 5 min. The mixture was partitioned between DCM (15 mL) and water. The organic phase was dried over Na2SO4 and concentrated. The resulting yellow oil was purified by chromatography on silica using EtOAc in hexane (20-80%) to give the desired product as a yellow solid (300 mg). LCMS (ES, pos.): calcd for C2H11ClN4O: 202.1. found: 203.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 5.93 (br. s., 1H); 3.60-3.70 (m, 2H); 3.49-3.58 (m, 2H); 3.38 (s, 3H); 2.42 (d, 3H).
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH:2]=[CH2:3].C(N(CC)CC)C.Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)(Cl)Cl.C(OC(=O)C)C>[CH2:1]([N:4]([C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH2:5])[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: C=CCNN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCN(N)C(C)(C)C(=O)OCC
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 70%-allylhydrazine (7.73 ml, 75 mmol) and triethylamine (1048 ml, 75 mmol) in chloroform (25 ml) was added ethyl 2-bromo-2-methylpropanoate (9.75 g, 50 mmol) and the mixture was sittred for 1 hr and then refluxed overnight. The reaction mixture was diluted with ethylacetate (150 ml) and washed with water (100 ml) and brine (100 ml). Then the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (eluent: chloroform:methanol=95:5) to obtain the title compound (5.0 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:5]([N+:14]([O-])=O)[CH:4]=1.O1CCCC1>O>[NH2:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: COc1ccc(-n2cccc2)c([N+](=O)[O-])c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2cccc2)c(N)c1

Procedure:
A stirred solution of 33.5 g (0.154 mole) of 1-(4-methoxy-2-nitrophenyl)pyrrole in 684 ml. of tetrahydrofuran and 340 ml. of water is treated according to the manipulative procedure described in Example 13(b) to give 1-(2-amino-4-methoxyphenyl)pyrrole, m.p. 42°-43° C.
Reaction SMILES: [OH:1]S(O)(=O)=O.[C:6]([O:10][C:11](=[O:27])[N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][CH2:24][OH:25])[CH:20]=[CH:19][C:18]=1[Cl:26])[CH:13]1[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>O.CC(C)=O>[C:6]([O:10][C:11]([N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][C:24]([OH:1])=[O:25])[CH:20]=[CH:19][C:18]=1[Cl:26])[CH:13]1[CH2:14][CH2:15]1)=[O:27])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)ccc1Cl)C1CC1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Conc. H2SO4 (98%, 5.80 mL) was carefully added to a suspension of CrO3 (6.70 g, 67.0 mmol) in water (12.5 mL). Water was slowly added up to a total volume of 22.5 mL, at which stage the mixture was a clear sol. This sol. was added dropwise to a sol. of [2-chloro-5-(2-hydroxy-ethyl)-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (13.0 g, 39.9 mmol) in acetone (140 mL) at 0° C. When the addition was complete, the mixture was stirred at 0° C. for 30 min. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and the resulting mixture was washed with aq. 1M HCl. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (12.2 g, 90%) that was used further without purification. LC-MS: tR=0.95 min; ES+: 325.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)=[CH:11][C:10]([CH:22]=O)=[N:9]1.[CH3:24][NH2:25].CO.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=2)=[CH:11][C:10]([CH2:22][NH:25][CH3:24])=[N:9]1
Reactant: CN
Reactant: COc1cccc(Sc2cc(C=O)nn2-c2ccccc2Cl)n1
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(Sc2cccc(OC)n2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 1-(2-chlorophenyl)-5-[(6-methoxypyridin-2-yl)thio]-1H-pyrazole-3-carbaldehyde (404 mg) in tetrahydrofuran (4 mL) were added 40% methylamine-methanol solution (1.5 mL) and methanol (4 mL) at 0° C. The mixture was stirred at room temperature for 14 hr, and concentrated under reduced pressure. The residue was dissolved in methanol (4 mL), sodium borohydride (76 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 436 mg, yield quantitative).
Reaction SMILES: C([NH:4][OH:5])(=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:14]=[C:15]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[C:46](F)[CH:45]=2)[CH:16]=[C:17]([Cl:43])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]2)[C:21]1=[O:42]>CN(C=O)C.O.C(OCC)(=O)C>[NH2:51][C:50]1[C:47]2[CH:48]=[CH:49][C:44]([C:15]3[CH:16]=[C:17]([Cl:43])[C:18]([CH2:19][C@@H:20]4[CH2:24][CH2:23][N:22]([N:25]5[CH2:30][CH2:29][CH:28]([O:31][Si:32]([CH:33]([CH3:35])[CH3:34])([CH:36]([CH3:37])[CH3:38])[CH:39]([CH3:40])[CH3:41])[CH2:27][CH2:26]5)[C:21]4=[O:42])=[C:13]([Cl:12])[CH:14]=3)=[CH:45][C:46]=2[O:5][N:4]=1
Reactant: CC(=O)NO
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C#N)c(F)c4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc5c(N)noc5c4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
Stir a mixture of acetohydroxamic acid (0.046 g, 0.61 mmol), potassium carbonate (0.169 g, 1.22 mmol) in DMF (5 mL) and water (2 mL) at room temperature for 10 minutes. To the mixture, add a solution of (R)-3′,5′-Dichloro-3-fluoro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carbonitrile (0.151 g, 0.244 mmol) and stir the reaction at room temperature for 5 hours and then at 60° C. for 1 hour. Cool the reaction, dilute with ethyl acetate (40 mL), and wash three times with water (15 mL each) then brine (15 mL). After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 0% to 50% ethyl acetate/hexane gradient to afford 0.095 g (62%) of the title compound. MS (m/z): 631 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([CH3:23])[C:19]([CH3:24])=[N:18][C:17]=2[C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:25]([C:16]3[C:17]4[N:18]=[C:19]([CH3:24])[C:20]([CH3:23])=[N:21][C:22]=4[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])=[CH:14][CH:15]=3)=[O:27])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3nc(C)c(C)nc23)c1Cl
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nc(C)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylic acid (Step 122.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture 18 h at rt. Title compound: ESI-MS: 595.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.15 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.Cl.[CH:20]1([NH:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C>[CH:20]1([N:26]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[F:8])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NNC1CCCCC1
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COc1ccc(-c2nn(C3CCCCC3)c3c(F)cccc23)cc1
Yield: 46.2 %

