Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[Br:12].[C:14]([C:18]1[CH:26]=[CH:25][C:21]([CH:22]=[N:23][OH:24])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:24]/[N:23]=[CH:22]/[C:21]2[CH:25]=[CH:26][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=2)=[CH:6][C:5]=1[Br:12]
Reactant: COC(=O)c1ccc(CBr)cc1Br
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CO/N=C/c2ccc(C(C)(C)C)cc2)cc1Br
Yield: 81.8 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.40 g, 1.30 mmol), 4-tert-butyl-benzaldehyde oxime (0.24 g, 1.36 mmol) and cesium carbonate (1.69 g, 5.20 mmol) in acetone (50 mL). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 6/94) to give 2-bromo-4-[({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)methyl]benzoic acid methyl ester (0.43 g, 83%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.13 (s, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.49 (d, 2H), 7.39-7.36 (m, 3H), 5.18 (s, 2H), 3.92 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[N:6]2[CH:26]=1)[CH3:2].[CH2:27]=O>C(O)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]2[N:6]3[C:7]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:21])[CH2:27][C:26]=13)=[CH:8][CH:9]=[CH:10]2)[CH3:2]
Reactant: C=O
Reactant: CCc1cn2c(CNCCCCCNS(=O)(=O)C(F)(F)F)cccc2n1
Solvent: CC(=O)O
Product: CCc1nc2cccc3n2c1CN(CCCCCNS(=O)(=O)C(F)(F)F)C3
Temperature: 100 °C
Yield: 65.2 %

Procedure:
To a solution of 785 mg (2.00 mmol) of 2-ethyl-5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 5 ml of acetic acid was added 2.25 ml (30.00 mmol) of a 37% aqueous solution of formalin. The mixture was heated for 30 minutes at 100° C. The solvent was then distilled off under reduced pressure. The residue was dissolved in 100 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized, under ice-cooling, with 1N HCl, which was extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 527 mg of the desired compound (65.2%, colorless liquid).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.CN(C)C=O.[H-].[Na+].[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[N:31]([CH2:32][CH2:33]OS(C)(=O)=O)[C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]=3[N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[N:31]([CH2:32][CH2:33][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)[C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]=3[N:28]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2cccn2)CC1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
Treat a stirred solution of pyrazole (0.22 g, 3.18 mmol, Aldrich Chemical Company) and dimethylformamide (5 mL) at room temperature portionwise with sodium hydride (0.15 g, 3.18 mmol). After 30 minutes, slowly add a solution of 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (0.93 g, 2.12 mmol, Preparation 28) and dimethylformamide, and then heat at 75° C. for 12 hours. Cool, add dichloromethane (100 mL) and wash with water (2×20 mL). Dry (Na2SO4) the organic phase, filter and concentrate. Dry the residue under high vacuum at 100° C. to remove residual dimethylformamide. Purify the residue by radial chromatography (silica gel, ethyl acetate:hexane, 1:1) to afford 4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.71 g), Rf=0.44 (silica gel, ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][C@H:9]1[C:15](=[O:28])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[S:36](Cl)([CH3:39])(=[O:38])=[O:37].Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:9]([C:15](=[O:28])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:26])[F:27])[CH:18]=2)[CH2:10][CH2:11][C@@H:12]1[CH2:13][O:14][S:36]([CH3:39])(=[O:38])=[O:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](COS(C)(=O)=O)CC[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,5R)-5-hydroxymethyl-2-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (390 mg, 0.97 mmol) in CH2Cl2 (3.5 mL) was added at 0° C. under nitrogen atmosphere Et3N (296 μl, 2.12 mmol) and mesylchloride (167 μl, 2.12 mmol) and the mixture was further stirred at RT for 3 h. CH2Cl2 and HCl 0.1N were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The crude organic extracts were washed with brine dried over Na2SO4, filtered and concentrated. The crude material was used without purification in the next step. MS (LC-MS): 383 [MH−Boc]+; tR (HPLC conditions b) 5.1 min.
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.C(N(C(C)C)C(C)C)C.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>C(#N)C>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=3)[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1cnc2c(n1)CCNCC2
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1cnc2c(n1)CCN(Cc1ccc(Cl)cc1)CC2
Reaction time: 48 h

