Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:18].[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:18]
Reactant: COc1ccc(C(=O)c2ccc(Br)c(C)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C(=O)c2ccc(O)cc2)ccc1Br
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 65 (2.00 g, 6.55 mmol) and AlCl3 (3.50 g, 26.2 mmol) were refluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100 mL) was cautiously added dropwise, and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration afforded 1.78 g (93%) of 66 that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 5.68 (br s, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.40 (dd, J=8.2 Hz, 1.8 Hz, 1H), 7.63 (m, 2H), 7.75 (d, J=8.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:27]([O:31][C:32](=[O:36])[CH2:33][O:34][NH2:35])([CH3:30])([CH3:29])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:27]([O:31][C:32](=[O:36])[CH2:33][O:34]/[N:35]=[CH:18]/[C:17]1[CH:20]=[CH:21][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:23]([F:26])([F:24])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:22])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Reactant: CC(C)(C)OC(=O)CON
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/OCC(=O)OC(C)(C)C
Yield: 56 %

Procedure:
A mixture of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, Example 1, 1.00 g), amino-oxyacetic-acid-tert-butyl-ester (403 mg), p-toluene sulfonic acid (43 mg) and toluene (20 mL) were heated to reflux for 30 min. After cooling, the mixture was washed with water, and the organic layer was dried over Na2SO4. After evaporation the residue was purified by flash chromatography on silica gel to yield the title compound (745 mg, 56%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][N:38]=1)=[O:36]>ClCCl>[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:45])=[CH:39][N:38]=1)=[O:36]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COC(=O)c1ccc(N=C=O)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (67.8 mg, 0.67 mmol) (Aldrich), followed by the addition of solution of 5-isocyanato-pyridine-2-carboxylic acid methyl ester in toluene (from Example 83c supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-5-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-pyridine-2-carboxylic acid methyl ester as a white solid. (Yield 83 mg, 56.1%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17](S(C)(=O)=O)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH2:44][NH2:45].C(N(CC)CC)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17]([NH:45][CH2:44][C:40]4[NH:39][CH:43]=[CH:42][N:41]=4)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 60 °C

Procedure:
N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide (0.1 g, 0.2 mmol) is dissolved in DMF (10 mL) and (1H-imidazol-2-ylmethyl)amine dihydrochloride (0.053 g, 0.4 mmol) is added followed by triethylamine (0.167 mL, 1.2 mmol). The mixture is heated to about 60° C. for about 3 h. The reaction is judged to be complete by LCMS and the crude mixture is purified via reversed-phase HPLC. HPLC indicates 95% pure (254 nm) and the desired product is obtained as a white powder (54 mg, 50%): LC-MS m/z 528 (M+H)+, 1.45 min (ret time).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:12]([Cl:27])[C:11]2=[O:28])[C:7]([CH3:29])=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:30]OC(OC)N(C)C.Cl.[OH:39][C:40]([CH3:45])([CH3:44])[C:41]([NH2:43])=[NH:42].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[C:7]([CH3:29])=[CH:6][N:5]=[C:4]([C:1]3[CH:2]=[CH:30][N:43]=[C:41]([C:40]([OH:39])([CH3:45])[CH3:44])[N:42]=3)[CH:9]=2)[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: COc1ccc(COc2cc(C)n(-c3cc(C(C)=O)ncc3C)c(=O)c2Cl)cc1
Reactant: CC(C)(O)C(=N)N
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ncc3C)c(=O)c2Cl)cc1
Temperature: 55 °C
Yield: 46.4 %

Procedure:
To a solution of 2′-acetyl-3-chloro-4-((4-methoxybenzyl)oxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one of step D (562 mg, 1.36 mmol) in N,N-dimethylformamide (5 mL) was added N,N-dimethylformamide dimethyl acetal (0.27 mL, 2.04 mmol) and the solution was heated to 55° C. for 18 hours. The solution was concentrated to half volume and partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate and concentrated to provide the crude enamine intermediate as an orange oil. The enamine was dissolved into N,N-dimethylformamide (7 mL) and 2-hydroxy-2-methylpropionamidine HCl (280 mg, 2.04 mmol) and potassium carbonate (563 mg, 4.08 mmol) were added. The slurry was heated at 75° C. for eighteen hours. The slurry was returned to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. The solution was concentrated and purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a light yellow solid (320 mg, 46%): MS (M+H) 508.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9]
Reactant: OB(O)c1cccs1
Reactant: Oc1cc(F)ccc1Br
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
Product: Oc1cc(F)ccc1-c1cccs1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
2-Bromo-5-fluoro-phenol (0.87 ml, 7.9 mmol) and 2-thiopheneboronic acid (2.02 g, 15.8 mmol) are dissolved in 100 ml dioxane. The resultingsolution is flushed with argon before tetrakis(triphenylphosphine)palladium (456 mg, 0.395 mmol) and 2 ml of aqueous 2M sodium carbonate solution (20 mmol) are added. After flushing again with argon the mixture is refluxed for 15 hours at 100° C. The solution is allowed to cool to room temperature and the mixture is filtered. The filtrate is evaporated and the residue is taken up in dichloromethane and extracted with water. The organic layer is dried with sodium sulfate then concentrated. The residue is purified by chromatography (CH2Cl2/EtOH gradient 100:0 to 98:2) to yield 1.13 g of 2-(thien-2-yl)-5-fluorophenol (74%).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[OH:11])[CH2:4][CH2:3]1.[CH2:12]=[O:13].[Mg+2].[Cl-].[Cl-]>CC#N>[OH:11][C:6]1[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[O:13]
