Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2C.Br[C:46]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:47]=1[C:48]1([C:80]3[C:71](=[CH:72][C:73]4[O:78][CH2:77][CH2:76][O:75][C:74]=4[CH:79]=3)[O:70][CH2:69]1)[C:49](=[O:68])[N:50]2[CH:55](C1C=CC=CC=1)C1C=CC=CC=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:46]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:47]=2[C:48]2([C:80]4[C:71](=[CH:72][C:73]5[O:78][CH2:77][CH2:76][O:75][C:74]=5[CH:79]=4)[O:70][CH2:69]2)[C:49](=[O:68])[N:50]3[CH3:55])=[CH:2]1
Reactant: OB(O)c1ccoc1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: OB(O)c1cnc2ccccc2c1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3ccoc3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 3-furanboronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-furan-3-yl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: mp 178-180° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 2H), 7.00 (d, J=7.9 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 6.04-6.01 (m, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53 (d, J=9.0 Hz, 1H), 4.23-4.09 (m, 4H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 155.5, 144.7, 144.3, 142.8, 140.5, 137.9, 130.8, 129.1, 128.1, 125.2, 122.6, 122.5, 111.2, 111.1, 107.4, 99.7, 76.7, 64.6, 64.0, 58.3, 26.8; MS (ES+) m/z 375.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1C
Yield: 89 %

Procedure:
A mixture of 0.074 g (0.38 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-methyl-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 132 mg of N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 88%).
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([B:17]([OH:20])[OH:18])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)cc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 73.7 %

Procedure:
t-BuLi (1.7 M in pentatne, 63 mL, 106 mmol, 2.1 equiv) was added dropwise to a cold (−78° C.) solution of 3,5-dimethoxy-bromobenzene (11 g, 50.7 mmol) in THF (400 mL), under an argon atmosphere. The yellow mixture si stirred for 45 min at −78° C. Trimethyl borate (20 mL, 179 mmol, 3.5 equiv) was then added. The colorless reaction mixture was allowed to warm to 0° C., quenched by addition of a saturated solution of NH4Cl (5 mL), and concentrated. The residue was diluted with EtOAc/NH4Cl (saturated aqueous solution), and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was triturated in Et2O to provide 6.8 g of the title compound as a white solid: ESI-MS: 183.1 [M+H]+; tR=2.70 min (System 1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N+:7]([C:10]1[CH:11]=[N:12][N:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:14]=1)([O-])=O>C1COCC1>[CH3:21][N:18]1[CH2:17][CH2:16][CH:15]([N:13]2[CH:14]=[C:10]([NH2:7])[CH:11]=[N:12]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc([N+](=O)[O-])cn2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(n2cc(N)cn2)CC1
Temperature: 60 °C
Yield: 91.4 %

Procedure:
To a suspension of lithium aluminum hydride (0.32 g, 8.4 mmol) in THF (15 mL) was added a solution of tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.7 mmol) in THF (10 mL) and the reaction mixture was stirred with heat at 60° C. for 16 h. The reaction mixture was cooled to 0° C. and quenched by the slow addition of ethanol (0.3 mL) then water (0.3 mL) and finally 3 N NaOH aq. (0.3 mL). The resulting mixture was stirred for 30 min, filtered and the filtrate was concentrated and dried to obtain the desired product (280 mg) which was used without any purification: ESI MS m/z 181 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C(C)(C)C)=O)[CH2:4]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:19]([NH:23][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 42.5 °C

Procedure:
A mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (10 grams), methanol (80 ml), n-butyl amine (20 ml) and potassium carbonate (10.6 grams) was heated to 40-45° C. and stirred up to completion of the reaction. The reaction mixture was distilled under reduced pressure and methylene chloride (100 ml) was added to the obtained residue at 25-30° C. and stirred for 15 minutes. The unwanted solid was filtered off and the filtrate was distilled off under reduced pressure to get the title compound.
Reaction SMILES: C1(=O)O[C:4](=O)[C:3]2=C[CH:8]=[CH:9][CH:10]=[C:2]12.[C:12](OCC1OC1)(=O)[C:13]([CH3:15])=[CH2:14]>>[CH:13]12[CH2:14][CH:9]([CH2:8][CH2:15]1)[CH:10]1[CH:12]2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C=C(C)C(=O)OCC1CO1
Product: C1CC2C3CCC(C3)C2C1