Procedure:
3.0 gm (9.2 mmols) of 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide were suspended in 100 ml of acetonitrile, 7.5 ml of N-ethyl-diisopropylamine were added to the suspension, and the mixture was admixed dropwise with 1.5 gm (9.3 mmols) of p-chloro-benzyl-chloride. The reaction mixture was stirred for 48 hours and then evaporated, the residue was acidified with dilute hydrochloric acid, and the mixture was extracted with methylene chloride. The aqueous phase was made alkaline and then exhaustively extracted with methylene chloride, the extracts were evaporated, and the residue was column-chromatographically purified on silicagel with ethyl acetate as the mobile phase.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=O)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([C:7](=[S:19])[NH2:9])[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=S)C1CCOCC1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of tetrahydro-2H-pyran-4-carboxamide (9.47 g, 73.3 mmol) and Lawesson's reagent (14.83 g, 36.7 mmol) in THF (98 mL) was heated to reflux for 6 h. The reaction was cooled to rt, poured into saturated aqueous NaHCO3 (200 mL) and extracted with diethyl ether (4×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residual solid was triturated with 1:1 EtOAc:hexanes (100 mL) and filtered to collect the solid. The filtrate was concentrated and re-subjected to trituration and filtration using the same conditions. The combined solids were dried under vacuum to afford tetrahydro-2H-pyran-4-carbothioamide (4.91 g, 32.1 mmol, 43.8% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (br. s., 1H), 6.84 (br. s., 1H), 3.94-4.32 (m, 2H), 3.31-3.62 (m, 2H), 2.52-3.03 (m, 1H), 1.81-1.93 (m, 4H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([CH3:25])=[CH:31][CH:30]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.20 (m, 4H), 5.40 (s, 2H), 3.79 (m, 4H), 3.37 (m, 2H), 3.28 (m, 2H), 2.49 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=401.1, found 401.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Oc1ccc(F)cc1
Product: COc1ccc2c(Oc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[C:17](F)=[CH:16][CH:15]=[CH:14][C:13]=1F)=O)[C:4]([O:6][CH2:7]C)=[O:5])#[N:2].C(OCC)(=O)C.[ClH:26]>C(OCC)(=O)C>[Cl:26][C:1]1[NH:2][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(=O)C(C#N)CC(=O)c1c(F)cccc1F
Reactant: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as a pale-yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1>>[O:20]1[CH2:21][CH2:22][N:17]([C:4]2[N:3]=[C:2]([C:27]3[CH:26]=[N:25][C:24]([NH2:23])=[N:29][CH:28]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH2:18][CH2:19]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(C4CCCCO4)c3n2)cn1

Procedure:
4-(2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (4.05 gm) was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A to give 4.75 g of 5-(6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)pyrimidin-2-amine which was refluxed in the presence of a catalytic amount of dimethylaminopyridine, 4 eq Boc-anhydride and 3 eq triethylamine in 60 mL of acetonitrile. Upon completion, the reaction was cooled, concentrated to dryness and purified via normal phase chromatography to yield 6.11 g of 2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:29][CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])=[O:32])[C:12]=2[CH:11]=1>C(OCC)(=O)C.CO.[Pd]>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][NH:33][C:31](=[O:32])[CH2:30][CH2:29][N:13]1[C:12]2[CH:11]=[C:10]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=3[O:8][CH3:9])[C:22]3[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=3[C:20]=2[C:19]2[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]1=2
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCC(=O)NCCN(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCC(=O)NCCN(C)C
Yield: 17.1 %

Procedure:
To a solution of amide (260) (40 mg, 0.07 mmol)) prepared as described in example 219 in ethyl acetate/methanol (1:1, 80 mL) was added 5% Pd-C (catalytic). The resulting suspension was hydrogenated at 60 psi with stirring for 4 days, with additional portions of Pd-C being added every 24 hours. The reaction mixture was then filtered through celite and concentrated under reduced pressure before being chromatographed on silica eluting with methanol/ethyl acetate/triethylamine (1:4:trace), to give amide (330) (6 mg, 16%) as a yellow powder, mp 232–238° C. 1H NMR δ [(CD3)2SO] 10.95 (br s, 1H), 9.33 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 8.01 (br s, 1H), 7.69 (s, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.43 (m, 1H), 7.34 (dd, J=7.5, 1.8 Hz, 1H), 7.13–7.05 (m, 3H), 4.67 (t, J=6.2 Hz, 2H), 3.69 (s, 3H), −3.2 (obscured m, 2H), 2.60 (t, J=6.2 Hz, 2H), 2.54–2.49 (obscured m, 8H). FABMS found [M+H]+: 501.2142. C28H28N4O5 requires 501.2138.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]([OH:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)=[CH:4][CH:3]=2)=[C:25]([OH:27])[CH:26]=1
Reactant: CC1(C)OB(c2ccc(Cl)cc2O)OC1(C)C
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: CN(c1ccc(-c2ccc(Cl)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1

