Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1.F[S:24]([C:27]1[N:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:26])=[O:25]>C1COCC1>[CH3:34][O:33][C:30]1[N:29]=[N:28][C:27]([S:24]([C:14]2[O:13][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[OH:22])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: O=C1COc2ccccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2oc3ccccc3c2O)nn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
n-Butyl lithium (12 mmol, 4.7 mL) was added dropwise to a solution of diisopropyl amine (12 mmol, 1.7 mL) in THF (5 mL) at −78° C. After 10 minutes, a solution of 3-coumaranone (10 mmol, 1.92 g) in THF (10 mL) was added. The temperature was maintained at −78° C. and stirred for 10 minutes. To this was added a solution of 3-fluorosulfonyl-6-methoxy-pyridazine. The reaction mixture was brought to room temperature over one hour and quenched with ammonium chloride (1 g) and extracted with EtOAc (2×25 mL). The EtOAc extract was washed with H20, the organic layer was collected, dried, filtered and the filtrate was evaporated to a residue. This residue was purified by silica gel chromatography (eluent: hexanes:EtOAc::9:1) to yield 3-methoxy-6-(3-hydroxy-benzofuran-2-sulfonyl)-pyridazine (17%, 622 mg).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@@H:24]([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH:17]=[CH:18][CH:19]=1.CI.[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C@H:20]2[CH2:25][C@:24]([CH3:1])([CH2:26][CH:27]=[CH2:28])[S:23][N:22]([CH:29]([CH3:31])[CH3:30])[C@@H:21]2[C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C)C)S1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a degassed solution of diisopropylamine (300 μL, 2.123 mmol) in THF (1.0 ml) was added dropwise at −78° C. n-butyllithium, 2.5 M in hexanes (800 μL, 2.000 mmol). After stirring the solution at −78° C. for 10 min, the reaction was warmed to room temperature. In a separate flask, a degassed solution of 111.9 mg (0.255 mmol) of (3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan (Example 117, Step E) and methyl iodide (0.6 ml, 9.62 mmol) in THF (1.0 ml) was heated to 50° C. After five minutes, the LDA solution was added dropwise to the other flask, and stirring continued for 14 hours at 50° C. Upon cooling to room temperature, the reaction was quenched with water (3 mL), then concentrated under reduced pressure. Purification by reverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in CH3CN/H2O, gradient 60% to 80% over 25 minutes provided the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][Si](C(C)(C)C)(C)C)=[CH:53][CH:52]=3)[CH:46]([OH:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=3)[CH:46]([OH:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(O)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.9 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 3H at 0° C. and then 3H at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexane/acetone) affording 23.9 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis are consistent with the desired structure).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:14]1([S:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[C:24]2[C:32](=[O:39])[CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([S:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[C:24]2[C:32]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)([OH:39])[CH2:33][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)(=[O:21])=[O:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CC1CCCC1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Reactant: Brc1ccc(I)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(C(O)(CC2CCCC2)c2ccc(Br)cn2)cc2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 5-bromo-2-iodopyridine (4.27 g, 15.0 mmol) in anhydrous tetrahydrofuran (60 mL) at 0° C. was added a solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 7.5 mL, 15.04 mmol) dropwise. After stirring for 30 min at 0° C., a solution of 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-ethanone (prepared as in Example 43, 1.38 g, 3.76 mmol) in dry tetrahydrofuran (10 mL) was added dropwise. The resulting mixture was stirred for 14 h at room temperature, quenched with a saturated sodium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 20% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-(5-bromo-pyridin-2-yl)-2-cyclopentyl-ethanol (870 mg, 15%) as a light yellow solid: LC/MS m/e calcd for C25H24BrN3O3S [M+H]+ 527.46, observed 527.