Procedure:
Prepared according to Method C step A (2,3-difluorophenyl)-(4-methoxyphenyl)-methanone (0.150 g, 0.6 mmol), cyclohexylhydrazine hydrochloride (0.90 g, 0.6 mmol) and DMAP (0.073 g, 0.6 mmol) to give 0.09 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:23][N:24](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].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>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Cl)cc1)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(C#N)cc1)C(C)(C)C
Temperature: 130 °C
Yield: 43 %

Procedure:
tert-Butyl 1-(4-chlorophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (Example 2a, 2.30 g, 7.06 mmol) and Zn(CN)2 (0.87 g, 7.4 mmol) were dissolved in DMF (20 mL) under N2 (g). Pd(PPh3)4 (0.86 g, 0.74 mmol) was added and the mixture was heated at 130° C. overnight. The mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The product was purified on a silica column (EtOAc:hexane 1:10) to give tert-butyl 1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (961 mg, 43%). tert-Butyl 1-(4-cyanophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (961 mg, 3.04 mmol) was dissolved in 1.25 M HCl in MeOH at 0° C. and the mixture was stirred at rt for 8 h. The solvent was removed and the residue dried in vacuo to give 4-(2-amino-3,3-dimethyl-butanoyl)-benzonitrile hydrochloride (110 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])=[O:9]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])=[O:9]
Reactant: CS(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)O)cc1Cl