Reactant: C=O
Reactant: CC1(c2ccccc2O)CC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: CC1(c2cccc(C=O)c2O)CC1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
step 1—To a solution of 2-(1-methylcyclopropyl)phenol (0.55 g, 3.4 mmol; CASRN 433684-77-6) in MeCN (7 mL) was added paraformaldehyde (0.68 g, 23 mmol), MgCl2 (0.48 g, 0.051 mmol) and TEA (1.3 g, 13 mmol). The mixture was stirred and heated at reflux for 5 h. After cooling to RT, the reaction mixture was partitioned between DCM and 1M aqueous HCl, and the organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.34 g (58%) of 2-hydroxy-3-(1-methylcyclopropyl)-benzaldehyde (128) as a light yellow oil.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN(C=O)C.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[O:1]=[C:2]1[O:6][C@H:5]([C:7]([Cl:18])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CC[C@@H](C(=O)O)O1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](C(=O)Cl)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of (2S)-5-oxotetrahydrofuran-2-carboxylic acid (compound 28a, 70 g, 539 mmol) and a drop of DMF in anhydrous DCM (500 mL) was added oxalyl dichloride (137 g, 1.07 mol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction was then concentrated in vacuo to afford 70 g crude product of (2S)-5-oxotetrahydrofuran-2-carbonyl chloride (compound 28b), which was used in next step without further purification.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O-])(O)=O.[Na+]>CO>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: [Na+]
Solvent: CO
Product: C=C(Cc1ccccc1)C(=O)OC
Yield: 95 %

Procedure:
a-Benzylacrylic acid (1.00 g, 6.17 mmol) in methanol (20 ml) was treated with BF3 ·Et2O (2 ml). The mixture was heated to reflux for 14 h, cooled, and poured into saturated NaHCO3 solution. Extraction with ether followed by drying over Na2SO4 and evaporation afforded 1.03 g (95%) of a mobile oil. 1H NMR (CDCl3) δ 7.17-7.35 (m,5H), 6.23 (m,1H), 5.47 (m,1H), 3.74 (s,3H), 3.63 (s,2H).
Reaction SMILES: [CH:1]1([C@H:6]2[C:35](=[O:36])[N:34]3[CH2:37][C@@H:31]([CH2:32][C@H:33]3[C:38]([O:40][CH3:41])=[O:39])[O:30][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:28][CH3:29])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:42][CH2:43][CH2:44][C@H:10]3[O:9][C:8](=[O:45])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.CO.[Rh]>[CH:1]1([C@H:6]2[C:35](=[O:36])[N:34]3[CH2:37][C@@H:31]([CH2:32][C@H:33]3[C:38]([O:40][CH3:41])=[O:39])[O:30][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:28][CH3:29])=[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[CH2:42][CH2:43][CH2:44][C@H:10]3[O:9][C:8](=[O:45])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CC2
Agent: [Rh]
Agent: CCOc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/C2
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCC2
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of methyl (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-19-ethoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxylate (Example 1, Step 4) (100 mg) in ethyl acetate (20 ml) and methanol (20 ml) was added 5% Rh/C (20 mg) and the mixture was stirred for 18 hours under hydrogen atmosphere. After exchanging the atmosphere for nitrogen, the reaction mixture was filtered and concentrated to give the desired product as a foam (100 mg). LRMS (ES+) M/Z (M+H)+ 622.1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[C:25]([O:35][CH2:36][CH3:37])(=[O:34])[CH:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[OH:27].C(N(CC)CC)C>CC(C)=O.O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:27][CH:26]([C:25]([O:35][CH2:36][CH3:37])=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:11]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(O)C(=O)OCC
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CC(OC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC
Yield: 66.7 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.8 g, 0.01 mole) in acetone (10 ml) was successively added diethyl DL malate (1.9 g, 0.01 mole) in acetone (10 ml) and triethylamine (1.01 g, 0.01 mole) in acetone (5 ml). A white precipitate quickly formed. The reaction was heated to reflux for 24 hours. Upon cooling, the reaction was poured in water (75 ml) and extracted twice with methylene chloride (25 ml @). The combined organic extracts were successively washed with 5% sodium hydroxide and brine solutions. The dried solution was stripped of solvent to give 3.56 g of an amber oil.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16]([CH3:18])([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: CC=CCC1C(=O)c2cc(OC)ccc2C1(C)C
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 40 minutes while stirring through a solution, cooled to -70°, of 5.86 g of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-dimethyl-1-indanone in 100 ml of anhydrous dichloromethane and 20 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.64 ml of dimethyl sulfide the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 60 ml of dichloromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloro-methane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 4.94 g (89%) of (RS)-2-(2-oxoethyl)-6-methoxy-3,3-dimethyl-1-indanone were obtained as a light yellow oil.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:20][C:21]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([Cl:32])[C:22]=1[C:23](Cl)=[O:24]>CO>[Cl:20][C:21]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[C:26]([Cl:32])[C:22]=1[C:23]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:24]