Procedure:
Intermediate 1-1 and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol were reacted according GENERAL METHOD 1-5 for Suzuki coupling. 5-Chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol was obtained as a yellow solid after HPLC purification. LCMS Rt=0.54 min [Method Q], MS (M+1)=375.2. 1H NMR (METHANOL-d4) δ 8.16 (d, J=9.6 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.45 (d, J=10.1 Hz, 1H), 6.91-7.05 (m, 2H), 5.28-5.44 (m, 1H), 3.06 (s, 3H), 1.88-2.05 (m, 4H), 1.65 (s, 6H), 1.52 (s, 6H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[F:58])#[N:51]>CN(C=O)C>[C:50]([C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[F:58])#[N:51]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: N#Cc1cc(-c2cccc(N)c2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(F)c(C#N)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′-cyano-4′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 82% yield: LCMS (ESI) m/z 415 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](OB(O)O)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)=[O:11])=[CH:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CN(C)Cc1ccc(NC(=O)CNc2ccc(Br)cc2)cc1
Product: CN(C)Cc1ccc(NC(=O)CNc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 130a starting from 2-(4-bromo-phenylamino)-N-(4-dimethylaminomethyl-phenyl)-acetamide (Example 163a) and 4-chloro-phenyl-boric acid.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:12](O)(=O)[CH2:13][C:14]([CH2:19][C:20](O)=O)([C:16]([OH:18])=O)O>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1](=[O:10])[CH:1]([CH2:2][CH3:3])[C:16]([C:14]2[CH:13]=[CH:12][C:5]([O:8][CH3:9])=[CH:20][CH:19]=2)=[O:18])=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCC(C(=O)c1ccc(OC)cc1)C(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-methoxybutyryl phenone (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,3-bis(4-methoxyphenyl)-2-ethylpropane-1,3-dione.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.O>[C:10]([C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:34][CH:31]1[CH2:30][CH2:29][N:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][CH:23]=2)(=[O:26])=[O:27])[CH2:33][CH2:32]1)#[N:11]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC(CC(C#N)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Sodium hydride (3.2 g, 80 mmol; 60% dispersion in oil) was added to a stirred solution of diphenylacetonitrile (13.5 g, 70 mmol) in toluene (200 ml) and the mixture was heated under reflux for 2 hours, treated with a solution of 1-(4-methylphenylsulphonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (25.0 g, 60 mmol--see Preparation 15) in toluene (50 ml), heated under reflux for a further 2 hours, allowed to cool to room temperature and diluted with water. The layers were separated and the organic layer was washed with water and saturated brine, dried over magnesium sulphate and evaporated. The residue was crystallised from ethanol to give the title compound (23.0 g, 86%) as colourless crystals, m.p. 130° C.
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])Cl)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH2:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])[NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)C1=Cc2c(c3ccccc3c3ccccc23)C1
Solvent: CCCCCC
Product: CC(C)(C)N[Si](C)(C)C1=Cc2c(c3ccccc3c3ccccc23)C1

Procedure:
To a 500 ml round bottom flask containing 1.98 g (0.0064 mole) of (1H-cyclopenta[1]phenanthrene-2-yl)dimethylchlorosilane and 250 ml of hexane was added 2.00 ml (0.0160 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (Celite™). washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 1.98 g (88.9 percent).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:34]/[OH:35])/[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:29]([O-:31])=[O:30])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH2:27][OH:28])=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:37]([O:43][CH2:44]I)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:34]/[OH:35])/[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:29]([O:31][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:30])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH2:27][OH:28])=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(COC(=O)N4CCC[C@H]4CO)CS[C@H]23)cs1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(COC(=O)N2CCC[C@H]2CO)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound obtained in Example 12 and iodomethyl pivalate were reacted, whereby the title compound was obtained.