Procedure:
4,8-Bis [(3'-methacroyl-2'-hydroxypropyl)-phthalatomethyl] tricyclo [5.2.1.02,6 ] decane was prepared from phthalic anhydride, 4,8-bis (hydroxymethyl)-tricyclo [5.2.1.0.2,6 ] decane, and glycidyl methacrylate according to the method described in Example A. (a): ##STR17## Refraction index (50° C.): 1.530
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][S:13][C:14]2[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([CH3:21])[N:15]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CS(C)=O>[CH3:21][C:16]1[N:15]=[C:14]([S:13][CH2:12][C:11]2[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:19]=[C:18]([OH:20])[CH:17]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(O)nc(SCc2cc3ccccc3nc2Cl)n1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(O)nc(SCc2cc3ccccc3nc2N2CCCCC2)n1
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of 2-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (0.5 g, 1.57 mmol) and piperidine (1.33 g, 15.7 mmol) in DMSO was heated overnight at 90° C. Water was then added, and the product was extracted in dichloromethane and back washed with water. The organic layer was separated, dried, and evaporated to provide the titled product as a beige solid (0.35 g, 61% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 2.31 (s, 3H), 4.95 (s, 2H), 6.04 (bs, 1H), 7.87 (t, J=7.8, 15.0 Hz, 1H), 8.08 9 m, 2H), 8.26 (d, J=8.1 Hz, 1H), 8.48 (d, J=8.2 Hz, 1H), 9.00 (d, J=8.2 Hz, 1H); M+ 366.5.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:21])=[C:18]([CH3:20])[CH:19]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27].Cl>CCCCCC.O1CCCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([F:21])=[C:16]([CH:26]([C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=2)[OH:27])[CH:15]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1cc(Br)ccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C(O)c2cccc(F)c2)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen gas, 74.1 ml of a 1.57 M solution of n-butyllithium in hexane was added to a solution of 16.3 ml of N,N-diisopropylamine in 400 ml tetrahydrofuran at 0° C., and the mixture was stirred at the same temperature for 30 minutes. After cooling to −78° C., a solution of 20.0 g of 5-bromo-2-fluorotoluene in 40 ml tetrahydrofuran was added dropwise. After stirring at the same temperature for 1 hour, 11.2 ml of 3-fluorobenzaldehyde was added dropwise and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was neutralized with 1 N hydrochloric acid and diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20), to give 20.6 g of the title compound as a colorless oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]([CH2:25][CH3:26])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:27][CH2:28][CH2:29][CH2:30]Br>CCCCCC.O1CCCC1>[Br:27][CH2:28][CH2:29][CH2:30][C:19]([CH2:25][CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: BrCCCBr
Reactant: CCC(CC(=O)OC)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCC(CCCBr)(CC(=O)OC)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
15 g (0.081 mol) of n-butyl lithium as a 2.5-molar solution in hexane are added dropwise to a solution of 11.35 ml (0.081 mol) of diisopropylamine in 200 ml of anhydrous tetrahydrofuran at −30° C. and stirred for 10 minutes at −10° C. 14.4 g (0.081 mol) of methyl 2-phenylbutanecarboxylate are added dropwise at −76° C. and stirred for 30 minutes at this temperature. Then 8.62 ml (0.085 mol) of 1,3-dibromopropane are added, when the addition has ended the cooling bath is removed and the mixture is stirred for 14 hours at ambient temperature. The reaction solution is poured onto 1.2 l of water and extracted with diethylether. The organic phases are extracted with water, dried over sodium sulphate and the solvent is eliminated. The residue is distilled under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:40]#[N:41])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C@H:34]3[CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:39])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C[C@H]2CCCO2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
327 mg (0.57 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoyl}amino)benzoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 2. Yield: 227 mg (purity 94%, 72% of theory)
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]3=[CH:8][CH:9]=2)[N:4]=1.CC[OH:20]>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]3[CH:13]=[CH:14][CH:15]=[CH:16][C:6]3=2)[CH:11]=[CH:12][C:3]=1[CH:2]=[O:20]
Reactant: BrC(Br)c1ccc2ccc3ccccc3c2n1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2ccc3ccccc3c2n1

