Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=N)[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.C(O)(=[O:34])C.Cl.C(=O)(O)[O-].[Na+]>O>[OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:34])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: CC(=O)O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Temperature: 25 °C

Procedure:
15.5 g of 5-[4-(6-hydroxy-2,5,7, 8-tetramethyl chroman-2-yl-methoxy) benzyl]-2-iminothiazolidine-4-one, prepared by the process as described in Example-1, was added to a mixture of 225 ml of acetic acid, 75 ml of conc. hydrochloric acid and 40 ml of water and the mixture was refluxed for 12 hrs. The reaction mixture was cooled to room temperature and 66.2 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue and the erode product was washed with a mixture of equal volumes of a saturated aq. sodium bicarbonate solution & water. The organic layer was dried over anhydrous sodium sulphate and the solvent was distilled off The resulting crude product was quickly eluted from a silica gel column with 50% ethylacetate-hexane to furnish 12.5 g of the required 5-{4-(6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl-methoxy) benzyl) thiazolidine-2,4-dione (Troglitazone) with a HPLC purity of ~67-70%.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.CCCCC.C([Li])(C)(C)C.[CH2:26]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1)[CH3:27].[Cl-].[NH4+]>CCOCC.O1CCCC1>[CH2:26]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]([C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[OH:33])=[CH:30][CH:29]=1)[CH3:27]
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Reactant: CCc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2ccncc2OCOCC[Si](C)(C)C)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Next, to a mixture of 3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (23.0 g, 102 mmol) and tetrahydrofuran (400 ml), a 1.47 mol/L t-butyllithium n-pentane solution (80 ml, 118 mmol) was added dropwise at −70° C. over 25 minutes. After stirring at −70° C. for 1 hour, an ether solution of 4-ethylbenzaldehyde (17.7 g, 132 mmol) was added over 25 minutes. The reaction mixture was stirred at −70° C. for 2 hours and at room temperature for 2 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give (4-ethylphenyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridin-4-yl]-methanol (20.1 g, 55%) as a light-yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=2)[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:28][CH2:27]2)[CH2:30][C:31]2[CH:32]=[C:33]([O:39][CH3:40])[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(CNC2CC2)cc(OC)c1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: COc1cc(CN(C(=O)CN(c2ccc(C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc(OC)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3,5-dimethoxy-benzyl)-amine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=1.C1N=[CH:35][N:34]([C:37](N2C=NC=C2)=[O:38])[CH:33]=1.CCN(C(C)C)C(C)C.CNC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:37](=[O:38])[N:34]([CH3:35])[CH3:33])[N:20]=[C:15]2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CN)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)N(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A flask was charged with (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.413 g, 0.944 mmol, Preparation #1.1), CDI (0.184 g, 1.13 mmol), DIEA (0.412 mL, 2.36 mmol) and THF (10 mL). The mixture was allowed to stir at rt for about 1 h. Dimethylamine (2.0 M in THF, 0.472 mL, 0.944 mmol) was added to the mixture. After about 4 h, additional dimethylamine (2.0 M in THF, 0.236 mL, 0.472 mmol) was added. After about 12 h, dimethylamine (2.0 M in THF, 0.236 mL, 0.472 mmol) was added. After about 8 h, the mixture was concentrated under reduced pressure and the residue was dissolved in DCM (10 mL). The organic solution was then washed with water (2×4 mL). The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0 to 10% MeOH/DCM to give 3-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)-1,1-dimethylurea (0.114 g, 24%): LC/MS (Table 2, Method b) Rt=2.62 min; MS m/z 509 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.O1CCC[CH2:22]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]([OH:19])[CH3:22])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: C1CCOC1