Reactant: O=C(Nc1nccc2cc[nH]c12)C1CC1
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: N#Cc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (1 g, 4.9 mmol) was added to a stirred suspension of aluminium chloride (3.30 g, 24.8 mmol) in dry dichloromehane (100 mL) and the mixture was stirred at room temperature for about 1 hour, followed by drop-wise addition of 2,6-dichloro-4-cyanobenzoyl chloride (1.16 g, 4.9 mmol). The resulting reaction mixture was stirred at room temperature for about 8 hours. Methanol (25 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The resulting residue was taken up in water followed by partitioning with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography using ethyl acetate and hexane gradient elution to afford N-[3-(2,6-dichloro-4-cyanobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7yl]cyclopropane carboxamide (0.75 g, 37.87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([OH:36])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH3:50]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH3:50])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCOCCBr
Reactant: Oc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol (0.054 g, 0.11 mmol) and potassium carbonate (0.059 g, 0.43 mmol) in DMF was added 1-bromo-2-(2-methoxyethoxy)ethane (0.057 ml, 0.43 mmol), the resulting mixture was stirred at 80° C. for 1 h. The crude product was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-60% (EtOAc-DCM) to afford 4-(4-chlorophenyl)-N-(4-(6-(2-(2-methoxyethoxy)ethoxy)quinolin-4-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS: m/z [M+H]+. 610.0 Calc'd for C34H29ClN4O3S: 609.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]=[C:9]([C:15]([OH:17])=O)[C:8]=2[CH:18]=1)([O-:3])=[O:2].[F:19][C:20]([F:24])([F:23])[CH2:21]N.C1C=C(SSC2N=CC=CC=2)[N:28]=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:19][C:20]([F:24])([F:23])[CH2:21][C:10]1[C:11]([CH3:13])([CH3:14])[O:12][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][C:8]=2[C:9]=1[C:15]([NH2:28])=[O:17]
Reactant: NCC(F)(F)F
Reactant: c1ccc(SSc2ccccn2)nc1
Reactant: CC1(C)C=C(C(=O)O)c2cc([N+](=O)[O-])ccc2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(C(N)=O)=C1CC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.00 g of 6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxylic acid, 0.44 g of 2,2,2-trifluoroethylamine, 0.97 g of 2,2'-dipyridyl disulfide, 1.16 g of triphenylphosphine, and 20 ml of dichloromethane was stirred at room temperature for 3 hours. The solvent was removed therefrom by distillation, and the residue was purified by silica gel column chromatography (developing solution; AcOEt:n-hexane=1:1) and then recrystallized from a mixture of n-hexane and ethyl acetate to obtain 0.98 g of N (2',2',2'-trifluoroethyl)-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])=[O:5])#[N:2].[CH:16]([CH:18]=[CH2:19])=O.COC(=O)C(C)=C>[Cl-].[Zn+2].[Cl-].O1CCOCC1>[C:1]([C:3](=[CH:19][CH:18]=[CH2:16])[C:4]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])=[O:5])#[N:2]
Reactant: C=CC=O
Reactant: C=C(C)C(=O)OCCCOC(=O)CC#N
Agent: C=C(C)C(=O)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: C=CC=C(C#N)C(=O)OCCCOC(=O)C(=C)C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
35.2 g of methacryloyloxypropyl cyanoacetate is mixed with 50 ml of dioxane. 13.5 g of zinc chloride is added during mixing. 13,25 g of acrolein are added dropwise over 10 minutes, taking care the reaction temperature not to exceed 20° C. The stirring is continued for a further 8 hours at room temperature yielding a clear yellow solution. 100 ml of methylmethacrylate are mixed in and then three consecutive extractions with 150 ml of 2N hydrochloric aced are performed. The organic layer is filtered and stripped under reduced pressure (0.7 mm Hg). The pot temperature is not to exceed 90° C. and a steady stream of air through the product is maintained during stripping. 25 g of methacryloyloxypropyl 2-cyanopenta-2,4-dienoate are obtained with nD20=1,5045. The IR spectrum (FIG. 3) confirms the chemical structure. The product possesses the same adhesive properties as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16]C)=[C:4]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)[Br:19].CO>ClCCl>[BrH:19].[NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(N)cccc1-c1ccc(C(=O)O)s1
Reactant: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Nc1cccc(-c2ccc(C(=O)O)s2)c1O
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
5-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid 12b (2.2 g, 8.83 mmol) was dissolved in 20 mL of dichloromethane followed by dropwise addition of boron tribromide (35 mL, 35.32 mmol/L). The reaction mixture was reacted at room temperature for 1.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. Then 5 mL of methanol was added and the mixture was concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate and stirred for 1.5 hours. The mixture was filtered and the filter cake was dried to obtain the title compound 5-(3-amino-2-hydroxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 12c (1.2 g, yield 57.1%) as a grey solid.