Procedure:
To a mixture of 2-(dibromomethyl)benzo[h]quinoline (52 mg, 0.148 mmol) in EtOH (2 mL) and THF (1 mL) was added a solution of AgNO3 (75 mg, 0.444 mmol) in H2O (1 mL). The mixture was stirred at reflux for 2 h. The solid was filtered off and the organic solvent was removed under reduced pressure. DCM (5 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (5 mL×2). The combined organic layers were washed with brine (2 mL) and dried by anhydrous Na2SO4. The organic layer was concentrated to give benzo[h]quinoline-2-carbaldehyde (30 mg) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:20])[NH:12][C:13]1[C:14]([OH:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1>[C:26]([O:25][C:23](=[O:24])[CH2:22][N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:20])[C:14]1=[O:19])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Nc1cccnc1O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Sodium hydride (0.070 g of a 60% suspension in mineral oil, 1.75 mmol, 1.0 equiv) was added to a solution of (2-hydroxypyridin-3-yl)carbamic acid benzyl ester prepared as described in Example 1) (0.415 g, 1.70 mmol, 1 equiv) in THF (20 mL) at 0° C. The reaction mixture was stirred for 20 min at 0° C., then tert-butyl bromoacetate (0.275 mL, 1.86 mmol, 1.1 equiv) was added. The reaction mixture was warmed to 23° C. for 45 min, then was partitioned between 0.5 M HCl (150 mL) and EtOAc (2×100 mL). The organic layers were dried over Na2SO4 and were concentrated. Purification of the residue by flash column chromatography (30% EtOAc in hexanes) provided the title compound (0.485 g, 85%) as an off-white solid: mp=88-90° C.; IR (cm−1) 3380, 1739, 1652, 1604; 1H NMR (CDCl3) δ 1.48 (s, 9H), 4.57 (s, 2H), 5.20 (s, 2H), 6.25 (t, 1H, J=7.1), 6.87 (dd, 1H, J=6.9, 1.7), 7.27-7.41 (m, 5H), 7.86 (s, br, 1H), 8.05 (d, br, 1H J=6.8); Anal. C19H22N2O5: C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.C(O[CH:11]=[C:12]([C:18]([C:20]([F:23])([F:22])[F:21])=O)[C:13]([O:15]CC)=[O:14])C>C(O)C.Cl>[CH3:7][C:5]1[CH:6]=[C:2]2[N:1]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:3]2[N:4]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: Cc1cc(N)n[nH]1
Agent: Cl
Solvent: CCO
Product: Cc1cc2ncc(C(=O)O)c(C(F)(F)F)n2n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 10.4 %

Procedure:
3-Amino-5-methylpyrazole (389 mg) and ethyl (ethoxymethylidene)trifluoroacetoacetate (960 mg) were dissolved in ethanol (10 ml) and stirred for 1.5 hours at 70° C. Conc. hydrochloric acid (1 mg) was added thereto, and the mixture was stirred for additional 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (10 ml) and 5 N sodium hydroxide solution (3 ml) were added to the residue and then stirred for 1 hour at 70° C. The mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give the title compound (102 mg, Y.:42%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[N:15][C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:17][N:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:26]([C:30]1[CH:34]=[C:33]([N:35]=[C:36]=[O:37])[N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:31]=1)([CH3:29])([CH3:28])[CH3:27].CCCCCC>C1COCC1.C(Cl)Cl>[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4=[N:18][CH:17]=[C:16]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)[N:15]=[C:14]4[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[F:1])=[O:37])[N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Reactant: Nc1ccc(Oc2ccnc3nc(N4CCOCC4)cnc23)cc1F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4nc(N5CCOCC5)cnc34)cc2F)n(-c2ccccc2)n1