Reactant: O=Cc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc2ccc(F)cc2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a stirring mixture of 2-(2-chlorophenyl)-7-fluoroquinoline-3-carbaldehyde (0.7588 g, 2.656 mmol) in tetrahydrofuran (26.56 mL, 2.656 mmol) was added methylmagnesium bromide 3 M in diethyl ether (1.328 mL, 3.984 mmol) dropwise at 0° C. (started at 4:00 pm), and the mixture was allowed to warm to room temperature with stirring over 19 h. The reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×1). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)ethanol as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (1 H, d, J=11.0 Hz), 8.20 (1 H, dd, J=8.6, 6.7 Hz), 7.75 (1 H, dd, J=10.6, 2.7 Hz), 7.42-7.66 (5 H, m), 5.39 (1 H, dd, J=57.5, 3.9 Hz), 4.59-4.69 (1 H, m), 1.20 (3 H, dd, J=58.7, 6.3 Hz); LC-MS (ESI) m/z 302.0 [M+H]+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C[Si](Cl)(C)C.[CH:25]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38]3([O:45][CH:44]=[CH:43][C:42](=[O:46])[CH2:41]3)[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[O:49][CH3:50])([CH3:27])[CH3:26]>C1COCC1.[Cu](I)I>[CH:25]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38]3([O:45][CH:44]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:43][C:42](=[O:46])[CH2:41]3)[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[O:49][CH3:50])([CH3:27])[CH3:26]
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)C=CO3)ccc1OC(C)C
Agent: I[Cu]I
Agent: C[Si](C)(C)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)CC(c2ccccc2)O3)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
A round bottom flask was heated with a heat-gun under vacuum followed by being flushed with Ar. The process was repeated three times. To the flask, copper iodide (2.32 g, 12.2 mmol) was placed followed by the addition of THF (5 mL). The suspension was purged with argon for 2 minutes and then cooled to −78° C. Phenylmagnesium bromide (122 mL of 1 M, 122 mmol) in THF was added dropwise at −78° C. under argon. The mixture was stirred at −78° C. for 20 minutes. HMPA (44.0 g, 244 mmol) was added. The mixture was stirred at −78° C. for 30 min. TMSCl (26.5 g, 244 mmol) was added to a solution of 3-(4-isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (7.30 g, 20.3 mmol) in THF (25 mL). The above solution was added to the reaction mixture dropwise. The mixture was slowly warmed to room temperature and was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution, repartitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (40-60% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methoxy-benzoyl)-10-phenyl-11-oxa-3-azaspiro[5.5]undecan-8-one (6 g). ESI-MS m/z calc. 437.22, found 438.0 (M+1)+; Retention time: 1.69 minutes (3 minute run).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C[O:33][CH2:32]C1>C(OCC)=O>[CH:32]([CH:12]1[C:11]2[CH:10]=[C:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][C:15]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:16][CH:17]=2)=[O:33]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cc(NC(=O)OC(C)(C)C)ccc1-2
Reactant: C1CCOC1
Solvent: CCOC=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(C=O)c1cc(NC(=O)OC(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Purified 2,7-di(Boc-amino)fluorene (5 g, 12.5 mmol) (prepared from step A, above), was dissolved in ethyl formate (50 mL) and anhydrous THF (60 mL) with gentle heating. (Note: ethyl formate was stored over K2CO3 to remove formic acid.) The solution was cooled in an ice bath and sodium hydride 60% in mineral oil was added portion-wise (5.5 eq, 69 mmol, 2.75 g). The reaction was slowly warmed to room temperature and then heated to 50° C. after fitting with a reflux condenser. After two hours, the reaction was cooled in an ice bath and quenched by the slow addition of deionized water (50 mL). The aqueous layer was adjusted to pH 5 with glacial acetic acid and extracted with ethyl acetate (2×400 mL). The combined organic layers were dried with Na2SO4, filtered and evaporated under reduced pressure. The crude product (dark brown solid) was purified by flash chromatography: silica gel 60 Å step-wise gradient elution 1-5% methanol in chloroform. Yield (4.8 g, ˜90%) of a yellow to brown solid, depending on purity. 1H-NMR (d6-DMSO): δ (ppm) 11.0 (s, 0.9H, enol); 9.3 (2 s, 1.9H, NH urethane); 7.2-8.3 (m, Ar, C10H enol); 6.5 (2 s, 0.1H, NH urethane); 4.1 (m, 0.3H, CH); 1.5 (s, 18H, Boc).