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[NH:16][N:15]=1.Br[C:33]1[S:37][C:36]([N:38]([CH2:42][C@@H:43]([N:51]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)C(=O)C)=[N:35][CH:34]=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.O>[NH2:51][C@@H:43]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:42][NH:38][C:36]1[S:37][C:33]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:13])=[CH:34][N:35]=1
Reactant: CC(=O)N(C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ncc(Br)s1
Reactant: Cc1n[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
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: C1COCCO1
Solvent: O
Product: Cc1n[nH]c2ccc(-c3cnc(NC[C@@H](N)Cc4ccccc4)s3)cc12
Temperature: 150 °C
Yield: 26.6 %

Procedure:
To a solution of 1.0 mL dioxane, 0.5 mL distilled water and sodium carbonate (35.0 mg, 0.33 mmol) in a 5 mL microwave tube, were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (32.0 mg, 0.124 mmol) and (S)—N-(5-bromothiazol-2-yl)-N-(2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropyl)acetamide (40.0 mg, 0.0826 mmol). The reaction mixture was degassed by bubbling nitrogen into the microwave tube for 30 seconds. Subsequently, tetrakis(triphenylphosphine)palladium(0) (10.0 mg, 0.0083 mmol) was added to the tube, and the mixture was heated at 150° C. in a Smith microwave synthesizer. After heating for 25 minutes, the reaction mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was evaporated off, and the resulting residue was diluted with 1.5 mL MeOH, 1.5 mL water, and 1.5 mL hydrazine. The resulting mixture was transferred to a 5 mL microwave tube and heated at 150° C. After heating for 33 minutes, silica gel (10.0 g) was added to the reaction mixture, and the mixture was concentrated to dryness. The resulting solid was directly loaded on a silica gel column and chromatography separation was performed with DCM:MeOH (97:3) as the eluant to afford the desired compound N—((S)-2-amino-3-phenylpropyl)-5-(3-methyl-1H-indazol-5-yl)thiazol-2-amine as a colorless solid (8.0 mg, 26.6%). HRMS Theoretical (M+H) 364.15904, found 364.15915.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH2:4][CH2:3]1.Br>>[F:25][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH2:4][CH2:3]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CC1CCC(F)(F)CC1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](CC3CCC(F)(F)CC3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
Trans-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.267 g, 0.75 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 5.87 mL, 33.53 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-((4,4-difluorocyclohexyl)methyl)-piperidin-4-yl)isoxazol-3(2H)-one (63 mg, 28%). 1H NMR (600 MHz, dmso) δ 0.99-1.19 (m, 3H), 1.27-1.35 (m, 1H), 1.38-1.46 (m, 1H), 1.46-1.55 (m, 1H), 1.61-1.87 (m, 7H), 1.87-1.98 (m, 2H), 2.54-2.61 (m, 1H), 2.61-2.70 (m, 1H), 2.72-2.79 (m, 1H), 3.03-3.09 (m, 1H), 5.75 (s, 1H). HRMS Calculated for [C15H22F2N2O2+H]+: 301.1728. Found: 301.1751
Reaction SMILES: [Mg].Br[C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([CH2:10][CH3:11])=[CH:9][C:5]=2[CH:4]=1.CI.[C:16](=[O:18])=[O:17].Cl>CCOCC>[C:16]([C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([CH2:10][CH3:11])=[CH:9][C:5]=2[CH:4]=1)([OH:18])=[O:17]
Reactant: O=C=O
Reactant: CCc1cc2cc(Br)ccc2o1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CI
Product: CCc1cc2cc(C(=O)O)ccc2o1
Reaction time: 0.08 h

Procedure:
Magnesium (1.50 g) was stirred in ether (30 ml) at room temperature. Thereto was dropwise added a solution of 5-bromo-2-ethylbenzo[b]furan (8.30 g) and methyl iodide (0.55 g) in ether (30 ml) over 30 min. Then, the mixture was refluxed for 50 min and cooled in an ice water bath. In a different container, pulverized dry ice was stirred in ether and the Grignard reagent prepared above was transferred over about 5 min. 2N Hydrochloric acid was added to the reaction mixture to acidify the solution, and the ether layer was separated. The solution was basified with a 5% aqueous solution of sodium hydroxide and the separated aqueous layer was acidified with 2N hydrochloric acid. After extraction with ether, the extract was dried over sodium sulfate and concentrated to give the objective compound (2.48 g).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:11](=[O:12])[N:10]2[CH:13]([C:17]([NH:19][CH:20]([C:29](=[O:42])[CH2:30][O:31][C:32](=[O:41])[C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])[CH2:14][CH2:15][CH2:16][N:9]2[C:8](=[O:43])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CO.[K+].[Br-]>O>[C:1]([NH:4][CH:5]1[C:11](=[O:12])[N:10]2[CH:13]([C:17]([NH:19][CH:20]([C:29](=[O:42])[CH2:30][O:31][C:32](=[O:41])[C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])[CH2:21][C:22]([OH:24])=[O:23])=[O:18])[CH2:14][CH2:15][CH2:16][N:9]2[C:8](=[O:43])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCC(=O)N2CCCC(C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c3c(Cl)cccc3Cl)N2C1=O
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)NC1CCC(=O)N2CCCC(C(=O)NC(CC(=O)O)C(=O)COC(=O)c3c(Cl)cccc3Cl)N2C1=O

Procedure:
was synthesized from 216c by the same method as compound 217e as a glassy white solid (166 mg, 66%): mp 85-175° C.; [α]D25 −156 (c 0.13, MeOH; IR (KBr) 3373, 2929, 1742, 1659, 1562, 1533, 1433, 1412, 1274, 1266, 1223, 1197, 1145, 1138, 1H NMR (CD3OD) δ7.38 (3H, s), 5.14-5.03 (1H, m), 4.49-4.32 (2H, m), 3.50-3.27 (1H, m), 3.11-2.92 (1H, m), 2.84-2.62 (2H, m), 2.46-2.11 (2H, m), 2.05-1.46 (5H, m), 1.92 (3H, s); Anal. Calcd for C24H26N4Cl2O9.H2O: C, 47.77; H, 4.68; N, 9.29. Found: C, 47.75; N, 4.59; N, 9.07. MS (ES+) 627/5/3 (M+K, 21%), 611/9/7 (M+Na, 87), 589/7/5 (M+ +1, 71), 266 (100); Accurate mass calculated for C24H27N4Cl2O9 (MH+): 585.1155. Found: 585.1134.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl:19]C(Cl)(N=NC1C(Cl)=CC(Cl)=CC=1Cl)C(OC)=O>>[Cl:18][C:12]([Cl:19])([N:11]=[N:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COC(=O)C(Cl)(Cl)N=Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Product: CCOC(=O)C(Cl)(Cl)N=Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
Following the same procedure but substituting methyl-, isopropyl- and butyl-chloroglyoxylate-2-(2,4,6-trichlorophenyl)hydrazone for ethyl chloroglyoxylate 2-(2,4,6-trichlorophenyl)hydrazone there were prepared methyl dichloro[(2,4,6-trichlorophenyl)azo]acetate,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CC=CC=1.Cl.[CH3:35][O:36][NH2:37]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:37][O:36][CH3:35])[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[C:17]([O:25][CH3:26])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON
Reactant: C#CCOc1ccc(CCNC(=O)C(=O)c2ccc(Cl)c(Cl)c2)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C#CCOc1ccc(CCNC(=O)C(=NOC)c2ccc(Cl)c(Cl)c2)cc1OC

Procedure:
To a solution of 1.30 g (3.20 mmol) 2-(3,4-dichloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-oxo-acetamide in 7.0 ml ethanol, 0.52 ml pyridine (0.64 mmol) and 0.33 g (3.98 mmol) O-methylhydroxylamine hydrochloride are added. The solution is heated at +80° C. for 4 hours. After evaporation of the solvent, the residue is submitted to flash-chromatography to yield the 2-(3,4-dichloro-phenyl)-2-methoxyimino-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide as a white solid (m.p. 107-108° C.)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13].[CH2:14]([O:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:22])[CH:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13])[C:19](=[O:21])[CH3:20])[CH3:15]
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2-chloro-4-methanesulfonylbenzene and 3-oxobutyric acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[N:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([N:24]6[CH:28]=[CH:27][CH:26]=[N:25]6)=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(-n3cccn3)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(-n5cccn5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-pyrazol-1-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 79.1.1) to give the title compound as a white solid. (HPLC: tR 2.64 min (Method A); M+H=437 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.68-8.66 (m, 1H), 8.59-8.57 (m, 1H), 8.16-8.12 (m, 2H), 8.10-7.98 (m, 3H), 7.87-7.85 (m, 1H), 7.60-7.58 (m, 1H), 6.62-6.59 (m, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([OH:21])=O)=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.C[CH2:23][N:24]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CN>CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([NH:24][CH3:23])=[O:21])=[CH:14][CH:15]=3)[N:10]=2)[CH2:6][CH2:7]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(trans-4-hydroxycyclohexyl)amino]quinazoline-7-carboxylic acid (116 mg, 0.404 mmol) in DMF (3 mL) was added EDCl (93 mg, 0.484 mmol), HOBt (60 mg, 0.444 mmol), NMM (0.111 mL, 1.01 mmol) followed by the methylamine solution (2 M in THF, 0.303 mL, 0.606 mmol) and the mixture stirred at ambient temperature for 16 hours. The solvents were removed in vacuo and the residue azeotroped with MeOH (10 mL). The resulting yellow gum was purified directly by Biotage 25M; loaded in 2% MeOH/DCM, and eluted with 2-7% MeOH/DCM over 520 mL. Product not fully eluted so continued over another 300 mL to 10% MeOH/DCM to give a solid that was then triturated with EtOAc, filtered and dried in vacuo to yield the title compound as a yellow solid, 78 mg, 65%. 1H NMR (400 MHz, DMSO-D6) □ ppm 9.11 (1H, s) 8.68 (1H, d, J=3.54 Hz) 7.90 (1H, s) 7.81 (1H, d, J=8.34 Hz) 7.57 (1H, d, J=8.34 Hz) 7.39 (1H, d, J=6.57 Hz) 4.56 (1H, d, J=4.29 Hz) 3.79 (1H, s) 3.36-3.50 (1H, m) 2.79 (3H, d, J=4.55 Hz) 1.80-2.03 (4H, m) 1.17-1.43 (4H, m); MS (API+) for C16H20N4O2 m/z 301.2 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.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>[CH3:17][C:3]1[C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:6]([CH3:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1

Procedure:
To a suspension of 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11, 300 mg, 0.88 mmol) and p-tolylboronic acid (313 mg, 2.3 mmol) in dimethoxyethane (6.3 mL) were added 2 M aqueous K2CO3 (2.2 mL, 4.4 mmol) and bis(triphenylphosphine)palladium(II) chloride (124 mg, 0.18 mmol), and the mixture were refluxed for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated to give brown oil. It was partitioned between dichloromethane and water. The separated organic layer was dried (Na2SO4), evaporated, and purified by TLC with hexane/ethyl acetate (1:1) to afford 349 mg (quant.) of the title compound as white solids: MS (ESI) m/z 307 [M+H]+, 1H-NMR (CDCl3) δ 7.43-7.20 (8H, m), 3.87 (2H, t, J=6.4 Hz), 2.91 (2H, t, J=6.4 Hz), 2.40 (3H, s), 2.31 (3H, s), 2.28 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21].BrC1C(=O)C(Br)=C(Br)C(C)([N+:30]([O-:32])=[O:31])C=1Br>FC(F)(F)C(O)=O.CCOC(C)=O>[NH2:1][C:2]1[C:14]([N+:30]([O-:32])=[O:31])=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21]
Reactant: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)cc1C2
Reactant: CC1([N+](=O)[O-])C(Br)=C(Br)C(=O)C(Br)=C1Br
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)c([N+](=O)[O-])c1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (243 mg, 0.845 mmol) in trifluoroacetic acid (1.7 mL) was treated with 2,3,5,6-tetrabromo-4-methyl-4-nitro-2,5-cyclohexadien-1-one (396 mg, 0.845 mmol). The resulting mixture was placed under a N2 atmosphere, sonicated briefly, and stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (50 mL), washed successively with water, 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to a brown oil (659 mg). The crude product was purified by flash chromatography on a Biotage 40S KP-Sil column, eluting with 10:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to an orange gum (113 mg, 40%) which was lyophilized from benzene to provide 7-amino-9a-butyl-6-fluoro-4-methyl-8-nitro-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:35])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CO)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 91.6 %

Procedure:
To a suspension of 6-benzyloxy-4-(3-fluorophenyl)-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (3.88 g, 9 mmol) in toluene (30 mL) was added thionyl chloride (1.3 mL, 18 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-3-chloromethyl-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.71 g, 91.8%) as an oil.