Procedure:
A solution of 2-fluoro-4-(3-morpholinopyrido[2,3-b]pyrazin-8-yloxy)aniline (47 mg, 138 μmol) in dry THF (5 mL) was treated with a solution of 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole (1.1 mL of a 0.25 M solution in CH2Cl2, 275 μmol) at 0° C. A yellow precipitate started to form gradually and after 1 h at RT, hexane (20 mL) was added and the yellow precipitate was filtered off. It was redissolved in MeOH/CH2Cl2 (1:1), evaporated onto silica gel and the product was eluted with a gradient of 0% to 20% MeOH in EtOAc to give the product as a light yellow solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[N:21][C:20]([CH3:24])=[C:19]([CH3:25])[N:18]=2)=[C:9]([O:26][CH3:27])[CH:8]=1)C>O>[CH3:23][C:22]1[C:17]([CH2:16][O:15][C:10]2[C:9]([O:26][CH3:27])=[CH:8][C:7]([C:6]([OH:28])=[O:5])=[CH:12][C:11]=2[O:13][CH3:14])=[N:18][C:19]([CH3:25])=[C:20]([CH3:24])[N:21]=1
Reactant: CCOC(=O)c1cc(OC)c(OCc2nc(C)c(C)nc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(=O)O)cc(OC)c1OCc1nc(C)c(C)nc1C
Yield: 95.4 %

Procedure:
Adding water (20 mL), NaOH (0.14 g, 3.5 mmol) into a 100 mL round-bottom flask, stirring to dissolve, then adding 95% alcohol (20 mL), 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-3,5-dimethoxybenzoic acid ethyl ester (1.00 g, 2.8 mmol), stifling under room temperature to react for 4 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.5, Rf of product=0), distilling out the alcohol under reduced pressure, adjusting pH of the reaction solution to 4-5 with 1.0M HCl while keeping the reaction solution cool to separate out solid, filtering, washing the solid with cool water for three times, processing with vacuum filtration, recrystallizing with anhydrous alcohol, drying under 70° C. for 8 hours to obtain 0.88 g white crystalloid of 4-((3,5,6-trimethylpyrazine-2-yl)methoxyl)-3,5-dimethoxybenzoic acid, wherein a yield is 95.4%, m.p.>218° C. (dec).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:23]1[C:24]([CH3:46])=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:29]>COCCOC.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>[CH3:46][C:24]1[C:23]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:37][C:27]([C:28]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:29])=[C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)Nc2cccnc2)cc1Br
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: COCCOC
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2cccnc2)cc1-c1cnn(C)c1
Temperature: 120 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (86 mg, 0.42 mmol), palladium tetrakis (26.2 mg, 0.02 mmol) and Na2CO3 (0.76 ml, 0.76 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 6; 150 mg, 0.38 mmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated at 120° C. in a microwave for 1 hour. The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 73 mg.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+]=[N-])[CH3:11].[O-]CC.[NH4+].[Cl-].C([O-])(=O)C=C>O.CCOCC.C(O)C>[CH2:10]([O:12][C:13]([C:14]1[NH:15][C:5]2[CH:4]=[C:3]([S:2][CH3:1])[S:7][C:6]=2[CH:8]=1)=[O:18])[CH3:11]
Reactant: CSc1ccc(C=O)s1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C=CC(=O)[O-]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc2sc(SC)cc2[nH]1

Procedure:
5-Methylsulfanyl-thiophene-2-carbaldehyde was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1 M of ester) to −20° C. ethoxide solution; allow to warm to 10° C. over 4 h; reaction poured into cold saturated aqueous NH4Cl; after ether extraction, acrylate organic phase washed with water until aqueous phase was neutral; crude acrylate solution heated at reflux for 2 h, allowed to cool to room temperature, stirred overnight).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[OH:18][C:19]([CH3:34])([C:23]([NH:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[O:24])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.Cl>O1CCCC1>[OH:18][C:19]([CH3:34])([C:23]([NH:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[O:24])[C:20]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:21]
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A solution of 101 mg (0.45 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 119 mg (0.45 mmol) (RS)-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in 15 ml tetrahydrofuran were cooled to 0° C. and 61.8 mg (0.45 mmol) 1-hydroxy-benzotriazole hydrate, 157 μl (0.90 mmol) diisopropylethylamine and 87.6 mg (0.45 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. The mixture was poured on ice/water and 1 N aqueous hydrochloric acid was added until pH=1 was reached. Extraction with diethylether, washing with saturated aqueous sodium hydrogen carbonate solution and brine and chromatography on silicagel with ethylacetate/cyclohexane 1/1 yielded 86.1 mg (41%) (R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as a white solid, MS (m/e): 472.1 (M+H)+.