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)[CH:3]([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.C1C(=O)N([O:37][C:38]([CH2:40][NH:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=O)C(=O)C1>CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[NH:41][CH2:40][C:38](=[O:37])[NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)[CH:3]([OH:6])[CH2:4][OH:5])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NC(Cc1cc(F)cc(OCc2ccccc2)c1)C(O)CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)NC(Cc1cc(F)cc(OCc2ccccc2)c1)C(O)CO
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 3-amino-4-(3-benzyloxy-5-fluoro-phenyl)-butane-1,2-diol (5.60 g, 18.34 mmol, 1.00 eq.), triethylamine (5.11 mL, 36.68 mmol, 2.00 eq.) and anhydrous DMF (100 mL) at 0° C. is added Z-glycine N-succinimidyl ester (6.18 g, 20.17 mmol, 1.10 eq.) with stirring under N2. After 2 hours, the reaction is quenched with 1N HCl, extracted with ethyl acetate, and washed with 10% NaHCO3 and then brine. The organic layer is then dried with MgSO4, filtered through Celite, and concentrated in vacuo, yielding the crude product as a light amber oil. Purification via flash chromatography in 5% MeOH/CHCl3 (rf. 0.33, KMnO4 stain), affords the final product as a white solid (5.40 g., 59% yield overall). Calculate mass for C27H29FN2O6: 496.20. Mass found for C27H29FN2O6: (OAMS) ES+: 497.5 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[S:8]1[CH:9]=[CH:10][C:6]([C:3](=[O:5])[CH2:4][C:15]([O:16][CH3:17])=[O:18])=[CH:7]1
Reactant: CC(=O)c1ccsc1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)c1ccsc1
Yield: 46 %

Procedure:
24 g (0.6 mmol) of sodium hydride (60%) are added in portions at 0° C., over a period of 10 minutes, to 25.2 g (0.2 mmol) of 3-acetylthiophene in 600 ml of dimethyl carbonate, and then the whole is heated at reflux for 30 minutes, allowed to cool and poured into 1 liter of a water/ice mixture containing 53 ml of acetic acid. Extraction is carried out 3 times with 250 ml of ether each time. The combined organic phases are dried over magnesium sulphate. After evaporation, the residue is chromatographed on silica (eluant:dichloromethane) to yield 17 g of the desired compound (yield: 46%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-])=O)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]>CO.[Fe]>[NH2:13][C:7]1[CH:6]=[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:4]([O:3][CH3:2])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Temperature: 60 °C

Procedure:
Concentrated hydrochloric acid (30 ml) was added to a suspension of 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide (5.67 g, 16.7 mmol) in methanol (150 ml) and the mixture was heated to 60° C. When the 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide had dissolved, iron powder (5.6 g, 100 mmol) was added in portions to the reaction mixture which was then heated at 60° C. for 90 minutes. After cooling, the insolubles were removed by filtration through diatomaceous earth, the volatiles were removed from the filtrate by evaporation and the residue was purified on a Diaion (trade mark of Mitsubishi) HP20SS resin colurnn, eluting with water and then with hydrochloric acid (pH2). Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 2-amino-5-methoxy4-(3-morpholinopropoxy)benzamide as a hydrochloride salt (4.67 g, 75%) as beige crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:46][O:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1>C(Cl)(Cl)(Cl)Cl.C1COCC1>[CH3:46][O:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][N:53]2[CH2:1][C:2]3[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=3)[CH2:12]2)=[CH:50][CH:49]=1