Procedure:
A solution of the more polar product from Example 2 step d) (35 mg) in TFA (2 ml) was stirred for 24 h. The solvent was removed in vacuo, the mixture was azeotroped with toluene and purified by chromatography (silica, CH2Cl2-MeOH—AcOH as eluent) to give the title compound (22 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:76][CH3:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH:70]1[CH2:75][CH2:74][CH2:73][CH2:72][NH:71]1)[CH3:64].FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH:70]1[CH2:69][CH2:68][CH2:67][CH2:66][N:65]([CH2:76][CH3:77])[CH2:63][CH3:64])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(CC)CCCCC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)CCCCC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and diethyl-(4-piperidin-2-yl-butyl)-amine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]2[S:23][C:22]([C:24]3([OH:28])[CH2:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:5]1[C:6]([O:8][CH3:9])=[N:7][C:2]([NH:11][C:12]2[CH:13]=[C:14]([C:19]3[S:23][C:22]([C:24]4([OH:28])[CH2:27][CH2:26][CH2:25]4)=[N:21][CH:20]=3)[CH:15]=[C:16]([CH3:18])[CH:17]=2)=[N:3][CH:4]=1
Reactant: COc1nc(Cl)ncc1Cl
Reactant: Cc1cc(N)cc(-c2cnc(C3(O)CCC3)s2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1nc(Nc2cc(C)cc(-c3cnc(C4(O)CCC4)s3)c2)ncc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A flask was charged with a stir bar, 2,5-dichloro-4-methoxypyrimidine (69 mg, 0.38 mmol), Intermediate 15 (100 mg, 0.38 mmol), Pd2(dba)3 (35.2 mg, 0.038 mmol), XPhos (92 mg, 0.19 mmol), and potassium carbonate (106 mg, 0.77 mmol). The vial was fully evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (1.30 mL) was added to the reaction mixture, which was sealed and stirred at 90° C. overnight. The reaction was then cooled to room temperature. The crude mixture was taken-up in DCM and directly purified by Chromatography on silica gel (0-100% ethyl acetate/hexanes) to provide 1-(5-{3-[(5-chloro-4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutanol (93 mg, 0.23 mmol, 60%) as a dark blue solid. MS ESI: [M+H]+ m/z 403.1. 1H NMR (500 MHz, dmso) δ 9.78 (s, 1H), 8.32 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 6.50 (s, 1H), 4.05 (s, 3H), 2.56-2.50 (m, 2H), 2.36-2.27 (m, 5H), 1.94-1.82 (m, 2H). rhSYK activity=+++
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Reactant: OB(O)c1cccs1
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: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCc1nc(-c2cc(-c3cccs3)cc(C(F)(F)F)c2)co1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
A suspension of methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44, 0.454 g, 1.20 mmol), thiophene-2-boronic acid (0.230 g, 1.80 mmol) and sodium carbonate (0.954 g, 9.00 mmol) in toluene (30.0 mL) was evacuated and purged with nitrogen. To this mixture was added tetrakis(triphenylphosphine)palladium(0) (0.208 g, 0.180 mmol) and the resulting reaction mixture was heated at 100° C. for 7 h. After this time, the reaction mixture was cooled to room temperature, quenched with 1.0 M hydrochloric acid (20.0 mL), diluted with ethyl acetate and separated. The organic layer was washed with water and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 9:1) to provide methyl 3-(4-(3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.145 g, 32%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[OH:22])[C:15]([O:17][CH3:18])=[O:16])=[O:11])[CH2:7]1)[CH3:2].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:30][CH:29]=1>>[CH:38]1([CH2:37][CH2:36][CH2:35][O:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][CH2:25][O:22][C:21]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=3[C:10]([N:8]3[CH2:7][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH2:9]3)=[O:11])=[CH:29][CH:30]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: CCOC(=O)CC1CN(C(=O)c2cc(C(=O)OC)ccc2O)C1
Reactant: BrCCCc1ccc(OCCCC2CCCCC2)cc1
Product: CCOC(=O)CC1CN(C(=O)c2cc(C(=O)OC)ccc2OCCCc2ccc(OCCCC3CCCCC3)cc2)C1

Procedure:
Preparation takes place in analogy to the process described in Example 22 from methyl 3-{[3-(2-ethoxy-2-oxoethyl)azetidin-1-yl]carbonyl}-4-hydroxybenzoate and 1-(3-bromopropyl)-4-(3-cyclohexylpropoxy)benzene.