Reactant: COC(=O)c1ccc(C)c(C)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccc(OC)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of methyl 3,4-dimethylbenzoate (1.334 g, 8.13 mmol), N-bromosuccinimide (3.173 g, 17.83 mmol) and benzoyl peroxide (0.143 g, 0.592 mmol) in carbon tetrachloride (5 mL) was heated at reflux for 1.5 hours. Upon cooling to room temperature, the solids present were removed by vacuum filtration and the resulting solution concentrated in vacuo. The residue obtained was re-dissolved in THF (30 mL). To the solution was added triethylamine (2.265 mL, 16.25 mmol) and a solution of 4-methoxy benzylamine (1.05 mL, 8.13 mmol) in THF (20 mL). The resulting reaction mixture was stirred overnight at room temperature. The precipitate was removed via filtration and the solution obtained was concentrated in vacuo. The residue obtained was purified via flash chromatography (15-30% EtOAc/hexane) to afford a light yellow oil (1.185 g). LCMS: (FA) ES+ 298; 1H NMR (CDCl3, 400 MHz) 7.89 (dd, J=7.8, 1.5 Hz, 1H), 7.84 (s, 1H), 8.74 (d, J=8.7 Hz, 2H), 7.313 (d, J=8.7 Hz 2H), 7.22 (d, J=7.2 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 3.93 (s, 4H), 3.89 (s, 3H), 3.85 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[NH:17][N:16]=1.O[CH2:26][CH:27]1[CH2:30][CH2:29][N:28]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH2:26][CH:27]3[CH2:30][CH2:29][N:28]3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[N:16]=[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:7][C:2]=3[F:1])[C:23]=12
Reactant: CC(C)(C)OC(=O)N1CCC1CO
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3F)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 175.4 %

Procedure:
To a mixture of 3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.930 mmol), tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (0.33 mL, 1.9 mmol) and PPh3 (733.86 mg, 2.8 mmol) in THF (10 mL) in ice bath, the DIAD (0.37 mL, 1.87 mmol) as a solution in 5 ml THF was slowly added. The mixture was stirred at RT overnight and then the solvent was removed. To the residue was added H2O and the mixture was extracted with EtOAc. The combined organic layer was washed with NaHCO3, then brine, and dried over Na2SO4. The solvent was removed to get tert-butyl 2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carboxylate weighing 800 mg, which was used without further purification for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[N:6][C:5]=2[S:4][N:3]=1.[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[CH2:21]([N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[N:3][S:4][C:5]=2[N:6]=[C:7]1[CH2:12][CH2:13][CH3:14])[C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1nc2snc(C)c2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a solution of 30 (730 mg, 3.5 mmol) in dioxane (10 mL) was added BnBr (830 μl, 7 mmol) and Cs2CO3 (1.6 g, 4.9 mmol). The reaction mixture was stirred at room temperature over night, then diluted with EtOAc, washed with water, dried and purified by silica gel column chromatography to give 31 (430 mg, 42%). 1H-NMR (400 MHz, CDCl3): δ 7.15–7.40 (m, 5H), 5.40 (s, 2H), 2.84 (s, 3H), 2.75 (t, J=7.61 Hz, 2H), 1.80 (m, 2H), 0.99 (t, J=7.38 Hz, 3H).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19])=[CH:9][Cl:10].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:19])=[O:20])=[CH:9][Cl:10]
Reactant: C=CCN=C=O
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CCNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl

Procedure:
A solution of 3.3. g of allyl isocyanate in 10 ml of methylene chloride is added dropwise to a mixture of 10.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide and 6.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of methylene chloride, with stirring. When the exothermic reaction has subsided, stirring of the reaction mixture is continued at 20° to 25° C. for a further hour and the solvent is then evaporated off. The residue is dissolved in 5% sodium carbonate solution. The solution is filtered and acidified with 10% hydrochloric acid, whereupon the product precipitates as crystals. After filtration and drying, 13.2 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N'-allylurea are obtained. Melting point: 187°-188° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=O)=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:37])[NH:34][C:33]=2[CH:38]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (93 mg, 71%).